PATENT ABSTRACT
Focused libraries of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of antibody peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. The libraries have length and sequence diversities that mimic that found in native human antibodies.

PATENT DESCRIPTION
[0001]    This application is a continuation of U.S. application Ser. No. 11/416,460, filed on May 1, 2006, now abandoned, which is a continuation of U.S. application Ser. No. 10/026,925, filed on Dec. 18, 2001, now abandoned, which claims the benefit under 35 USC §120 of U.S. provisional application 60/256,380, filed Dec. 18, 2000 the entire content of each of which is herein incorporated by reference. The provisional application and the Tables attached to it are specifically incorporated by reference herein. 
     
    
       [0002]    The present invention relates to focused libraries of genetic packages that each display, display and express, or comprise a member of a diverse family of peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. The focused diversity of the libraries of this invention comprises both sequence diversity and length diversity. In a preferred embodiment, the focused diversity of the libraries of this invention is biased toward the natural diversity of the selected family. In more preferred embodiment, the libraries are biased toward the natural diversity of human antibodies and are characterized by variegation in their heavy chain and light chain complementarity determining regions (“CDRs”). 
         [0003]    The present invention further relates to vectors and genetic packages (e.g., cells, spores or viruses) for displaying, or displaying and expressing a focused diverse family of peptides, polypeptides or proteins. In a preferred embodiment the genetic packages are filamentous phage or phagemids or yeast. Again, the focused diversity of the family comprises diversity in sequence and diversity in length. 
         [0004]    The present invention further relates to methods of screening the focused libraries of the invention and to the peptides, polypeptides and proteins identified by such screening. 
       BACKGROUND OF THE INVENTION 
       [0005]    It is now common practice in the art to prepare libraries of genetic packages that individually display, display and express, or comprise a member of a diverse family of peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the amino acid diversity of the family. In many common libraries, the peptides, polypeptides or proteins are related to antibodies (e.g., single chain Fv (scFv), Fv, Fab, whole antibodies or minibodies (i.e., dimers that consist of V H  linked to V L )). Often, they comprise one or more of the CDRs and framework regions of the heavy and light chains of human antibodies. 
         [0006]    Peptide, polypeptide or protein libraries have been produced in several ways in the prior art. See e.g., Knappik et al., J. Mol. Biol., 296, pp. 57-86 (20004, which is incorporated herein by references. One method is to capture the diversity of native donors, either naive or immunized. Another way is to generate libraries having synthetic diversity. A third method is combination of the first two. Typically, the diversity produced by these methods is limited to sequence diversity, i.e., each member of the library differs from the other members of the family by having different amino acids or variegation at a given position in the peptide, polypeptide or protein chain. Naturally diverse peptides, polypeptides or proteins, however, are not limited to diversity only in their amino acid sequences. For example, human antibodies are not limited to sequence diversity in their amino acids, they are also diverse in the lengths of their amino acid chains. 
         [0007]    For antibodies, diversity in length occurs, for example, during variable region rearrangements. See e.g., Corbett et al., J. Mol. Biol., 270, pp. 587-97 (1997). The joining of V genes to J genes, for example, results in the inclusion of a recognizable D segment in CDR3 in about half of the heavy chain antibody sequences, thus creating regions encoding varying lengths of amino-acids. The following also may occur during joining of antibody gene segments: (i) the end of the V gene may have zero to several base deleted or changed; (ii) the end of the D segment may have zero to many bases removed or changed; (iii) a number of random bases may be inserted between V and D or between D and J; and (iv) the 5′ end of J may be edited to remove or to change several bases. These rearrangements result in antibodies that are diverse both in amino acid sequence and in length. 
         [0008]    Libraries that contain only amino acid sequence diversity are, thus disadvantaged in that they do not reflect the natural diversity of the peptide, polypeptide or protein that the library is intended to mimic. Further, diversity in length may be important to the ultimate functioning of the protein, peptide or polypeptide. For example, with regard to a library comprising antibody regions, many of the peptides, polypeptides, proteins displayed, displayed and expressed, or comprised by the genetic packages of the library may not fold properly or their binding to an antigen may be disadvantaged, if diversity both in sequence and length are not represented in the library. 
         [0009]    An additional disadvantage of prior art libraries of genetic packages that display, display and express, or comprise peptides, polypeptides and proteins is that they are not focused on those members that are based on natural occurring diversity and thus on members that are most likely to be functional. Rather, the prior art libraries, typically, attempt to include as much diversity or variegation at every amino acid residue as possible. This makes library construction time-consuming and less efficient than possible. The large number of members that are produced by trying to capture complete diversity also makes screening more cumbersome than it needs to be. This is particularly true given that many members of the library will not be functional. 
       SUMMARY OF THE INVENTION 
       [0010]    One objective of this invention is focused libraries of vectors or genetic packages that encode members of a diverse family of peptides, polypeptides or proteins wherein the libraries encode populations that are diverse in both length and sequence. The diverse length comprising components contain motifs that are likely to fold and function in the context of the parental peptide, polypeptide or protein. 
         [0011]    Another object of this invention is focused libraries of genetic packages that display, display and express, or comprise a member of a diverse family of peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. These libraries are diverse not only in their amino acid sequences, but also in their lengths. And, their diversity is focused so as to more closely mimic or take into account the naturally-occurring diversity of the specific family that the library represents. 
         [0012]    Another object of this invention is diverse, but focused, populations of DNA sequences encoding peptides, polypeptides or proteins suitable for display or display and expression using genetic packages (such as phage or phagemids) or other regimens that allow selection of specific binding components of a library. 
         [0013]    A further object of this invention is focused libraries comprising the CDRs of human antibodies that are diverse in both their amino acid sequence and in their length (examples of such libraries include libraries of single chain Fv(scFv), Fv, Fab, whole antibodies or minibodies (i.e., dimers that consist of V H  linked to V L ). Such regions may be from the heavy or light chains or both and may include one or, more of the CDRs of those chains. More preferably, they diversity or variegation occurs in all of the heavy chain and light chain CDRs. 
         [0014]    It is another object of this invention to provide methods of making and screening the above libraries and the peptides, polypeptides and proteins obtained in such screening. 
         [0015]    Among the preferred embodiments of this invention are the following: 
         [0016]    1. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR1 selected from the group consisting of:
       (1) &lt;1&gt; 1 Y 2 &lt;1&gt; 3 M 4 &lt;1&gt; 5  (SEQ ID NO:100), wherein &lt;1&gt; is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y;   (2) (S/T) 1 (S/G/X) 2 (S/G/X) 3 Y 4 Y 5 W 6 (S/G/X) 7  (SEQ ID NO:101) wherein (S/T) is a 1:1 mixture of S and T residues, (S/G/X) is a mixture of 0.2025 S, 0.2025 G and 0.035 of each of amino acid residues A, D, E, F, H, I, K, L, H, N, P, Q, R, T, V, W, and Y;   (3) V 1 S 2 G 3 G 4 S 5 I 6 S 7 &lt;1&gt; 8 &lt;1&gt; 9 &lt;1&gt; 10 Y 11 Y 12 W 13 &lt;1&gt; 14  (SEQ ID NO:1), wherein &lt;1&gt; is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; and   (4) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio: HC CDR1s (1):(2):(3)::0.80:0.17:0.02.       
 
         [0021]    2. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express or comprise at least a portion of the diversity of the antibody facility, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR2 selected from the group consisting of:
       (1) &lt;2&gt;I&lt;2&gt;&lt;3&gt;SGG&lt;1&gt;T&lt;1&gt;YADSVKG (SEQ ID NO:2), wherein &lt;1&gt; is an equimolar mixture of each of amino acid residues 2 1 1, 0, E, F, G, H, I, K, L, M, N, P, 0, P, S, T, V, W, and Y; &lt;2&gt; is an equimolar mixture of each of amino acid residues Y, R, W, V, G, and S; and &lt;3&gt; is an equimolar mixture of each of amino acid residues P, S, and G or an equimolar mixture of P and S;   (2) &lt;1&gt;I&lt;4&gt;&lt;1&gt;&lt;1&gt;&lt;G&gt;&lt;5&gt;&lt;1&gt;&lt;1&gt;&lt;1&gt;YADSVKG (SEQ ID NO:3), wherein &lt;1&gt; is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; &lt;4&gt; is an equimolar mixture of residues D, I, N, S, W, Y; and &lt;5&gt; is an equimolar mixture of residues S, G, D and N;   (3) &lt;1&gt;I&lt;4&gt;&lt;1&gt;&lt;1&gt;G&lt;5&gt;&lt;1&gt;&lt;1&gt;YNPSLKG (SEQ ID NO:4), wherein &lt;1&gt; is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N; P, Q, R, S, T, V, W and Y, and &lt;4&gt; and &lt;5&gt; are as defined above;   (4) &lt;1&gt;I&lt;8&gt;S&lt;1&gt;&lt;1&gt;&lt;1&gt;GGYY&lt;1&gt;YAASVKG (SEQ ID NO:5), wherein &lt;1&gt; is an equimolar mixture of each amino acid residues A, D, E, F, Gill, I, K, L, M, N, P, Q, R, S, T, V, and Y; &lt;8&gt; is 0.27 R and 0.027 of each of ADEFGHIKLMNPQSTVWY; and   (5) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio: HC CDR2s: (1)/(2) (equimolar):(3):(4)::0.54:0.43:0.03.       
 
         [0027]    3. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR3 was selected from the group consisting of:
       (1) YYCA21111YFDYWG (SEQ ID NO:6), Wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;   (2) YYCA2111111YFDYWG (SEQ ID NO:7), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;   (3) YYCA211111111YFDAYTG (SEQ ID NO:8), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, 1, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;   (4) YYCAR111S2S3111YFDYWG (SEQ ID NO:9), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of S and G; and 3 is an equimolar mixture of Y and W;   (5) YYCA2111CSG11CY1YFDYWG (SEQ ID NO:10), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R;   (6) YYCA211S1TIFG11111YFDYWG (SEQ ID NO:11), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R.   (7) YYCAR111YY2S3344111YFDYWG (SEQ ID NO:12), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; 2 is an equimolar mixture of D and S; and 3 is an equimolar mixture of S and G;   (8) YYCAR1111YC2231CY111YFDYWG (SEQ ID NO:13), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; 2 is an equimolar mixture of S and G; and 3 is an equimolar mixture of T, D and G; and   (9) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably the HC CDR3s (1) through (8) are in the following proportions in the mixture:   (1) 0.10   (2) 0.14   (3) 0.25   (4) 0.13   (5) 0.13   (6) 0.11   (7) 0.04 and   (8) 0.10; and more preferably the HC CDR3s (1) through (8) are in the following proportions in the mixture:   (1) 0.02   (2) 0.14   (3) 0.25   (4) 0.14   (5) 0.14   (6) 0.12   (7) 0.08 and   (8) 0.11.       
 
         [0053]    Preferably, 1 in one or all of HC CDR3s (1) through (8) is 0.095 of each of G and Y and 0.048 of each of A, D, E, F H, 1, K, L, M, N, P, Q, R, S, T, V, and W. 
         [0054]    4. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encodes a kappa light chain CDR1 selected from the group consisting of:
       (1) RASQ&lt;1&gt;V&lt;2&gt;&lt;2&gt;&lt;3&gt;LA (SEQ ID NO:14)   (2) RASQ&lt;1&gt;V&lt;2&gt;&lt;2&gt;&lt;2&gt;&lt;3&gt;LA (SEQ ID NO:15);
 
wherein &lt;1&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; &lt;2&gt; is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and &lt;3&gt; is 0.2Y and 0.044 each of ADEFGHIKLMNPQRTVW and Y; and
   (3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio CDR1s (1):(2)::0.68:0.32.       
 
         [0058]    5. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family the vectors or genetic packages being characterized by variegated DNA sequences that encode a kappa light-chain CDR2 having the sequence:
       &lt;1&gt;AS&lt;2&gt;R&lt;4&gt;&lt;1&gt; (SEQ ID NO:102),
 
wherein &lt;1&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; &lt;2&gt; is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and &lt;4&gt; is 0.2.A and 0.044 each of DEFGHIKLMNPQRSTVWY.
       
 
         [0060]    6. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a kappa light chain CDR3 selected from the groups consisting of:
       (1) QQ&lt;3&gt;&lt;1&gt;&lt;1&gt;&lt;1&gt;P&lt;1&gt;T (SEQ ID NO:16),
 
wherein &lt;1&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; &lt;3&gt; is 0.2 Y and 0.044 each of ADEFGHIKIMNPQRTVW;
   (2) QQ33111P (SEQ ID NO:103), wherein 1 and 3 are as defined in (1) above;   (3) QQ3211PP1T (SEQ ID NO:17), wherein 1 and 3 are as defined in (1) above and 2 is 0.2 S and 0.044 each of ADEFGHIKLMNPQRTVWY; and   (4) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio CDA3s (1):(2):(3)::0.65:0.1:0.25.       
 
         [0065]    7. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR1 selected from the group consisting of:
       (1) TG&lt;1&gt;SS&lt;2&gt;VG&lt;1&gt;&lt;3&gt;&lt;2&gt;&lt;3&gt;VS(SEQ ID NO:18), wherein &lt;1&gt; is 0.27 T, 0.27 G and 0.027 each of ADEFRIKLMNPQRSVWY: &lt;2&gt; is 0.27 D, 0.27 N and 0.027 each of AEFGHIKLMPQRSTVWY, and &lt;3&gt; is 0.36 Y and 0.036 each of ADEFGHIKLMNPQRSTVW;   (2) G&lt;2&gt;&lt;4&gt;L&lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;3&gt;&lt;4&gt;&lt;4&gt; (SEQ ID NO:104),
 
wherein &lt;2&gt; is as defined in (1) above and &lt;4&gt; is an equimolar mixture of amino acid residues ADEFGHIKIMNPQRSTVWY; and
   (3) mixtures of vectors or genetic packages 5 characterized by any of the above DNA sequences, preferably in the ratio CDR1 (1):(2)::0.67:0.33;       
 
         [0069]    8. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR2 has the sequence:
       &lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;2&gt;RPS (SEQ ID NO:105)
 
wherein &lt;2&gt; is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKIMPQRSTVWY and &lt;4&gt; is an equimolar mixture of amino acid residues ADEFGHIKLONPQRSTVW.
       
 
         [0071]    9. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR3 selected from the group consisting of:
       (1) &lt;4&gt;&lt;5&gt;&lt;4&gt;&lt;2&gt;&lt;4&gt;S&lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;4&gt;V (SEQ ID NO:106), wherein &lt;2&gt; is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKIMPQRSTVWY; &lt;4&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMVPQRSTVW; and &lt;5&gt; is 0.36 S and 0.6355 each of ADEFGHIKLMNPQRTVWY;   (2) &lt;5&gt;SY&lt;1&gt;&lt;5&gt;S&lt;5&gt;&lt;1&gt;&lt;4&gt;V (SEQ ID NO:19), wherein &lt;1&gt; is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and &lt;4&gt; and 5 &lt;5&gt; are as defined in (1) above; and   (3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio CDR3s       
 
         [0075]    10. A focused library comprising variegated-DNA sequences that encode a heavy chain CDR selected from the group consisting of:
       (1) one or more of the heavy chain CDR&#39;s of paragraph 1 above;   (2) one or more of the heavy chin CDR2s of paragraph 2 above;   (3) one or more of the heavy chain CDR3s of paragraph 3 above; and   (4) mixtures of vectors or genetic-packages characterized by (1), (2) and (3).       
 
         [0080]    11. The focused library comprising one or more of the variegated DNA sequences that encodes a heavy chain CDR of paragraphs 1, 2 and 3 and further comprising variegated DNA sequences that encodes a light chain CDR selected from the group consisting of
       (1) one or more the kappa light chain CDR1s of paragraph 4;   (2) the kappa light chain. CDR2 of paragraph 5;   (3) one or more of the kappa light chain CDR3s of paragraph 6;   (4) one or more of the kappa light chain CDR1s of paragraph 7;   (5) the lambda light chain ‘CDR2’ of paragraph 8   (6) one or more of the lambda light chain CDR3s of paragraph. 9; and   (7) mixtures of vectors and genetic packages characterized by one or more of (1) through (6).       
 
         [0088]    12. A population of variegated DNA sequences as described in paragraphs 1-11 above. 
         [0089]    13. A population of vectors comprising the variegated DNA sequences as described in paragraphs 1-11 above. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0090]    Antibodies (“Ab”) concentrate their diversity into those regions that are involved in determining affinity and specificity of the Ab for particular targets. These regions may be diverse in sequence or in length. Generally, they are diverse In both ways. However, within families of human antibodies the diversities, both in sequence and in length, are not truly random. Rather, some amino acid residues are preferred at certain positions of the CDRs and some CDR lengths are preferred. These preferred diversities account for the natural diversity of the antibody family. 
         [0091]    According to this invention, and as more fully described below, libraries of vectors and genetic packages that more closely mirror the natural diversity, both in sequence and in length, of antibody families, or portions thereof are prepared and used. 
       Human Antibody Heavy Chain Sequence and Length Diversity 
       [0092]    (a) Framework 
         [0093]    The heavy chain (“HC”) Germ-Line Gene (GLG) 3-23 (also known as 1/1)-47) accounts for about 12% of all human Abs and is preferred as the framework in the preferred embodiment of the invention. It should, however, be understood that other well-known frameworks, such as 4-34, 3-30, 3-30.3 and 4-30.1, may also be used without departing from the principles of the focused diversities of this invention. 
         [0094]    In addition, JH4 (YFDYWGQGTLVTVSS; SEQ ID NO:20) occurs more often than JH3 in native antibodies. Hence, it is preferred for the focused libraries of this invention. However, JH3 (AFDIWGQGTMVTVSS; SEQ ID NO:21) could as well be used. 
         [0095]    (b) Focused Length Diversity: CDR1, 2 and 3 
         [0096]    (i) CDR1 
         [0097]    For CDR1, GLGs provide CDR1s only Of the lengths 5, 6, and 7. Mutations during the maturation of the v-domain gene, however, can lead to CDR1s having lengths as short as 2 and as long as 16. Nevertheless, length 5, predominates. Accordingly, in the preferred embodiment of this invention the preferred HC CDR1 is 5 amino acids, with less preferred CDR1s having lengths of 7 and 14. In the most preferred libraries of this invention, all three lengths are used in proportions similar to those found in natural antibodies. 
         [0098]    (ii) CDR2 
         [0099]    GLGs provide CDR2s only of the lengths 15:19, but mutations during maturation may result in CDR2s of lengths from 16 to 28 amino acids. The lengths 16 and 17 predominate in mature Ab genes. Accordingly, length 17 is the preferred length for HC CDR2 of the present invention. Less preferred HC CDR2s of this invention have lengths 16 and 19. In the most preferred focused libraries of this invention, all three lengths are included in proportions similar to those found in natural antibody families. 
         [0100]    (iii) CDR3 
         [0101]    HC CDR3s vary in length. About half of human HCs consist of the components: V::nz::D::ny::JHn where V is a V gene, nz is a series of bases (mean 12) that are essentially random, D is a D segment, often with heavy editing at both ends, ny is a series of bases (mean 6) that are essentially random, and JH is one of the six JH segments, often with heavy editing at the 5′ end. The D segments appear to provide spacer segments that allow folding of the IgG. The greatest diversity is at the junctions of y with D and of D with JH. 
         [0102]    In the preferred-libraries of this invention both types of HC CDR3s are used. In HC CDR3s that have no identifiable D segment, the structure is V::nz::JHn where JH is usually edited at the 5′ end. In HC CDR3s that have an identifiable D segment, the structure is V::nz::D::ny::JHn. 
         [0103]    (c) Focused Sequence Diversity: CDR1, 2 and 3 
         [0104]    (i) CDR1 
         [0105]    In 5 amino acid length CDR1, examination of a 3D model of a humanized Ab showed that the side groups of residues 1, 3, and 5 were directed toward the combining pocket. Consequently, in the focused libraries of this invention, each of these positions may be selected from any of the native amino acid residues, except cysteine (“C”). Cysteine can form disulfide bonds, which are an important component of the canonical Ig fold. Having free thiol groups Could, thus, interfere with proper folding of the HC and could lead to problems in production or manipulation of selected Abs. Thus, in the focused libraries of this invention cysteine is excluded from positions 1; 3 and 5 of the preferred 5 amino acid CDR1s. The other 19 natural amino acids residues may be used at positions 1, 3 and 5. Preferably, each is present in equimolar ratios in the variegated libraries of this invention. 
         [0106]    3D modeling also suggests that the side groups of residue 2 in a 5 amino acid CDR1 are directed away from the combining pocket. Although this position shows substantial diversity, both in GLG and mature genes, in the focused libraries of this invention this residue is preferably Tyr (Y) because it occurs in 681/820 mature antibody genes. However, any of the other native amino acid residues, except Cys (C), could also be used at this position. 
         [0107]    For position 4, there is also some diversity in GLG and mature antibody genes. However, almost all mature genes have uncharged hydrophobic amino acid residues: A, G, L, P, F, M, W, I, V, at this position. Inspection of a 3D model also shows that the side group of residue 4 is packed into the innards of the HC. Thus, in the preferred embodiment of this invention which uses framework 3-23, residue 4 is preferably Met because it is likely to fit very well into the framework of 3-23. With other frameworks, a similar fit consideration is used to assign residue 4. 
         [0108]    Thus, the most preferred HC − CDR1 of this invention consists of the amino acid sequence &lt;1&gt;Y&lt;I&gt;M&lt;1&gt; where &lt;1&gt; can be any one of amino acid residues: A, D, E, G, H, I, K, L, M, N, R, Q, S, T, V, W, Y (not C), preferably present at each position in an equimolar amount. This diversity is shown in the context of a framework 3-23:JH4 in Table 1. It has a diversity of 6859-fold. 
         [0109]    The two less preferred HC CDR1s of this invention have length 7 and length 14. For length 7, a preferred variegation is (S/T) 1 (S/G/&lt;1&gt;) 2 (S/G/&lt;1&gt;) 3 Y 4 Y 5 W 6 (S/G/&lt;1&gt;) 7  (SEQ ID NO:107); where (S/T) indicates an equimolar mixture of Ser and Thr codons; (S/G/&lt;1&gt;) indicates a mixture Of 0.2025 S, 0.2025 G, and 0.035 for each of A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, Y. This design gives a predominance of Ser and Gly at positions 2, 3, and 7, as occurs in mature HC genes. For length 14, a preferred variegation is VSGGSIS&lt;1&gt;&lt;1&gt;&lt;1&gt;YYW&lt;1&gt; (SEQ ID NO:108), where &lt;1&gt; is an equimolar mixture of the 19 native amino acid residues, except Cys (C). 
         [0110]    The DNA that encodes these preferred HC CDR1s is preferably synthesized using trinucleotide building blocks so that each amino acid residue ii present in essentially equimolar or other described amounts. The preferred codons for the &lt;1&gt; amino acid residues are gct, gat, gag, ttt, ggt, cat, att, aag, ctt, atg, aat, cct, cag, cgt, tct, act, gtt, tgg, and tat. Of course, other codons for the chosen amino acid residue could also be used. 
         [0111]    The diversity oligonucleotide (ON) is preferably synthesized from BspEI to BstXI (as shown in Table 1) and can, therefore, be incorporated either by PCR synthesis using overlapping ONs or introduced by ligation of BspEI/BstXI-cut fragments. Table 2 shows the oligonucleotides that embody the specified variegations of the preferred length 5 HC CDR1s of this invention. PCR using ON-R1V1vg, ON-R1top, and ON-Rlbot gives a dsDNA product of 73 base-pairs, cleavage with 14spEI and BstXI trims 11 and 13 bases from the ends and provides cohesive ends that can be ligated to similarly cut vector having the 3-23 domain shown in Table 1. Replacement of ON-R1V1vg with either ONR1V2vg or ONR1V3vg (see Table 2) allows synthesis of the two alternative diversity patterns—the 7 residue length and the 14 residue length HC CDR1. 
         [0112]    The more preferred libraries of this invention comprise the 3 preferred HC CDR1 length diversities. Most preferably, the 3 lengths should be incorporated in approximately the ratios in which they are observed in antibodies selected without reference to the length of the CDRs. For example, one sample of 1095 HC genes have the three lengths present in the ratio: L=5:L=7:L=14::820:175:23::0.80:0.17:0.02. This is the preferred ratio in accordance with this invention. 
         [0113]    (ii) CDR2 
         [0114]    Diversity in HC CDR2 was designed with the same considerations as for HC CORI: GLG sequences, mature sequences and 3D structure. A preferred length for CDR2 is 17, as shown in Table 1. For this preferred 17 length CDR2, the preferred variegation in accordance with the invention is: &lt;2&gt;I&lt;2&gt;&lt;3&gt;SGG&lt;1&gt;T&lt;1&gt;YADSVKG (SEQ ID NO:2), where &lt;2&gt; indicates any amino acid residue selected from the group of Y, R, W, V, G and S (equimolar mixture), &lt;3&gt; is P, S and G or P and S only (equimolar mixture), and &lt;1&gt; is any native amino acid residue except C (equimolar mixture). 
         [0115]    ON-R2V1vg shown in Table 3 embodies this diversity pattern. It is preferably synthesized so that fragments of dsDNA containing the BstXI and XbaI site can be generated by PCR. PCR with ON-R2V1vg, ON-R2top, and ONR2bot gives a dsDNA product of 122 base pairs. Cleavage with BstXI and XbaI removes about 10 bases from each end and produces cohesive ends that can be ligated to similarly cut vector that contains the 3-23 gene-shown in Table 1. 
         [0116]    In an alternative embodiment for a 17 length HC CDR2, the following variegation may be used; &lt;1&gt;I&lt;4&gt;&lt;1&gt;&lt;1&gt;G&lt;5&gt;&lt;1&gt;&lt;1&gt;&lt;1&gt;YADSVKG (SEQ ID NO:3), where &lt;1&gt; is as described above for the more preferred alternative of HC CDR2; &lt;4&gt; indicates an equimolar mixture of DINSWY, and &lt;5&gt; indicates an equimolar mixture of SGDN. This diversity pattern is embodied in ON-R2V2vg shown in Table 3. Preferably, the two embodiments are used in equimolar mixtures in the libraries of this invention. 
         [0117]    Other preferred HC CDR2s have lengths 16 and 19. 
         [0118]    Length 16: &lt;1&gt;I&lt;4&gt;&lt;1&gt;&lt;1&gt;G&lt;5&lt;1&gt;&lt;1&gt;YNPSLKG (SEQ ID NO:4); Length:19: &lt;1&gt;I&lt;8&gt;S&lt;1&gt;&lt;1&gt;&lt;1&gt;GGYY&lt;1&gt;YAASVKG (SEQ ID NO:5), wherein &lt;1&gt; is an equimolar mixture of all native amino acid residues except C; &lt;4&gt; is a equimolar mixture of DINSWY; &lt;5&gt; is an equimolar mixture of SGDN; and &lt;8&gt; is 0.27 R and 0:0 7 of each of residues ADEFGHIKLMNPQSTVWY. Table 3 shows ON-R2V3vg which embodies a preferred aDR2 variegation of length 16 and ON7R2V4vg which embodies a preferred CDR2 variegation of length 19. To prepare these variegations ON-R2V3vg may be PCR amplified with ON-A2top and ON-R2bo3 and ON-R2V4vg may be PCR amplified with ON-R2top and ON-R2-bo4. See Table 3. In the most preferred embodiment of this invention, all three HC CDR2 lengths are used. Preferably, they are present in a ratio 17:16:19::579:464:31::0.54:0.43:0.03. 
         [0119]    (iii) CDR3 
         [0120]    The preferred libraries of this invention comprise several BC CDR3 components. Some of these will have only sequence diversity. Others will have sequence diversity with embedded D segments to extend the length, while also incorporating sequences known to allow Igs to fold. The HC CDR3 components of the preferred libraries of this invention and their diversities are depicted in Table 4: Components 1-8. 
         [0121]    This set of components was chosen after studying the sequences of 1383 human BC sequences. The proposed components are meant to fulfill the following goals: 
         [0122]    1) approximately the same distribution of lengths as seen in native Ab genes; 
         [0123]    2) high level of sequence diversity at places having high diversity in native Ab genes; and 
         [0124]    3) incorporation of constant sequences often seen in native Ab genes. 
         [0125]    Component 1 represents all the genes having lengths 0 to 8 (counting from the YYCAR motif at the end of FR3 to the WG dipeptide motif near the start of the J region, i.e., FR4). Component 2 corresponds the all the genes having lengths 9 or 10. Component 3. corresponds to the genes having lengths 11 or 12 plus half the genes having length 13. Component 4 corresponds to those having length 14 plus half those having length 13. Component 5 corresponds to the genes having length 15 and half of those having length 16. Component 6 corresponds to genes of length 17 plus half of those with length 16. Component 7 corresponds to those with length 18. Component 8 corresponds to those having length 19 and greater. See Table 4. 
         [0126]    For each HC CDR3 residue having the diversity &lt;1&gt;, equimolar ratios are preferably not used. Rather, the following ratios are used 0.095 [G and Y] and 0.048 [A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, and W]. Thus, there is a double dose of G and Y with the other residues being in equimolar ratios. For the other diversities, e.g., KR or SG, the residues are present in equimolar mixtures. 
         [0127]    In the preferred libraries of this invention the eight components are present in the following fractions: 1 (0.10), 2 (0.14), 3 (0.25), 4 (0.13), 5 (0.13), 6 (0.11), 7 (0.04) and 8 (0.10). See Table 4. 
         [0128]    In the more preferred embodiment of this invention, the amounts of the eight components is adjusted because the first component is not complex enough to justify including it as 10% of the library. For example, if the final library were to have 1×10 9  members, then 1×10 8  sequences would come from component 1, but it has only 2.6×10 5  CDR3 sequences so that each one would occur in ˜385 CDR1/2 contexts. Therefore, the more preferred amounts of the eight components are 1(0.02), 2(0.14), 3(0.25), 4(0.14), 510.14), 6(0.12), 7(0.68), 8(0.11). In accordance with the more preferred embodiment component 1 occurs in ˜77 CDR1/2 contexts and the other, longer CDR3s occur more often. 
         [0129]    Table 5 shows vgDNA that embodies each of the eight HC CDR3 components shown in Table 4. In Table 5, the oligonucleotides (ON) Ctop25, CtprmA, C8prmB, and CBot25 allow PCR amplification of each of the variegated ONs (vgDNA): C1t08, C2t10, C3t12, C4t14, C5t15, C6t17, C7t18, and C8t19. After amplification, the dsDNA can be cleaved with AfiII and BstEII (or KpnI) and ligated to similarly cleaved vector that contains the remainder of the 3-23 domain. Preferably, this vector already contains diversity in one, or both, of CDR1 and CDR2 as disclosed herein. Most preferably, it contains diversity in both the CDR1 and CDR2 regions. It is, of course, to be understood that the various diversities can be incorporated into the vector in any order. 
         [0130]    Preferably, the recipient vector originally contains a stuffer in place of CDR1, CDR2 and CDR3 so that there will be no parental sequence that would then occur in the resulting library. Table 6 shows a version of the V3-23 gene segment with each CDR replaced by a short segment that contains both stop codons and restriction sites that will allow specific cleavage of any vector that does not have the stuffer removed. The stuffer can either be short and contain a restriction enzyme site that will not occur in the finished library, allowing removal of vectors that are not cleaved by both AfiII and BstEII (or Aionl) and religated. Alternatively, the stuffer could be 200-400 bases long so that uncleaned or once-cleaved vector can be readily separated from doubly cleaved vector. 
       Human Antibody Light Chain: Sequence and Length Diversity 
       [0131]    (i) Kappa Chain 
         [0132]    (a) Framework 
         [0133]    In the preferred embodiment of this invention, the kappa light chain is built in an A27 framework with a JK1 region. These are the most common V and J regions in the native genes. Other frameworks, such as 012, L2, and All, and other J regions, such as JK4, however, may be used without departing from the scope of this invention. 
         [0134]    (b) CDR1 
         [0135]    In native human kappa chains, CDR1s with lengths of 11, 12, 13, 16, and 17 were observed with length 11 being predominant and length 12 being well represented. Thus, in the preferred embodiments of this invention LC CDR1s of length 11 and 12 are used in an and mixture similar to that observed in native antibodies), length 11 being most preferred. Length 11 has the following sequence: RASQ&lt;1&gt;V&lt;2&gt;&lt;2&gt;&lt;3&gt;LA (SEQ ID NO:14) and Length 12 hag the following sequence: RASQ&lt;1&gt;V&lt;25&lt;2&gt;&lt;2&gt;&lt;3&gt;LA (SEQ ID NO:15), wherein &lt;1&gt; is an equimolar mixture of ill of the native amino acid residues, except C, &lt;2&gt; is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY, and &lt;3&gt; is 0.2.Y and 0.044 each of A, D, E, F, G, H, 1, K, L, M, N, Q, R, T, V, W and Y. In the most preferred embodiment of this invention, both CDR1. lengths are used. Preferably, they are present in a ratio of 11:12::154:73:0.68:0.32. 
         [0136]    (c) CDR2 
         [0137]    In native kappa, CDR2 exhibits only length 7. This length is used in the preferred embodiments of-this invention. It has the sequence &lt;1&gt;AS&lt;2&gt;R&lt;4&gt;&lt;1&gt;, wherein &lt;1&gt; is an-equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; &lt;2&gt; is 0.2 S and 0.004 of each of ADEFGHIKLMNPQRTVWY; and &lt;4&gt; is 0.2 A and 0.044 of each of DEFGHIKLMNPQRSTUWY. 
         [0138]    (d) CDR3 
         [0139]    In native kappa, CDR3 exhibits lengths of 4, 6, 7; 8, 9, 10, 11, 12, 13, 0.0 . . . and 19. While any of these lengths and mixtures of them can be employed in this invention, we prefer lengths 8, 9 and 10, length 9 being more preferred. For the preferred Length 9, the sequence is, QQ&lt;3&gt;&lt;1&gt;&lt;1&gt;&lt;1&gt;P&lt;1&gt;T, wherein &lt;1&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY and &lt;3&gt; is 0.2? and 0.044 each of ADEFGHIKLWQRSVW. Length 8 is preferably QQ33111P and Length 10 is Preferably QQ3211PP1T, wherein 1 and 3 are as defined for Length 9 and 2 is S (0.2) and 0.044 each of ADEFGHIKLMNPQRTVWY. A mixture of all 3 lengths being most preferred (ratios as in native antibodies), i.e., 8:9:10i28:166:63::0.1:0.65:0.25. 
         [0140]    Table 7 shows a kappa chain gene of this invention, including a PlacZ promoter a ribosome-binding site, and signal sequence (MI3 III signal). The DNA sequence encodes the GLG amino acid sequence but does not comprise the GLG DNA sequence. Restriction sites are designed to fall within each framework region so that diversity can be cloned into the CDRs. XmaI and Espl are in FR1, SexAI is in FR2, RsrII is in FR3, and KpnI (or Acc65I), are in FR4. Additional sites are provided in the constant kappa chain to facilitate construction of the gene. 
         [0141]    Table 7 also shows a suitable scheme of variegation for kappa. In CDR1, the most preferred length 11 is depicted. However, most preferably both lengths 11 and 12 are used. Length 12 in CDR1 can be construed by introducing codon 51 as &lt;2&gt; (i.e. a Ser-biased mixture). CDR2 of kappa is always 7 codons. Table 7 shows a preferred variegation scheme for CDR2. Table 7 Shows a variegation scheme for the most preferred CDR3 (length 9). Similar variegations can be lied for CDRs of length 8 and 10. In the preferred embodiment of this invention, those three lengths (8, 9 and 10) are included in the libraries of this invention in the native ratios, as described above. 
         [0142]    Table 9 shows series of diversity oligonucleotides and primers that may be used to construct the kappa chain diversities depicted in Table 7. 
         [0143]    (ii) Lambda Chain 
         [0144]    (a) Framework 
         [0145]    The lambda chain is preferably built in a 2a2 framework with an L2J region. These are the most common V and J regions in the native genes. Other frameworks, such as 31, 4b, 1a and 6a, and other J regions, such as L1J, L3J and L7J, however, may be used without departing from the scope of this invention. 
         [0146]    (b) CDR1 
         [0147]    In native human lambda chains, CDR1s with length 14 predominate, lengths 11, 12 and 13 also occur. While any of these can be used in this invention, lengths 11 and 14 are preferred. For length 11 the sequence is: TG&lt;2&gt;&lt;4&gt;L&lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;3&gt;&lt;4&gt;&lt;4&gt; (SEQ ID NO:22) and for Length 14 the sequence is: TG&lt;1&gt;SS&lt;2&gt;VG&lt;1&gt;&lt;3&gt;&lt;2&gt;&lt;3&gt;VS (SEQ ID NO:18), wherein &lt;1&gt; is 0.27 T, 0.21 G and 0.027 each of ADEFHIKLMNPQRSVWY; &lt;2&gt; is 0.27 D, 0.27 N and 0.027 each of AEFGHIKLMPQRSTVWY; &lt;3&gt; is 0.36 Y and 0.0355 each of ADEFGHIKLMNPQRSTVW; and &lt;4&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY. Most preferably, Mixtures (similar to those occurring in native antibodies) preferably, the ratio is 11:14::23:46::0.33:0.67 of the three lengths are used. 
         [0148]    (c) CDR2 
         [0149]    In native human lambda chains 4 . CDR2s with length 7 are by far the most common. This length is preferred in this invention. The sequence of this Length 7 CDR2 is &lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;2&gt;RPS, wherein &lt;2&gt; is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKLMPQRTVWY and &lt;4&gt; is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVW. 
         [0150]    (d) CDR3 
         [0151]    In native human lambda chains, CDR3s of length 10 and 11 predominate, while length 9 is also common. Any of these three lengths can be used in the invention. Length 11 is preferred and mixtures of 10 and 11 more preferred. The sequence of Length 11 is &lt;4&gt;&lt;5&gt;&lt;4&gt;&lt;2&gt;&lt;4&gt;S&lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;4&gt;V, where &lt;2&gt; and &lt;4&gt; are as defined for the lambda CORI and &lt;5&gt; is 0.36 S and 0.0355 each of ADFFGHIKLMNFORTVWY. The sequence of Length 10 is &lt;5&gt;SY&lt;1&gt;&lt;5&gt;S&lt;5&gt;&lt;1&gt;&lt;4&gt;V (SEQ ID NO:19), wherein &lt;1&gt; is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and &lt;4&gt; and &lt;5&gt; are as defined for Length 11. The preferred mixtures of this invention comprise an equimolar mixture of Length 10 and Length 11. Table 8 shows a preferred focused lambda light chain diversity in accordance with this invention. 
         [0152]    Table 9 shows a series of diversity oligonucleotides and primers that may be used to construct 10 the lambda chain diversities depicted in Table 7. 
       Method of Construction of the Genetic Package 
       [0153]    The diversities of heavy chain and the kappa and lambda light chains are best constructed in separate vector&#39;s. First a synthetic gene is designed to embody each of the synthetic variable domains. The light chains are bounded by restriction sites for ApaLI (positioned at the very end of the signal sequence) and AscI (positioned after the stop codon). The heavy chain is bounded by SfiI (positioned within the PelB signal sequence) and NotI (positioned in the linker between CH1 and the anchor protein). Signal sequences other than PelB may also need, e.g., a M13 pIII signal sequence. 
         [0154]    The initial genes are made with “stutter” sequences in place of the desired CDRs. A “stutter” is a sequence that is to be cut away and replaced by diverse DNA but which does not allow expression of a functional antibody gene. For example, the stuffer may contain several stop codons and restriction sites that will not occur in the correct finished library vector. For example, in Table 10, the stuffer for CDR1 of kappa A27 contains a StuI site. The vgDNA for CDR1 is introduced as a cassette from EspI, XmaI, or AflII to dither SexAI or KasI. After the ligation, the DNA is cleaved with Still; there should be no StuI sites in the desired vectors. 
         [0155]    The sequences of the heavy chain gene with stuffers is depicted in Table 6. The sequences of the kappa light chain gene with stuffers is depicted in Table 10. The sequence of the lambda light chain gene with stuffers is depicted in Table 11. 
         [0156]    In another embodiment of the present invention the diversities of heavy chain and the kappa or lambda light chains are constructed in a single vector or genetic packages (e.g., for display or display and expression) having appropriate restriction sites that allow cloning of these chains. The processes to construct such vectors are well known and widely used in the art. Preferably, a heavy chain and Kappa light Chain library and a heavy chain and lambda light chain library would be prepared separately. The two libraries, most preferably, will then be mixed in equimolar amounts to attain maximum diversity. 
         [0157]    Most preferably, the display is had on the surface of a derivative of M13 phage. The most preferred vector contains all the genes of M13, an antibiotic resistance-gene, and the display cassette. The preferred vector is provided with restriction sites that allow introduction and excision of members of the diverse family of genes, as cassettes. The preferred vector is stable against rearrangement under the growth conditions used to amplify phage. 
         [0158]    In another embodiment of this invention, the diversity captured by the methods of the present invention may be displayed and/or expressed in a phagemid vector (e.g., pCES1) that displays and/or expresses the peptide, polypeptide or protein. Such vectors may also be used to store the diversity for subsequent display and/or expression using other vectors or phage. 
         [0159]    In another embodiment of this invention, the diversity captured by the methods of the present invention may be displayed and/or expressed in a yeast vector. 
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 3-23: JH4 CDR1/2 diversity = 1.78 × 10 8   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                                            FR1(VP47/V3-23)--------------- 
               
               
                                 20 21 22    23  24  25  26  27  28  29  30 
               
               
                 (SEQ ID NO: 99) A  M  A     E   V   Q   L   L   E   S   G 
               
               
                 ctgtctgaac     cc atg gcc  gaa/gtt/caa/ttg/tta/gag/tct/ggt/ 
               
               
                 Scab.....     NcoI....          MfeI 
               
               
                   
               
               
                     ---------- FR1--------------------------------- 
               
               
                      31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                       G   G   L   V   Q   P   G   G   S   L   R   L   S   C   A 
               
               
                     /ggc/ggt/ctt/gtt/cag/cct/ggt/ggt/tct/tta/cgt/ctt/tct/tgc/gct/ 
               
               
                   
               
               
                        Sites of variegation        &lt;1&gt;&lt;1&gt; &lt;1&gt; &lt;1&gt;    6859-fold diversity 
               
               
                     ----FR1 -------------&gt;/ .. CDR1........... ./---FR2----- 
               
               
                      46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                       A   S   G   F   T   F   S   -   Y   -   M   -   W   V   R 
               
               
                     /gct/tcc/gga/ttc/act/ttc/tct/ - /tac/ - /atg/ - /tgg/gtt/cgc/ 
               
               
                         BspEI                       BsiWI                      BstXI. 
               
               
                   
               
               
                                       Sites of variegation-&gt;&lt;2&gt;      &lt;2&gt; &lt;3&gt; 
               
               
                     -----FR2-------------------- &gt;/ ..CDR2 
               
               
                     61   62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                     Q    A   P   G   K   G   L   E   W   V   S   -   I   -   - 
               
               
                    /caa/gct/cct/gtt/aaa/ggt/ttg/gag/tgg/gtt/tct/ - /atc/ - / - / 
               
               
                 ...BstXI 
               
               
                   
               
               
                              &lt;1&gt;     &lt;1&gt;  25992-fold diversity in CDR2 
               
               
                  ...CDR2 ..................................... /---FR3----- 
               
               
                  76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                   S   G   G   -   T   -   Y   A   D   S   V   K   G   R   F 
               
               
                 /tct/ggt/ggc/ - /act/ - /tat/gct/gac/tcc/gtt/aaa/ggt/cgc/ttc/ 
               
               
                   
               
               
                 -- - - FR3------------------------------------------------- 
               
               
                  91  92  93  94  95  96  97  98  99  100 101 102 103 104 105 
               
               
                  T    I   S   R   D   N   S   K   N   T   L   Y   L   Q   M 
               
               
                 /act/atc/tct/aga/gac/aac/tct/aag/aat/act/ctc/tac/ttg/cag/atg/ 
               
               
                          XbaI 
               
               
                   
               
               
                 ---FR3------------------------------------------------------ 
               
               
                  106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                   N   S   L   R   A   E   D   T   A   V   Y   Y   C   A   K 
               
               
                 /aac/agc/tta/agg/gct/gag/gac/acc/gct/gtc/tac/tac/tgc/gcc/aaa/ 
               
               
                       Af1II 
               
               
                   
               
               
                  .....CDR3................../ Replaced by the various components! 
               
               
                  121 122 123 124 125 126 127 
               
               
                   D   Y   E   G   T   G   Y   (SEQ ID NO: 24) 
               
               
                 /gac/tat/gaa/ggt/act/ggt/tat/ (SEQ ID NO: 23) 
               
               
                   
               
               
                 /----------  FR4 ---(JH4)-------------------------------------------------- 
               
               
                    Y   F   D   Y    W   G   Q   G   T   L   V   T   V   S   S (SEQ ID NO: 26) 
               
               
                 /tat/ttc/gat/tat/tgg/ggt/caa/ggt/acc/ctg/gtc/acc/gtc/tct/agt/.(SEQ ID NO: 25) 
               
               
                                               KpnI               BstEII 
               
               
                   
               
               
                 &lt;1&gt; = Codons for ADEFGHIKLMNPQRSTVWY (equimolar mixture) 
               
               
                 &lt;2&gt; = Codons for YRWVGS (equimolar mixture) 
               
               
                 &lt;3&gt; = Codons for PS or PS and G (equimolar mixture) 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
             
               
               
             
               
             
               
               
             
               
             
               
               
             
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Oligonucleotides used to variegate CDR1 of human HC 
               
               
                   
               
             
             
               
                 CDR1-5 residues 
               
             
          
           
               
                 (ON-R1V1vg): 
                 5′-ct/tcc/gga/ttc/act/ttc/tct/&lt;1&gt;/tac/&lt;1&gt;/atg/&lt;1&gt;/tgg/gtt/cgc/caa/gct/cct/gg-3′ 
               
               
                   
                 (SEQ ID NO: 27) 
               
             
          
           
               
                 &lt;1&gt; = Codons of ADEFGHIKLMNPQRSTVWY 1:1 
               
               
                   
               
             
          
           
               
                 (ON-Rltop): 
                 5′-cctactgtct/tcc/gga/ttc/act/ttc/tct-3′ (SEQ ID NO: 28) 
               
               
                   
               
               
                 (ON-Rlbot) [RC]: 
                 5′-′tgg/gtt/cgc/caa/gct/cct/ggttgctcactc-3′ (SEQ ID NO: 29) 
               
               
                   
               
             
          
           
               
                 CDR1-7 residues 
               
             
          
           
               
                 (ON-R1V2vg): 
                 5′-ct/tcc/gga/ttc/act/ttc/tct/&lt;6&gt;/&lt;7&gt;/&lt;7&gt;/tac/tac/tgg/&lt;7&gt;/tgg/gtt/cgc/caa/gct/ 
               
               
                   
                 cct/gg-3′ (SEQ ID NO: 30) 
               
             
          
           
               
                 &lt;6&gt; = Codons for ST, 1:1 
               
               
                 &lt;7&gt; 0.2025(Codons for SG) + 0.035(Codons for ADEFHIKLMNPQRTVWY) 
               
               
                   
               
               
                 CDR1-14 residues 
               
             
          
           
               
                 (ON-R1V3vg): 
                 5′-ct/tcc/gga/ttc/act/ttc/tct/atc/agc/ggt/ggt/tct/atc/tcc/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/- 
               
               
                   
                 tac/tac/tgg/&lt;1&gt;/tgg/gtt/cgc/caa/gct/cct/gg-3′ (SEQ ID NO: 31) 
               
             
          
           
               
                 &lt;1&gt; = Codons for ADEFGHIKLMNPQRSTVWY 1:1 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
             
               
               
             
               
             
               
               
             
               
             
               
               
             
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Oligonucleotides used to variegate CDR2 of human HC 
               
               
                   
               
             
             
               
                 CDR2-17 residues 
               
             
          
           
               
                 (ON-R2V1vg): 
                 5′-ggt/ttg/gag/tgg/gtt/tct/&lt;2&gt;/atc/&lt;2&gt;/&lt;3&gt;/tct/ggt/ggc/&lt;1&gt;/act/&lt;l&gt;/tat/gct/- 
               
               
                   
                 gac/tcc/gtt/aaa/gg-3′ (SEQ ID NO: 32) 
               
               
                   
               
               
                 (ON-R2top): 
                 5′-ct/tgg/gtt/cgc/caa/gct/cct/ggt/aaa/ggt/ttg/gag/tgg/gtt/tct-3′ (SEQ ID NO: 33) 
               
               
                   
               
               
                 (ON-R2bot) [RC]: 
                 5′-tat/gct/gac/tcc/gtt/aaa/ggt/cgc/ttc/act/atc/tct/aga/ttcctgtcac-3′ 
               
               
                   
                 (SEQ ID NO: 34) 
               
             
          
           
               
                 &lt;I&gt; = Codons for A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y (equimolar mixture) 
               
               
                 &lt;2&gt; = Codons for Y, R, W, V, G and S (equimolar mixiure) 
               
               
                 &lt;a&gt; = Codons for P and S (equimolar mixture) or P, S and G (equimolar mixture) 
               
               
                   
               
             
          
           
               
                 (ON-R2V2vg): 
                 5′-ggt/ttg/gag/tgg/gtt/tct/&lt;1&gt;/atc/&lt;4&gt;/&lt;1&gt;/&lt;1&gt;/ggt/&lt;5&gt;/&lt;1&gt;/&lt;l&gt;/&lt;l&gt;/tat/gct/- 
               
               
                   
                 gac/tcc/gtt/aaa/gg-3′ (SEQ ID NO: 35) 
               
             
          
           
               
                 &lt;4&gt; = Codons for DINSWY (equimolar mixture) 
               
               
                 &lt;5&gt; = Codons for SGDN, (equimolar mixture) 
               
               
                   
               
               
                 CDR2-16 residues 
               
             
          
           
               
                 (ON-R2V3vg): 
                 5′-ggt/ttg/gag/tgg/gtt/tct/&lt;1&gt;/att/&lt;4&gt;/&lt;1&gt;/&lt;1&gt;/ggt/ 
               
               
                   
                 &lt;5&gt;/&lt;1&gt;/&lt;1&gt;/tat/aac/cct/tcc/ctt/aag/gg-3′ (SEQ ID NO: 36) 
               
               
                   
               
               
                 (ON-R2bo3)[RC]: 
                 5′-tat/aac/cct/tcc/ctt/aag/ggt/cgc/ttc/act/atc/tct/aga/ttcctgtcac-3′ 
               
               
                   
                 (SEQ ID NO: 37) 
               
               
                   
               
             
          
           
               
                 CDR2 19 residues 
               
             
          
           
               
                 (ON-R2V4vg): 
                 5′-ggt/ttg/gag/tgg/gtt/tct/&lt;1&gt;/atc/&lt;8&gt;/agt/&lt;1&gt;/&lt;1&gt;/ 
               
               
                   
                 &lt;1&gt;/ggt/ggt/act/act/&lt;1&gt;/tat/gcc/gct/tcc/gtt/aag/gg-3′ (SEQ ID NO: 38) 
               
               
                   
               
               
                 (ON-R2bo4)[RC]: 
                 5′-tat/gcc/gct/tcc/gtt/aag/ggt/cgc/ttc/act/atc/tct/aga/ttcctgtcac′-3′ 
               
               
                   
                 (SEQ ID NO: 39) 
               
             
          
           
               
                 &lt;1&gt;, &lt;2&gt;, &lt;3&gt;, &lt;4&gt; and &lt;5&gt; are as defined above 
               
               
                 &lt;8&gt; is 0.27 R and 0.027 each of ADEFGHIKLMNPQSTVWY 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Preferred Components 
               
             
          
           
               
                   
                   
                   
                   
                 Preferred 
               
               
                   
                   
                   
                 Fraction of 
                 Adjusted 
               
               
                 Component 
                 Length 
                 Complexity 
                 Library 
                 Fraction 
               
               
                   
               
             
          
           
               
                 1 
                 YYCA21111YFDYWG. 
                  8 
                 2.6 × 10 5   
                 .10 
                 .02 
               
               
                   
                 (SEQ ID NO: 6) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = K and R) 
                   
                   
               
               
                   
               
             
          
           
               
                 2 
                 YYCA2111111YFDYWG. 
                 10 
                 9.4 × 10 7   
                 .14 
                 .14 
               
               
                   
                 (SEQ ID NO: 7) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = K and R) 
                   
                   
               
               
                   
               
             
          
           
               
                 3 
                 YYCA211111111YFDYTG. 
                 12 
                 3.4 × 10 10   
                 .25 
                 .25 
               
               
                   
                 (SEQ ID NO: 8) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = K and R) 
                   
                   
               
               
                   
               
             
          
           
               
                 4 
                 YYCAR111S2S3111YFDYWG. 
                 14 
                 1.9 × 10 8   
                 .13 
                 .14 
               
               
                   
                 (SEQ ID NO: 9) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = S and G; 3 = Y and W) 
                   
                   
               
               
                   
               
             
          
           
               
                 5 
                 YYCA2111CSG11CY1YFDYWG. 
                 15 
                 9.4 × 10 7   
                 .13 
                 .14 
               
               
                   
                 (SEQ ID NO: 10) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue except C; 2 = K and R) 
                   
                   
               
               
                   
               
             
          
           
               
                 6 
                 YYCA211S1TIFG11111YFDYWG. 
                 17 
                 1.7 × 10 10   
                 .11 
                 .12 
               
               
                   
                 (SEQ ID NO: 11) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = K and R ) 
                   
                   
               
               
                   
               
             
          
           
               
                 7 
                 YYCAR111YY2S33YY111YFDYMG. 
                 18 
                 3.8 × 10 8   
                 .04 
                 .08 
               
               
                   
                 (SEQ ID NO: 12) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = D or G; 3 = S and G) 
                   
                   
               
               
                   
               
             
          
           
               
                 8 
                 YYCAR1111YC2231CY111YFDYWG. 
                 19 
                 2.0 × 10 11   
                 .10 
                 .11 
               
               
                   
                 (SEQ ID NO: 13) 
                   
                   
                   
                   
               
             
          
           
               
                   
                 (1 = any amino acid residue, except C; 2 = S and G; 3 = T, D and G) 
                   
                   
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Oligonucleotides used to variegate the eight components of HC CDR3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (Ctop25): 
               
               
                 5′-gctctggtcaac/tta/agg/gct/gag/g-3′ (SEQ ID NO: 40) 
               
               
                   
               
               
                 (CtprmA): 
               
               
                 5′-gctctggtcaac/tta/agg/gct/gag/gac/acc/gct/gtc/tac/tac/tgc/gcc-3′ 
               
               
                           AflLL . . . (SEQ ID NO: 41) 
               
               
                   
               
               
                 (CBprmB)[RC]: 
               
               
                 5′-/tac/ttc/gat/tac/tgg/ggc/caa/ggt/acc/ctg/gtc/acc/tcgctccacc-3′ 
               
               
                 (SEQ ID NO: 42)                             BstEII . . . 
               
               
                   
               
               
                 (CBot25)[RC]: 
               
               
                 5′-/ggt/acc/ctg/gtc/acc/tcgctccacc-3′ (SEQ ID NO: 43) 
               
               
                   
               
               
                 The 20 bases at 3′ end of CtprmA are identical to the most 5′ 20 bases 
               
               
                 of each of the vgDNA molecules. 
               
               
                   
               
               
                 Ctop25 is identical to the most 5′ 25 bases of CtprmA. 
               
               
                 The 23 most 3′ bases of CBprmB are the reverse complement of the 
               
               
                 most 3′ 23 bases of each of the vgDNA molecules. 
               
               
                 CBot25 is identical to the 25 bases at the 5′ end of CBprmB. 
               
               
                   
               
               
                 Component 1 
               
               
                 (C1t08): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/&lt;2&gt;/&lt;l&gt;/&lt;l&gt;/&lt;l&gt;/&lt;l&gt;/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′ 
               
               
                 (SEQ ID NO: 44) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of the residues ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = K and R 
               
               
                 (equimolar mixture) 
               
               
                   
               
               
                 component 2 
               
               
                 (C2t10): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/&lt;2&gt;/&lt;l&gt;/&lt;l&gt;/&lt;l&gt;/&lt;l&gt;/&lt;1&gt;/&lt;1&gt;/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′ 
               
               
                 (SEQ ID NO: 45) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = K and R (equimolar 
               
               
                 mixture) 
               
               
                   
               
               
                 Component 3 
               
               
                 (C3t12): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/&lt;2&gt;/&lt;l&gt;/&lt;l&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/tac/ttc/gat/tac/- 
               
               
                 tgg/ggc/caa/gg-3′ (SEQ ID NO: 46) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = K and R (equimolar 
               
               
                 mixture) 
               
               
                   
               
               
                 Component 4 
               
               
                 (C4t140): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/cgt/&lt;1&gt;/&lt;l&gt;l&lt;1&gt;/tct/&lt;2&gt;/tct/&lt;3&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/tac/ttc/gat/- 
               
               
                 tac/tgg/ggc/caa/gg-3′ (SEQ ID NO: 47) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = S and G (equimolar 
               
               
                 mixture); &lt;3&gt; = Y and W (equimolar mixture) 
               
               
                   
               
               
                 Component 5 
               
               
                 (C5t15): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/&lt;2&gt;/&lt;1&gt;/&lt;l&gt;/&lt;1&gt;/tgc/tct/ggt/&lt;l&gt;/&lt;1&gt;/tgc/tat/&lt;1&gt;/tac/- 
               
               
                 ttc/gat/tac/tgg/ggc/caa/gg-3′ (SEQ ID NO: 48) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = K and R (equimolar 
               
               
                 mixture) 
               
               
                   
               
               
                 Component 6 
               
               
                 (C6t17): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/&lt;2&gt;/&lt;l&gt;/&lt;1&gt;/tct/&lt;l&gt;/act/atc/ttc/ggt/&lt;l&gt;/&lt;1&gt;/&lt;1&gt;/&lt;l&gt;/- 
               
               
                 &lt;1&gt;/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′ (SEQ ID NO: 49) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = K and R (equimolar 
               
               
                 mixture) 
               
               
                   
               
               
                 Component 7 
               
               
                 (C7t18): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/cgt/&lt;l&gt;/&lt;1&gt;/&lt;1&gt;/tat/tac/&lt;2&gt;/tct/&lt;3&gt;/&lt;3&gt;/tac/tat/- 
               
               
                 &lt;1&gt;/&lt;1&gt;/&lt;1&gt;/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′ (SEQ ID NO: 50) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = D and G (equimolar 
               
               
                 mixture); &lt;3&gt; = S and G (equimolar mixture) 
               
               
                   
               
               
                 Component 8 
               
               
                 (c8t19): 
               
               
                 5′-cc/gct/gtc/tac/tac/tgc/gcc/cgt/&lt;1&gt;/&lt;l&gt;/&lt;1&gt;/&lt;1&gt;/tat/tgc/&lt;2&gt;/&lt;2&gt;/&lt;3&gt;/&lt;1&gt;/tgc/tat/- 
               
               
                 &lt;1&gt;/&lt;1&gt;/&lt;1&gt;/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′ (SEQ ID NO: 51) 
               
               
                 &lt;1&gt; = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW, no C; &lt;2&gt; = S and G (equimolar 
               
               
                 mixture); &lt;3&gt; = TDG (equimolar mixture); 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 3-23:: JH4 Stuffers in place of CDRs 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                                                          FR1(DP47/V3-23)------------------------ 
               
               
                            20 21  22                     23   24  25  26  27  28  29  30 
               
               
                            A   M   A                     E    V   Q   L   L   E   S   G 
               
               
                 ctgtctgaac cc atg gcc                    gaa/gtt/caa/ttg/tta/gag/tct/ggt/ 
               
               
                 (SEQ ID NO: 99) 
               
               
                 Scab .......NcoI....                              MfeI 
               
               
                   
               
               
                      ---------------------------- FR1---------------------------- 
               
               
                        31  32  33  34  35  36  37  38 39  40  41  42  43  44  45 
               
               
                        G   G   L   V   Q   P   G   G   S   L   R   L   S   C   A 
               
               
                      /ggc/ggt/ctt/gtt/cag/cct/ggt/ggt/tct/tta/cgt/ctt/tct/tgc/gct/ 
               
               
                   
               
               
                      ---FR1---------------------&gt;/...CDR1 stuffer..../---FR2------ 
               
               
                       46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                        A   S   G   F   T   F   S   S   Y   A   /   /   W   V   R 
               
               
                      /gct/tcc/gga/ttc/act/ttc/tct/tcg/tac/gct/tag/taa/tgg/gtt/cgc/ 
               
               
                            BspEI                     BsiWI                       BstXI. 
               
               
                   
               
               
                      -------FR2--------------------------------&gt;/...CDR2 stuffer. 
               
               
                      61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                       Q   A   P   G   K   G   L   E   W   V   S   /   P   R   / 
               
               
                     /caa/gct/cct/ggt/aaa/ggt/ttg/gag/tgg/gtt/tct/taa/cct/agg/tag/ 
               
               
                  ...BstXI                                        AvrII.. 
               
               
                   
               
               
                     ....CDR2 stuffer..................................../---FR3--- 
               
               
                       91  92  93  94  95  96  97  98  99 100 101 102 103 104 105 
               
               
                       T   I   S   R   D   N   S   K   N   T   L   Y   L   Q   M 
               
               
                     /act/atc/tct/aga/gac/aac/tct/aag/aat/act/ctc/tac/ttg/cag/atg/ 
               
               
                               XbaI 
               
               
                   
               
               
                     --FR3------------..&gt; CDR3 Stuffer ------------&gt;/ 
               
               
                      106 107 108 109 110 
               
               
                       N   S   L   R   A   (SEQ ID NO: 53) 
               
               
                     /aac/agc/tta/agg/gct/tag taa agg cct taa (SEQ ID NO: 52) 
               
               
                           AflII                    StuI... 
               
               
                   
               
               
                     /-----FR4 ---(JH4)------------------------------------------- 
               
               
                     Y   F   D   Y   W   G   Q   G   T   L   V   T   V   S   S  (SEQ ID NO: 26) 
               
               
                   /tat/ttc/gat/tat/tgg/ggt/caa/ggt/acc/ctg/gtc/acc/gtc/tct/agt/... (SEQ ID NO: 25) 
               
               
                                                 KpnI        BstEII 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 A27: JH1 Human Kappa light chain gene 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 gaggacc attgggcccc ctccgagact ctcgagcgca 
               
               
                 Scab ......Eco0109I          XhoI 
               
               
                            ApaI  
               
               
                   
               
               
                 acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc 
               
               
                      ..−35..          Plac                      ..−10. 
               
               
                   
               
               
                 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga 
               
               
                   
               
               
                 aacagctatg accatgatta 
               
               
                   
               
               
                 cgccaagctt tggagccttt tttttggaga ttttcaac (SEQ ID NO: 54) 
               
               
                   pflMI....... 
               
               
                          Hind III 
               
               
                   
               
               
                 M13 III signal sequence (AA seg)------------------------------ 
               
               
                  1   2   3   4   5   6   7   8   9   10  11  12  13  14  15 
               
               
                  M   K   K   L   L   F   A   I   P   L   V   V   P   F   Y 
               
               
                 gtg aag aag ctc cta ttt get atc ccg ctt gtc gtt ccg ttt tac 
               
               
                   
               
               
                 --Signal--&gt;FR1---------------------------------------------&gt; 
               
               
                  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30 
               
               
                   S   H   S   A   Q   S   V   L   T   Q   S   P   G   T   L 
               
               
                 /agc/cat/agt/gca/caa/tcc/gtc/ctt/act/caa/tct/cct/ggc/act/ctt/ 
               
               
                           ApaLI... 
               
               
                   
               
               
                 ---- FR1 --------------------------------------&gt;/ CDR1----&gt; 
               
               
                  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                   S   L   S   P   G   E   R   A   T   L   S   C   R   A   S (SEQ ID NO: 55) 
               
               
                 /tcg/cta/agc/ccg/ggt/gaa/cgt/gct/acc/tta/agt/tgc/cgt/gct/tcc/ (SEQ ID 
               
               
                 NO: 54; Cont&#39;d) 
               
               
                    EspI.....                      AflII ... 
               
               
                             XmaI... 
               
               
                   
               
               
                 For CDR1: 
               
               
                 &lt;1&gt; ADEFGHIKLMNPQRSTVWY 1:1 
               
               
                 &lt;2&gt; S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each) 
               
               
                 &lt;3&gt; Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each) 
               
               
                   
               
               
                 (CDR1 installed as AflII-(SexAI or KasI) cassette.) For the most preferred l1 length codon 51 
               
               
                 (XXX) is omitted; for the preferred 12 length this codon is &lt;2&gt; 
               
               
                   
               
               
                        ------ CDR1--------------------- ---&gt;/--- FR2-------------&gt; 
               
               
                             &lt;1&gt;    &lt;2&gt;  &lt;2&gt; xxx &lt;3&gt; 
               
               
                         46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                          Q   -   V   -   -   -   -   L   A   W   Y   Q   Q   K   P (SEQ ID NO: 55; Cont&#39;d) 
               
               
                        /cag/ - /gtt/ - / - / - / - /ctt/gct/tgg/tat/caa/cag/aaa/cct/(SEQ ID NO: 54; Cont&#39;d) 
               
               
                                                                              SexAI.... 
               
               
                   
               
               
                 For CDR2: 
               
               
                 &lt;1&gt; ADEFGHIKLMNPQRSTVWY 1:1 
               
               
                 &lt;2&gt; S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each) 
               
               
                 &lt;4&gt; A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each) 
               
               
                   
               
               
                 CDR2 installed as (SexAI or KasI) to (BamHI or RsrII) cassette.) 
               
               
                   
               
               
                      ----- FR2 -------------------------&gt;/------CDR2-----------&gt; 
               
               
                                                          &lt;1&gt;         &lt;2&gt;     &lt;4&gt; 
               
               
                       61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                        G   Q   A   P   R   L   L   I   Y   -   A   S   -   R   - (SEQ ID NO: 55; Cont&#39;d) 
               
               
                      /ggt/cag/gcg/ccg/cgt/tta/ctt/att/tat/ - /gct/tct/ - /cgc/ - (SEQ ID NO: 54; Cont&#39;d) 
               
               
                      SexAI....   KasI.... 
               
               
                   
               
               
                 CDR2--&gt;/--- FR3 -------------------------------------------&gt; 
               
               
                   &lt;1&gt; 
               
               
                   76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                    -   G   I   P   D   R   F   S   G   S   G   S   G   T   D 
               
               
                  / - /ggg/atc/ccg/gac/cgt/ttc/tct/ggc/tct/ggt/tca/ggt/act/gac/ 
               
               
                         BamHI 
               
               
                                 RsrII ..... 
               
               
                   
               
               
                 --------FR3------------------------------------------------&gt; 
               
               
                  91  92  93  94  95  96  97  98  99  100 101 102 103 104 105 
               
               
                   F   T   L   T   I   S   R   L   E   P   E   D   F   A   V (SEQ ID NO: 55′ Cont&#39;d) 
               
               
                 /ttt/acc/ctt/act/att/tct/aga/ttg/gaa/cct/gaa/gac/ttc/gct/gtt/ (SEQ ID NO: 54; 
               
               
                 Cont&#39;d)              XbaI 
               
               
                   
               
               
                 For CDR3 (Length 9): 
               
               
                 &lt;1&gt; ADEFGHIKLMNPQRSTVWY 1:1 
               
               
                 &lt;3&gt; Y(0.2) ADEFGHIKLMNPQRTVW (0.044 each) 
               
               
                   
               
               
                 For CDR3 (Length 8): QQ33111P 
               
               
                 1 and 3 as defined for Length 9 
               
               
                   
               
               
                 For CDR3 (Length 10): QQ3211PP1T 
               
               
                 1 and 3 as defined for Length 9 
               
               
                 2 S(0.2) and 0.044 each of ADEFGHIKLMNPQRTVWY 
               
               
                   
               
               
                 CDR3 installed as XbaI to (StyI Or BsiWI)cassette. 
               
               
                   
               
               
                 -------------&gt;/----CDR3--------------------------&gt;/----FR4---&gt; 
               
               
                                      &lt;3&gt; &lt;1&gt; &lt;1&gt; &lt;1&gt;     &lt;1&gt; 
               
               
                  106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                   Y   Y   C   Q   Q   -   -   -   -   P   -   T   F   G   Q (SEQ ID NO: 55; Cont&#39;d) 
               
               
                 /tat/tat/tgc/caa/cag/ - / - / - / - /cct/ - /act/ttc/ggt/caa/ (SEQ ID NO: 54; Cont&#39;d) 
               
               
                               BstXI......... 
               
               
                   
               
               
                  ----FR4--------------------&gt;/            &lt;--------Ckappa ------------- 
               
               
                  121 122 123 124 125 126 127                128 129 130 131 132 133 134 
               
               
                   G   T   K   V   E   I   K                  R   T   V   A   A   P   S 
               
               
                 /ggt/acc/aag/gtt/gaa/atc/aag/              /cgt/acg/gtt/gcc/gct/cct/agt/ 
               
               
                       StyI....                               BsiWI.. 
               
               
                   
               
               
                  135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 
               
               
                   V   F   I   F   P   P   S   D   E   Q   L   K   S   G   T 
               
               
                 /gtg/ttt/atc/ttt/cct/cct/tct/gac/gaa/caa/ttg/aag/tca/ggt/act/ 
               
               
                                                       MfeI... 
               
               
                   
               
               
                  150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 
               
               
                   A   S   V   V   C   L   L   N   N   F   Y   P   R   E   A (SEQ ID NO: 55; Cont&#39;d) 
               
               
                 /gct/tct/gtc/gta/tgt/ttg/ctc/aac/aat/ttc/tac/cct/cgt/gaa/gct/ (SEQ ID NO: 54; Cont&#39;d) 
               
               
                                                              BssSI.. 
               
               
                   
               
               
                  165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 
               
               
                   K   V   Q   W   K   V   D   N   A   L   Q   S   G   N   S 
               
               
                 /aaa/gtt/cag/tgg/aaa/gtc/gat/aac/gcg/ttg/cag/tcg/ggt/aac/agt/ 
               
               
                                               MluI.... 
               
               
                   
               
               
                  180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 
               
               
                   Q   E   S   V   T   E   Q   D   S   K   D   S   T   Y   S 
               
               
                 /caa/gaa/tcc/gtc/act/gaa/cag/gat/agt/aag/gac/tct/acc/tac/tct/ 
               
               
                   
               
               
                  195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 
               
               
                   L   S   S   T   L   T   L   S   K   A   D   Y   E   K   H 
               
               
                 /ttg/tcc/tct/act/ctt/act/tta/tca/aag/gct/gat/tat/gag/aag/cat/ 
               
               
                   
               
               
                  210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 
               
               
                   K   V   Y   A   C   E   V   T   H   Q   G   L   S   S   P (SEQ ID NO: 55; Cont&#39;d) 
               
               
                 /aag/gtc/tat/GCt/TGC/gaa/gtt/acc/cac/cag/ggt/ctg/agc/ttc/cct/ (SEQ ID NO: 54; Cont&#39;d) 
               
               
                                                                SacI.... 
               
               
                   
               
               
                  225 226 227 228 229 230 231 232 233 234 
               
               
                   V   T   K   S   F   N   R   G   E   C                    (SEQ ID NO: 55; Cont&#39;d) 
               
               
                 /gtt/acc/aaa/agt/ttc/aac/cgt/ggt/gaa/tgc/taa/tag ggcgcgcc 
               
               
                                       DsaI....                   AscI.... 
               
               
                                                                    BssHII 
               
               
                   
               
               
                 acgcatctctaa gcggccgc aacaggaggag                          (SEQ ID NO: 54; Cont&#39;d) 
               
               
                              NotI.... 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 2a2: JH2 Human lambda-chain gene 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 gaggaccatt gggcccc ttactccgtgac 
               
               
                 Scab...... Eco0109I 
               
               
                   
               
               
                          ---------FR1--------------------------------------------&gt; 
               
               
                          1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                  S   A   Q   S   A   L   T   Q   P   A   S   V   S   G   S   P   G  (SEQ ID NO: 57) 
               
               
                 agt/gca/caa/tcc/gct/ctc/act/cag/cct/gct/agc/gtt/tcc/ggg/tca/cct/ggt/ (SEQ ID NO: 56) 
               
               
                  ApaLI...                            NheI...         BstEII... 
               
               
                                                                          SexAI.... 
               
               
                   
               
               
                 For CDR1 (length 14): 
               
               
                 &lt;1&gt; = 0.27 T, 0.27 G, 0.027 each of ADEFHIKLMNPQRSVWY, no C 
               
               
                 &lt;2&gt; = 0.27 D, 0.27 N,. 0.027 each of AEFGHIKLMPQRSTVWY, no C 
               
               
                 &lt;3&gt; = 0.36 Y, 0.0355 each of ADEFGHIKLMNPQRSTVW, no C 
               
               
                   
               
               
                                             T   G   &lt;1&gt;  S   S  &lt;2&gt;  V   G 
               
               
                  -----FR1 ----------------&gt; /----CDR1----------------------- 
               
               
                  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30 
               
               
                   Q   S   I   T   I   S   C   T   G   -   S   S   -   V   G 
               
               
                 /caa/agt/atc/act/att/tct/tgt/aca/ggt/ - /tct/tct/ - /gtt/ggc/ 
               
               
                                          BsrGI.. 
               
               
                   
               
               
                  &lt;1&gt; &lt;3&gt; &lt;2&gt; &lt;3&gt;  V   S = vg Scheme #1, length = 14 
               
               
                 -----CDR1 -------------&gt; /------------- FR2----------------- 
               
               
                  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                   -   -   -   -   V   S   W   Y   Q   Q   H   P   G   K   A  (SEQ ID NO: 57; Cont&#39;d) 
               
               
                 / - / - / - / - /gtt/tct/tgg/tat/caa/caa/cac/ccg/ggc/aag/gcg/ (SEQ ID NO:56; Cont&#39;d) 
               
               
                                                           XmaI....     KasI..... 
               
               
                                                           AvaI.... 
               
               
                   
               
               
                 A second Vg scheme for CDR1 gives segments of length 11: 
               
               
                 T 22 G&lt;2&gt;&lt;4&gt;L&lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;3&gt;&lt;4&gt;&lt;4&gt; where 
               
               
                 &lt;4&gt; = equimolar mixture of each of ADEFGHIKLMNPQRSTVWY, no C 
               
               
                 &lt;3&gt; = as defined above for the alternative CDR1 
               
               
                   
               
               
                 For CDR2: 
               
               
                 &lt;2&gt; and &lt;4&gt; are the same variegation as for CDR1 
               
               
                   
               
               
                                            &lt;4&gt; &lt;4&gt; &lt;4&gt; &lt;2&gt;  R   P   S 
               
               
                     --FR2---------------&gt; /-------CDR2--------- -----&gt;/------FR3- 
               
               
                     46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                      P   K   L   M   I   Y   -   -   -   -   R   P   S   G   V 
               
               
                    /ccg/aag/ttg/atg/atc/tac/ - / - / - / - /cgt/cct/tct/ggt/gtt/ 
               
               
                 KasI.... 
               
               
                   
               
               
                    --------FR3------------------------------------------------- 
               
               
                     61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                      S   N   R   F   S   G   S   K   S   G   N   T   A   S   L (SEQ ID NO: 57; Cont&#39;d) 
               
               
                    /agc/aat/cgt/ttc/tcc/gga/tct/aaa/tcc/ggt/aat/acc/gca/agc/tta/ (SEQ ID NO: 56; Cont&#39;d) 
               
               
                                      BspEI..                          HindIII. 
               
               
                                          BsaBI..............(blunt) 
               
               
                   
               
               
                  ------FR3-------------------------------------------------&gt; 
               
               
                  76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                   T   I   S   G   L   Q   A   E   D   E   A   D   Y   Y   C  (SEQ ID NO: 57; Cont&#39;d) 
               
               
                 /act/atc/tct/ggt/ctg/cag/gct/gaa/gac/gag/gct/gac/tac/tat/tgt/ (SEQ ID NO: 56; Cont&#39;d) 
               
               
                                   PstI... 
               
               
                   
               
               
                 CDR3 (Length 11): 
               
               
                 &lt;2&gt; and &lt;4&gt; are the same variegation as for CDR1 
               
               
                 &lt;5&gt; = 0.36 S, 0.0355 each of ADEFGHIKLMNPQRTVWY no C 
               
               
                   
               
               
                 CDR3 (Length 10): &lt;5&gt; SY &lt;1&gt; &lt;5&gt; S &lt;5&gt; &lt;1&gt; &lt;4&gt; V 
               
               
                 &lt;1&gt; is an equimolar mixture of ADEFGHIKLMNPQRSTVWY, no C 
               
               
                 &lt;4&gt; and &lt;5&gt; are as defined for Length 11 
               
               
                   
               
               
                        &lt;4&gt; &lt;5&gt; &lt;4&gt; &lt;2&gt; &lt;4&gt; S &lt;4&gt; &lt;4&gt; &lt;4&gt; &lt;4&gt; V 
               
               
                   ------CDR3--------------------------------&gt;/----FR4------- 
               
               
                    91  92  93  94  95  96  97  98  99  100 101 102 103 104 105 
               
               
                     -   -   -   -   -   S   -   -   -   -   V   F   G   G   G 
               
               
                   / - / - / - / - / - /tct/ - / - / - / - /gtc/ttc/ggc/ggt/ggt/ 
               
               
                                                                            KpnI.. 
               
               
                   
               
               
                     -------FR4-------------&gt; 
               
               
                     106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                      T   K   L   T   V   L   G   Q   P   K   A   A   P   S   V 
               
               
                    /acc/aaa/ctt/act/gtc/ctc/ggt/caa/cct/aag/gct/gct/cct/tcc/gtt/ 
               
               
                 KpnI...                      HincII.. 
               
               
                                                    Bsu36I... 
               
               
                   
               
               
                     121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 
               
               
                      T   L   F   P   P   S   S   E   E   L   Q   A   N   K   A  (SEQ ID NO: 57; Cont&#39;d) 
               
               
                    /act/ctc/ttc/cct/cct/agt/tct/gaa/gag/ctt/caa/gct/aac/aag/gct/ (SEQ ID NO: 56; Cont&#39;d) 
               
               
                                                  SapI..... 
               
               
                   
               
               
                     136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 
               
               
                      T   L   V   C   L   I   S   D   F   Y   P   G   A   V   T 
               
               
                    /act/ctt/gtt/tgc/ttg/atc/agt/gac/ttt/tat/cct/ggt/gct/gtt/act/ 
               
               
                                      BclI.... 
               
               
                   
               
               
                     151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 
               
               
                      V   A   W   K   A   D   S   S   P   V   K   A   G   V   E 
               
               
                    /gtc/gct/tgg/aaa/gcc/gat/tct/tct/cct/gtt/aaa/gct/ggt/gtt/gag/ 
               
               
                                                                                 BsmBI... 
               
               
                   
               
               
                     166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 
               
               
                      T   T   T   P   S   K   Q   S   N   N   K   Y   A   A   S 
               
               
                    /acg/acc/act/cct/tct/aaa/caa/tct/aac/aat/aag/tac/gct/gcg/agc/ 
               
               
                 BsmBI...                                                  SacI.... 
               
               
                   
               
               
                     181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 
               
               
                      S   Y   L   S   L   T   P   E   Q   W   K   S   H   K   S  (SEQ ID NO: 57; Cont&#39;d) 
               
               
                    /tct/tat/ctt/tct/ctc/acc/cct/gaa/caa/tgg/aag/tct/cat/aaa/tcc/ (SEQ ID NO: 56; Cont&#39;d) 
               
               
                 SacI... 
               
               
                   
               
               
                     196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 
               
               
                      Y   S   C   Q   V   T   H   E   G   S   T   V   E   K   T 
               
               
                    /tat/tcc/tgt/caa/gtt/act/cat/gaa/ggt/tct/acc/gtt/gaa/aag/act/ 
               
               
                                          BspHI... 
               
               
                   
               
               
                    211 212 213 214 215 216 217 218 219 
               
               
                      V   A   P   T   E   C   S (SEQ ID NO: 57; Cont&#39;d) 
               
               
                    /gtt/gcc/cct/act/gag/tgt/tct/tag/tga/ggcgcgcc 
               
               
                                                        AscI.... 
               
               
                                                          BssHII 
               
               
                   
               
               
                    aacgatgttc aag gcggccgc aacaggaggag (SEQ ID NO: 56; Cont&#39;d) 
               
               
                                   NotI.... Scab....... 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                 Oligonucleotides For Kappa and Lambda Light Chain Variegation 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (Ctop25): 
                 5′-gctctggtcaac/tta/agg/gct/gag/g-3′ (SEQ ID NO: 58) 
               
               
                   
               
               
                 (CtprmA): 
                 5′-gctctggtcaac/tta/agg/gct/gag/gac/acc/gct/gtc/tac/tac/tgc/gcc-3′ 
               
               
                   
                 (SEQ ID NO: 59) AflII... 
               
               
                   
               
               
                 (CBprmB)[RC]: 
                 5′-/tac/ttc/gat/tac/ttg/ggc/caa/ggt/acc/ctg/gtc/acc/tcgctccacc-3′ 
               
               
                   
                 (SEQ ID NO: 60)                            BstEII... 
               
               
                   
               
               
                 (CBot25) [RC]: 
                 5′-/ggt/acc/ctg/gtc/acc/tcgaccacc-3′ (SEQ ID NO: 61) 
               
               
                   
               
               
                 Kappa chains: 
                 CDR1 (“1”), CDR2 (“2”), CDR1 (“3”) 
               
               
                   
               
               
                 CDR1 
                   
               
               
                 (KalTop610): 
                 5′-ggtctcagttg/cta/agc/ccg/ggt/gaa/cgt/gct/acc/tta/agt/tgc/cgt/gct/tcc/cag-3′ 
               
               
                   
                 (SEQ ID NO: 62) 
               
               
                   
               
               
                 (KalSTp615): 
                 5′-ggtctcagttg/cta/agc/ccg/ggt/g-3′ (SEQ ID NO: 63) 
               
               
                   
               
               
                 (KalBot620) [RC]: 
                 ′5′-ctt/gct/tgg/tat/caa/cag/aaa/cct/ggt/cag/gcg/ccaagtcgtgtc-3′ 
               
               
                   
                 (SEQ ID NO: 64) 
               
               
                   
               
               
                 (KalSB625) [RC]: 
                 5′-cct/ggt/cag/gcg/ccaagtcgtgtc-3′(SEQ ID NO: 65) 
               
               
                   
               
               
                 (Kalvg600): 
                 5′-gct/acc/tta/agt/tgc/cgt/gct/tcc/cag- 
               
               
                   
                 /&lt;1&gt;/gtt/&lt;2&gt;/&lt;2&gt;/&lt;3&gt;/ctt/gct/tgg/tat/caa/cag/aaa/cc-3′ (SEQ ID NO: 66) 
               
               
                   
               
               
                 (Kalvg600-12): 
                 5′-gct/acc/tta/agt/tgc/cgt/gct/tcc/cag- 
               
               
                   
                 /&lt;1&gt;/gtt/&lt;2&gt;/&lt;2&gt;/&lt;2&gt;/&lt;3&gt;/ctt/gct/tgg/tat/caa/cag/aaa/cc-3′ (SEQ ID NO: 67) 
               
               
                   
               
               
                 CDR2 
                   
               
               
                 (Ka2Tshort657): 
                 5′-cacgagtccta/cct/ggt/cag/gc-3′ (SEQ ID NO: 68) 
               
               
                   
               
               
                 (Ka2Tlong655): 
                 5′-cacgagtccta/cct/ggt/cag/gcg/ccg/cgt/tta/ctt/att/tat-3′ (SEQ ID NO: 69) 
               
               
                   
               
               
                 (Ka2Bshort660):[RC]: 
                 5′-/gac/cgt/ttc/tct/ggt/tctcacc-3′ (SEQ ID NO: 70) 
               
               
                   
               
               
                 (Ka2vg650): 
                 5′-cag/gcg/ccg/cgt/tta/ctt/att/tat/&lt;1&gt;/gct/tct/&lt;2&gt;/- 
               
               
                   
                 /cgc/&lt;4&gt;/&lt;1&gt;/ggg/atc/ccg/gac/cgt/ttc/tct/ggt/tctcacc-3′ (SEQ ID NO: 71) 
               
               
                   
               
               
                 CDR3 
                   
               
               
                 (Ka3Tlon672): 
                 5′-gacgagtccttct/aga/ttg/gaa/cct/gaa/gac/ttc/gct/gtt/tat/tat/tgc/caa/c-3′ 
               
               
                   
                 (SEQ ID NO: 72) 
               
               
                   
               
               
                 (Ka3BotL682) [RC]: 
                 5′-act/ttc/ggt/caa/ggt/acc/aag/gtt/gaa/atc/aag/cgt/acg/tcacaggtgag-3′ 
               
               
                   
                 (SEQ ID NO: 73) 
               
               
                   
               
               
                 (Ka3Bsho694) [RC]: 
                 5′-gaa/atc/aag/cgt/acg/tcacaggtgag-3′(SEQ ID NO: 74) 
               
               
                   
               
               
                 (Ka3vg670): 
                 5′-gac/ttc/gct/gtt/- 
               
               
                   
                 /tat/tat/tgc/caa/cag/&lt;3&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/cct/&lt;1&gt;/act/ttc/ggt/caa/- 
               
               
                   
                 /ggt/acc/aag/gtt/g-3′ (SEQ ID NO: 75) 
               
               
                   
               
               
                 (Ka3v670-8): 
                 5′-gac/ttc/gct/gtt/- 
               
               
                   
                 /tat/tat/tgc/caa/cag/&lt;3&gt;/&lt;3&gt;/&lt;1&gt;/&lt;1&gt;/&lt;1&gt;/cct/ttc/ggt/caa/- 
               
               
                   
                 /ggt/acc/aag/gtt/g-3′ (SEQ ID NO: 76) 
               
               
                   
               
               
                 (Ka3vg670-10): 
                 5′-gac/ttc/gct/gtt/tat/- 
               
               
                   
                 /tat/tgc/caa/cag/&lt;3&gt;/&lt;2&gt;/&lt;1&gt;/&lt;1&gt;/cct/cct/&lt;1&gt;/act/ttc/ggt/caa/- 
               
               
                   
                 /ggt/acc/aag/gtt/g-3′ (SEQ ID NO: 77) 
               
               
                   
               
               
                 Lambda Chains: 
                 CDR1 (“1”), CDR2 (“2”), CDR3(“3”) 
               
               
                   
               
               
                 CDR1 
                   
               
               
                 (Lm1TPri75): 
                 5′-gacgagtcctgg/tca/cct/ggt/-3′ (SEQ ID NO: 78) 
               
               
                   
               
               
                 (Lm1t1o715): 
                 5′-gacgagtcctgg/tca/cct/ggt/caa/agt/atc/act/att/tct/tgt/aca/ggt-3′ 
               
               
                   
                 (SEQ ID NO: 79) 
               
               
                   
               
               
                 (Lm1b1o724)[rc]: 
                 5′-/gtt/tct/tgg/tat/caa/caa/cac/ccg/ggc/aag/gcg/agatcttcacaggtgag-3′ 
               
               
                   
                 (SEQ ID NO: 80) 
               
               
                   
               
               
                 (Lm1bsh737)[rc]: 
                 5′-gc/aag/gcg/agatcttcacaggtgag-3′ (SEQ ID NO: 81) 
               
               
                   
               
               
                 (Lm1vg710b): 
                 5′-gt/atc/act/att/tct/tgt/aca/ggt/&lt;2&gt;/&lt;4&gt;/ctc/&lt;4&gt;/&lt;4&gt;/&lt;4&gt;/- 
               
               
                   
                 /&lt;3&gt;/&lt;4&gt;/&lt;4&gt;/tgg/tat/caa/caa/cac/cc-3′ (SEQ ID NO: 82) 
               
               
                   
               
               
                 (Lmlvg710): 
                 5′-gt/atc/act/att/tct/tgt/aca/ggt/&lt;1&gt;/tct/tct/&lt;2&gt;/gtt/ggc/- 
               
               
                   
                 /&lt;1&gt;/&lt;3&gt;/&lt;2&gt;/&lt;3&gt;/gtt/tct/tgg/tat/caa/caa/cac/cc-3′ (SEQ ID NO: 83) 
               
               
                   
               
               
                 CDR2 
                   
               
               
                 (Lm2TSh757): 
                 5′-gagcagaggac/ccg/ggc/aag/gc-3′(SEQ ID NO: 84) 
               
               
                   
               
               
                 (Lm2TLo753): 
                 5′-gagcagaggac/ccg/ggc/aag/gcg/ccg/aag/ttg/atg/atc/tac/-3′ (SEQ ID NO: 85) 
               
               
                   
               
               
                 (Lm2BLo762) [RC]: 
                 5′-cgt/cct/tct/ggt/gtc/agc/aat/cgt/ttc/tcc/gga/tcacaggtgag-3′ 
               
               
                   
                 (SEQ ID NO: 86) 
               
               
                   
               
               
                 (Lm2Bsh765) [RC]: 
                 5′-cgt/ttc/tcc/gga/tcacaggtgag-3′ (SEQ ID NO: 87) 
               
               
                   
               
               
                 (Lm2vg750): 
                 5′-g/ccg/aag/ttg/atg/atc/tac/- 
               
               
                   
                 &lt;4&gt;/&lt;4&gt;/&lt;4&gt;/&lt;2&gt;/cgt/cct/tct/ggt/gtc/agc/aat/c-3′ (SEQ ID NO: 88) 
               
               
                   
               
               
                 CDR3 
                   
               
               
                 (Lm3TSh822): 
                 5′-ctg/cag/gct/gaa/gac/gag/gct/gac-3′ (SEQ ID NO: 89) 
               
               
                   
               
               
                 (Lm3TLo819): 
                 5′-ctg/cag/gct/gaa/gac/gag/gct/gac/tac/tat/tgt/-3′ (SEQ ID NO: 90) 
               
               
                   
               
               
                 (Lm3BLo825) [RC]: 
                 5′-gtc/ttc/ggc/ggt/ggt/acc/aaa/ctt/act/gtc/ctc/ggt/caa/cct/aag/g- 
               
               
                   
                 acacaggtgag-3′ (SEQ ID NO: 91) 
               
               
                   
               
               
                 (Lm3BSh832) (RC]: 
                 5′ c/ggt/caa/cct/aag/gacacaggtgag (SEQ ID NO: 92) 
               
               
                   
               
               
                 (Lm3vg17): 
                 5′-gac/gag/gct/gac/tac/tat/tgt/- 
               
               
                   
                 /&lt;4&gt;/&lt;5&gt;/&lt;4&gt;/&lt;2&gt;/&lt;4&gt;/tct/&lt;4&gt;/&lt;4&gt;/&lt;4&gt;/&lt;4&gt;/- 
               
               
                   
                 Gtc/ttc/ggc/ggt/ggt/acc/aaa/ctt/ac-3′ (SEQ ID NO: 93) 
               
               
                   
               
               
                 (Lm3vg817-10): 
                 5′- gac/gag/gct/gac/tac/tat/tgt/- 
               
               
                   
                 /&lt;5&gt;/agc/tat/&lt;1&gt;/&lt;5&gt;/tct/&lt;5&gt;/&lt;1&gt;/&lt;4&gt;/gtc/ttc/ggc/ggt/ggt/- 
               
               
                   
                 /acc/aaa/ctt/ac-3′ (SEQ ID NO: 94) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 10 
               
               
                   
               
               
                 A27: JH1 Kappa light chain gene with stuffers in place of CDRs 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Each stuffer contains at least one stop codon and a 
               
               
                 restriction site that will be unique within the diversity vector. 
               
               
                     gaggacc attgggcccc ctccgagact ctcgagcgca 
               
               
                        Scab..... Eco0109I 
               
               
                                  ApaI.             XhoI.. 
               
               
                   
               
               
                     acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc 
               
               
                           ..−35..         Plac                     ..−10. 
               
               
                   
               
               
                 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatgac 
               
               
                 catgatta cgccaagctt tggagccttt tttttggaga ttttcaac (SEQ ID NO: 95) 
               
               
                            Pf1MI ............. 
               
               
                               Hind3. 
               
               
                   
               
               
                 M13 III signal sequence (AA seq)--------------------------&gt; 
               
               
                  1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                  M   K   K   L   L   F   A   I   P   L   V   V   P   F   Y 
               
               
                 gtg aag aag ctc cta ttt get atc ccg ctt gtc gtt ccg ttt tac 
               
               
                   
               
               
                 --Signal--&gt; FR1-------------------------------------------- 
               
               
                  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30 
               
               
                   S   H   S   A   Q   S   V   L   T   Q   S   P   G   T   L 
               
               
                 /agc/cat/agt/gca/caa/tcc/gtc/ctt/act/caa/tct/cct/ggc/act/ctt/ 
               
               
                          ApaLI... 
               
               
                   
               
               
                 ----- FR1------------------- --------------&gt;/---------Stuffer-&gt; 
               
               
                  31  32  33  34  35  36  37  38  39  40  41  42  43 
               
               
                   S   L   S   P   G   E   R   A   T   L   S   /   / (SEQ ID NO: 96) 
               
               
                 /tcg/cta/agc/ccg/ggt/gga/cgt/gct/acc/tta/agt/tag/taa/gct/ccc/ (SEQ ID NO: 95; Cont&#39;d) 
               
               
                    EspI.....                      AflII... 
               
               
                            XmaI.... 
               
               
                   
               
               
                 - Stuffer for CDR1--&gt; FR2 ---------------FR2--- &gt;/    Stuffer for CDR2 
               
               
                                        59  60  61  62  63  64  65  66 
               
               
                                         K   P   G   Q   A   P   R 
               
               
                 /agg/cct/ctt/tga/tct/g/aaa/cct/ggt/cag/gcg/ccg/cgt/taa/tga/aagcgctaatggccaacagtg 
               
               
                 StuI...                  SexAI...   KasI....               AfeI..   MscI.. 
               
               
                   
               
               
                 Stuffer--&gt;/--- FR3 -------------------------------------------&gt; 
               
               
                  76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                   T   G   I   P   D   R   F   S   G   S   G   S   G   T   D(SEQ ID NO: 96; Cont&#39;d) 
               
               
                 /act/ggg/atc/ccg/gac/cgt/ttc/tct/ggc/tct/ggt/tca/ggt/act/gac/ (SEQ ID NO: 95; Cont&#39;d) 
               
               
                        BamHI... 
               
               
                              RsrII............ 
               
               
                   
               
               
                 --------FR3------&gt;----------------STUFFER for CDR3-------------------&gt; 
               
               
                  91  92  93  94  95  96  97 
               
               
                   F   T   L   T   I   S   R   /   / 
               
               
                 /ttt/acc/ctt/act/att/tct/aga/taa/tga/ gttaac tag acc tacgta acc tag 
               
               
                                      XbaI...          HpaI..         SnaBI. 
               
               
                   
               
               
                 ----------------------CDR3 stuffer---------------&gt;/------FR4-------&gt; 
               
               
                                                                         118 119 120 
               
               
                                                                          F   G   Q 
               
               
                                                                        /ttc/ggt/caa/ 
               
               
                   
               
               
                 -----FR4--------------------&gt;           &lt;--------Ckappa ----------- 
               
               
                  121 122 123 124 125 126 127            128 129 130 131 132 133 134 
               
               
                   G   T   K   V   E   I   K              R   TV   A   A  P   S (SEQ ID NO: 96; Cont&#39;d) 
               
               
                 /ggt/acc/aag/gtt/gaa/atc/aag/          /cgt/acg/gtt/gcc/gct/cct/agt/ 
               
               
                       StyI....                          BsiWI.. (SEQ ID NO: 95; Cont&#39;d) 
               
               
                   
               
               
                  135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 
               
               
                   V   F   I   F   P   P   S   D   E   Q   L   K   S   G   T (SEQ ID NO: 96; Cont&#39;d) 
               
               
                 /gtg/ttt/atc/ttt/cct/cct/tct/gac/gaa/caa/ttg/aag/tca/ggt/act/ 
               
               
                                                       MfeI... 
               
               
                   
               
               
                 acgcatctctaa gcggccgc aacaggaggag (SEQ ID NO: 95; Cont&#39;d) 
               
               
                              NotI.... 
               
               
                                EagI.. 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 11 
               
               
                   
               
               
                 2a2: JH2 Human lambda-chain gene with stuffers in place of CDR3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                     gaggaccatt gggcccc ttactccgtgac 
               
               
                     Scab.....  Eco0109I 
               
               
                                ApaI 
               
               
                   
               
               
                              ----------FR1-------------- ------------------------------&gt; 
               
               
                              1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                      S   A   Q   S   A   L   T   Q   P   A   S   V   S   G   S   P   G 
               
               
                     agt/gca/caa/tcc/gct/ctc/act/cag/cct/gct/agc/gtt/tcc/ggg/tca/cct/ggt/ 
               
               
                     ApaLI...                            NheI...         BstEll... 
               
               
                                                                               SexAI.... 
               
               
                   
               
               
                     -------FR1----------------&gt; /---------stuffer for CDR1 --------- 
               
               
                      16  17  18  19  20  21  22  23 
               
               
                       Q   S   I   T   I   S   C   T (SEQ ID NO: 98) 
               
               
                     /caa/agt/atc/act/att/tct/tgt/aca/tct tag tga ctc(SEQ ID NO: 97) 
               
               
                                              BsrGI.. 
               
               
                   
               
               
                     ----Stuffer-----------------------------&gt;--------FR2-------&gt; 
               
               
                      31   32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                      R   S   /   /   P   /                   H   P   G   K   A 
               
               
                     aga tct taa tga ccg tag                 cac/ccg/ggc/aag/gcg/ 
               
               
                      BglII                                    XmaI....     KasI..... 
               
               
                                                               AvaI.... 
               
               
                   
               
               
                     --/--------------Stuffer for CDR2----------------------------------&gt; 
               
               
                      P 
               
               
                     /ccg/taa/tga/atc tcg tac g                            ct/ggt/gtt/ 
               
               
                 KasI....             BsiWI... 
               
               
                   
               
               
                     -------FR3 
               
               
                     61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                      S   N   R   F   S   G   S   K   S   G   N   T   A   S   L (SEQ ID NO: 98; Cont&#39;d) 
               
               
                    /agc/aat/cgt/ttc/tcc/gga/tct/aaa/tcc/ggt/aat/acc/gca/agc/tta/ (SEQ ID NO: 97; Cont&#39;d) 
               
               
                                     BseEI..                           HindIII. 
               
               
                                            BsaBI..........(blunt) 
               
               
                   
               
               
                 ------FR3-------------&gt;/--Stuffer for ODR3-------------------&gt;/ 
               
               
                  76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                   T   I   S   G   L   Q 
               
               
                 /act/atc/tct/ggt/ctg/cag/gtt ctg tag ttc caattg ctt tag tga ccc 
               
               
                                  PstI...                 MfeI.. 
               
               
                   
               
               
                     -----Stuffer------------------------------&gt;/---FR4--------- 
               
               
                                                                   103 104 105 
               
               
                                                                    G   G   G 
               
               
                                                                  /ggc/ggt/ggt/ 
               
               
                                                                            KpnI... 
               
               
                   
               
               
                     --------FR4--------------&gt; 
               
               
                      106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                        T   K   L   T   V   L   G   Q   P   K   A   A   P   S (SEQ ID NO: 98; Cont&#39;d) 
               
               
                     V/acc/aaa/ctt/act/gtc/ctc/ggt/caa/cct/aag/gct/gct/cct/tcc/gtt/ (SEQ ID NO: 97; Cont&#39;d) 
               
               
                     KpnI...                      HincII.. 
               
               
                                                       Bsu36I... 
               
               
                   
               
               
                 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 
               
               
                   T   L   F   P   P   S   S   E   E   L   Q   A   N   K   A 
               
               
                 /act/ctc/ttc/cat/cct/agt/tct/gaa/gag/ctt/caa/gct/aac/aag/gct/ 
               
               
                                              SapI..... 
               
               
                   
               
               
                  136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 
               
               
                   T   L   V   C   L   I   S   D   F   Y   P   G   A   V   T (SEQ ID NO: 98; Cont&#39;d) 
               
               
                 /act/cct/gtt/tgc/ttg/atc/agt/gac/ttt/tat/cct/ggt/gct/gtt/act/ (SEQ ID NO: 97; Cont&#39;d) 
               
               
                                   BclI.... 
               
               
                   
               
             
          
         
       
     
         [0160]    The invention relates to generation of useful diversity in synthetic antibody (Ab) gene, especially to Ab genes having frameworks derived from human Abs. 
       Background of the Invention: 
       [0161]    Antibodies are highly useful molecules because of their ability to bind almost any substance with high specificity and affinity and their ability to remain in circulation in blood for prolonged periods as therapeutic or diagnostic agents. For treatment of humans, Abs derived from human Abs are much preferred to avoid immune response to the Ab. For example, murine Abs very often cause Human Anti Mouse Antibodies (HAMA) which at a minimum prevent the therapeutic effects of the murine Ab. For many medical applications, monoclonal Abs are preferred. Nowadays the preferred method of obtaining a human Ab having a particular binding specificity is to select the Ab from a library of human-derived Abs displayed on a genetic package, such as filamentous phage. 
         [0162]    Libraries of phage-displayed Fabs and scFvs have been produced in several ways. One method is to capture the diversity of donors, either naive or immunized. Another way is to generate libraries having synthetic diversity. The present invention relates to methods of generating useful diversity in human Ab scaffolds. 
         [0163]    As is well known, typical Abs consist of two heavy chains (HC) and two light chains (LC). There are several types of HCs: gamma, mu, epsilon, delta, etc. Each type has an N-terminal V domain followed by three or more constant domains. The LCs comprise an N-terminal V domain followed by a constant domain. LCs come in two types: kappa and lambda. 
         [0164]    Within each V domain (LC or HC) there are seven canonical regions, named FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4, where “FR” stands for “Framework Region” and “CDR” stands for “Complementarity Determining Region”. For LC and HC, the FR and CDR GLGs have been selected over time to be secretable, stable, non-antigenic and these properties should be preserved as much as possible. Actual Ab genes contain mutations in the FR regions and some of these mutations contribute to binding, but such useful FR mutations are rare and are not necessary to obtain high-affinity binding. Thus, the present invention will concentrate diversity in the CDR regions. 
         [0165]    In LC, FR1 up to FR3 and part of CDR3 comes from a genomic collection of genes called “V-genes”. The remainder of CDR3 and FR4 comes from a genomic collection of genes called “J-genes”. The joining may involve a certain degree of mutation, allowing diversity in CDR3 that is not present in the genomic sequences. After the LC gene is formed, somatic mutations can give rise to mature, rearranged LC genes that have higher affinity for an antigen (Ag) than does any LC encoded by genomic sequences. A large fraction of somatic mutations occur in CDRs. 
         [0166]    The HC V region is more complicated. A V gene is joined to a J gene with the possible inclusion of a D segment. About half of HC Abs sequences contain a recognizable D segment in CDR3. The joining is achieved with an amazing degree of molecular sloppiness. Roughly, the end of the V gene may have zero to several bases deleted or changed, the D segment may have zero to many bases removed or changed at either end, a number of random bases may be inserted between V and D or between D and J, and the 5′ end of J may be edited to remove or change several bases. Withal, it is amazing that human heavy chains work, but they do. The upshot is that the CDR3 is highly diverse both in encoded amino-acid sequences and in length. In designing synthetic libraries, there is the temptation to just throw in a high degree of synthetic diversity and let the phage sort it out. Nevertheless, D regions serve a function. They cause the Ab repertoire to be rich in sequences that a) allow Abs to fold correctly, and b) are conducive to binding to biological molecules, i.e. antigens. 
         [0167]    One purpose of the present invention is to show how a manageable collection of diversified sequences can confer these advantages on synthetic Ab libraries. Another purpose of the present invention is to disclose analysis of known mature Ab sequences that lead to improved designs for diversity in the CDR1 and CDR2 of HC and the three CDRs of lambda and kappa chains. 
       Brief Statement of the Invention: 
       [0168]    The invention is directed to methods of preparing synthetically diverse populations of Ab genes suitable for display on genetic packages (such as phage or phagemids) or for other regimens that allow selection of specific binding. Said populations concentrate the diversity into regions of the Ab that are likely to be involved in determining affinity and specificity of the Ab for particular targets. In particular, a collection of actual Ab genes has been analyzed and the sites of actual diversity have been identified. In addition, structural considerations were used to determine whether the diversity is likely to greatly influence the binding activity of the Ab. Schemes of variegation are presented that encode populations in which the majority of members will fold correctly and in which there is likely to be a plurality of members that will bind to any given Ag. Specifically, a plan of variegation is presented for each CDR of the human heavy chain, kappa light chain, and lambda light chain. The variegated CDRs are presented in synthetic HC and LC frameworks. 
         [0169]    In one embodiment, the invention involves variegation of human HC variable domains based on a synthetic 3-23 domain joined to a JH4 segment in which the variability in CDR1 and CDR2 comprises sequence variation of segments of fixed length while in CDR3 there are several components such that the population has lengths roughly corresponding to lengths seen in human Abs and having embedded D segments in a portion of the longer segments. In the light chains, the kappa chain is built in an A27 framework and a JK1 while lambda is built in a 2a2 framework with an L2 J region. 
       EXAMPLES 
     Choice of a Heavy-Chain V Domain 
       [0170]    The HC Germ-Line Gene (GLG) 3-23 (also known as VP-47) accounts for about 12% of all human Abs and it suitable for the framework of the library. Certain types of Ags elicit Abs having particular types of VH genes; in some cases, the types elicited are otherwise rarely found. This apparent Ag/Ab type specificity has been ascribed to possible structural differences between the various families of V genes. It is also possible that the selection has to do with the availability of particular AA types in the GLG CDRs. Suppose, for example, that the sequence YR at positions 4 and 5 of CDR2 is particularly effective in binding a particular type of Ag. Only the V gene 6-1 provides this combination. Most Abs specific for the Ag will come from GLG 6-1. If Y4-R5 were provided in other frameworks, then other frameworks are likely to be as effective in binding the Ag. 
       Analysis of HC CDR1 and CDR2: 
       [0171]    In CDR1 and CDR2 of HCs, the GLGs provide limited length diversity as shown in Table 15P. Note that GLGs provide CDR1s only of the lengths 5, 6, and 7. Mutations during the maturation of the V-domain gene leads to CDR1s having lengths as short as 2 and as long as 16. Nevertheless, length 5 predominates. The preferred length for the present invention is 5 AAs in CDR1 with a possible supplemental components having lengths of 7 and 14. 
         [0172]    GLGs provide CDR2s only of the lengths 15-19, but mutations during maturation result in CDR2s of length from 16 to 28 AAs. The lengths 16 and 17 predominate in mature Ab genes and length 17 is the most preferred length for the present invention. Possible supplementary components of length 16 and 19 may also be incorporated. 
         [0173]    Table 20P shows the AA sequences of human GLG CDR1s and CDR2. Table 21P shows the frequency of each amino-acid type at each position in the GLGs. The GLGs as shown in Table 20P have been aligned by inserting gaps near the middle of the segment so that the ends align. 
         [0174]    The 1398 mature V-domain genes used in studying D segments (vide infra) were scanned for examples in which CDR1 and CDR2 could be readily identified. Of this sample 1095 had identifiable CDR1, 2, and 3. The CDRs were identified by finding subsequences of the GLGs in an open reading frame. There are 51 human HC V genes. At the end of FR1, there are 20 different 9-mers. At the start of FR2, there are 11 different 9-mers. At the end of FR2 there are 14 different 9-mers. At the start of FR3, there are 14 different 9-mers. At the end of FR3, there are 13 different 9-mers. At the start of JH, there are three different 9-mers. These motifs were compared to the reported gene in frame and a match, at the site of maximum similarity, of seven out of nine was deemed acceptable. Only when all three CDRs were identified were any of the CDRs included in the analysis. In addition, the type of the gene was determined by comparing the framework regions to the GLG frameworks; the results are shown in Table 22P. 
       Design of HC CDR1 and CDR2 Diversity. 
       [0175]    Diversity in CDR1 and CDR2 was designed from: a) the diversity of the GLGs, b) observed diversity in mature HC genes, and c) structural considerations. In CDR1, examination of a 3D model of a humanized Ab showed that the side groups of residues 1, 3, and 5 were directed toward the combining pocket. Consequently, we allow each of these positions to be any amino-acid type except cysteine. Cysteine can form disulfide bonds. Disulfide bonds are an important component of the canonical Ig fold. Having free thiol groups could interfere with proper folding of the HC and could lead to problems in production or manipulation of selected Abs. Thus, I exclude cysteine from the menu. The side groups of residue 2 is directed away from the combining pocket. Although this position shows substantial diversity, both in GLG and mature genes, I fixed this residue as Tyr because it occurs in 681/820 mature genes (Table 21P). Position 4 is fixed as Met. There is some diversity here, but almost all mature genes have uncharged hydrophobic AA types: M, W, I, V, etc. (Table 21P). Inspection of a 3D model shows that the side group of residue 4 is packed into the innards of the HC. Since we are using a single framework (3-23), we retain the Met that 3-23 has because it is likely to fit very well into the framework of 3-23. Thus, the most preferred CDR1 library consists of XYXMX (SEQ ID NO:109) where X can be any one of [A,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y] (no C). The DNA that encodes this is preferably synthesized using trinucleotide building blocks so that each AA type is present in essentially equimolar amounts. Specifically, the X codons are synthesized using a mixture of the codons [gct, gat, gag, ttt, ggt, cat, att, aag, atg, aat, cct, cag, cgt, tct, act, gtt, tgg, tat]. This diversity is shown in the context of a synthetic 3-23 gene in Table 18P. The diversity oligonucleotide (ON) is synthesized from BspEI to BstXI and can be incorporated either by PCR synthesis using overlapping ONs or introduced by ligation of BspEI/BstXI-cut fragments. Table 22P shows ONs that embody the specified variegation. PCR using ON-R1V1vg, ON-Rltop, and ON-Rlbot gives a dsDNA product of 73 base pairs, cleavage with BspEI and BstXI trims 11 and 13 bases from the ends and provides cohesive ends that can be ligated to similarly cut vector having the synthetic 3-23 domain shown in Table 18P. Replacement of ON-R1V1vg with either ONR1V2vg or ONR1V3vg allows synthesis of the two alternative diversity patterns given below. 
         [0176]    Alternatively, one can include CDR1s of length 7 and/or 14. For length 7, a preferred diversity is (S/T) 1 (S/G/x) 2 (S/G/x) 3 Y 4 Y 5 W 6 (S/G/x) 7  (SEQ ID NO:107); where (S/T) indicates an equimolar mixture of Ser and Thr codons; (S/G/x) indicates a mixture of 0.2025 S, 0.2025 G, and 0.035 for each of A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, Y. Other proportions could be used. The design gives a predominance of Ser and Gly at positions 2, 3, and 7, as occurs in mature HC genes. For length 14, a preferred pattern of diversity is VSGGSISXXXYYWX (SEQ ID NO:1) where X can be any AA type except Cys. This pattern appears to arise by insertions into the GLG sequences (SGGYYWS; SEQ ID NO:110, (4-30.1 and 4-31) and similar sequences. There is a preference for a hydrophobic residue at position 1 (V or C) with a second insertion of SISXXX (SEQ ID NO:111) between GG and YY. Diversity ONs having CDR1s of length 7 or 14 are synthesized from BspEI to BstXI and introduced into the library in appropriate proportions to the CDR1 of length 5. The components should be incorporated in approximately the ratios in which they are observed in antibodies selected without reference to the length of the CDRs. For example, the sample of 1095 HC genes examined here have them in the ratios (L=5:L=7:L=14::820:175:23::0.80:0.17:0.02). 
       CDR2 
       [0177]    Diversity at CDR2 was designed with the same considerations: GLG sequences, mature sequences and 3D structure. A preferred length for CDR2 is 17, as shown in Table 18P. Examination of a 3D model suggests that the residues shown as varied in Table 18P are the most likely to interact directly with Ag. Thus a preferred pattern of variegation is: &lt;2&gt;I&lt;2&gt;&lt;3&gt;SGG&lt;1&gt;T&lt;1&gt;YADSVKG (SEQ ID NO:2), where &lt;2&gt; indicates a mixture of YRWVGS, &lt;3&gt; is a mixture of P and S, and &lt;1&gt; is a mixture of ADEFGHIKLMNPQRSTVWY (no C). ON-R2V1vg shown in Table 22P embodies this diversity pattern. PCR with ON-R2V1vg, ON-R2top, and ONR2bot gives a dsDNA product of 122 base pairs. Cleavage with BstXI and XbaI removes about 10 bases from each end and produces cohesive ends that can be ligated to similarly cut vector that contains the 3-23 gene shown in Table 18P. 
         [0178]    An alternative pattern would include the variability seen in mature CDR2s as shown in Table 21P: &lt;1&gt;I&lt;4&gt;&lt;1&gt;&lt;1&gt;G&lt;5&gt;&lt;1&gt;&lt;1&gt;&lt;1&gt;YADSVKG (SEQ ID NO:3), where &lt;4&gt; indicates a mixture of DINSWY, and &lt;5&gt; indicates a mixture of SGDN. This diversity pattern is embodied in ON-R2V2vg shown in Table 22P. For either case, the variegated ONs would be synthesized so that fragments of dsDNA containing the BstXI and XbaI site can be generated by PCR. ON-R2V2vg embodies this diversity pattern. 
         [0179]    Alternatively, one can allow shorter or longer CDR2s. Table 22P shows ON-R2V3vg which embodies a CDR2 of length 16 and ON-R2V4vg which embodies a CDR2 of length 19. Table 22P shows ON-R2V3vg is PCR amplified with ON-R2top and ON-R2bo3 while ON-R2V4vg is amplified with ON-R2top and ONR2-bo4. 
       Analysis of HC CDR3: 
       [0180]    CDR3s of HC vary in length and in sequence. About half of human HCs consist of the components: V::nz::D::ny::JHn where V is a V gene, nz is a series of bases (mean 12) that are essentially random, D is a D segment, often with heavy editing at both ends, ny is a series of bases (mean 6) that are essentially random, and JH is one of the six JH segments, often with heavy editing at the 5′ end. In HCs that have no identifiable D segment, the structure is V::nz::JHn where JH is usually edited at the 5′ end. Our goal is to mimic the diversity of CDR3, but not to duplicate it (which would be impossible). The D segments appear to provide spacer segments that allow folding of the IgG. The greatest diversity is at the junctions of V with D and of D with JH. The planned CDR3 library will consist of several components. Some of these will have only sequence diversity. Others will have sequence diversity with embedded D segments to extend the length while incorporating sequences known to allow Igs to fold. 
         [0181]    There are many papers on D segments. Corbett et al. (1997) show which D segments are used in which reading frames. My analysis basically confirms their findings. They did not report, however, the level of editing of each D segment and this information is needed for design of an effective library. 
         [0182]    The following diversified sequences would be incorporated in the indicated proportions: “1” stands for 0.095 [G, Y] and 0.048 [A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, W]; double dose of Gly and Tyr plus all other AAs except Cys at equal level. 
         [0183]    The amount of each component is assigned from the tabulation of lengths of the collection of natural VH genes. Component 1 represents all the genes having length 0 to 8 (counting from the YYCAR (SEQ ID NO:112) motif to the WG dipeptide motif). Component 2 corresponds the all the chains having length 9 or 10. Component 3 corresponds to the genes having length 11 or 12 plus half the genes having length 13. Component 4 corresponds to those having length 14 plus half those having length 13. Component 5 corresponds to the genes having length 15 and half of those having length 16. Component 6 corresponds to genes of length 17 plus half of those with length 16. Component 7 corresponds to those with length 18. Component 8 corresponds to those having length 19 and greater. 
         [0184]    The composition has been adjusted because the first component is not complex enough to justify including it as 10% of the library. If the final library were to be 1. E 9, then 1. E 8 sequences would come from component 1, but it has only 2.6 E 5 CDR3 sequences so that each one would occur in ˜385 CDR1/2 contexts. I think it better to have this short CDR3 diversity occur in ˜77 CDR1/2 contexts and have the other, longer CDR3s occur more often. 
         [0185]    The ONs would be PCR amplified with the primers CtprmA and CBprmB, cut with AflII and BstEII, and ligated to similarly cut V3-23. 
         [0186]    This set of components was designed after studying the sequences of 1383 human HC sequences as described below. The proposed components are meant to fulfill the goals: 
         [0000]    1) approximately the same distribution of lengths as seen in real Ab genes,
 
2) high level of sequence diversity at places having high diversity in real Ab genes, and
 
3) incorporation of constant sequences often seen in real Ab genes.
 
         [0187]    Note that the design uses JH4 (YFDYWGQGTLVTVSS; SEQ ID NO:20), which is found more often, instead of JH3 (AFDIWGQGTMVTVSS; SEQ ID NO:21). This involves three changes in AA sequence, shown as double underscored bold. An alternative JH segment is shown. 
         [0000]    How the Library Components were Designed: 
         [0188]    The processing of sequence data was accomplished by a series of custom-written FORTRAN programs, each of which carries out a fairly simple transformation on the data and writes its results as one or more ASCII files. The next program then uses these files as input. 
         [0189]    A set of 2049 human heavy-chain genes was selected from the version of GenBank that was available at Dyax on the Sun server on 26 Jun. 2000. A program named “Reformat” changed the format of the files to that of GenBank from the GCG format, creating one file per sequence. A second program named “IDENT_CDR3” processed each of these files as follows. Files were tested for duplication by previous entries, duplicates were discarded. Each reading frame was tested. Most entries had a single open reading frame (ORF), none had two, and some had none. Entries with multiple stops in every reading frame were discarded because this indicates poor quality of sequencing. The sequence was written in triplets in the ORF or in all three reading frames if no ORF was found. The sequence was examined for three motifs: a) AA sequence=“YYCxx”, b) DNA sequence=“tgg ggc (=WG)”, and DNA sequence=“g gtc acc (=BstEII)”. FR3 ends with a conserved motif YYCAR or a close approximation. When writing the DNA sequence, IDENT_CDR3 prints the DNA mostly in lower case. Cysteine codons (TGT or TGC) are printed in uppercase. When the motif “tay tay tgy” is found, IDENT_CDR3 starts a new line that contains “&lt; &gt; xxx xxx xxx xxx xxx” where the xxx&#39;s stand for the actual five codons that encode YYC and the next two codons (most often AR or AK). The following DNA is printed in triplets on new lines. A typical processed entry appears as in Table 1P. 
         [0190]    Following the YYC motif, IDENT_CDR3 seeks the sequence “TGG GGC” (the “WG” motif) in the correct reading frame, 5/6 bases is counted as a hit. If found, the DNA is made uppercase. Following the WG motif (if found) or the YYC motif (if no WG found), IDENT_CDR3 seeks the sequence “G GTC ACC” (the BstEII site) in the correct reading frame, 6/7 bases is counted as a hit. If found, the bases are made upper case. If either the WG or BstEII motif are not found, a note is inserted saying that the feature was not identified. The output of IDENT_CDR3 was processed by hand. In many cases, the lacking YYC motif could be seen as a closely related sequence, such as YFC, FYC, or HYC. When this was supported by an appropriately positioned WG and/or BstEII site, the effective YYC site was marked and the sequence retained for further analysis. If the YYC motif could not be identified or if the WG or BstEII sites could not be found, the entry was discarded. For example, the entry in Table 2P had no YYC motif. 
         [0191]    The double underscored sequence encodes YHCAS and is taken as the end of FR3. Note that there is a WG motif at bases 403-408 (bold upper case) and a BstEII site at bases 420-426 (bold upper case). Using WordPerfect, I first made all occurrences of TGC and TGT bold. I then searched for “YYC not found”. If I could see the “YYC”-related sequence quickly, I edited the entry so that a YYC was shown. The entry above would be converted to that shown in Table 3P. This processing reduced the list of entries to 1669. 
         [0192]    A third program named “New_DJ” processed the output of IDENT_CDR3. The end of the YYC motif (including the two codon following TGy=Cys) was taken as the end of FR3. The WG motif was taken as the end of the region that might contain a D segment. If WG was not observed and BstEII was, the WG site was assumed to be 17 bases upstream of BstEII. Using the WG motif for alignment, the sequence was compared to each human GLG JH segment (1-6) and the best one identified (New_DJ always assigned a JH segment). Starting from the WG motif of JH and moving toward the 5′ end, the program looked for the first codon having more than one mismatch. The region from YYCxx (SEQ ID NO:113) to this codon was taken as the region that might contain a D segment. 
         [0193]    The region that might contain a D segment was tested against all the germ-line genes (GLGs) of human D segments and the best D segment was identified. The scoring involved matching the observed sequence to the GLG sequence in all possible ways. Starting at each base, multiply by 4 for a match and divide by 4 for a mismatch. Record the maximum value obtained for this function. The match was deemed significant if 7/7, 8/9, 9/11, etc. or more bases matched. Of the 1383 sequences examined for D segments, 
         [0194]    “Assign_D” processes the output of New_DJ. For each sequence that had a significant match with a GLG D segment, a file was written containing the putative D segment, the DJ segment, the identified GLG D segment, the identified JH segment, the phase of the match between observed and GLG gene. For example, “D1 — 1-01_Phz0_hsa239356.txt” is a file recording the match of entry hsa239356 with D1-01 in phase 0. The file contains the information shown in Table 4P. The final DV of the second sequence immediately precedes the WG in JH and is ascribed to JH3. Other files that begin D1 — 1-01_Phz0 match the same GLG D segment and these can be aligned by sliding amino-acid sequences across each other. 
         [0195]    Table 5P shows how sequence hs6d4xb7 is first assigned to JH4 and then to D3-22. Note that the DNA sequence TGGGGG is aligned to the TGG GGC of the GLG and that the sequence is truncated on the left to fit. The program finds that JH4 has the best fit (5 misses and 18 correct out of 23). From the right, the program sees that DYWGQ (underscored) come from JH, but then the match drops off and the rest of the sequence on the left comes either from added bases or a D segment. 
         [0196]    The lower part of Table 5P shows that the possible D segment matches D#13 (3-23) is a very good match. 
         [0197]    Of 1383 files accepted by Assign_D, 757 had identifiable D segments. The tally of JHs in Table 6P shows that JH4 is by far the most common. 
         [0198]    JH4 is most common, JH6 next, followed by JH3 and JH5. JH1 and JH2 are seldom used. Table 7P shows the length distributions of each JH class; they do not differ significantly class to class. These lengths count only amino-acids that are not accounted for by JH and so are shorter that the lengths given in Table 8P which cover from YYCAR (SEQ ID NO:112) to WG. 
         [0199]    Table 8P contains the distribution of lengths for a) all the CDR3 segments, b) the CDR3 segments with identified D segments, and c) the CDR3 segments having no identifiable D segment. The CDR3s with identifiable D segments (13.9) are systematically longer than are those that lack D segments (11.2). 
         [0200]    The identified CDR3 segments can be collated in two ways: aligned to the left (looking for a pattern following YYCAR; SEQ ID NO:112) or aligned to the right (looking for a pattern preceding WG). Table 9P shows the collation of left-aligned sequences while Table 10P shows the right-aligned sequences. For each position, I have tabulated the frequency of each AA type (A-M in the first block and N-Y in the second). The column headed “#” shows how many sequences have some AA at that position. The final column shows all of the AA types seen at that position with the most frequent first and the least frequent last. In the left-aligned sequences, we see that Gly is highly over-represented in the first seven positions while Tyr is over-represented at positions 8-16. 
         [0201]    In Table 11P, I have tabulated the AA frequencies for the sequences having between 7 and 15 AAs between YYCAR (SEQ ID NO:112) and WG. The last four positions can be viewed as coming from JH and so would be given lower levels of diversity than would earlier positions. From these tabulations, I conclude that most AA types are allowed at all the positions, but there is a fairly strong tendency to have Gly at the early positions and to end in Asp-Tyr (DY). We could use these tendencies in designing a pattern of variegation. I would not exclude any AA except Cys, but I might increase the frequency of Gly in the first several positions and Tyr in the last few. 
         [0202]    There are 80 sequences (5.8%) having a pair of cysteines in CDR3. It is more surprising that 53 (3.8%) have a single Cys in CDR3. 
         [0203]    MS-DOS was used to make a list of the files written by Assign_D. “Filter” converts the output of MS-DOS Dir into a form that can be read into WordPerfect and sorted to bring a files belonging to the same D region together. 
         [0204]    “Filter2” collects the sequences and produces a draft table of sequences, grouped by the D-segment used, and written so that the sequences can be aligned. The output of Filter2 were edited by hand. For each group, the translation of the GLG was inserted and the collection of observed sequences was aligned to the conserved part of the GLG. “Filter3” collated the aligned sequences. Table 12P shows an example of an alignment and the tabulation of AA types. The entries are as follows: “Entry” is the name used in the data base, “Seq1” is the sequence from the YYCAR (SEQ ID NO:112) motif to the first amino acid not assigned to JH and “L1” is the length of the segment. The segments are shown aligned to the identified D segment. Seq2 is the sequence from the YYCAR (SEQ ID NO:112) motif to the WG motif (i.e. including part of JH) and “L2” is the length of that sequence. JH is the identified JH segment for this sequence. “P” is the phase of the match. For positive values of P, P bases are found in the observed sequence that do not correspond to any from the GLG, i.e. the observed sequence has had that many bases inserted. For negative values of P, there are |P| bases in the GLG sequence for which there are no corresponding bases in the observed sequence. “Score” is approximately 1/(probability of accidental match). This is calculated by looking at all possible alignments. For each alignment, the score is first set to 1.0. Base by base, the score is multiplied by 4. if the bases match and divided by 4. if they do not. This is done for all starting points and ending points and the maximum value is recorded. 
         [0205]    Table 13P is a summary of how often each D segment was identified and in which reading frame. I have not been consistent with Corbett et al. in assigning the phases of the GLG D segments. The MRC Web page that I took the GLGs from did not have D segments D1-14, D4-11, D5-18, or D6-25. None of these contribute to any great extent and this omission is unlikely to have any serious effect on the conclusions. The column headed “%” contains the percentage of the sequences examined here. The column headed “C %” contains the percentage reported by Corbett et al. I assume that the data used in Corbett et al. is mostly included in my collection. Nevertheless, the observed frequencies differ in detail. For example, my compilation shows that 10.7% of the collection contains a D segment encoding two cysteines while they have only 4.16% in this category. In D3 phase “0”, I see 19.4% of the collection while they report 11.8%. 
         [0206]    The most common actual D segments were further analyzed. The GLGs are heavily edited at either end. The aligned sequences were aligned. For each D-segment having more than seven examples, Filter3 produced a table of the frequency of each amino-acid type at each position. From these tabulations, library components shown in Table 17P were designed. At each position where at least half the examples have an amino acid, I entered either the dominant AA type or “x”. An AA type was “dominant” if it occurred more than 50% of the time. L is the length and f is the number of sequences observed that have related sequences. 
         [0207]    Table 14P shows possible library components for a library of CDR3&#39;s. “L” is the length of the insert and “f” is the frequency of the motif in the assayed collection. Table 17P shows vgDNA that embodies each of the components shown in Table 14P. In Table 17P, the oligonucleotides (ON) Ctop25, CtprmA, CBprmB, and CBot25 allow PCR amplification of each of the variegated ONs (vgDNA): C1t08, C2t10, C3t12, C4t14, C5t15, C6t17, C7t18, and c8t19. After amplification, the dsDNA can be cleaved with AflII and BstEII (or KpnI) and ligated to similarly cleaved vector that contains the remainder of the 3-23 synthetic domain. Preferably, this vector already contains diversity in CDR1 and CDR2 as disclosed herein. Preferably, the recipient vector contains a stuffer in place of CDR3 so that there will be no parental sequence that would then occur in the resulting library. Table 50P shows a version of the V3-23 gene segment with each CDR replaced by a short segment that contains both stop codons and restriction sites that will allow specific cleavage of any vector that does not have the stuffer removed. The stuffer can either be short and contain a restriction enzyme site that will not occur in the finish library, allowing removal of vectors that are not cleaved by both AflII and BstEII (or KpnI) and religated. Alternatively, the stuffer could be 200-400 bases long so that uncleaved or once cleaved vector can be readily separated from doubly cleaved vector. 
         [0208]    In the vgDNA for HC CDR3, &lt;1&gt; means a mixture comprising 0.27 Y, 0.27 G, and 0.027 of each of the amino-acid codons {A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, W}; &lt;2&gt; means an equimolar mixture of K and R; and &lt;3&gt; means an equimolar mixture of S and G. 
       Analysis of Human Kappa Light Chains and Preferred Variegation Scheme: 
       [0209]    A collection of 285 human kappa chains was assembled from the public data base. Table 27 shows the names of the entries used. The GLG sequences of nine bases at each end of the framework regions were used to find the FR/CDR junctions. Only in cases where all six junctions could be found was the sequences included. Table 25P shows the distribution of lengths in CDRs in human kappas. CDR1s with lengths of 11, 12, 13, 16, and 17 were observed with 11 being predominant and 12 well represented. CDR2 exhibits only length 7. CDR3 exhibits lengths of 1, 4, 6, 7, 8, 9, 10, 11, 12, 13, and 19. Essentially all examples are in the 8, 9, or 10 length groups. 
         [0210]    Table 26P shows the distribution of V and J genes seen in the sample. A27 is the most common V and JK1 is the most common J. Thus, a suitable synthetic kappa gene comprises A27 joined to JK1. Table 30P shows a suitable synthetic kappa chain gene, including a PlacZ promoter, ribosome-binding site, and signal sequence (M13 III signal). The DNA sequence encodes the GLG amino-acid sequence, but does not comprise the GLG DNA sequence. Restriction sites are designed to fall within each framework region so that diversity can be cloned into the CDRs. XmaI and EspI are in FR1, SexAI is in FR2, RsrII is in FR3, and KpnI (or Acc65I) are in FR4. Additional sites are provided in the constant kappa chain to facilitate construction of the gene. 
         [0211]    Table 30P also shows a suitable scheme of variegation for kappa. In CDR1, a preferred length is 11 codons. The A27 GLG has a CDR1 of 12 codons, but the sample of mature kappa chains has length 11 predominating. One could also introduce a component of kappas having length 12 in CDR1 by introducing codon 52 as &lt;2&gt; (i.e. a Ser-biased mixture). CDR2 of kappa is always 7 codons. Table 31P shows a tally of 285 CDR2s and a preferred variegation scheme for CDR2. The predominant length of CDR3 in kappa chains is 9 codons. Table 32P shows a tally of 166 CDR3s from human kappas and a preferred variegation scheme (which is also shown in Table 30P). 
       Analysis of Lambda Chains and Preferred Variegation Scheme: 
       [0212]    A collection of 158 lambda sequences was obtained from the public data base. Of these 93 contained sequences in which the FR/CDR boundaries could be identified automatically. Table 33P shows the distribution of lengths of CDRs. 
       Method of Construction: 
       [0213]    The diversity of HC, kappa, and lambda are best constructed in separate vectors. First a synthetic gene is designed to embody each of the synthetic variable domains. The light chains are bounded by restriction sites for ApaLI (positioned at the very end of the signal sequence) and AscI (positioned after the stop codon). The heavy chain is bounded by SfiI (positioned within the Pe1B signal sequence) and NotI (positioned in the linker between CH1 and the anchor protein. The initial genes are made with “stuffer” sequences in place of the desired CDRs. A “Stuffer” is a sequence the is to be cut away and replaced by diverse DNA but which does not allow expression of a functional antibody gene. For example, the stuffer may contain several stop codons and restriction sites that will not occur in the correct finished library vector. In Table 40P, the stuffer for CDR1 of kappa A27 contains a StuI site. The vgDNA for CDR1 is introduced as a cassette from EspI, XmaI, or AflII to either SexAI or KasI. After the ligation, the DNA is cleaved with StuI; there should be no StuI sites in the desired vectors. 
       REFERENCES 
       [0000]    
       
         Corbett, S J, Tomlinson, I M, Sonnhammer, E L L, Buck, D, Winter, G. “Sequences of the Human Immunoglobulin Diversity (D) Segment Locus: A Systematic Analysis Provides No Evidence for the Use of DIR Segments, Inverted D Segments, ‘Minor’ D Segments or D-D Recombination”.  J Molec Biol  (1997) 270:587-597. 
       
     
       Tables 
       [0215]      
         [0000]    
       
         
               
             
               
             
               
               
             
               
             
           
               
                 TABLE 1P 
               
               
                   
               
               
                 Typical entry in which YYC motif is found. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ++++C:\tmp\haj10335.txt 
               
             
          
           
               
                 LOCUS 
                 HAJ10335 306 bp mRNA PRI 18-AUG-1998 
               
               
                   
               
               
                 DEFINITION 
                   Homo sapiens  mRNA for immunoglobulin heavy chain variable region, 
               
               
                   
                 clone ELD16/6. 
               
               
                   
               
               
                 ACCESSION 
                 AJ010335 
               
               
                   
               
               
                 VERSION 
                 AJ010335.1 GI: 3445266 
               
               
                   
               
               
                 Ngene = 
                 306 
               
               
                   
               
             
          
           
               
                 Stop codons in reading frame 1 
               
               
                 49 115 124 253 277 
               
               
                   
               
               
                 No stops in reading frame 2 
               
               
                   
               
               
                 Stop codons in reading frame 3 
               
               
                 12 60 81 147 204 213 
               
               
                   
               
               
                   1   t ttg ggg tcc ctg aga ctc tcc TGT gca gcc tct gga ttc acc 
               
               
                  44 gtc agt agc aac tac atg acc tgg gtc cgc cag gct cta ggg aag 
               
               
                  89 ggg ctg gag tgg gtc tca gtt att tat agc ggt ggt agc aca tac 
               
               
                 134 tac gca gac tcc gtg aag ggc gga ttc acc atc tcc aga gac aat 
               
               
                 179 tcc aag aac aca ctg tat ctt caa atg aac agc ctg aga ccc gag 
               
               
                 224 gac acg gct gtg 
               
               
                 &lt;     &gt; TAT TAC TGT gcg aca 
               
               
                 251 ggt aat cgc ctg gaa atg gct gca att aac TGG GGC caa gga acc 
               
               
                 263 ctG GTC ACC aa (SEQ ID NO: 113) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
               
               
             
               
             
           
               
                 TABLE 2P 
               
               
                   
               
               
                 entry in which YYC motif was not automatically identified 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ++C:\tmp\hs202g3.txt 
               
               
                 !!NA_SEQUENCE 1.0 
               
             
          
           
               
                 LOCUS 
                 HS202G3 522 bp mRNA PRI 03-AUG-1995 
               
               
                   
               
               
                 DEFINITION 
                   H. sapiens  mRNA for immunoglobulin variable region (clone 202-G3). 
               
               
                   
               
               
                 ACCESSION 
                 Z47259 
               
               
                   
               
               
                 VERSION 
                 Z47259.1 GI: 619470 
               
               
                   
               
               
                 Ngene = 
                 522 
               
               
                   
               
             
          
           
               
                 No stops in reading frame 1 
               
               
                   
               
               
                 Stop codons in reading frame 2 
               
               
                 89 110 305 314 
               
               
                   
               
               
                 Stop codons in reading frame 3 
               
               
                 84 192 321 351 369 
               
               
                   
               
               
                   1 atg gac tgg acc tgg agg ttc ctc ttt gtg gtg gca gca gct aca 
               
               
                  46 ggt gtc cag tcc cag gtg cag ctg gtg cag tct ggg gct gag gtg 
               
               
                  91 aag aag cct ggg tcc tcg gtg aag gtc tcc  TGC  aag gct tct gga 
               
               
                 136 ggc acc ttc agc agc tat gct atc agc tgg gtg cga cag gcc cct 
               
               
                 181 gga caa ggg ctt gag tgg atg gga ggg atc atc cct atc ttt ggt 
               
               
                 226 aca gca aac tac gca cag aag ttc cag ggc aga gtc acg att acc 
               
               
                 271 gcg gac gaa tcc acg agc aca gcc tac atg gag ctg agc agc ctg 
               
               
                 316 aga tct gag gac acg gcc gtg tat cac  TGT  gcg agt gag gga tgg 
               
               
                 361 gag agt  TGT  agt ggt ggt ggc  TGC  tac gac ggt atg gac gtc  TGG   
               
               
                 406  GGC  caa ggg acc ac G GTC ACC  gtc tcc tca gct tcc acc aag ggc 
               
               
                 451 cca tcg gtc ttc ccc ctg gcg ccc  TGC  tcc agg agc acc tct ggg 
               
               
                 496 ggc aca gcg gcc ctg ggc  TGC  ctg (SEQ ID NO: 114) 
               
               
                 YYC not found !!! 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
               
               
             
               
             
           
               
                 TABLE 3P 
               
               
                   
               
               
                 Entry of Table 2P after editting. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ++C:\tmp\hs202g3.txt 
               
               
                 !!NA_SEQUENCE 1.0 
               
             
          
           
               
                 LOCUS 
                 HS202G3 522 bp mRNA PRI 03-AUG-1995 
               
               
                   
               
               
                 DEFINITION 
                   H. sapiens  mRNA for immunoglobulin variable region (clone 202-G3). 
               
               
                   
               
               
                 ACCESSION 
                 Z47259 
               
               
                   
               
               
                 VERSION 
                 Z47259.1 GI:619470 
               
               
                   
               
               
                 Ngene = 
                 522 
               
               
                   
               
             
          
           
               
                 No stops in reading frame 1 
               
               
                   
               
               
                 Stop codons in reading frame 2 
               
               
                 89 110 305 314 
               
               
                   
               
               
                 Stop codons in reading frame 3 
               
               
                 84 192 321 351 369 
               
               
                   
               
               
                   1 atg gac tgg acc tgg agg ttc ctc ttt gtg gtg gca gca gct aca 
               
               
                  46 ggt gtc cag tcc cag gtg cag ctg gtg cag tct ggg gct gag gtg 
               
               
                  91 aag aag cct ggg tcc tcg gtg aag gtc tcc  TGC  aag gct tct gga 
               
               
                 136 ggc acc ttc agc agc tat gct atc agc tgg gtg cga cag gcc cct 
               
               
                 181 gga caa ggg ctt gag tgg atg gga ggg atc atc cct atc ttt ggt 
               
               
                 226 aca gca aac tac gca cag aag ttc cag ggc aga gtc acg att acc 
               
               
                 271 gcg gac gaa tcc acg agc aca gcc tac atg gag ctg agc agc ctg 
               
               
                 316 aga tct gag gac acg gcc gtg  
               
               
                 &lt;YHCAS&gt; tat cac  TGT  gcg agt 
               
               
                 (SEQ ID NO: 116) 
               
               
                 gag gga tgg 
               
               
                 361 gag agt  TGT  agt ggt ggt ggc  TGC  tac gac ggt atg gac gtc  TGG   
               
               
                 406  GGC  caa ggg acc ac G GTC ACC  gtc tcc tca gct tcc acc aag ggc 
               
               
                 451 cca tcg gtc ttc ccc ctg gcg ccc  TGC  tcc agg agc acc tct ggg 
               
               
                 496 ggc aca gcg gcc ctg ggc  TGC  ctg (SEQ ID NO: 115) 
               
               
                 YYC not found !!! 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 4P 
               
               
                   
               
               
                 contents of file D1_1-01_Phz0_hsa239356.txt 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 DRGGKYQLAPKGGM (SEQ ID NO: 117) 
               
               
                   
                   
               
               
                   
                 DRGGKYQLAPKGGMDV (SEQ ID NO: 118) 
               
               
                   
                   
               
               
                   
                 JH3 D# 1 Phase 15 Score 6.55D + 04 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
               
               
             
               
             
           
               
                 TABLE 5P 
               
               
                   
               
               
                 alignment of a CDR3::JH segment to GLG JHs and D-segments. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 +C:\tmp\hs6d4xb7.txt 
               
             
          
           
               
                   
                          1    1    2    2    3    3   3 
               
               
                   
                 1234567890    5    0    5    0    5   9 
               
               
                 Observed 
                 tatgatagtagtgggtcatactccgactacTGGGGGcag (SEQ ID NO: 119) 
               
               
                 JH1 
                 ------------ g ctga atact t c c a gc ac tggggccagggcaccctggtcaccgtctcctcag--(SEQ ID NO: 120) 
               
               
                   
                 Miss =  9 Nt = 27 
               
               
                 JH2 
                 -----------ctac t gg tact t cga tct c tggggccgtggcaccctggtcactgtctcctcag--(SEQ ID NO: 121) 
               
               
                   
                 Miss = 13 Nt = 28 
               
               
                 JH3 
                 --------------tgatgct t tt ga tat c tggggccaagggacaatggtcaccgtctcttcag--(SEQ ID NO: 122) 
               
               
                   
                 Miss = 14 Nt = 25 
               
               
                 JH4 
                 ----------------ac tact tt gactac tggggccagggaaccctggtcaccgtctcctcag--(SEQ ID NO: 123) 
               
               
                   
                 Miss =  5 Nt = 23 
               
               
                 JH5 
                 -------------acaac t gg t t cgac cc c tggggccagggaaccctggtcaccgtctcctcag--(SEQ ID NO: 124) 
               
               
                   
                 Miss = 11 Nt = 26 
               
               
                 JH6 
                 - a tt a ctactactac t acggtatg gac gt c tggggccaagggaccacggtcaccgtctcctcag--(SEQ ID NO: 125) 
               
               
                   
                 Miss = 23 Nt = 38 
               
               
                   
               
               
                 4 
                 tat gat agt agt ggg tca TAC Tcc GAC TAC TGG GGg CAG (SEQ ID NO: 126) 
               
               
                   
                  Y   D   S   S   G   S   Y   S   D   Y   W   G   Q  (SEQ ID NO: 127) 
               
               
                   
               
               
                 JH4 
                 --- --- --- --- --- -ac tac ttt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc  
               
               
                   
                  -   -   -   -   -   -   Y   F   D   Y   W   G   Q   G   T   L   V   T   V   S    
               
               
                   
               
               
                   
                 tca g-- (SEQ ID NO: 128) 
               
               
                   
                  S   -  (SEQ ID NO: 129) 
               
               
                   
               
             
          
           
               
                 Fract = 0.783 = 18/23 
               
               
                   
               
               
                 Matching the rest to D segments: 
               
               
                 D#13 --------gtattactatgatagtagtggttattactac GLG      (SEQ ID NO: 130) 
               
               
                      gatcgccacaattactatgatagtagtgggtcatactcc Observed (SEQ ID NO: 131) 
               
               
                      --------gt...................t.at....a. . = match 
               
               
                 D#13 Phase = 9 Score = 4.3980E+12 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6P 
               
             
             
               
                   
               
               
                 Number of sequences identified as 
               
               
                 having JH derived from GLG JHn 
               
             
          
           
               
                   
                 JH 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
               
               
                   
                   
               
               
                   
                 # sequences 
                 17 
                 40 
                 198 
                 707 
                 160 
                 261 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
           
               
                 TABLE 7P 
               
               
                   
               
               
                 Distribution of CDR3 fragments that might contain D segments. 
               
               
                   
               
             
             
               
                 For JH1 
               
             
          
           
               
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                   
               
               
                 0 
                 0 
                 1 
                 1 
                 3 
                 1 
                 1 
                 2 
                 0 
                 3 
                 1 
                 1 
                 1 
                 2 
               
               
                   
               
             
          
           
               
                 Total = 17 Median = 8.0 
               
               
                 For JH2 
               
             
          
           
               
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 0 
                 0 
                 0 
                 0 
                 0 
                 2 
                 4 
                 6 
                 2 
                 6 
                 3 
                 4 
                 5 
                 2 
                 3 
               
               
                 15 
                 16 
                 17 
                 18 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 2 
                 0 
                 0 
                 1 
               
               
                   
               
             
          
           
               
                 Total = 40 Median = 9.0 
               
               
                 For JH3 
               
             
          
           
               
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 0 
                 0 
                 2 
                 6 
                 16 
                 12 
                 17 
                 17 
                 15 
                 22 
                 20 
                 20 
                 18 
                 13 
                 4 
               
               
                 15 
                 16 
                 17 
                 18 
                 19 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 8 
                 3 
                 2 
                 1 
                 2 
               
               
                   
               
             
          
           
               
                 Total = 198 Median = 8.6 
               
               
                 For JH4 
               
             
          
           
               
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 0 
                 0 
                 7 
                 15 
                 19 
                 40 
                 63 
                 82 
                 81 
                 77 
                 81 
                 53 
                 57 
                 44 
                 30 
               
               
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
               
               
                 15 
                 23 
                 8 
                 3 
                 5 
                 2 
                 0 
                 1 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
             
          
           
               
                 Total = 707 Median = 8.6 
               
               
                 For JH5 
               
             
          
           
               
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 0 
                 0 
                 0 
                 3 
                 4 
                 6 
                 13 
                 19 
                 12 
                 14 
                 22 
                 18 
                 10 
                 18 
                 10 
               
               
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
               
               
                 5 
                 1 
                 1 
                 0 
                 0 
                 1 
                 1 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 39 
                 40 
                 41 
                 42 
                 43 
                 44 
               
               
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
                 0 
                 0 
               
               
                 45 
                 46 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 0 
                 1 
               
               
                   
               
             
          
           
               
                 Total = 160 Median = 9.4 
               
               
                 For JH6 
               
             
          
           
               
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 2 
                 0 
                 1 
                 2 
                 5 
                 15 
                 20 
                 18 
                 22 
                 29 
                 29 
                 28 
                 23 
                 16 
                 10 
               
               
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 14 
                 9 
                 9 
                 4 
                 2 
                 3 
               
               
                   
               
             
          
           
               
                 Total = 261 Median = 9.6 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8P 
               
               
                   
               
               
                 Lengths of CDR3 segments from YYCAR to WG. 
               
               
                   
               
             
             
               
                 Distribution of lengths from end of FR3 to WG motif all sequences. 
               
             
          
           
               
                 L 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 N 
                 6 
                 0 
                 0 
                  4 
                  2 
                  9 
                 13 
                 38 
                  61 
                  88 
                 101 
                 118 
                 154 
                 150 
                 118 
               
               
                 Sum(N) 
                 6 
                 6 
                 6 
                 10 
                 12 
                 21 
                 34 
                 72 
                 133 
                 221 
                 322 
                 440 
                 594 
                 744 
                 862 
               
               
                 f 
                 .004 
                 .004 
                 .004 
                 .007 
                 .009 
                 .015 
                 .025 
                 .052 
                 .096 
                 .160 
                 .233 
                 .318 
                 .430 
                 .538 
                 .623 
               
               
                 L 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
               
               
                 N 
                 125 
                  105 
                  84 
                  61 
                  46 
                  42 
                  16 
                  17 
                   7 
                   9 
                   2 
                   1 
                   0 
                   2 
                   1 
               
               
                 SN 
                 987 
                 1092 
                 1176 
                 1237 
                 1283 
                 1325 
                 1341 
                 1358 
                 1365 
                 1374 
                 1376 
                 1377 
                 1377 
                 1379 
                 1380 
               
               
                 f 
                 .714 
                 .790 
                 .850 
                 .894 
                 .928 
                 .958 
                 .970 
                 .982 
                 .987 
                 .993 
                 .995 
                 .996 
                 .996 
                 .997 
                 .998 
               
               
                 L 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 39 
                 40 
                 41 
                 42 
                 43 
                 44 
               
               
                 N 
                   0 
                   0 
                   0 
                   0 
                   0 
                   0 
                   0 
                   1 
                   0 
                   0 
                   0 
                   0 
                   1 
                   0 
                   0 
               
               
                 SN 
                 1380 
                 1380 
                 1380 
                 1380 
                 1380 
                 1380 
                 1380 
                 1381 
                 1381 
                 1381 
                 1381 
                 1381 
                 1382 
                 1382 
                 1382 
               
               
                 f 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
               
               
                 L 
                 45 
                 46 
               
               
                 N 
                   0 
                   1 
               
               
                 SN 
                 1382 
                 1383 
               
               
                 f 
                 .999 
                 1.0 
               
               
                   
               
               
                 Median = 12.65 
               
             
          
           
               
                 Distribution of lengths from end of FR3 to WG motif with assigned D. 
               
             
          
           
               
                 L 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 N 
                 3 
                 0 
                 0 
                 0 
                 0 
                 0 
                 3 
                  9 
                 21 
                 15 
                 39 
                  64 
                  77 
                  97 
                  72 
               
               
                 SN 
                 3 
                 3 
                 3 
                 3 
                 3 
                 3 
                 6 
                 15 
                 36 
                 51 
                 90 
                 154 
                 231 
                 328 
                 400 
               
               
                 f 
                 .004 
                 .004 
                 .004 
                 .004 
                 .004 
                 .004 
                 .008 
                 .019 
                 .046 
                 .065 
                 .115 
                 .196 
                 .294 
                 .418 
                 .510 
               
               
                 L 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
               
               
                 N 
                  77 
                  75 
                  63 
                  45 
                  35 
                  38 
                  15 
                  15 
                  6 
                  9 
                  2 
                  1 
                  0 
                  1 
                  1 
               
               
                 SN 
                 477 
                 552 
                 615 
                 660 
                 695 
                 733 
                 748 
                 763 
                 769 
                 778 
                 780 
                 781 
                 781 
                 782 
                 783 
               
               
                 f 
                 .608 
                 .703 
                 .783 
                 .841 
                 .885 
                 .934 
                 .953 
                 .972 
                 .980 
                 .991 
                 .994 
                 .995 
                 .995 
                 .996 
                 .997 
               
               
                 L 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 39 
                 40 
                 41 
                 42 
                 43 
                 44 
               
               
                 N 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  1 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
               
               
                 SN 
                 783 
                 783 
                 783 
                 783 
                 783 
                 783 
                 783 
                 784 
                 784 
                 784 
                 784 
                 784 
                 784 
                 784 
                 784 
               
               
                 f 
                 .997 
                 .997 
                 .997 
                 .997 
                 .997 
                 .997 
                 .997 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
                 .999 
               
               
                 L 
                 45 
                 46 
               
               
                 N 
                  0 
                  1 
               
               
                 SN 
                 784 
                 785 
               
               
                 f 
                 .999 
                 1.0 
               
               
                   
               
               
                 Median = 13.90 
               
             
          
           
               
                 Distribution of lengths from end of FR3 to WG motif with no assigned D. 
               
             
          
           
               
                 L 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                 N 
                 3 
                 0 
                 0 
                 4 
                 2 
                  9 
                 10 
                 29 
                 40 
                  73 
                  62 
                  54 
                  77 
                  53 
                  46 
               
               
                 SN 
                 3 
                 3 
                 3 
                 7 
                 9 
                 18 
                 28 
                 57 
                 97 
                 170 
                 232 
                 286 
                 363 
                 416 
                 462 
               
               
                 f 
                 .005 
                 .005 
                 .005 
                 .012 
                 .015 
                 .030 
                 .047 
                 .095 
                 .162 
                 .284 
                 .388 
                 .478 
                 .607 
                 .696 
                 .773 
               
               
                 L 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
               
               
                 N 
                  48 
                  30 
                  21 
                  16 
                  11 
                  4 
                  1 
                  2 
                  1 
                  0 
                  0 
                  0 
                  0 
                  1 
                  0 
               
               
                 SN 
                 510 
                 540 
                 561 
                 577 
                 588 
                 592 
                 593 
                 595 
                 596 
                 596 
                 596 
                 596 
                 596 
                 597 
                 597 
               
               
                 f 
                 .853 
                 .903 
                 .938 
                 .965 
                 .983 
                 .990 
                 .992 
                 .995 
                 .997 
                 .997 
                 .997 
                 .997 
                 .997 
                 .998 
                 .998 
               
               
                 L 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 36 
                 37 
                 38 
                 39 
                 40 
                 41 
                 42 
               
               
                 N 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  0 
                  1 
               
               
                 SN 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 597 
                 598 
               
               
                 f 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 .998 
                 1.0 
               
               
                   
               
               
                 Median = 11.17 
               
               
                 L is the length 
               
               
                 N is the number of examples 
               
               
                 Sum(N) = SN is the sum of the Ns 
               
               
                 f is the cumulative fraction seen 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 9P 
               
               
                   
               
               
                 Tally of left-aligned CDR3 sequences 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
                   
               
               
                   
               
               
                 1 
                 74 
                 6 
                 278 
                 109 
                 11 
                 319 
                 50 
                 18 
                 11 
                 60 
                 8 
                 1383 
                 GDERVASLHTNQPIWYFKMCX 
                   
               
               
                 2 
                 50 
                 9 
                 64 
                 32 
                 29 
                 249 
                 43 
                 42 
                 41 
                 109 
                 22 
                 1377 
                 GRPSLDVYTANHIQKEFMWCX 
                   
               
               
                 3 
                 81 
                 18 
                 74 
                 39 
                 25 
                 214 
                 29 
                 42 
                 16 
                 83 
                 19 
                 1377 
                 GSYRTVLADPIWEQHNFMCK| 
                   
               
               
                 4 
                 70 
                 23 
                 92 
                 49 
                 50 
                 228 
                 23 
                 58 
                 21 
                 70 
                 16 
                 1373 
                 GSYDRVALTIPFEWNCHQKMX 
                   
               
               
                 5 
                 86 
                 28 
                 106 
                 32 
                 59 
                 217 
                 21 
                 41 
                 16 
                 72 
                 19 
                 1371 
                 GYSDAVTLRFIPWNECHMQK|X 
                   
               
               
                 6 
                 88 
                 17 
                 104 
                 28 
                 94 
                 171 
                 17 
                 48 
                 12 
                 50 
                 17 
                 1362 
                 GYSDFATVRWPLINEQCHMK| 
                   
               
               
                 7 
                 69 
                 15 
                 110 
                 21 
                 89 
                 176 
                 22 
                 50 
                 15 
                 81 
                 12 
                 1349 
                 GSYDFVLTAPRWINHEQCKM|X 
                   
               
               
                 8 
                 53 
                 19 
                 141 
                 17 
                 90 
                 150 
                 18 
                 47 
                 17 
                 68 
                 11 
                 1311 
                 YSGDFLTVWAPIRNCHEKQM| 
                   
               
               
                 9 
                 44 
                 21 
                 120 
                 24 
                 102 
                 174 
                 24 
                 36 
                 20 
                 71 
                 11 
                 1250 
                 YGSDFLNVRTAWPIEHCKQM| 
                   
               
               
                 10 
                 39 
                 31 
                 129 
                 23 
                 124 
                 116 
                 23 
                 42 
                 9 
                 58 
                 32 
                 1162 
                 YDFGSLIARPTVWNMCEHQK 
                   
               
               
                 11 
                 36 
                 12 
                 158 
                 17 
                 137 
                 83 
                 13 
                 18 
                 10 
                 40 
                 21 
                 1061 
                 YDFGSPLVANWMTRIEHCKQX 
                   
               
               
                 12 
                 34 
                 11 
                 164 
                 10 
                 82 
                 74 
                 34 
                 30 
                 1 
                 31 
                 20 
                 943 
                 YDFGPSVAHLINMRTWCEQKX 
                   
               
               
                 13 
                 32 
                 2 
                 121 
                 6 
                 84 
                 56 
                 10 
                 26 
                 7 
                 43 
                 32 
                 789 
                 YDFGLSPVAMIWRTHNKQEC 
                   
               
               
                 14 
                 23 
                   
                 131 
                 5 
                 59 
                 65 
                 10 
                 16 
                 4 
                 25 
                 34 
                 639 
                 YDGFMVLAPISWNRHTQEKX 
                   
               
               
                 15 
                 15 
                 4 
                 107 
                 5 
                 43 
                 42 
                 1 
                 23 
                   
                 20 
                 34 
                 521 
                 YDFGVMILWAPRSENCQTH| 
                   
               
               
                 16 
                 4 
                 2 
                 80 
                 3 
                 33 
                 26 
                 4 
                 5 
                 1 
                 10 
                 29 
                 396 
                 YDVFMGPSLNTRIWAHECQ|K 
                   
               
               
                 17 
                 3 
                 1 
                 63 
                   
                 19 
                 19 
                 9 
                 13 
                   
                 12 
                 21 
                 291 
                 DYVMFGILHPSTWAQRCNX 
                   
               
               
                 18 
                 3 
                   
                 47 
                   
                 16 
                 13 
                 1 
                 4 
                   
                 7 
                 23 
                 207 
                 DYVMFGPSLTIAHN 
                   
               
               
                 19 
                 5 
                 1 
                 39 
                 1 
                 4 
                 13 
                 3 
                 3 
                   
                 1 
                 14 
                 146 
                 DYVMGAFHINRSCELPQW 
                   
               
               
                 20 
                 2 
                   
                 17 
                   
                 4 
                 5 
                   
                 3 
                   
                 4 
                 12 
                 100 
                 VYDMGFLIPSARWQ 
                   
               
               
                 21 
                   
                   
                 17 
                   
                 3 
                 8 
                 1 
                 1 
                   
                   
                 4 
                 58 
                 DVGYMFHINTW 
                   
               
               
                 22 
                 1 
                   
                 7 
                   
                 6 
                 1 
                   
                 1 
                   
                   
                 5 
                 42 
                 VDFMYSAGITW 
                   
               
               
                 23 
                   
                   
                 9 
                   
                   
                 1 
                   
                 1 
                   
                 1 
                 1 
                 25 
                 DVYGILMPS 
                   
               
               
                 24 
                 1 
                   
                 2 
                   
                   
                   
                 1 
                   
                   
                 1 
                 1 
                 18 
                 VYDAHLMPT 
                   
               
               
                 25 
                   
                   
                 1 
                   
                   
                 3 
                   
                   
                   
                   
                   
                 9 
                 GVDPSY 
                   
               
               
                 26 
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                 2 
                 7 
                 GMSTV 
                   
               
               
                 27 
                   
                   
                 2 
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                 6 
                 DKMST 
                   
               
               
                 28 
                 1 
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                   
                 6 
                 VADGS 
                   
               
               
                 29 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 4 
                 DPSV 
                   
               
               
                 30 
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                 3 
                 FST 
                   
               
               
                 31 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                 3 
                 KLV 
                   
               
               
                 32 
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                   
                 3 
                 FGP 
                   
               
               
                 33 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 3 
                 PG 
                   
               
               
                 34 
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                 3 
                 HLS 
                   
               
               
                 35 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 AVW 
                   
               
               
                 36 
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                   
                   
                 3 
                 DFP 
                   
               
               
                 37 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 PSY 
                   
               
               
                 38 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                 2 
                 LS 
                   
               
               
                 39 
                 1 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 2 
                 AK 
                   
               
               
                 40 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 PS 
                   
               
               
                 41 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 ST 
                   
               
               
                 42 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 S 
                   
               
               
                 43 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 1 
                 K 
                   
               
               
                 44 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 S 
                   
               
               
                 45 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 T 
                   
               
               
                 46 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 S 
                   
               
               
                   
                 816 
                 220 
                 2186 
                 421 
                 1166 
                 2428 
                 358 
                 568 
                 205 
                 920 
                 421 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
                   
               
               
                   
               
               
                 1 
                 35 
                 23 
                 31 
                 108 
                 63 
                 50 
                 94 
                 16 
                 13 
                   
                 6 
                 1383 
                 GDERVASLHTNQPIWYFKMCX 
                   
               
               
                 2 
                 44 
                 114 
                 42 
                 169 
                 114 
                 59 
                 62 
                 21 
                 60 
                   
                 2 
                 1377 
                 GRPSLDVYTANHIQKEFMWCX 
                   
               
               
                 3 
                 26 
                 73 
                 37 
                 110 
                 140 
                 97 
                 89 
                 42 
                 122 
                 1 
                   
                 1377 
                 GSYRTVLADPIWEQHNFMCK| 
                   
               
               
                 4 
                 48 
                 51 
                 22 
                 79 
                 141 
                 65 
                 77 
                 49 
                 139 
                   
                 2 
                 1373 
                 GSYDRVALTIPFEWNCHQKMX 
                   
               
               
                 5 
                 37 
                 41 
                 18 
                 61 
                 157 
                 75 
                 85 
                 38 
                 158 
                 2 
                 2 
                 1371 
                 GYSDAVTLRFIPWNECHMQK|X 
                   
               
               
                 6 
                 32 
                 54 
                 23 
                 67 
                 152 
                 80 
                 78 
                 64 
                 165 
                 1 
                   
                 1362 
                 GYSDFATVRWPLINEQCHMK| 
                   
               
               
                 7 
                 44 
                 59 
                 18 
                 58 
                 157 
                 73 
                 85 
                 54 
                 139 
                 1 
                 1 
                 1349 
                 GSYDFVLTAPRWINHEQCKM|X 
                   
               
               
                 8 
                 38 
                 48 
                 14 
                 41 
                 167 
                 68 
                 59 
                 59 
                 185 
                 1 
                   
                 1311 
                 YSGDFLTVWAPIRNCHEKQM| 
                   
               
               
                 9 
                 52 
                 40 
                 14 
                 47 
                 123 
                 45 
                 48 
                 41 
                 192 
                 1 
                   
                 1250 
                 YGSDFLNVRTAWPIEHCKQM| 
                   
               
               
                 10 
                 33 
                 37 
                 12 
                 39 
                 73 
                 36 
                 36 
                 35 
                 235 
                   
                   
                 1162 
                 YDFGSLIARPTVWNMCEHQK 
                   
               
               
                 11 
                 33 
                 49 
                 7 
                 20 
                 68 
                 21 
                 37 
                 29 
                 251 
                   
                 1 
                 1061 
                 YDFGSPLVANWMTRIEHCKQX 
                   
               
               
                 12 
                 30 
                 53 
                 10 
                 19 
                 45 
                 19 
                 42 
                 18 
                 215 
                   
                 1 
                 943 
                 YDFGPSVAHLINMRTWCEQKX 
                   
               
               
                 13 
                 10 
                 34 
                 7 
                 22 
                 40 
                 15 
                 33 
                 25 
                 184 
                   
                   
                 789 
                 YDFGLSPVAMIWRTHNKQEC 
                   
               
               
                 14 
                 13 
                 22 
                 6 
                 12 
                 15 
                 10 
                 26 
                 14 
                 148 
                   
                 1 
                 639 
                 YDGFMVLAPISWNRHTQEKX 
                   
               
               
                 15 
                 5 
                 12 
                 3 
                 12 
                 12 
                 3 
                 40 
                 20 
                 119 
                 1 
                   
                 521 
                 YDFGVMILWAPRSENCQTH| 
                   
               
               
                 16 
                 10 
                 24 
                 2 
                 6 
                 12 
                 7 
                 49 
                 5 
                 82 
                 2 
                   
                 396 
                 YDVFMGPSLNTRIWAHECQ|K 
                   
               
               
                 17 
                 1 
                 8 
                 2 
                 2 
                 8 
                 5 
                 42 
                 4 
                 58 
                   
                 1 
                 291 
                 DYVMFGILHPSTWAQRCNX 
                   
               
               
                 18 
                 1 
                 13 
                   
                   
                 8 
                 5 
                 31 
                   
                 35 
                   
                   
                 207 
                 DYVMFGPSLTIAHN 
                   
               
               
                 19 
                 2 
                 1 
                 1 
                 2 
                 2 
                   
                 24 
                 1 
                 29 
                   
                   
                 146 
                 DYVMGAFHINRSCELPQW 
                   
               
               
                 20 
                   
                 3 
                 1 
                 2 
                 3 
                   
                 23 
                 2 
                 19 
                   
                   
                 100 
                 VYDMGFLIPSARWQ 
                   
               
               
                 21 
                 1 
                   
                   
                   
                   
                 1 
                 14 
                 1 
                 7 
                   
                   
                 58 
                 DVGYMFHINTW 
                   
               
               
                 22 
                   
                   
                   
                   
                 2 
                 1 
                 12 
                 1 
                 5 
                   
                   
                 42 
                 VDFMYSAGITW 
                   
               
               
                 23 
                   
                 1 
                   
                   
                 1 
                   
                 5 
                   
                 5 
                   
                   
                 25 
                 DVYGILMPS 
                   
               
               
                 24 
                   
                 1 
                   
                   
                   
                 1 
                 5 
                   
                 5 
                   
                   
                 18 
                 VYDAHLMPT 
                   
               
               
                 25 
                   
                 1 
                   
                   
                 1 
                   
                 2 
                   
                 1 
                   
                   
                 9 
                 GVDPSY 
                   
               
               
                 26 
                   
                   
                   
                   
                 1 
                 1 
                 1 
                   
                   
                   
                   
                 7 
                 GMSTV 
                   
               
               
                 27 
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                 6 
                 DKMST 
                   
               
               
                 28 
                   
                   
                   
                   
                 1 
                   
                 2 
                   
                   
                   
                   
                 6 
                 VADGS 
                   
               
               
                 29 
                   
                 1 
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                 4 
                 DPSV 
                   
               
               
                 30 
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                 3 
                 FST 
                   
               
               
                 31 
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                 3 
                 KLV 
                   
               
               
                 32 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 FGP 
                   
               
               
                 33 
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 PG 
                   
               
               
                 34 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 3 
                 HLS 
                   
               
               
                 35 
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                 3 
                 AVW 
                   
               
               
                 36 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 DFP 
                   
               
               
                 37 
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                   
                 3 
                 PSY 
                   
               
               
                 38 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 2 
                 LS 
                   
               
               
                 39 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 AK 
                   
               
               
                 40 
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 2 
                 PS 
                   
               
               
                 41 
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                 2 
                 ST 
                   
               
               
                 42 
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                 2 
                 S 
                   
               
               
                 43 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 K 
                   
               
               
                 44 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 1 
                 S 
                   
               
               
                 45 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                 T 
                   
               
               
                 46 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 1 
                 S 
                   
               
               
                   
                 495 
                 769 
                 270 
                 876 
                 1518 
                 741 
                 1104 
                 540 
                 2572 
                 10 
                 17 
                   
                   
                 18621 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10P 
               
               
                   
               
               
                 Tally of right-aligned sequences 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 5 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                 G 
               
               
                 6 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 S 
               
               
                 7 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                 G 
               
               
                 8 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                 G 
               
               
                 9 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 RV 
               
               
                 10 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 RV 
               
               
                 11 
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                 2 
                 GI 
               
               
                 12 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 V 
               
               
                 13 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 TY 
               
               
                 14 
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                   
                 3 
                 DGN 
               
               
                 15 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 3 
                 ISY 
               
               
                 16 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 DSY 
               
               
                 17 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 APY 
               
               
                 18 
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                 3 
                 DFM 
               
               
                 19 
                   
                   
                 2 
                   
                   
                 1 
                   
                   
                   
                   
                   
                 3 
                 DG 
               
               
                 20 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                 3 
                 ILV 
               
               
                 21 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 WP 
               
               
                 22 
                   
                   
                   
                   
                   
                 3 
                   
                   
                   
                   
                   
                 4 
                 GS 
               
               
                 23 
                   
                   
                   
                   
                   
                 2 
                 1 
                   
                   
                   
                   
                 6 
                 GHQSV 
               
               
                 24 
                 1 
                   
                   
                   
                   
                 3 
                   
                   
                   
                 1 
                   
                 6 
                 GALR 
               
               
                 25 
                 1 
                   
                 2 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 7 
                 DTAIS 
               
               
                 26 
                 1 
                 1 
                 1 
                   
                   
                 1 
                   
                   
                 1 
                 1 
                 1 
                 9 
                 ACDGKLMST 
               
               
                 27 
                 2 
                   
                 5 
                 1 
                   
                 2 
                   
                 1 
                   
                 1 
                   
                 18 
                 DAGVEILNQRS 
               
               
                 28 
                   
                   
                 2 
                 2 
                   
                 3 
                   
                 1 
                   
                 2 
                   
                 25 
                 TGQSDELPRIV 
               
               
                 29 
                 3 
                   
                 5 
                 6 
                   
                 7 
                   
                   
                 1 
                 1 
                 1 
                 42 
                 GEDVAPQRSKLMTY| 
               
               
                 30 
                 2 
                   
                 9 
                   
                 1 
                 9 
                 1 
                 4 
                   
                 5 
                 2 
                 58 
                 DGRLSIVPAMQTFHNY 
               
               
                 31 
                 4 
                 2 
                 19 
                 9 
                 2 
                 18 
                 1 
                 2 
                 1 
                 3 
                   
                 100 
                 DGSERVYALPTCFINHKW 
               
               
                 32 
                 10 
                 5 
                 18 
                 5 
                 3 
                 16 
                 3 
                 3 
                 2 
                 14 
                 1 
                 146 
                 DGLRVAPYSTCEQFHINWKM 
               
               
                 33 
                 20 
                   
                 18 
                 10 
                 7 
                 34 
                 7 
                 8 
                 2 
                 6 
                 1 
                 207 
                 GARDPSYTEVIFHLQWKM 
               
               
                 34 
                 13 
                 4 
                 31 
                 18 
                 9 
                 37 
                 8 
                 16 
                 4 
                 14 
                 4 
                 291 
                 GDRYPVEILASTFHQWCKMNX| 
               
               
                 35 
                 17 
                 5 
                 32 
                 23 
                 10 
                 70 
                 12 
                 10 
                 6 
                 25 
                 1 
                 396 
                 GRSDYLEVTPAHNFIWKCQM| 
               
               
                 36 
                 23 
                 6 
                 51 
                 21 
                 9 
                 79 
                 19 
                 15 
                 14 
                 36 
                 9 
                 521 
                 GDSYRLTVPAEHIKNFMWCQ| 
               
               
                 37 
                 35 
                 12 
                 56 
                 23 
                 15 
                 110 
                 14 
                 17 
                 5 
                 24 
                 4 
                 639 
                 GYDVRSTAPLEIFHNCWQKMX 
               
               
                 38 
                 28 
                 19 
                 68 
                 27 
                 29 
                 133 
                 26 
                 31 
                 12 
                 43 
                 7 
                 789 
                 GSYDVRLPTIFAEHCNWKQM 
               
               
                 39 
                 51 
                 25 
                 80 
                 27 
                 33 
                 162 
                 16 
                 30 
                 18 
                 55 
                 15 
                 943 
                 GSDRYVLATPFWIECKHMQNX 
               
               
                 40 
                 44 
                 14 
                 73 
                 36 
                 46 
                 161 
                 27 
                 32 
                 17 
                 59 
                 8 
                 1061 
                 GSRDYVTLPFAEIWHQNKCM 
               
               
                 41 
                 54 
                 21 
                 74 
                 25 
                 23 
                 178 
                 23 
                 52 
                 15 
                 57 
                 11 
                 1162 
                 GSYTDRVLPAIWNQEFHCKMX| 
               
               
                 42 
                 57 
                 13 
                 82 
                 40 
                 42 
                 190 
                 14 
                 39 
                 15 
                 82 
                 15 
                 1250 
                 GSYDLVRTANPFEIWQKMHC| 
               
               
                 43 
                 75 
                 18 
                 54 
                 25 
                 35 
                 242 
                 13 
                 29 
                 18 
                 49 
                 12 
                 1311 
                 GYSTARVPDLWNFIQECKHM| 
               
               
                 44 
                 63 
                 17 
                 79 
                 15 
                 43 
                 197 
                 20 
                 38 
                 14 
                 76 
                 8 
                 1349 
                 YGSTDLRAPVWNFIQHCEKM 
               
               
                 45 
                 59 
                 16 
                 69 
                 35 
                 55 
                 165 
                 26 
                 23 
                 23 
                 75 
                 9 
                 1362 
                 YGSLRTDNAFPVWEHIKCQM 
               
               
                 46 
                 41 
                 19 
                 125 
                 26 
                 27 
                 208 
                 31 
                 14 
                 16 
                 38 
                 8 
                 1371 
                 YGDSNRWATLPHFEVQCKIM 
               
               
                 47 
                 160 
                 10 
                 24 
                 13 
                 53 
                 332 
                 36 
                 16 
                 11 
                 40 
                 10 
                 1373 
                 GYAWPSFRLHTVNDIEKCMQX 
               
               
                 48 
                 21 
                 4 
                 8 
                 5 
                 680 
                 27 
                 4 
                 44 
                 5 
                 145 
                 288 
                 1377 
                 FMLISGVYPAWTDNQREKCHX 
               
               
                 49 
                 23 
                 2 
                 1181 
                 29 
                 1 
                 30 
                 15 
                 4 
                 2 
                 8 
                 1 
                 1377 
                 DGEAHNQSYVLPTIRCKW|FMX 
               
               
                 50 
                 7 
                 7 
                 15 
                   
                 42 
                 3 
                 41 
                 135 
                 3 
                 59 
                 4 
                 1383 
                 YVIPSLFHNDTACXMGKQRW| 
               
               
                   
                 816 
                 220 
                 2186 
                 421 
                 1166 
                 2428 
                 358 
                 568 
                 205 
                 920 
                 421 
                   
                   
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 G 
               
               
                 6 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 1 
                 S 
               
               
                 7 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 G 
               
               
                 8 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 G 
               
               
                 9 
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                 2 
                 RV 
               
               
                 10 
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                 2 
                 RV 
               
               
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 GI 
               
               
                 12 
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                 2 
                 V 
               
               
                 13 
                   
                   
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                 2 
                 TY 
               
               
                 14 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 DGN 
               
               
                 15 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                   
                 3 
                 ISY 
               
               
                 16 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                   
                 3 
                 DSY 
               
               
                 17 
                   
                 1 
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 3 
                 APY 
               
               
                 18 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 DFM 
               
               
                 19 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 DG 
               
               
                 20 
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                 3 
                 ILV 
               
               
                 21 
                   
                 1 
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                 3 
                 WP 
               
               
                 22 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 4 
                 GS 
               
               
                 23 
                   
                   
                 1 
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                 6 
                 GHQSV 
               
               
                 24 
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                 6 
                 GALR 
               
               
                 25 
                   
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                 7 
                 DTAIS 
               
               
                 26 
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                 9 
                 ACDGKLMST 
               
               
                 27 
                 1 
                   
                 1 
                 1 
                 1 
                   
                 2 
                   
                   
                   
                   
                 18 
                 DAGVEILNQRS 
               
               
                 28 
                   
                 2 
                 3 
                 2 
                 3 
                 4 
                 1 
                   
                   
                   
                   
                 25 
                 TGQSDELPRIV 
               
               
                 29 
                   
                 3 
                 3 
                 2 
                 2 
                 1 
                 5 
                   
                 1 
                 1 
                   
                 42 
                 GEDVAPQRSKLMTY| 
               
               
                 30 
                 1 
                 3 
                 2 
                 7 
                 5 
                 2 
                 4 
                   
                 1 
                   
                   
                 58 
                 DGRLSIVPAMQTFHNY 
               
               
                 31 
                 2 
                 3 
                   
                 7 
                 10 
                 3 
                 7 
                 1 
                 6 
                   
                   
                 100 
                 DGSERVYALPTCFINHKW 
               
               
                 32 
                 3 
                 9 
                 4 
                 12 
                 8 
                 6 
                 12 
                 3 
                 9 
                   
                   
                 146 
                 DGLRVAPYSTCEQFHINWKM 
               
               
                 33 
                   
                 16 
                 6 
                 19 
                 15 
                 12 
                 10 
                 3 
                 13 
                   
                   
                 207 
                 GARDPSYTEVIFHLQWKM 
               
               
                 34 
                 2 
                 20 
                 5 
                 31 
                 12 
                 12 
                 20 
                 5 
                 23 
                 1 
                 2 
                 291 
                 GDRYPVEILASTFHQWCKMNX| 
               
               
                 35 
                 12 
                 18 
                 5 
                 39 
                 35 
                 19 
                 23 
                 7 
                 26 
                 1 
                   
                 396 
                 GRSDYLEVTPAHNFIWKCQM| 
               
               
                 36 
                 11 
                 24 
                 6 
                 42 
                 47 
                 29 
                 28 
                 7 
                 44 
                 1 
                   
                 521 
                 GDSYRLTVPAEHIKNFMWCQ| 
               
               
                 37 
                 14 
                 33 
                 9 
                 54 
                 52 
                 37 
                 55 
                 11 
                 58 
                   
                 1 
                 639 
                 GYDVRSTAPLEIFHNCWQKMX 
               
               
                 38 
                 18 
                 33 
                 12 
                 46 
                 77 
                 32 
                 58 
                 17 
                 73 
                   
                   
                 789 
                 GSYDVRLPTIFAEHCNWKQM 
               
               
                 39 
                 11 
                 38 
                 12 
                 70 
                 94 
                 42 
                 61 
                 33 
                 68 
                   
                 2 
                 943 
                 GSDRYVLATPFWIECKHMQNX 
               
               
                 40 
                 24 
                 52 
                 27 
                 74 
                 140 
                 61 
                 66 
                 29 
                 71 
                   
                   
                 1061 
                 GSRDYVTLPFAEIWHQNKCM 
               
               
                 41 
                 31 
                 55 
                 29 
                 70 
                 156 
                 76 
                 61 
                 51 
                 97 
                 1 
                 2 
                 1162 
                 GSYTDRVLPAIWNQEFHCKMX| 
               
               
                 42 
                 48 
                 47 
                 24 
                 68 
                 171 
                 68 
                 70 
                 39 
                 125 
                 1 
                   
                 1250 
                 GSYDLVRTANPFEIWQKMHC| 
               
               
                 43 
                 38 
                 58 
                 28 
                 73 
                 164 
                 76 
                 66 
                 43 
                 194 
                 1 
                   
                 1311 
                 GYSTARVPDLWNFIQECKHM| 
               
               
                 44 
                 48 
                 60 
                 24 
                 69 
                 131 
                 86 
                 57 
                 52 
                 252 
                   
                   
                 1349 
                 YGSTDLRAPVWNFIQHCEKM 
               
               
                 45 
                 62 
                 51 
                 16 
                 75 
                 116 
                 74 
                 50 
                 39 
                 324 
                   
                   
                 1362 
                 YGSLRTDNAFPVWEHIKCQM 
               
               
                 46 
                 97 
                 38 
                 21 
                 55 
                 110 
                 39 
                 26 
                 55 
                 377 
                   
                   
                 1371 
                 YGDSNRWATLPHFEVQCKIM 
               
               
                 47 
                 25 
                 54 
                 9 
                 44 
                 54 
                 34 
                 32 
                 122 
                 292 
                   
                 2 
                 1373 
                 GYAWPSFRLHTVNDIEKCMQX 
               
               
                 48 
                 8 
                 22 
                 7 
                 6 
                 28 
                 10 
                 25 
                 16 
                 23 
                   
                 1 
                 1377 
                 FMLISGVYPAWTDNQREKCHX 
               
               
                 49 
                 15 
                 6 
                 13 
                 4 
                 13 
                 5 
                 9 
                 2 
                 11 
                 2 
                 1 
                 1377 
                 DGEAHNQSYVLPTIRCKW|FMX 
               
               
                 50 
                 23 
                 122 
                 3 
                 3 
                 67 
                 9 
                 350 
                 3 
                 480 
                 1 
                 6 
                 1383 
                 YVIPSLFHNDTACXMGKQRW| 
               
               
                 50 
                 495 
                 769 
                 270 
                 876 
                 1518 
                 741 
                 1104 
                 540 
                 2572 
                 10 
                 17 
                 18621 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 11P 
               
               
                   
               
               
                 Tallies of AA frequencies in all CDR3 by length 
               
               
                   
               
             
             
               
                 Tally of sequences of length 7 # = 38 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 1 
                   
                 
                   8 
                 
                 1 
                 1 
                 
                   14 
                 
                 1 
                   
                 1 
                 5 
                   
                 38 
                 GDLRWAEFHKS 
               
               
                 2 
                 1 
                   
                 1 
                   
                 2 
                 6 
                 3 
                   
                 2 
                 1 
                 1 
                 38 
                 RGNHVFKTYADLMW 
               
               
                 3 
                 1 
                   
                 4 
                   
                 1 
                 5 
                 1 
                 2 
                   
                 2 
                   
                 38 
                 GSDWYPVILTAFHN 
               
               
                 4 
                 3 
                   
                 1 
                   
                 1 
                 
                   12 
                 
                 1 
                 1 
                   
                 1 
                   
                 38 
                 GYSANRVDFHILPT 
               
               
                 5 
                 2 
                   
                   
                 1 
                 14 
                 3 
                   
                 4 
                 1 
                 3 
                 3 
                 38 
                 FIGLMARVYEKP 
               
               
                 6 
                   
                   
                 26 
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                 38 
                 DVPTHISWY 
               
               
                 7 
                 1 
                   
                 2 
                   
                   
                   
                 2 
                 3 
                   
                 1 
                   
                 38 
                 YVINDHSALR 
               
               
                   
                 9 
                   
                 42 
                 2 
                 19 
                 40 
                 9 
                 11 
                 4 
                 13 
                 4 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                   
                   
                   
                 3 
                 1 
                   
                   
                 2 
                   
                   
                   
                 38 
                 GDLRWAEFHKS 
               
               
                 2 
                 6 
                   
                   
                 7 
                   
                 2 
                 3 
                 1 
                 2 
                   
                   
                 38 
                 RGNHVFKTYADLMW 
               
               
                 3 
                 1 
                 3 
                   
                   
                 5 
                 2 
                 3 
                 4 
                 4 
                   
                   
                 38 
                 GSDWYPVILTAFHN 
               
               
                 4 
                 2 
                 1 
                   
                 2 
                 4 
                 1 
                 2 
                   
                 6 
                   
                   
                 38 
                 GYSANRVDFHILPT 
               
               
                 5 
                   
                 1 
                   
                 2 
                   
                   
                 2 
                   
                 2 
                   
                   
                 38 
                 FIGLMARVYEKP 
               
               
                 6 
                   
                 2 
                   
                   
                 1 
                 2 
                 3 
                 1 
                 1 
                   
                   
                 38 
                 DVPTHISWY 
               
               
                 7 
                 3 
                   
                   
                 1 
                 2 
                   
                 7 
                   
                 16 
                   
                   
                 38 
                 YVINDHSALR 
               
               
                   
                 12 
                 7 
                   
                 15 
                 13 
                 7 
                 20 
                 8 
                 31 
                   
                   
                 266 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 8 # = 61 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 3 
                   
                 7 
                 3 
                   
                 
                   14 
                 
                 2 
                 2 
                   
                 5 
                   
                 61 
                 GDLTVRSAEHINWPQY 
               
               
                 2 
                 1 
                   
                 9 
                 1 
                 1 
                 
                   15 
                 
                   
                 1 
                 2 
                 1 
                   
                 61 
                 GDTNRSVKWYAEFILPQ 
               
               
                 3 
                 2 
                   
                 3 
                   
                 1 
                 
                   10 
                 
                 1 
                 1 
                   
                 7 
                 1 
                 61 
                 GLSTYVDPRAFHIMNQW 
               
               
                 4 
                 4 
                 1 
                 3 
                 1 
                 1 
                 
                   15 
                 
                 1 
                   
                   
                 4 
                   
                 61 
                 GYRALQDSWVCEFHNPT 
               
               
                 5 
                 
                   10 
                 
                   
                 2 
                 1 
                   
                 9 
                 5 
                   
                 1 
                 5 
                 1 
                 61 
                 AGYHLTPRVDSEKMW 
               
               
                 6 
                 5 
                 1 
                   
                   
                 24 
                 2 
                   
                 7 
                   
                 5 
                 2 
                 61 
                 FIALPSVYGMCQRW 
               
               
                 7 
                 5 
                   
                 
                   37 
                 
                 2 
                   
                   
                 4 
                 1 
                   
                 2 
                   
                 61 
                 DAHSELNVIP| 
               
               
                 8 
                 1 
                   
                 2 
                   
                 3 
                   
                 1 
                 12 
                   
                 3 
                   
                 61 
                 YISFLVDNAHPRT 
               
               
                   
                 31 
                 2 
                 63 
                 8 
                 30 
                 65 
                 14 
                 24 
                 3 
                 32 
                 4 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 2 
                 1 
                 1 
                 4 
                 4 
                 5 
                 5 
                 2 
                 1 
                   
                   
                 61 
                 GDLTVRSAEHINWPQY 
               
               
                 2 
                 6 
                 1 
                 1 
                 4 
                 3 
                 8 
                 3 
                 2 
                 2 
                   
                   
                 61 
                 GDTNRSVKWYAEFILPQ 
               
               
                 3 
                 1 
                 3 
                 1 
                 3 
                 7 
                 7 
                 5 
                 1 
                 7 
                   
                   
                 61 
                 GLSTYVDPRAFHIMNQW 
               
               
                 4 
                 1 
                 1 
                 4 
                 5 
                 3 
                 1 
                 2 
                 3 
                 
                   11 
                 
                   
                   
                 61 
                 GYRALQDSWVCEFHNPT 
               
               
                 5 
                   
                 4 
                   
                 4 
                 2 
                 5 
                 4 
                 1 
                 7 
                   
                   
                 61 
                 AGYHLTPRVDSEKMW 
               
               
                 6 
                   
                 3 
                 1 
                 1 
                 3 
                   
                 3 
                 1 
                 3 
                   
                   
                 61 
                 FIALPSVYGMCQRW 
               
               
                 7 
                 2 
                 1 
                   
                   
                 4 
                   
                 2 
                   
                   
                 1 
                   
                 61 
                 DAHSELNVIP| 
               
               
                 8 
                 2 
                 1 
                   
                 1 
                 7 
                 1 
                 3 
                   
                 24 
                   
                   
                 61 
                 YISFLVDNAHPRT 
               
               
                   
                 14 
                 15 
                 8 
                 22 
                 33 
                 27 
                 27 
                 10 
                 55 
                 1 
                   
                 488 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 9 # = 88 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 9 
                   
                 12 
                 4 
                   
                 21 
                 1 
                 1 
                 2 
                 5 
                   
                 88 
                 GDARNVLEQTKWHIPSY 
               
               
                 2 
                 2 
                   
                 2 
                 3 
                 3 
                 13 
                 4 
                   
                 3 
                 7 
                 2 
                 88 
                 GPSRLNTHEFKYADMQW 
               
               
                 3 
                 4 
                 2 
                 3 
                 3 
                 3 
                 15 
                   
                   
                   
                 1 
                 1 
                 88 
                 GTPSQNRVWYADEFCLM 
               
               
                 4 
                 5 
                 1 
                 6 
                 3 
                 6 
                 22 
                 2 
                 4 
                 1 
                 6 
                 1 
                 88 
                 GSDFLARITYENPWHVCKM 
               
               
                 5 
                 7 
                 1 
                 4 
                 3 
                 4 
                 14 
                 2 
                   
                   
                 7 
                 2 
                 88 
                 GSYALNDFVERWHMQTCP 
               
               
                 6 
                 13 
                   
                 2 
                 1 
                 3 
                 13 
                 6 
                 2 
                 1 
                 4 
                 1 
                 88 
                 YAGHNLPSVFTWDIEKMQR 
               
               
                 7 
                 4 
                   
                 2 
                   
                 41 
                 2 
                   
                 3 
                 1 
                 14 
                 5 
                 88 
                 FLMAPWIDGSVKNQTY 
               
               
                 8 
                 1 
                 1 
                 73 
                 2 
                   
                 2 
                 1 
                   
                   
                 2 
                   
                 88 
                 DEGLSACHNQRV 
               
               
                 9 
                   
                 1 
                 1 
                   
                 4 
                 1 
                 3 
                 8 
                   
                 2 
                   
                 88 
                 YVISFHPLNTCDGR 
               
               
                   
                 45 
                 6 
                 105 
                 19 
                 64 
                 103 
                 19 
                 18 
                 8 
                 48 
                 12 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 7 
                 1 
                 3 
                 8 
                 1 
                 3 
                 7 
                 2 
                 1 
                   
                   
                 88 
                 GDARNVLEQTKWHIPSY 
               
               
                 2 
                 5 
                 11 
                 2 
                 10 
                 11 
                 5 
                   
                 2 
                 3 
                   
                   
                 88 
                 GPSRLNTHEFKYADMQW 
               
               
                 3 
                 5 
                 7 
                 6 
                 5 
                 7 
                 11 
                 5 
                 5 
                 5 
                   
                   
                 88 
                 GTPSQNRVWYADEFCLM 
               
               
                 4 
                 3 
                 3 
                   
                 5 
                 7 
                 4 
                 2 
                 3 
                 4 
                   
                   
                 88 
                 GSDFLARITYENPWHVCKM 
               
               
                 5 
                 6 
                 1 
                 2 
                 3 
                 12 
                 2 
                 4 
                 3 
                 11 
                   
                   
                 88 
                 GSYALNDFVERWHMQTCP 
               
               
                 6 
                 5 
                 4 
                 1 
                 1 
                 4 
                 3 
                 4 
                 3 
                 17 
                   
                   
                 88 
                 YAGHNLPSVFTWDIEKMQR 
               
               
                 7 
                 1 
                 4 
                 1 
                   
                 2 
                 1 
                 2 
                 4 
                 1 
                   
                   
                 88 
                 FLMAPWIDGSVKNQTY 
               
               
                 8 
                 1 
                   
                 1 
                 1 
                 2 
                   
                 1 
                   
                   
                   
                   
                 88 
                 DEGLSACHNQRV 
               
               
                 9 
                 2 
                 3 
                   
                 1 
                 8 
                 2 
                 9 
                   
                 43 
                   
                   
                 88 
                 YVISFHPLNTCDGR 
               
               
                   
                 35 
                 34 
                 16 
                 34 
                 54 
                 31 
                 34 
                 22 
                 85 
                   
                   
                 792 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 10 # = 101 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 8 
                 1 
                 19 
                 7 
                 1 
                 16 
                 3 
                   
                 2 
                 3 
                 2 
                 101 
                 DGNAERTSQVHLWKMYCF 
               
               
                 2 
                 3 
                   
                 8 
                 3 
                 5 
                 13 
                   
                 5 
                   
                 15 
                 2 
                 101 
                 LGRDSPVFINTAEQYMW 
               
               
                 3 
                 6 
                   
                 9 
                   
                 1 
                 26 
                 1 
                 3 
                 1 
                 4 
                 1 
                 101 
                 GSYDAVTLNRIPWFHKMQ 
               
               
                 4 
                 7 
                   
                 6 
                   
                 1 
                 25 
                 1 
                 5 
                   
                 4 
                 1 
                 101 
                 GSYARDINPLTVWQFHM 
               
               
                 5 
                 6 
                   
                 5 
                 9 
                 4 
                 16 
                 1 
                   
                 3 
                 4 
                   
                 101 
                 GYTESANDPRFLVKQWH 
               
               
                 6 
                 6 
                 1 
                 6 
                 5 
                 4 
                 23 
                 2 
                 4 
                 3 
                 3 
                 1 
                 101 
                 GYRSWADEFINKLTHCMQV 
               
               
                 7 
                 13 
                   
                 3 
                 1 
                 5 
                 9 
                 3 
                 1 
                   
                 4 
                 1 
                 101 
                 YASGPRWFTVLDHNEIMQ 
               
               
                 8 
                 2 
                 1 
                   
                 1 
                 57 
                 3 
                   
                 4 
                   
                 15 
                 4 
                 101 
                 FLIMSGWANPVCEY 
               
               
                 9 
                 3 
                   
                 78 
                 2 
                   
                 6 
                   
                 1 
                 1 
                 1 
                   
                 101 
                 DGAQENIKLPRSW 
               
               
                 10 
                   
                   
                 3 
                   
                 4 
                   
                 4 
                 13 
                   
                 1 
                   
                 101 
                 YIPSVFHNDL 
               
               
                   
                 54 
                 3 
                 137 
                 28 
                 82 
                 137 
                 15 
                 36 
                 10 
                 54 
                 12 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 9 
                   
                 4 
                 6 
                 5 
                 6 
                 4 
                 3 
                 2 
                   
                   
                 101 
                 DGNAERTSQVHLWKMYCF 
               
               
                 2 
                 5 
                 6 
                 3 
                 11 
                 8 
                 4 
                 6 
                 1 
                 3 
                   
                   
                 101 
                 LGRDSPVFINTAEQYMW 
               
               
                 3 
                 4 
                 3 
                 1 
                 4 
                 14 
                 5 
                 6 
                 2 
                 10 
                   
                   
                 101 
                 GSYDAVTLNRIPWFHKMQ 
               
               
                 4 
                 5 
                 5 
                 3 
                 7 
                 11 
                 4 
                 4 
                 4 
                 8 
                   
                   
                 101 
                 GSYARDINPLTVWQFHM 
               
               
                 5 
                 6 
                 5 
                 2 
                 5 
                 8 
                 10 
                 4 
                 2 
                 11 
                   
                   
                 101 
                 GYTESANDPRFLVKQWH 
               
               
                 6 
                 4 
                   
                 1 
                 8 
                 7 
                 3 
                 1 
                 7 
                 12 
                   
                   
                 101 
                 GYRSWADEFINKLTHCMQV 
               
               
                 7 
                 2 
                 7 
                 1 
                 7 
                 11 
                 5 
                 5 
                 6 
                 17 
                   
                   
                 101 
                 YASGPRWFTVLDHNEIMQ 
               
               
                 8 
                 2 
                 2 
                   
                   
                 4 
                   
                 2 
                 3 
                 1 
                   
                   
                 101 
                 FLIMSGWANPVCEY 
               
               
                 9 
                 2 
                 1 
                 3 
                 1 
                   
                   
                   
                 1 
                   
                   
                   
                 101 
                 DGAQENIKLPRSW 
               
               
                 10 
                 4 
                 8 
                   
                   
                 7 
                   
                 5 
                   
                 52 
                   
                   
                 101 
                 YIPSVFHNDL 
               
               
                   
                 43 
                 37 
                 18 
                 49 
                 76 
                 37 
                 37 
                 29 
                 116 
                   
                   
                 1010 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 11 # = 118 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 7 
                 1 
                 21 
                 11 
                   
                 23 
                 5 
                 2 
                   
                 7 
                   
                 118 
                 GDEVRALQHSPTINCWY 
               
               
                 2 
                 1 
                 2 
                 9 
                 1 
                 1 
                 24 
                 5 
                 6 
                 2 
                 7 
                 3 
                 118 
                 GSRDYLPIVHQTMNCKWAEFX 
               
               
                 3 
                 4 
                   
                 4 
                 2 
                 4 
                 13 
                 2 
                 3 
                 1 
                 7 
                 2 
                 118 
                 SGTVRLYWADFNQIEHMKP 
               
               
                 4 
                 10 
                   
                 3 
                 3 
                 2 
                 25 
                 1 
                 2 
                   
                 4 
                 3 
                 118 
                 SGARTWYLVDEMQFINPH 
               
               
                 5 
                 5 
                 2 
                 10 
                 1 
                 4 
                 24 
                 2 
                   
                 1 
                 5 
                 1 
                 118 
                 GSVYDTNALRFWCHQEKM 
               
               
                 6 
                 6 
                   
                 4 
                 2 
                 7 
                 19 
                 2 
                 3 
                 1 
                 5 
                 1 
                 118 
                 GSYWTFAVLRDINEHQKMP 
               
               
                 7 
                 4 
                 1 
                 8 
                 5 
                 2 
                 20 
                 4 
                 1 
                   
                 2 
                 1 
                 118 
                 GYSNRDWTEPAHFLQVCIM 
               
               
                 8 
                 13 
                 2 
                 6 
                 1 
                 8 
                 12 
                 4 
                   
                 2 
                 7 
                   
                 118 
                 YAGWFLDPRSTHCKVE 
               
               
                 9 
                 2 
                   
                 2 
                   
                 68 
                 2 
                   
                 5 
                   
                 14 
                 7 
                 118 
                 FLMYVITADGP 
               
               
                 10 
                 2 
                 1 
                 100 
                 5 
                   
                 3 
                 2 
                   
                   
                 1 
                 1 
                 118 
                 DEGAHCLMNPQ 
               
               
                 11 
                   
                   
                 2 
                   
                 6 
                   
                 1 
                 7 
                 1 
                 6 
                 1 
                 118 
                 YPVISFLNDHKM 
               
               
                   
                 54 
                 9 
                 169 
                 31 
                 102 
                 165 
                 28 
                 29 
                 8 
                 65 
                 20 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 2 
                 4 
                 7 
                 8 
                 5 
                 3 
                 10 
                 1 
                 1 
                   
                   
                 118 
                 GDEVRALQHSPTINCWY 
               
               
                 2 
                 3 
                 7 
                 4 
                 10 
                 11 
                 4 
                 6 
                 2 
                 9 
                   
                 1 
                 118 
                 GSRDYLPIVHQTMNCKWAEFX 
               
               
                 3 
                 4 
                 1 
                 4 
                 8 
                 25 
                 12 
                 9 
                 6 
                 7 
                   
                   
                 118 
                 SGTVRLYWADFNQIEHMKP 
               
               
                 4 
                 2 
                 2 
                 3 
                 9 
                 26 
                 8 
                 4 
                 6 
                 5 
                   
                   
                 118 
                 SGARTWYLVDEMQFINPH 
               
               
                 5 
                 6 
                   
                 2 
                 5 
                 15 
                 9 
                 11 
                 4 
                 11 
                   
                   
                 118 
                 GSVYDTNALRFWCHQEKM 
               
               
                 6 
                 3 
                 1 
                 2 
                 5 
                 16 
                 9 
                 6 
                 11 
                 15 
                   
                   
                 118 
                 GSYWTFAVLRDINEHQKMP 
               
               
                 7 
                 9 
                 5 
                 2 
                 9 
                 11 
                 6 
                 2 
                 7 
                 19 
                   
                   
                 118 
                 GYSNRDWTEPAHFLQVCIM 
               
               
                 8 
                   
                 6 
                   
                 5 
                 5 
                 5 
                 2 
                 11 
                 29 
                   
                   
                 118 
                 YAGWFLDPRSTHCKVE 
               
               
                 9 
                   
                 1 
                   
                   
                   
                 4 
                 6 
                   
                 7 
                   
                   
                 118 
                 FLMYVITADGP 
               
               
                 10 
                 1 
                 1 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 118 
                 DEGAHCLMNPQ 
               
               
                 11 
                 3 
                 13 
                   
                   
                 7 
                   
                 11 
                   
                 60 
                   
                   
                 118 
                 YPVISFLNDHKM 
               
               
                   
                 33 
                 41 
                 25 
                 59 
                 121 
                 60 
                 67 
                 48 
                 163 
                   
                 1 
                 1298 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 12 # = 154 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 5 
                   
                 31 
                 12 
                   
                 37 
                 6 
                 1 
                 1 
                 7 
                 3 
                 154 
                 GDRESVLHAPMNQTWYIK 
               
               
                 2 
                 5 
                 1 
                 7 
                 6 
                 1 
                 25 
                 3 
                 7 
                 3 
                 13 
                 2 
                 154 
                 GSRLPDIQEAVYHKNTMWCF 
               
               
                 3 
                 10 
                 2 
                 7 
                 5 
                 1 
                 19 
                   
                 5 
                 4 
                 12 
                 2 
                 154 
                 GRSYLATVPDQEIKWCMNF 
               
               
                 4 
                 8 
                   
                 9 
                 6 
                 8 
                 27 
                   
                 6 
                 5 
                 6 
                 1 
                 154 
                 GVSDNAFRTYEILKWPQM 
               
               
                 5 
                 18 
                 1 
                 8 
                 5 
                 6 
                 42 
                 1 
                 9 
                 1 
                 7 
                 3 
                 154 
                 GSAIDYLFPTEQVMNWCHK 
               
               
                 6 
                 13 
                   
                 12 
                 4 
                 10 
                 23 
                 1 
                 7 
                   
                 8 
                 1 
                 154 
                 GAVDSFYTLPRWINEQHM 
               
               
                 7 
                 11 
                 2 
                 4 
                 3 
                 10 
                 15 
                 1 
                 4 
                   
                 12 
                   
                 154 
                 YGSPLRAFWTNVDIECQH 
               
               
                 8 
                 3 
                 2 
                 18 
                 3 
                 3 
                 25 
                 4 
                 2 
                 5 
                 6 
                   
                 154 
                 YGDSNLTKRWHPAEFCIQV 
               
               
                 9 
                 15 
                 1 
                 2 
                   
                 8 
                 33 
                 4 
                 7 
                 1 
                 5 
                 1 
                 154 
                 GYWARFISPLHTDQCKMN 
               
               
                 10 
                 1 
                 1 
                 2 
                 1 
                 79 
                 1 
                 2 
                 5 
                 1 
                 19 
                 26 
                 154 
                 FMLIPYDHVWACEGKNQRST 
               
               
                 11 
                 2 
                   
                 135 
                 2 
                   
                 4 
                 2 
                   
                   
                   
                   
                 154 
                 DGYAEHSVNR 
               
               
                 12 
                   
                 1 
                 1 
                   
                 6 
                 1 
                 9 
                 16 
                   
                 4 
                   
                 154 
                 YVPIHFSLNCDGW 
               
               
                   
                 91 
                 11 
                 236 
                 47 
                 132 
                 252 
                 33 
                 69 
                 21 
                 99 
                 39 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 3 
                 4 
                 3 
                 14 
                 10 
                 3 
                 10 
                 2 
                 2 
                   
                   
                 154 
                 GDRESVLHAPMNQTWYIK 
               
               
                 2 
                 3 
                 11 
                 7 
                 22 
                 24 
                 3 
                 5 
                 2 
                 4 
                   
                   
                 154 
                 GSRLPDIQEAVYHKNTMWCF 
               
               
                 3 
                 2 
                 8 
                 6 
                 17 
                 17 
                 9 
                 9 
                 4 
                 15 
                   
                   
                 154 
                 GRSYLATVPDQEIKWCMNF 
               
               
                 4 
                 9 
                 4 
                 4 
                 7 
                 17 
                 7 
                 18 
                 5 
                 7 
                   
                   
                 154 
                 GVSDNAFRTYEILKWPQM 
               
               
                 5 
                 3 
                 6 
                 4 
                   
                 20 
                 6 
                 4 
                 2 
                 8 
                   
                   
                 154 
                 GSAIDYLFPTEQVMNWCHK 
               
               
                 6 
                 5 
                 8 
                 3 
                 8 
                 11 
                 9 
                 13 
                 8 
                 10 
                   
                   
                 154 
                 GAVDSFYTLPRWINEQHM 
               
               
                 7 
                 5 
                 14 
                 2 
                 12 
                 15 
                 6 
                 5 
                 9 
                 24 
                   
                   
                 154 
                 YGSPLRAFWTNVDIECQH 
               
               
                 8 
                 10 
                 4 
                 2 
                 5 
                 15 
                 6 
                 2 
                 5 
                 34 
                   
                   
                 154 
                 YGDSNLTKRWHPAEFCIQV 
               
               
                 9 
                 1 
                 6 
                 2 
                 10 
                 7 
                 3 
                   
                 18 
                 30 
                   
                   
                 154 
                 GYWARFISPLHTDQCKMN 
               
               
                 10 
                 1 
                 4 
                 1 
                 1 
                 1 
                 1 
                 2 
                 2 
                 3 
                   
                   
                 154 
                 FMLIPYDHVWACEGKNQRST 
               
               
                 11 
                 1 
                   
                   
                 1 
                 2 
                   
                 2 
                   
                 3 
                   
                   
                 154 
                 DGYAEHSVNR 
               
               
                 12 
                 2 
                 18 
                   
                   
                 5 
                   
                 32 
                 1 
                 58 
                   
                   
                 154 
                 YVPIHFSLNCDGW 
               
               
                   
                 45 
                 87 
                 34 
                 97 
                 144 
                 53 
                 102 
                 58 
                 198 
                   
                   
                 1848 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 13 # = 150 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 4 
                 2 
                 28 
                 9 
                 3 
                 37 
                 8 
                 3 
                 3 
                 5 
                   
                 150 
                 GDTESHRVLPAQFIKCNW 
               
               
                 2 
                 11 
                 4 
                 4 
                 1 
                 2 
                 32 
                 3 
                 1 
                 5 
                 11 
                 3 
                 150 
                 GRSPALTKVCDYHMQWFEIN 
               
               
                 3 
                 7 
                 2 
                 8 
                 4 
                 4 
                 23 
                 11 
                 1 
                 4 
                 6 
                 2 
                 150 
                 GSYHQTDPRAVLEFKNCMWI 
               
               
                 4 
                 6 
                 2 
                 6 
                 4 
                 6 
                 30 
                 1 
                 8 
                   
                 6 
                 1 
                 150 
                 GSWYTIADFLPVEQRCHMNX 
               
               
                 5 
                 8 
                   
                 10 
                 4 
                 2 
                 28 
                 1 
                 2 
                   
                 22 
                 3 
                 150 
                 GLSYDATWPREQMNVFIH 
               
               
                 6 
                 10 
                 2 
                 11 
                 1 
                 6 
                 21 
                   
                 2 
                 2 
                 5 
                 1 
                 150 
                 GYSPTDAQVFRLNWCIKEM 
               
               
                 7 
                 5 
                 1 
                 8 
                 1 
                 4 
                 19 
                 1 
                 6 
                 5 
                 21 
                 2 
                 150 
                 LGYSTDPIRVAKFNWMQCEH 
               
               
                 8 
                 7 
                 5 
                 22 
                 5 
                 3 
                 12 
                 3 
                 3 
                 3 
                 8 
                 1 
                 150 
                 YDSGLARTCEQVNPFHIKWM 
               
               
                 9 
                 1 
                 2 
                 12 
                 3 
                 1 
                 26 
                 7 
                 2 
                 4 
                 7 
                 2 
                 150 
                 NGYDSWHLPRKETVCIMAFQ 
               
               
                 10 
                 19 
                 1 
                 2 
                 2 
                 17 
                 24 
                 5 
                 2 
                   
                 5 
                 1 
                 150 
                 YGAFWHLPTNSVDEIQRCM 
               
               
                 11 
                 1 
                   
                   
                 1 
                 105 
                 2 
                   
                 2 
                 1 
                 13 
                 14 
                 150 
                 FMLYGIVAEKPQRSWX 
               
               
                 12 
                   
                   
                 130 
                 3 
                   
                 5 
                 1 
                   
                   
                   
                   
                 150 
                 DGYEQNHT 
               
               
                 13 
                 1 
                   
                 2 
                   
                 5 
                   
                 5 
                 14 
                   
                 18 
                 1 
                 150 
                 YVLIPSFHTDAMN 
               
               
                   
                 80 
                 21 
                 243 
                 38 
                 158 
                 259 
                 46 
                 46 
                 27 
                 127 
                 31 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 2 
                 5 
                 4 
                 8 
                 9 
                 11 
                 8 
                 1 
                   
                   
                   
                 150 
                 GDTESHRVLPAQFIKCNW 
               
               
                 2 
                 1 
                 13 
                 3 
                 20 
                 17 
                 7 
                 5 
                 3 
                 4 
                   
                   
                 150 
                 GRSPALTKVCDYHMQWFEIN 
               
               
                 3 
                 3 
                 8 
                 11 
                 8 
                 16 
                 11 
                 7 
                 2 
                 12 
                   
                   
                 150 
                 GSYHQTDPRAVLEFKNCMWI 
               
               
                 4 
                 1 
                 6 
                 4 
                 4 
                 18 
                 10 
                 6 
                 16 
                 14 
                   
                 1 
                 150 
                 GSWYTIADFLPVEQRCHMNX 
               
               
                 5 
                 3 
                 6 
                 4 
                 5 
                 19 
                 8 
                 3 
                 7 
                 15 
                   
                   
                 150 
                 GLSYDATWPREQMNVFIH 
               
               
                 6 
                 3 
                 15 
                 8 
                 6 
                 16 
                 13 
                 8 
                 3 
                 17 
                   
                   
                 150 
                 GYSPTDAQVFRLNWCIKEM 
               
               
                 7 
                 4 
                 7 
                 2 
                 6 
                 15 
                 14 
                 6 
                 4 
                 19 
                   
                   
                 150 
                 LGYSTDPIRVAKFNWMQCEH 
               
               
                 8 
                 4 
                 4 
                 5 
                 7 
                 15 
                 7 
                 5 
                 2 
                 29 
                   
                   
                 150 
                 YDSGLARTCEQVNPFHIKWM 
               
               
                 9 
                 31 
                 5 
                 1 
                 5 
                 10 
                 3 
                 3 
                 9 
                 16 
                   
                   
                 150 
                 NGYDSWHLPRKETVCIMAFQ 
               
               
                 10 
                 3 
                 5 
                 2 
                 2 
                 3 
                 4 
                 3 
                 15 
                 35 
                   
                   
                 150 
                 YGAFWHLPTNSVDEIQRCM 
               
               
                 11 
                   
                 1 
                 1 
                 1 
                 1 
                   
                 2 
                 1 
                 3 
                   
                 1 
                 150 
                 FMLYGIVAEKPQRSWX 
               
               
                 12 
                 2 
                   
                 3 
                   
                   
                 1 
                   
                   
                 5 
                   
                   
                 150 
                 DGYEQNHT 
               
               
                 13 
                 1 
                 14 
                   
                   
                 13 
                 4 
                 21 
                   
                 51 
                   
                   
                 150 
                 YVLIPSFHTDAMN 
               
               
                   
                 58 
                 89 
                 48 
                 72 
                 152 
                 93 
                 77 
                 63 
                 220 
                   
                 2 
                 1950 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 14 # = 118 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 6 
                   
                 29 
                 7 
                 2 
                 32 
                 8 
                 1 
                 1 
                 2 
                   
                 118 
                 GDVHERTAFLPSIKNQ 
               
               
                 2 
                 4 
                   
                 10 
                 1 
                 5 
                 22 
                 7 
                 3 
                 4 
                 7 
                   
                 118 
                 GPDRYSVHLFAKIQTENW 
               
               
                 3 
                 11 
                 2 
                 7 
                 2 
                 3 
                 25 
                   
                 5 
                 1 
                 9 
                 2 
                 118 
                 GVARYLSDITFWCEMPK 
               
               
                 4 
                 5 
                 2 
                 7 
                 7 
                 3 
                 12 
                 4 
                 4 
                 3 
                 6 
                   
                 118 
                 SGVYPDELRTANHIFKWC 
               
               
                 5 
                 6 
                 5 
                 12 
                   
                 2 
                 18 
                 2 
                 2 
                 2 
                 4 
                 1 
                 118 
                 GYSDTVARCLPFHIKNWMQ 
               
               
                 6 
                 6 
                   
                 10 
                 5 
                 4 
                 16 
                   
                 5 
                 3 
                 2 
                 1 
                 118 
                 YGSTDRAEIFVKWLPQMN 
               
               
                 7 
                 4 
                   
                 4 
                 1 
                 4 
                 32 
                 2 
                 2 
                 2 
                   
                 1 
                 118 
                 GSVTYNADFHIKPQRWEM 
               
               
                 8 
                 6 
                 1 
                 5 
                 1 
                 4 
                 18 
                 2 
                 5 
                   
                 3 
                 2 
                 118 
                 GSYTWAPRDIFNVLHMCE 
               
               
                 9 
                 5 
                 2 
                 4 
                 1 
                 2 
                 11 
                 2 
                 1 
                 5 
                 9 
                 1 
                 118 
                 YSGTLVAKNRDWCFHPEIM 
               
               
                 10 
                 2 
                 5 
                 9 
                 2 
                 3 
                 21 
                   
                 2 
                 2 
                 4 
                   
                 118 
                 YGSDNTCQLRFWAEIKPV 
               
               
                 11 
                 12 
                   
                 1 
                 3 
                 5 
                 25 
                 2 
                   
                   
                 2 
                 1 
                 118 
                 YGWAPVFNEHLTDMQR 
               
               
                 12 
                 1 
                   
                   
                   
                 64 
                 5 
                 1 
                 5 
                   
                 12 
                 16 
                 118 
                 FMLGIPSVAHQTY 
               
               
                 13 
                 3 
                   
                 97 
                 4 
                   
                 5 
                 1 
                 1 
                 1 
                 1 
                   
                 118 
                 DGEANQHIKLV 
               
               
                 14 
                 2 
                   
                   
                   
                 3 
                   
                 4 
                 12 
                   
                 6 
                   
                 118 
                 YVPILHFANS 
               
               
                   
                 73 
                 17 
                 195 
                 34 
                 104 
                 242 
                 35 
                 48 
                 24 
                 67 
                 25 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 1 
                 2 
                 1 
                 7 
                 2 
                 7 
                 10 
                   
                   
                   
                   
                 118 
                 GDVHERTAFLPSIKNQ 
               
               
                 2 
                 1 
                 13 
                 2 
                 10 
                 8 
                 2 
                 8 
                 1 
                 10 
                   
                   
                 118 
                 GPDRYSVHLFAKIQTENW 
               
               
                 3 
                   
                 2 
                   
                 11 
                 8 
                 4 
                 13 
                 3 
                 10 
                   
                   
                 118 
                 GVARYLSDITFWCEMPK 
               
               
                 4 
                 5 
                 8 
                   
                 6 
                 13 
                 6 
                 12 
                 3 
                 12 
                   
                   
                 118 
                 SGVYPDELRTANHIFKWC 
               
               
                 5 
                 2 
                 3 
                 1 
                 6 
                 15 
                 10 
                 7 
                 2 
                 18 
                   
                   
                 118 
                 GYSDTVARCLPFHIKNWMQ 
               
               
                 6 
                 1 
                 2 
                 2 
                 7 
                 16 
                 12 
                 4 
                 3 
                 19 
                   
                   
                 118 
                 YGSTDRAEIFVKWLPQMN 
               
               
                 7 
                 5 
                 2 
                 2 
                 2 
                 18 
                 12 
                 13 
                 2 
                 10 
                   
                   
                 118 
                 GSVTYNADFHIKPQRWEM 
               
               
                 8 
                 4 
                 6 
                   
                 6 
                 16 
                 12 
                 4 
                 9 
                 14 
                   
                   
                 118 
                 GSYTWAPRDIFNVLHMCE 
               
               
                 9 
                 5 
                 2 
                   
                 5 
                 14 
                 10 
                 8 
                 4 
                 27 
                   
                   
                 118 
                 YSGTLVAKNRDWCFHPEIM 
               
               
                 10 
                 6 
                 2 
                 5 
                 4 
                 13 
                 6 
                 2 
                 3 
                 27 
                   
                   
                 118 
                 YGSDNTCQLRFWAEIKPV 
               
               
                 11 
                 4 
                 7 
                 1 
                 1 
                   
                 2 
                 6 
                 14 
                 32 
                   
                   
                 118 
                 YGWAPVFNEHLTDMQR 
               
               
                 12 
                   
                 4 
                 1 
                   
                 4 
                 1 
                 3 
                   
                 1 
                   
                   
                 118 
                 FMLGIPSVAHQTY 
               
               
                 13 
                 2 
                   
                 2 
                   
                   
                   
                 1 
                   
                   
                   
                   
                 118 
                 DGEANQHIKLV 
               
               
                 14 
                 2 
                 14 
                   
                   
                 2 
                   
                 20 
                   
                 53 
                   
                   
                 118 
                 YVPILHFANS 
               
               
                   
                 38 
                 67 
                 17 
                 65 
                 129 
                 84 
                 111 
                 44 
                 233 
                   
                   
                 1652 
               
               
                   
               
             
          
           
               
                 Tally of sequences of length 15 # = 125 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                 7 
                   
                 26 
                 8 
                 3 
                 29 
                 1 
                 3 
                   
                 10 
                   
                 125 
                 GDLREASTVNFIPYH 
               
               
                 2 
                 6 
                   
                 2 
                 3 
                   
                 22 
                 3 
                 4 
                 1 
                 9 
                   
                 125 
                 RGPLNSTYAVIQEHWDK 
               
               
                 3 
                 4 
                 4 
                 5 
                 7 
                 2 
                 19 
                 2 
                 6 
                 2 
                 9 
                 2 
                 125 
                 GRYLSVEPIDTACQWFHKMN 
               
               
                 4 
                 7 
                 4 
                 14 
                 6 
                 6 
                 15 
                 2 
                 7 
                 5 
                 7 
                 4 
                 125 
                 GDYAILVEFRKSTCMNPWHQ 
               
               
                 5 
                 6 
                 3 
                 10 
                 2 
                 5 
                 18 
                   
                 4 
                 2 
                 3 
                 2 
                 125 
                 GSYVDRWAFTICLNEKMP 
               
               
                 6 
                 6 
                 2 
                 7 
                 2 
                 5 
                 10 
                 1 
                 5 
                   
                 7 
                 1 
                 125 
                 SRYGTDLWAPFIVNCEQHM 
               
               
                 7 
                 8 
                 4 
                 14 
                 2 
                 2 
                 22 
                 3 
                 3 
                 1 
                 9 
                 1 
                 125 
                 GSDLAVRPYCTHIWEFNKM 
               
               
                 8 
                 6 
                 2 
                 4 
                   
                   
                 22 
                   
                 2 
                 2 
                 3 
                   
                 125 
                 GYSVWRATDNPLCIKQ 
               
               
                 9 
                 4 
                 3 
                 8 
                   
                 4 
                 20 
                 4 
                 3 
                 1 
                 6 
                   
                 125 
                 YGSDLPTRVAFHQCINKW 
               
               
                 10 
                 3 
                 4 
                 5 
                 8 
                 8 
                 17 
                 1 
                 3 
                   
                 7 
                   
                 125 
                 YGEFNTLSRDVCPAIWH 
               
               
                 11 
                 4 
                 2 
                 15 
                 3 
                 3 
                 17 
                 1 
                 1 
                 1 
                   
                   
                 125 
                 YGDSNPAWEFRTCQHIKV 
               
               
                 12 
                 22 
                 3 
                   
                   
                 2 
                 31 
                 3 
                 1 
                   
                 3 
                 3 
                 125 
                 GYAWPSNCHLMFQRVITX 
               
               
                 13 
                   
                   
                   
                   
                 71 
                 1 
                   
                 4 
                   
                 6 
                 30 
                 125 
                 FMLISQTVGPRY 
               
               
                 14 
                   
                   
                 115 
                 2 
                 1 
                 1 
                 1 
                   
                   
                   
                   
                 125 
                 DNEFGHPQ 
               
               
                 15 
                   
                 3 
                   
                   
                 5 
                 1 
                 1 
                 20 
                   
                 7 
                 1 
                 125 
                 YVILPFSCNGHMQ 
               
               
                   
                 83 
                 34 
                 225 
                 43 
                 117 
                 245 
                 23 
                 66 
                 15 
                 86 
                 44 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                 4 
                 3 
                   
                 10 
                 7 
                 6 
                 6 
                   
                 2 
                   
                   
                 125 
                 GDLREASTVNFIPYH 
               
               
                 2 
                 8 
                 11 
                 4 
                 23 
                 7 
                 7 
                 5 
                 3 
                 7 
                   
                   
                 125 
                 RGPLNSTYAVIQEHWDK 
               
               
                 3 
                 2 
                 7 
                 3 
                 13 
                 9 
                 5 
                 8 
                 3 
                 13 
                   
                   
                 125 
                 GRYLSVEPIDTACQWFHKMN 
               
               
                 4 
                 4 
                 4 
                 1 
                 6 
                 5 
                 5 
                 7 
                 3 
                 13 
                   
                   
                 125 
                 GDYAILVEFRKSTCMNPWHQ 
               
               
                 5 
                 3 
                 2 
                   
                 8 
                 18 
                 5 
                 11 
                 8 
                 15 
                   
                   
                 125 
                 GSYVDRWAFTICLNEKMP 
               
               
                 6 
                 3 
                 6 
                 2 
                 12 
                 24 
                 9 
                 4 
                 7 
                 12 
                   
                   
                 125 
                 SRYGTDLWAPFIVNCEQHM 
               
               
                 7 
                 2 
                 6 
                   
                 7 
                 21 
                 4 
                 8 
                 3 
                 5 
                   
                   
                 125 
                 GSDLAVRPYCTHIWEFNKM 
               
               
                 8 
                 4 
                 4 
                 2 
                 7 
                 19 
                 5 
                 12 
                 10 
                 21 
                   
                   
                 125 
                 GYSVWRATDNPLCIKQ 
               
               
                 9 
                 3 
                 6 
                 4 
                 5 
                 19 
                 6 
                 5 
                 1 
                 23 
                   
                   
                 125 
                 YGSDLPTRVAFHQCINKW 
               
               
                 10 
                 8 
                 4 
                   
                 6 
                 7 
                 8 
                 5 
                 2 
                 29 
                   
                   
                 125 
                 YGEFNTLSRDVCPAIWH 
               
               
                 11 
                 7 
                 5 
                 2 
                 3 
                 14 
                 3 
                 1 
                 4 
                 39 
                   
                   
                 125 
                 YGDSNPAWEFRTCQHIKV 
               
               
                 12 
                 4 
                 7 
                 2 
                 2 
                 6 
                 1 
                 2 
                 8 
                 24 
                   
                 1 
                 125 
                 GYAWPSNCHLMFQRVITX 
               
               
                 13 
                   
                 1 
                 2 
                 1 
                 4 
                 2 
                 2 
                   
                 1 
                   
                   
                 125 
                 FMLISQTVGPRY 
               
               
                 14 
                 3 
                 1 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 125 
                 DNEFGHPQ 
               
               
                 15 
                 2 
                 7 
                 1 
                   
                 5 
                   
                 33 
                   
                 39 
                   
                   
                 125 
                 YVILPFSCNGHMQ 
               
               
                   
                 57 
                 74 
                 24 
                 103 
                 165 
                 66 
                 109 
                 52 
                 243 
                   
                 1 
                 1875 
               
               
                   
               
             
          
           
               
                 Distribution of D-JH with number of cys′s 
               
               
                    0   1   2   3   4 
               
               
                 1248  53  80   1   1 
               
               
                   
               
               
                 Tally of AAs in the YYCar motif 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 # 
                   
               
               
                   
               
               
                 1 
                   
                   
                 1 
                 1 
                 
                   14 
                 
                   
                 1 
                   
                   
                   
                   
                 1383 
                 YFDEH 
               
               
                 2 
                   
                 4 
                 1 
                   
                 
                   92 
                 
                   
                 11 
                   
                   
                 4 
                   
                 1383 
                 YFHCLSWDR 
               
               
                 3 
                   
                 
                   1379 
                 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1383 
                 CRS 
               
               
                 4 
                 
                   1207 
                 
                   
                 3 
                   
                 2 
                 12 
                   
                 2 
                   
                 2 
                   
                 1383 
                 AVTSGNDFILRQX 
               
               
                 5 
                 14 
                   
                   
                 1 
                 4 
                 18 
                 17 
                 9 
                 
                   187 
                 
                 4 
                 1 
                 1383 
                 RKTSGHAIVNFLQYPEM| 
               
               
                   
                 1221 
                 1383 
                 5 
                 2 
                 112 
                 30 
                 29 
                 11 
                 187 
                 10 
                 1 
               
               
                   
               
               
                   
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   1366 
                 
                   
                   
                 1383 
                 YFDEH 
               
               
                 2 
                   
                   
                   
                 1 
                 3 
                   
                   
                 2 
                 
                   1265 
                 
                   
                   
                 1383 
                 YFHCLSWDR 
               
               
                 3 
                   
                   
                   
                 2 
                 2 
                   
                   
                   
                   
                   
                   
                 1383 
                 CRS 
               
               
                 4 
                 4 
                   
                 1 
                 2 
                 17 
                 51 
                 
                   79 
                 
                   
                   
                   
                 1 
                 1383 
                 AVTSGNDFILRQX 
               
               
                 5 
                 7 
                 2 
                 3 
                 
                   992 
                 
                 55 
                 56 
                 9 
                   
                 3 
                 1 
                   
                 1383 
                 RKTSGHAIVNFLQYPEM| 
               
               
                   
                 11 
                 2 
                 4 
                 997 
                 77 
                 107 
                 88 
                 2 
                 2634 
                 1 
                 1 
                 6915 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12P 
               
               
                   
               
               
                 Alignment and tabulation of sequences having 3-22 D segments 
               
               
                   
               
             
             
               
                 D3: 3-22_Phz0 YYYDSSGYYY (SEQ ID NO: 448) = GLG 
               
             
          
           
               
                   
                 Entry 
                 Seq1 
                 L1 
                 Seq2 
                 L2 
                 JH 
                 P 
                 Score 
               
               
                   
               
               
                 1 
                 hs3d6hcv 
                 GRDYYDSGGYFT 
                 12 
                 GRDYYDSGGYFTVAFDI 
                 17 
                 3 
                 6 
                 1.76D + 13 
               
               
                   
                   
                 (SEQ ID NO: 334) 
                   
                 (SEQ ID NO: 335) 
                   
                   
                   
                   
               
               
                 2 
                 hs6d4xb7 
                 DRHNYYDSSGSYS 
                 13 
                 DRHNYYDSSGSYSDY 
                 15 
                 4 
                 9 
                 4.40D + 12 
               
               
                   
                   
                 (SEQ ID NO: 336) 
                   
                 (SEQ ID NO: 337) 
                   
                   
                   
                   
               
               
                 3 
                 hs6d4xg3 
                 DCPAPAKMYYYGSGICT 
                 17 
                 DCPAPAKMYYYGSGICTFDY 
                 20 
                 4 
                 3 
                 6.55D + 04 
               
               
                   
                   
                 (SEQ ID NO: 338) 
                   
                 (SEQ ID NO: 339) 
                   
                   
                   
                   
               
               
                 4 
                 hs83x6f2 
                 AFYDSAD 
                 7 
                 AFYDSADDY 
                 9 
                 4 
                 −4 
                 2.62D + 05 
               
               
                   
                   
                 (SEQ ID NO: 340) 
                   
                 (SEQ ID NO: 341) 
                   
                   
                   
                   
               
               
                 5 
                 hsa230644 
                 RDYYDSSGPEAG 
                 12 
                 RDYYDSSGPEAGFDI 
                 15 
                 3 
                 3 
                 6.87D + 10 
               
               
                   
                   
                 (SEQ ID NO: 342) 
                   
                 (SEQ ID NO: 343) 
                   
                   
                   
                   
               
               
                 6 
                 hsa239386 
                 DGTLIDTSAYYYL 
                 13 
                 DGTLIDTSAYYYLY 
                 14 
                 4 
                 6 
                 6.87D + 10 
               
               
                   
                   
                 (SEQ ID NO: 344) 
                   
                 (SEQ ID NO: 345) 
                   
                   
                   
                   
               
               
                 7 
                 hsa234232 
                 NSSDSS 
                 6 
                 NSSDSSVLDV 
                 10 
                 6 
                 −4 
                 6.55D + 04 
               
               
                   
                   
                 (SEQ ID NO: 346) 
                   
                 (SEQ ID NO: 347) 
                   
                   
                   
                   
               
               
                 8 
                 hsa239378 
                 DQVFDSGGYNHR 
                 12 
                 DQVFDSGGYNHRFDS 
                 15 
                 4 
                 3 
                 1.07D + 09 
               
               
                   
                   
                 (SEQ ID NO: 348) 
                   
                 (SEQ ID NO: 349) 
                   
                   
                   
                   
               
               
                 9 
                 hsa239367 
                 DLEYYYDSGGHYSP 
                 14 
                 DLEYYYDSGGHYSPFHY 
                 17 
                 4 
                 9 
                 1.10D + 12 
               
               
                   
                   
                 (SEQ ID NO: 350) 
                   
                 (SEQ ID NO: 351) 
                   
                   
                   
                   
               
               
                 10 
                 hsa239339 
                 DDSSGY 
                 6 
                 DDSSGYYYIDY 
                 11 
                 4 
                 −10 
                 1.72D + 10 
               
               
                   
                   
                 (SEQ ID NO: 352) 
                   
                 (SEQ ID NO: 353) 
                   
                   
                   
                   
               
               
                 11 
                 hsa245311 
                 GHYYDSPGQYSYS 
                 13 
                 GHYYDSPGQYSYSEY 
                 15 
                 4 
                 3 
                 1.07D + 09 
               
               
                   
                   
                 (SEQ ID NO: 354) 
                   
                 (SEQ ID NO: 355) 
                   
                   
                   
                   
               
               
                 12 
                 hsa240578 
                 GGFRPPPYDYESSAYRTYR 
                 19 
                 GGFRPPPYDYESSAYRTYRLDF 
                 22 
                 4 
                 21 
                 2.75D + 11 
               
               
                   
                   
                 (SEQ ID NO: 356) 
                   
                 (SEQ ID NO: 357) 
                   
                   
                   
                   
               
               
                 13 
                 hsa245359 
                 DSDTRAY 
                 7 
                 DSDTRAYYWYFDL 
                 13 
                 2 
                 −7 
                 1.68D + 07 
               
               
                   
                   
                 (SEQ ID NO: 358) 
                   
                 (SEQ ID NO: 359) 
                   
                   
                   
                   
               
               
                 14 
                 hsa245028 
                 GRHYYDSSGYYSTPE 
                 15 
                 GRHYYDSSGYYSTPENYFDY 
                 20 
                 4 
                 6 
                 1.80D + 16 
               
               
                   
                   
                 (SEQ ID NO: 360) 
                   
                 (SEQ ID NO: 361) 
                   
                   
                   
                   
               
               
                 15 
                 hsa245019 
                 DPSYYYDSSGLPL 
                 13 
                 DPSYYYDSSGLPLHGMDV 
                 18 
                 6 
                 9 
                 4.40D + 12 
               
               
                   
                   
                 (SEQ ID NO: 362) 
                   
                 (SEQ ID NO: 363) 
                   
                   
                   
                   
               
               
                 16 
                 hsa244991 
                 TYYYDSSGYLLTR 
                 13 
                 TYYYDSSGYLLTRYFQH 
                 17 
                 1 
                 3 
                 4.50D + 15 
               
               
                   
                   
                 (SEQ ID NO: 364) 
                   
                 (SEQ ID NO: 365) 
                   
                   
                   
                   
               
               
                 17 
                 hsa244945 
                 NAPHYDSSGYYQT 
                 13 
                 NAPHYDSSGYYQTFDY 
                 16 
                 4 
                 6 
                 7.04D + 13 
               
               
                   
                   
                 (SEQ ID NO: 366) 
                   
                 (SEQ ID NO: 367) 
                   
                   
                   
                   
               
               
                 18 
                 hsa244943 
                 GYHSSSYA 
                 8 
                 GYHSSSYADAFDI 
                 13 
                 3 
                 −7 
                 6.71D + 07 
               
               
                   
                   
                 (SEQ ID NO: 368) 
                   
                 (SEQ ID NO: 369) 
                   
                   
                   
                   
               
               
                 19 
                 hsa245289 
                 PIGYCSGGSC 
                 10 
                 PIGYCSGGSCYSFDY 
                 15 
                 4 
                 −4 
                 2.62D + 05 
               
               
                   
                   
                 (SEQ ID NO: 370) 
                   
                 (SEQ ID NO: 371) 
                   
                   
                   
                   
               
               
                 20 
                 hsa240554 
                 THGTYVTSGYYPKI 
                 14 
                 THGTYVTSGYYPKI 
                 14 
                 4 
                 6 
                 2.68D + 08 
               
               
                   
                   
                 (SEQ ID NO: 372) 
                   
                 (SEQ ID NO: 373) 
                   
                   
                   
                   
               
               
                 21 
                 hsa279533 
                 GATYYYESSGNYP 
                 13 
                 GATYYYESSGNYPDY 
                 15 
                 4 
                 9 
                 7.04D + 13 
               
               
                   
                   
                 (SEQ ID NO: 374) 
                   
                 (SEQ ID NO: 375) 
                   
                   
                   
                   
               
               
                 22 
                 hsa389177 
                 AFYHYDSTGYPNRRY 
                 15 
                 AFYHYDSTGYPNRRYYFDY 
                 19 
                 4 
                 6 
                 4.29D + 09 
               
               
                   
                   
                 (SEQ ID NO: 376) 
                   
                 (SEQ ID NO: 377) 
                   
                   
                   
                   
               
               
                 23 
                 hsa7321 
                 SYSYYYDSSGYWGG 
                 14 
                 SYSYYYDSSGYWGGYFDY 
                 18 
                 4 
                 9 
                 4.50D + 15 
               
               
                   
                   
                 (SEQ ID NO: 378) 
                   
                 (SEQ ID NO: 379) 
                   
                   
                   
                   
               
               
                 24 
                 hsaj2772 
                 LSPYYYDSSSYH 
                 12 
                 LSPYYYDSSSYHDAFDI 
                 17 
                 3 
                 6 
                 2.62D + 05 
               
               
                   
                   
                 (SEQ ID NO: 380) 
                   
                 (SEQ ID NO: 381) 
                   
                   
                   
                   
               
               
                 25 
                 hsb7g4f08 
                 EEDYYDSSGQAS 
                 12 
                 EEDYYDSSGQASYNWFXP 
                 18 
                 5 
                 6 
                 2.75D + 11 
               
               
                   
                   
                 (SEQ ID NO: 382) 
                   
                 (SEQ ID NO: 383) 
                   
                   
                   
                   
               
               
                 26 
                 hsb7g3b02 
                 ETNYYDSGGYPG 
                 12 
                 ETNYYDSGGYPGFDF 
                 15 
                 4 
                 6 
                 4.40D + 12 
               
               
                   
                   
                 (SEQ ID NO: 384) 
                   
                 (SEQ ID NO: 385) 
                   
                   
                   
                   
               
               
                 27 
                 hsb7g3c12 
                 GDHYYDRSGYRH 
                 12 
                 GDHYYDRSGYRHSYYYYAMDV 
                 21 
                 6 
                 6 
                 2.75D + 11 
               
               
                   
                   
                 (SEQ ID NO: 386) 
                   
                 (SEQ ID NO: 387) 
                   
                   
                   
                   
               
               
                 28 
                 hsb8g3b07 
                 DRSSGN 
                 6 
                 DRSSGNYFDGMDV 
                 13 
                 6 
                 −10 
                 6.55D + 04 
               
               
                   
                   
                 (SEQ ID NO: 388) 
                   
                 (SEQ ID NO: 389) 
                   
                   
                   
                   
               
               
                 29 
                 hsfog1h 
                 GRSRYSGYG 
                 9 
                 GRSRYSGYGFYSGMDV 
                 16 
                 6 
                 −4 
                 2.62D + 05 
               
               
                   
                   
                 (SEQ ID NO: 390) 
                   
                 (SEQ ID NO: 391) 
                   
                   
                   
                   
               
               
                 30 
                 hsgvh0209 
                 DDTSGYGP 
                 8 
                 DDTSGYGPYYFYYGMDV 
                 17 
                 6 
                 −10 
                 2.68D + 08 
               
               
                   
                   
                 (SEQ ID NO: 392) 
                   
                 (SEQ ID NO: 393) 
                   
                   
                   
                   
               
               
                 31 
                 hsgvh55 
                 RAYYDTSFYFEY 
                 12 
                 RAYYDTSFYFEYY 
                 13 
                 4 
                 3 
                 1.72D + 10 
               
               
                   
                   
                 (SEQ ID NO: 394) 
                   
                 (SEQ ID NO: 395) 
                   
                   
                   
                   
               
               
                 32 
                 hsgvh0304 
                 DRIDYYKSGYYLGSA 
                 15 
                 DRIDYYKSGYYLGSADS 
                 17 
                 4 
                 6 
                 1.68D + 07 
               
               
                   
                   
                 (SEQ ID NO: 396) 
                   
                 (SEQ ID NO: 397) 
                   
                   
                   
                   
               
               
                 33 
                 hsgvh0332 
                 DTDSSSHYG 
                 9 
                 DTDSSSHYGRFDP 
                 13 
                 5 
                 −7 
                 1.68D + 07 
               
               
                   
                   
                 (SEQ ID NO: 398) 
                   
                 (SEQ ID NO: 399) 
                   
                   
                   
                   
               
               
                 34 
                 hsgvh0328 
                 VSISHYDSSGRPQRVF 
                 16 
                 VSISHYDSSGRPQRVFYGMDV 
                 21 
                 6 
                 9 
                 1.07D + 09 
               
               
                   
                   
                 (SEQ ID NO: 400) 
                   
                 (SEQ ID NO: 401) 
                   
                   
                   
                   
               
               
                 35 
                 hsgvh536 
                 QARENVFYDSSGPTAP 
                 16 
                 QARENVFYDSSGPTAPFDH 
                 19 
                 4 
                 15 
                 1.72D + 10 
               
               
                   
                   
                 (SEQ ID NO: 402) 
                   
                 (SEQ ID NO: 403) 
                   
                   
                   
                   
               
               
                 36 
                 hshcmg42 
                 VPAGNYYDTSGPDN 
                 14 
                 VPAGNYYDTSGPDNAD 
                 16 
                 4 
                 12 
                 1.72D + 10 
               
               
                   
                   
                 (SEQ ID NO: 404) 
                   
                 (SEQ ID NO: 405) 
                   
                   
                   
                   
               
               
                 37 
                 hsig001vh 
                 WYYFDTSGYYPRNFYYMDV 
                 19 
                 WYYFDTSGYYPRNFYYMDV 
                 19 
                 4 
                 3 
                 2.81D + 14 
               
               
                   
                   
                 (SEQ ID NO: 406) 
                   
                 (SEQ ID NO: 407) 
                   
                   
                   
                   
               
               
                 38 
                 hsig13g10 
                 GYYYDSGGNYNG 
                 12 
                 GYYYDSGGNYNGDY 
                 14 
                 4 
                 3 
                 1.10D + 12 
               
               
                   
                   
                 (SEQ ID NO: 408) 
                   
                 (SEQ ID NO: 409) 
                   
                   
                   
                   
               
               
                 39 
                 hsighpat3 
                 DLRSYDPSGYYN 
                 12 
                 DLRSYDPSGYYNDGFDI 
                 17 
                 3 
                 6 
                 2.75D + 11 
               
               
                   
                   
                 (SEQ ID NO: 410) 
                   
                 (SEQ ID NO: 411) 
                   
                   
                   
                   
               
               
                 40 
                 hsigh13g7 
                 GYYYDRGGNCNG 
                 12 
                 GYYYDRGGNCNGDY 
                 14 
                 4 
                 3 
                 6.87D + 10 
               
               
                   
                   
                 (SEQ ID NO: 412) 
                   
                 (SEQ ID NO: 413) 
                   
                   
                   
                   
               
               
                 41 
                 hsigh13g1 
                 GYYYDRGGNYNG 
                 12 
                 GYYYDRGGNYNGDY 
                 14 
                 4 
                 3 
                 1.10D + 12 
               
               
                   
                   
                 (SEQ ID NO: 414) 
                   
                 (SEQ ID NO: 415) 
                   
                   
                   
                   
               
               
                 42 
                 hsighxx20 
                 THYDSSGL 
                 8 
                 THYDSSGLDAFDI 
                 13 
                 3 
                 −4 
                 1.72D + 10 
               
               
                   
                   
                 (SEQ ID NO: 416) 
                   
                 (SEQ ID NO: 417) 
                   
                   
                   
                   
               
               
                 43 
                 hsihr9 
                 DDSSGS 
                 6 
                 DDSSGSYYFDY 
                 11 
                 4 
                 −10 
                 1.07D + 09 
               
               
                   
                   
                 (SEQ ID NO: 418) 
                   
                 (SEQ ID NO: 419) 
                   
                   
                   
                   
               
               
                 44 
                 hsihv11 
                 LSGGYYS 
                 7 
                 LSGGYYSDFDY 
                 11 
                 4 
                 −13 
                 2.68D + 08 
               
               
                   
                   
                 (SEQ ID NO: 420) 
                   
                 (SEQ ID NO: 421) 
                   
                   
                   
                   
               
               
                 45 
                 hs ej1f 
                 GDYSDSSDSYI 
                 11 
                 GDYSDSSDSYIDAFDV 
                 16 
                 3 
                 3 
                 1.10D + 12 
               
               
                   
                   
                 (SEQ ID NO: 422) 
                   
                 (SEQ ID NO: 423) 
                   
                   
                   
                   
               
               
                 46 
                 hsmvh5l 
                 GETYYYDSRGYA 
                 12 
                 GETYYYDSRGYAFDH 
                 15 
                 4 
                 6 
                 2.62D + 05 
               
               
                   
                   
                 (SEQ ID NO: 424) 
                   
                 (SEQ ID NO: 425) 
                   
                   
                   
                   
               
               
                 47 
                 hsmvh517 
                 PTRDSSGY 
                 8 
                 PTRDSSGYYVGY 
                 12 
                 4 
                 −4 
                 1.07D + 09 
               
               
                   
                   
                 (SEQ ID NO: 426) 
                   
                 (SEQ ID NO: 427) 
                   
                   
                   
                   
               
               
                 48 
                 hsmvh0406 
                 GSFYYDSSGYPP 
                 12 
                 GSFYYDSSGYPPFDC 
                 15 
                 4 
                 6 
                 6.87D + 10 
               
               
                   
                   
                 (SEQ ID NO: 428) 
                   
                 (SEQ ID NO: 429) 
                   
                   
                   
                   
               
               
                 49 
                 hst14x14 
                 GPYYYDSSGYYL 
                 12 
                 GPYYYDSSGYYLLDY 
                 15 
                 4 
                 6 
                 1.80D + 16 
               
               
                   
                   
                 (SEQ ID NO: 430) 
                   
                 (SEQ ID NO: 431) 
                   
                   
                   
                   
               
               
                 50 
                 hsvhig2 
                 EEGYYDSSGYYSLGA 
                 15 
                 EEGYYDSSGYYSLGASDY 
                 18 
                 4 
                 6 
                 4.50D + 15 
               
               
                   
                   
                 (SEQ ID NO: 432) 
                   
                 (SEQ ID NO: 433) 
                   
                   
                   
                   
               
               
                 51 
                 hsvhia2 
                 RPDSSGSRW 
                 9 
                 RPDSSGSRWYFDY 
                 13 
                 4 
                 −7 
                 6.71D + 07 
               
               
                   
                   
                 (SEQ ID NO: 434) 
                   
                 (SEQ ID NO: 435) 
                   
                   
                   
                   
               
               
                 52 
                 hsy14936 
                 GYYDISGYYF 
                 10 
                 GYYDISGYYFDAFNI 
                 15 
                 3 
                 −4 
                 2.81D + 14 
               
               
                   
                   
                 (SEQ ID NO: 436) 
                   
                 (SEQ ID NO: 437) 
                   
                   
                   
                   
               
               
                 53 
                 hsy14934 
                 DRGYDSSGYYGN 
                 12 
                 DRGYDSSGYYGNLDC 
                 15 
                 4 
                 3 
                 1.76D + 13 
               
               
                   
                   
                 (SEQ ID NO: 438) 
                   
                 (SEQ ID NO: 439) 
                   
                   
                   
                   
               
               
                 54 
                 hsy14935 
                 DRGYDSIGYYGN 
                 12 
                 DRGYDSIGYYGNLDC 
                 15 
                 4 
                 3 
                 1.10D + 12 
               
               
                   
                   
                 (SEQ ID NO: 440) 
                   
                 (SEQ ID NO: 441) 
                   
                   
                   
                   
               
               
                 55 
                 hsz80519 
                 AEDLTYYYDRSGWGVHGLL 
                 19 
                 AEDLTYYYDRSGWGVHGLLYYFDY 
                 24 
                 4 
                 15 
                 4.40D + 12 
               
               
                   
                   
                 (SEQ ID NO: 442) 
                   
                 (SEQ ID NO: 443) 
                   
                   
                   
                   
               
               
                 56 
                 hsz80429 
                 LYPHYDSSGYYYV 
                 13 
                 LYPHYDSSGYYYVLDY 
                 16 
                 4 
                 6 
                 4.50D + 15 
               
               
                   
                   
                 (SEQ ID NO: 444) 
                   
                 (SEQ ID NO: 445) 
                   
                   
                   
                   
               
               
                 57 
                 hsz80461 
                 DRVGYYDSSGYPPGSP 
                 16 
                 DRVGYYDSSGYPPGSPLDY 
                 19 
                 4 
                 9 
                 1.76D + 13 
               
               
                   
                   
                 (SEQ ID NO: 446) 
                   
                 (SEQ ID NO: 447) 
               
               
                   
               
             
          
           
               
                 Frequency of each AA type at each position in 57 Sequences having D3-22 segments 
               
             
          
           
               
                 Pos 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
                 # 
                   
               
               
                   
               
               
                 1 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 2 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
               
               
                 3 
                 1 
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
               
               
                 4 
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                 4 
                   
               
               
                 5 
                   
                   
                 5 
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                   
                 2 
                   
                 1 
                 1 
                   
                 1 
                   
                   
                   
                   
                 12 
                   
               
               
                 6 
                 3 
                   
                 3 
                 4 
                   
                 6 
                   
                   
                   
                 3 
                   
                 1 
                 2 
                   
                 2 
                 2 
                 1 
                   
                   
                 1 
                   
                   
                 28 
                 x 
               
               
                 7 
                 1 
                   
                 5 
                 4 
                 1 
                 7 
                 2 
                 1 
                   
                 1 
                   
                 1 
                 3 
                   
                 5 
                 3 
                 4 
                 1 
                 1 
                 1 
                   
                   
                 41 
                 x 
               
               
                 8 
                 2 
                 1 
                 4 
                   
                 1 
                 5 
                 3 
                 1 
                   
                   
                   
                 4 
                 4 
                 1 
                 3 
                 1 
                 3 
                 1 
                   
                 14 
                   
                   
                 48 
                 x 
               
               
                 9 
                   
                   
                 4 
                   
                 2 
                 3 
                 5 
                 1 
                   
                 1 
                   
                   
                 1 
                   
                 2 
                 2 
                 2 
                 1 
                   
                 
                   28 
                 
                   
                   
                 52 
                 Y 
               
               
                 10 
                 1 
                   
                 4 
                   
                 2 
                 1 
                   
                 1 
                   
                   
                   
                   
                 1 
                   
                 1 
                 4 
                 1 
                   
                   
                 
                   40 
                 
                   
                   
                 56 
                 Y 
               
               
                 11 
                   
                   
                 
                   46 
                 
                 2 
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                 1 
                   
                 2 
                   
                   
                 1 
                   
                 3 
                   
                   
                 57 
                 D 
               
               
                 12 
                 1 
                 1 
                 1 
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                 1 
                   
                 4 
                 
                   39 
                 
                 7 
                   
                   
                 1 
                   
                   
                 57 
                 S 
               
               
                 13 
                 1 
                   
                   
                   
                   
                 8 
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                 1 
                 
                   43 
                 
                 1 
                   
                   
                   
                   
                   
                 57 
                 S 
               
               
                 14 
                 3 
                   
                 2 
                   
                 1 
                 
                   45 
                 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 1 
                 3 
                   
                   
                   
                   
                   
                   
                 56 
                 G 
               
               
                 15 
                   
                   
                   
                   
                   
                 2 
                 2 
                   
                   
                 2 
                   
                 5 
                 3 
                 2 
                 1 
                 4 
                   
                   
                 1 
                 
                   33 
                 
                   
                   
                 55 
                 Y 
               
               
                 16 
                 2 
                 1 
                 1 
                 1 
                 2 
                 3 
                 1 
                   
                   
                 1 
                   
                 1 
                 6 
                   
                 3 
                 1 
                 1 
                   
                 1 
                 24 
                   
                   
                 49 
                 x 
               
               
                 17 
                 3 
                 1 
                   
                 1 
                 1 
                 5 
                 2 
                 1 
                   
                 4 
                   
                 6 
                 6 
                 2 
                   
                 7 
                 2 
                 1 
                 1 
                 3 
                   
                   
                 46 
                 x 
               
               
                 18 
                   
                   
                   
                   
                   
                 8 
                 1 
                   
                 1 
                 2 
                   
                 2 
                 2 
                   
                 4 
                   
                 3 
                 1 
                   
                 3 
                   
                   
                 27 
                   
               
               
                 19 
                   
                   
                   
                   
                   
                 2 
                   
                 1 
                   
                   
                   
                 1 
                 1 
                   
                 3 
                 4 
                   
                 1 
                   
                   
                   
                   
                 13 
                   
               
               
                 20 
                 2 
                   
                   
                 1 
                 2 
                 1 
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 9 
                   
               
               
                 21 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 3 
                   
               
               
                 22 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 2 
                   
               
               
                 23 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 2 
                   
               
               
                 24 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
               
               
                 25 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                 1 
               
               
                   
               
               
                 Average Dseg = 11.9 Average DJ = 15.7 
               
               
                 Median D = 12 12 Shortest 6 Longest 19 
               
               
                 Median DJ = 32 15 15 Shortest 9 Longest 24 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 13P 
               
             
             
               
                   
               
               
                 Frequency of D-segments. “|” stands for a stop codon. 
               
             
          
           
               
                 D seg 
                 “0” 
                 % 
                 C % 
                 GLG 
                 “1” 
                 % 
                 C % 
                 GLG 
                 “2” 
                 % 
                 C % 
                 GLG 
               
               
                   
               
             
          
           
               
                 1-01 
                 1 
                 0.13 
                 0 
                 VQLERX (SEQ ID 
                 4 
                 0.53 
                 0.22 
                 GTTGTX(SEQ ID 
                 5 
                 0.66 
                 0.34 
                 YNWND(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 132) 
                   
                   
                   
                 NO: 133) 
                   
                   
                   
                 NO: 134) 
               
               
                   
               
               
                 1-07 
                 0 
                 0 
                 0 
                 V|LELX(SEQ ID 
                 3 
                 0.4 
                 0.11 
                 GITGTX(SEQ ID 
                 9 
                 1.19 
                 0.34 
                 YNWNY(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 135) 
                   
                   
                   
                 NO: 136) 
                   
                   
                   
                 NO: 137) 
               
               
                   
               
               
                 1-20 
                 0 
                 0 
                 0 
                 V|LERX(SEQ ID 
                 1 
                 0.13 
                 0.22 
                 GITGTX(SEQ ID 
                 4 
                 0.53 
                 0.45 
                 YNWND(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 138) 
                   
                   
                   
                 NO: 139) 
                   
                   
                   
                 NO: 140) 
               
               
                   
               
               
                 1-26 
                 4 
                 0.53 
                 0 
                 V|WELLX(SEQ ID 
                 13 
                 1.72 
                 0.90 
                 GIVGATX(SEQ ID 
                 36 
                 4.76 
                 0.78 
                 YSGSYY(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 141) 
                   
                   
                   
                 NO: 142) 
                   
                   
                   
                 NO: 143) 
               
               
                   
               
               
                 2-02 
                 31 
                 4.1 
                 2.47 
                 GYCSSTSCYT(SEQ 
                 4 
                 0.53 
                 0.22 
                 RIL||YQLLYX(SEQ 
                 9 
                 1.19 
                 2.47 
                 DIVVVPAAIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 144) 
                   
                   
                   
                  ID NO: 145) 
                   
                   
                   
                 ID NO: 146) 
               
               
                   
               
               
                 2-08 
                 5 
                 0.66 
                 0.56 
                 GYCTNGVCYT(SEQ 
                 0 
                 0 
                 0 
                 RILY|WCMLYX(SEQ 
                 3 
                 0.4 
                 0.56 
                 DIVLMVYAIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 147) 
                   
                   
                   
                  ID NO: 148) 
                   
                   
                   
                 ID NO: 149) 
               
               
                   
               
               
                 2-15 
                 29 
                 3.83 
                 1.57 
                 GYCSGGSCYS(SEQ 
                 2 
                 0.26 
                 0.11 
                 RIL|WWILLLX(SEQ 
                 7 
                 0.92 
                 1.57 
                 DIVVVPAAIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 150) 
                   
                   
                   
                  ID NO: 151) 
                   
                   
                   
                 ID NO: 152) 
               
               
                   
               
               
                 2-21 
                 16 
                 2.11 
                 0.67 
                 AYCGGDCYS(SEQ 
                 0 
                 0 
                 0 
                 SILWW|LLFX(SEQ 
                 7 
                 0.92 
                 0.67 
                 HIVVVTAIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 153) 
                   
                   
                   
                 ID NO: 154) 
                   
                   
                   
                 ID NO: 155) 
               
               
                   
               
               
                 3-03 
                 32 
                 4.23 
                 2.80 
                 YYDFWSGYYT(SEQ 
                 7 
                 0.92 
                 0.90 
                 VLRFLEWLLYX(SEQ 
                 27 
                 3.57 
                 1.12 
                 ITIFGVVIIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 156) 
                   
                   
                   
                  ID NO: 157) 
                   
                   
                   
                 ID NO: 158) 
               
               
                   
               
               
                 3-09 
                 13 
                 1.72 
                 1.35 
                 YYDILTGYYN(SEQ 
                 5 
                 0.66 
                 0.78 
                 VLRYFDWLL|X(SEQ 
                 0 
                 0 
                 0 
                 ITIF|LVIIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 159) 
                   
                   
                   
                  ID NO: 160) 
                   
                   
                   
                 ID NO: 161) 
               
               
                   
               
               
                 3-10 
                 42 
                 5.55 
                 4.26 
                 YYYGSGSYYN(SEQ 
                 13 
                 1.72 
                 0.89 
                 VLLWFGELL|X(SEQ 
                 11 
                 1.45 
                 2.91 
                 ITMVRGVIIX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 162) 
                   
                   
                   
                 ID NO: 163) 
                   
                   
                   
                 ID NO: 164) 
               
               
                   
               
               
                 3-16 
                 18 
                 2.38 
                 0.67 
                 YYDYVWGSYRYT 
                 8 
                 1.06 
                 0 
                 VLILRLGELSLYX 
                 5 
                 0.66 
                 0.34 
                 IMITFGGVIVIX 
               
               
                   
                   
                   
                   
                 (SEQ ID 
                   
                   
                   
                 (SEQ ID NO: 166) 
                   
                   
                   
                 (SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 165) 
                   
                   
                   
                   
                   
                   
                   
                 NO: 167) 
               
               
                   
               
               
                 3-22 
                 57 
                 7.53 
                 3.36 
                 YYYDSSGYYY(SEQ 
                 1 
                 0.13 
                 0.11 
                 VLL|||WLLLX 
                 6 
                 0.79 
                 0.34 
                 ITMIVVVITX(SEQ 
               
               
                   
                   
                   
                   
                 ID NO: 168) 
                   
                   
                   
                 (SEQ ID 
                   
                   
                   
                 ID NO: 170) 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 NO: 169) 
                   
                   
                   
                   
               
               
                   
               
               
                 4-04 
                 5 
                 0.66 
                 0.28 
                 DYSNY(SEQ ID 
                 2 
                 0.26 
                 0 
                 |LQ|LX(SEQ ID 
                 2 
                 0.26 
                 0.06 
                 TTVTX(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 171) 
                   
                   
                   
                 NO: 172) 
                   
                   
                   
                 NO: 173) 
               
               
                   
               
               
                 4-17 
                 29 
                 3.83 
                 1.45 
                 DYGDY(SEQ ID 
                 0 
                 0 
                 0 
                 |LR|LX(SEQ ID 
                 20 
                 2.64 
                 0.90 
                 TTVTX(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 174) 
                   
                   
                   
                 NO: 175) 
                   
                   
                   
                 NO: 176) 
               
               
                   
               
               
                 4-23 
                 10 
                 1.32 
                 0.56 
                 DYGGNS(SEQ ID 
                 1 
                 0.13 
                 0 
                 |LRW|LX(SEQ ID 
                 4 
                 0.53 
                 0.56 
                 TTVVTX(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 177) 
                   
                   
                   
                 NO: 178) 
                   
                   
                   
                 NO: 179) 
               
               
                   
               
               
                 5-05 
                 3 
                 0.4 
                 0.06 
                 WIQLWLX(SEQ ID 
                 10 
                 1.32 
                 0.39 
                 VDTAMVX(SEQ ID 
                 31 
                 4.1 
                 0.73 
                 GYSYGY(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 180) 
                   
                   
                   
                 NO: 181) 
                   
                   
                   
                 NO: 182) 
               
               
                   
               
               
                 5-12 
                 0 
                 0 
                 0 
                 WI|WLRLX(SEQ 
                 8 
                 1.06 
                 0.45 
                 VDIVATIX(SEQ 
                 14 
                 1.85 
                 1.12 
                 GYSGYDY(SEQ ID 
               
               
                   
                   
                   
                   
                 ID NO: 183) 
                   
                   
                   
                 ID NO: 184) 
                   
                   
                   
                 NO: 185) 
               
               
                   
               
               
                 5-24 
                 11 
                 1.45 
                 0 
                 |RWLQLX(SEQ ID 
                 5 
                 0.66 
                 0.34 
                 VEMATIX(SEQ ID 
                 13 
                 1.72 
                 0.44 
                 RDGYNY(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 186) 
                   
                   
                   
                 NO: 187) 
                   
                   
                   
                 NO: 188) 
               
               
                   
               
               
                 6-06 
                 11 
                 1.45 
                 0.78 
                 SIAARX(SEQ ID 
                 9 
                 1.19 
                 0.48 
                 EYSSSS(SEQ ID 
                 1 
                 0.13 
                 0.11 
                 V|QLVX(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 189) 
                   
                   
                   
                 NO: 190) 
                   
                   
                   
                 NO: 191) 
               
               
                   
               
               
                 6-13 
                 19 
                 2.51 
                 1.01 
                 GIAAAGX(SEQ ID 
                 35 
                 4.62 
                 2.13 
                 GYSSSWY(SEQ ID 
                 2 
                 0.26 
                 0.31 
                 V|QQLVX(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 192) 
                   
                   
                   
                 NO: 193) 
                   
                   
                   
                 NO: 194) 
               
               
                   
               
               
                 6-19 
                 14 
                 1.85 
                 2.12 
                 GIAVAGX(SEQ ID 
                 48 
                 6.34 
                 2.02 
                 GYSSGWY(SEQ ID 
                 4 
                 0.53 
                 0.56 
                 V|QWLVX(SEQ ID 
               
               
                   
                   
                   
                   
                 NO: 195) 
                   
                   
                   
                 NO: 196) 
                   
                   
                   
                 NO: 197) 
               
               
                   
               
               
                 D7: 7- 
                 1 
                 0.13 
                 0 
                 ILGX 
                 2 
                 0.26 
                 0.68 
                 LTGX(SEQ ID 
                 2 
                 0.26 
                 0.22 
                 NWG 
               
               
                 27 
                   
                   
                   
                   
                   
                   
                   
                 NO: 198) 
               
               
                   
               
               
                 Total = 757 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 14P 
               
             
             
               
                   
               
               
                 Possible library components. 
               
             
          
           
               
                   
                 Component 
                 L 
                 f 
                   
               
               
                   
               
               
                 D2_2-02_Phz0 
                 xxxY C SSTS C xxx 
                 13, 
                 31, 
                 (SEQ ID NO: 199) 
               
               
                   
               
               
                 D3_3-16_Phz0 
                 xxxxYVWGSYxxx 
                 13, 
                 18, 
                 (SEQ ID NO: 200) 
               
               
                   
               
               
                 D5_5-12_Phz2 
                 xxxxxxxSGYxxx 
                 13, 
                 14, 
                 (SEQ ID NO: 201) 
               
               
                   
               
               
                 D3_3-09_Phz0 
                 xxxYDILTGYYxx 
                 13, 
                 13, 
                 (SEQ ID NO: 202) 
               
               
                   
               
               
                 D2_2-02_Phz2 
                 xxxVVVPAAxxxx 
                 13, 
                  9, 
                 (SEQ ID NO: 203) 
               
               
                   
               
               
                 D3_3-22_Phz0 
                  xxxYYDSSGYxx 
                 12, 
                 57, 
                 (SEQ ID NO: 204) 
               
               
                   
               
               
                 D3_3-03_Phz0 
                  xxxDFWSGxxxx 
                 12, 
                 32, 
                 (SEQ ID NO: 205) 
               
               
                   
               
               
                 D3_3-03_Phz2 
                  xxxTIFGVxxxx 
                 12, 
                 27, 
                 (SEQ ID NO: 206) 
               
               
                   
               
               
                 D5_5-12_Phz1 
                  xxxxIVATxxxx 
                 12, 
                  8, 
                 (SEQ ID NO: 207) 
               
               
                   
               
               
                 D3_3-10_Phz0 
                   xxxYGSGSYYx 
                 11, 
                 42, 
                 ! could add one 
               
               
                   
                   
                   
                   
                 x at either end 
               
               
                   
                   
                   
                   
                 (SEQ ID NO: 208) 
               
               
                   
               
               
                 D5_5-05_Phz2 
                   xxxxYSYGxxx 
                 11, 
                 31, 
                 (SEQ ID NO: 209) 
               
               
                   
               
               
                 D2_2-15_Phz0 
                   xxx C SGxx C Yx 
                 11, 
                 29, 
                 (SEQ ID NO: 210) 
               
               
                   
               
               
                 D6_6-13_Phz0 
                   xxxxAAAGxxx 
                 11, 
                 19, 
                 (SEQ ID NO: 211) 
               
               
                   
               
               
                 D4_4-23_Phz0 
                   xGxxxGGNxxx 
                 11, 
                 10, 
                 (SEQ ID NO: 212) 
               
               
                   
               
               
                 D1_1-26_Phz2 
                    xxxSGSYxxx 
                 10, 
                 35, 
                 (SEQ ID NO: 213) 
               
               
                   
               
               
                 D6_6-13_Phz1 
                    xxxSSSWxxx 
                 10, 
                 35, 
                 (SEQ ID NO: 214) 
               
               
                   
               
               
                 D4_4-17_Phz2 
                    xxxxTTVTTx 
                 10, 
                 20, 
                 (SEQ ID NO: 215) 
               
               
                   
               
               
                 D2_2-21_Phz0 
                 xxx C (SG)GDx C x 
                 10, 
                 16, 
                 (SEQ ID NO: 216) 
               
               
                   
               
               
                 D6_6-19_Phz0 
                 xxx(IV)AVAGxx 
                 10, 
                 14, 
                 (SEQ ID NO: 217) 
               
               
                   
               
               
                 D3_3-10_Phz1 
                    xxLWFGELxx 
                 10, 
                 13, 
                 (SEQ ID NO: 218) 
               
               
                   
               
               
                 D5_5-24_Phz0 
                    GxxWLxxxxF 
                 10, 
                 11, 
                 (SEQ ID NO: 219) 
               
               
                   
               
               
                 D5_5-05_Phz1 
                    xxxDTxMVxx 
                 10, 
                 10, 
                 (SEQ ID NO: 220) 
               
               
                   
               
               
                 D3_3-16_Phz1 
                    xxxxxGExxx 
                 10, 
                  8, 
                 (SEQ ID NO: 221) 
               
               
                   
               
               
                 D6_6-19_Phz1 
                     xxxxSGWxx 
                  9, 
                 48, 
                 (SEQ ID NO: 222) 
               
               
                   
               
               
                 D5_5-24_Phz2 
                     xxxxGYNxx 
                  9, 
                 13, 
                 (SEQ ID NO: 223) 
               
               
                   
               
               
                 D3_3-10_Phz2 
                     xxxVRGVxx 
                  9, 
                 11, 
                 (SEQ ID NO: 224) 
               
               
                   
               
               
                 D6_6-06_Phz0 
                     xxxIAAxxx 
                 9, 
                 11, 
                 (SEQ ID NO: 225) 
               
               
                   
               
               
                 D1_1-07_Phz2 
                     xxYxWNxxx 
                  9, 
                  9, 
                 (SEQ ID NO: 226) 
               
               
                   
               
               
                 D4_4-17_Phz0 
                      xxxYGDxx 
                  8, 
                 29, 
                 (SEQ ID NO: 227) 
               
               
                   
               
               
                 D1_1-26_Phz1 
                      xxVGATxx 
                  8, 
                 13, 
                 (SEQ ID NO: 228) 
               
               
                   
               
               
                 D6_6-06_Phz1 
                      xxxYSSSx 
                  8, 
                  9, 
                 (SEQ ID NO: 229) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 15P 
               
               
                   
               
               
                 Lengths of CDRs: 1095 actual VH domains and 51 VH GLGs. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Length 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
               
               
                   
               
               
                 CDR1 
                 0 
                 0 
                 10 
                 0 
                 1 
                 820 
                 38 
                 175 
                 1 
                 1 
                 5 
                 1 
                 11 
                 0 
                 23 
                 1 
                 7 
                 0 
               
             
          
           
               
                 GLG 
                 0 
                 0 
                 0 
                 0 
                 0 
                 38 
                 3 
                 10 
                 0 
                 0 . . . 
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 CDR2 
                 0 
                 0 
                 0 
                 0 
                 0 
                 2 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 464 
                 579 
               
               
                 GLG 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
                 17 
                 28 
               
               
                 CDR3 
                 0 
                 0 
                 0 
                 4 
                 2 
                 8 
                 6 
                 28 
                 40 
                 65  
                 77  
                 90 
                 117 
                 117 
                 88 
                 105 
                 86 
                 81 
               
               
                   
               
             
          
           
               
                 Length 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 28 
                 29 
                 30 
                 31 
                 32 
                 (33 or more) 
               
               
                   
               
             
          
           
               
                 CDR2 
                 9 
                 31 
                 1 
                  3 
                  3 
                 1 
                 0 
                 0 
                 0 
                 0 
                 2 
                 0 
                 0 . . . 
                   
                   
               
             
          
           
               
                 GLG 
                 1 
                 4 
                 0 
                 0 . . . 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
             
          
           
               
                 CDR3 
                 45 
                 36 
                 36 
                 16 
                 16 
                 8 
                 8 
                 2 
                 3 
                 0 
                 2 
                 1 
                 0 
                 0 
                 1 
                 5 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 16P 
               
             
             
               
                   
               
               
                 Library of HC CDR3 
               
             
          
           
               
                 Component 
                 Fraction of 
                 Length 
                 #X 
                 Complexity 
                 library 
                 Adjusted 
               
               
                   
               
             
          
           
               
                 1: 
                 YYCA21111YFDYWG. 
                 8 
                 4 
                 2.6 E 5 
                 .10 (0-8) 
                 .02 
               
               
                   
                 (2 = KR; SEQ ID NO: 6) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 2: 
                 YYCA2111111YFDYWG. 
                 10 
                 6 
                 9.4 E 7 
                 .14 (9-10) 
                 .14 
               
               
                   
                 (2 = KR; SEQ ID NO: 7) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 3: 
                 YYCA211111111YFDYTG. 
                 12 
                 8 
                 3.4 E 10 
                 .25 (11 + 12 + 13/2) 
                 .25 
               
               
                   
                 (2 = KR; SEQ ID NO: 8) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 4: 
                 YYCAR111S2S3111YFDYWG. 
                 14 
                 6 
                 1.9 e 8 
                 .13 (14 + 13/2) 
                 .14 
               
               
                   
                 (2 = SG 3 = YW; SEQ ID NO: 9) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 5: 
                 YYCA2111 C SG11 C Y1YFDYWG. 
                 15 
                 6 
                 9.4 E 7 
                 .13 (15 + 16/2) 
                 .14 
               
               
                   
                 (2 = KR; SEQ ID NO: 10) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 6: 
                 YYCA211S1TIFG11111YFDYWG. 
                 17 
                 8 
                 1.7 E 10 
                 .11 (17 + 16/2) 
                 .12 
               
               
                   
                 (2 = KR; SEQ ID NO: 11) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 7: 
                 YYCAR111YY2S33YY111YFDYWG. 
                 18 
                 6 
                 3.8 E 8 
                 .04 (18) 
                 .08 
               
               
                   
                 (2 = D|G; 3 = S|G; SEQ ID NO: 12) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 8: 
                 YYCAR1111Y C 2231 C Y111YFDYWG. 
                 19 
                 8 
                 2.0 E 11 
                 .10 (19 on) 
                 .11 
               
               
                   
                 (2 = S|G; 3 = T|D|G; SEQ ID NO: 13) 
               
               
                   
               
               
                 Allowed lengths: 8, 10, 12, 14, 15, 17, 18, &amp; 19 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 17P 
               
               
                   
               
               
                 vgDNA encoding the CDR3 elements of the library 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ! CDR3 library components 
               
               
                 (Ctop25) 5′-gctctggtcaa  C|TTA|A Gg|gct|gag|g-3′ (SEQ ID NO: 40) 
               
               
                 (CtprmA) 5′-gctctggtcaa  C|TTA|A Gg|gct|gag|gac- 
               
               
                 !                       AflII... 
               
               
                             |a cc|gct|gtc|tac|tac|tgc|gcc -3′ (SEQ ID NO: 41) 
               
               
                 ! 
               
               
                 (CBprmB)[RC] 5′- |tac|ttc|gat|tac|ttg|ggc|caa|GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′(SEQ ID NO: 42) 
               
               
                 !                                                      BstEII... 
               
               
                 (CBot25)[RC]                             5′- |GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′(SEQ ID NO: 43) 
               
               
                 ! 
               
               
                 ! N.B. [RC] means the the actual oligonucleotide is the reverse complement 
               
               
                 ! of the one shown. 
               
               
                 ! N.B. The 20 bases at 3′ end of CtprmA are identical to the most 5′ 20 bases 
               
               
                 ! of each of the vgDNA molecules. 
               
               
                 ! N.B. Ctop25 is identical to the most 5′ 25 bases of CtprmA. 
               
               
                 ! N.B. The 23 most 3′ bases of CBprmB are the reverse complement of the 
               
               
                 ! most 3′ 23 bases of each of the vgDNA molecules. 
               
               
                 ! N.B. CBot25 is identical to the 25 bases at the 5′ end of CBprmB. 
               
               
                 ! 
               
               
                 (C1t08)   5′- cc|gct|gtc|tac|tac|tgc|gcc| - 
               
               
                                  &lt;2&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;- 
               
               
                                  |tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 44) 
               
               
                 ! 2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C 
               
               
                 ! 
               
               
                 (C2t10)    5′-cc|gct|gtc|tac|tac|tgc|gcc| - 
               
               
                                  &lt;2&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                                 tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 45) 
               
               
                 ! 2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C 
               
               
                 ! 
               
               
                 (C3t12)    5′-cc|gct|gtc|tac|tac|tgc|gcc| - 
               
               
                                  &lt;2&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                                 tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 46) 
               
               
                 ! 2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C 
               
               
                 ! 
               
               
                 (C4t14)   5′- cc|gct|gtc|tac|tac|tgc|gcc|cgt| - 
               
               
                                |&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|tct|&lt;2&gt;|tct|&lt;3&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                               tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 47) 
               
               
                 ! 2 = SG, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C, 3 = YW 
               
               
                 ! 
               
               
                 (C5t15)    5′-cc|gct|gtc|tac|tac|tgc|gcc| - 
               
               
                                   &lt;2&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|tgc|tct|ggt|&lt;1&gt;|&lt;1&gt;|tgc|tat|&lt;1&gt;|- 
               
               
                                 tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 48) 
               
               
                 ! 2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C 
               
               
                 ! 
               
               
                 (C6t17)   5′-cc|gct|gtc|tac|tac|tgc|gcc|- 
               
               
                                 &lt;2&gt;|&lt;1&gt;|&lt;1&gt;|tct|&lt;1&gt;|act|atc|ttc|ggt|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                                tac|ttc|gat|tac|ttg|ggc|caa|GG-3′ (SEQ ID NO: 49) 
               
               
                 ! 2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C 
               
               
                 ! 
               
               
                 (C7t18)   5′-cc|gct|gtc|tac|tac|tgc|gcc|cgt|- 
               
               
                      |&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|tat|tac|&lt;2&gt;|tct|&lt;3&gt;|&lt;3&gt;|tac|tat|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                                tac|ttc|gat|tac|ttg|ggc|caa|GG-3′ (SEQ ID NO: 50) 
               
               
                 ! 2 = DG, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C, 3 = SG 
               
               
                 ! 
               
               
                 (c8t19)   5′-cc|gct|gtc|tac|tac|tgc|gcc|cgt|- 
               
               
                      |&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|tat|tgc|&lt;2&gt;|&lt;2&gt;|&lt;3&gt;|&lt;1&gt;|tgc|tat|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                                tac|ttc|gat|tac|ttg|ggc|caa|GG-3′ (SEQ ID NO: 51) 
               
               
                 ! 2 = SG, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C, 3 = TDG 
               
               
                 ------------------------------------------------------------------------------ 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 19 
               
               
                   
               
               
                 Names of 1398 GeneBank entries examined 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 haj10335 
                 hsa006165 
                 hsa234190 
                 hsa234288 
                 hsa239366 
                 hsa240594 
                 hsa244963 
               
               
                 hs201e3 
                 hsa006167 
                 hsa234191 
                 hsa234290 
                 hsa239367 
                 hsa240595 
                 hsa244965 
               
               
                 hs201g1 
                 hsa006169 
                 hsa234193 
                 hsa234291 
                 hsa239368 
                 hsa240599 
                 hsa244966 
               
               
                 hs201m2 
                 hsa006171 
                 hsa234194 
                 hsa234294 
                 hsa239369 
                 hsa240604 
                 hsa244967 
               
               
                 hs202e2 
                 hsa006173 
                 hsa234196 
                 hsa234296 
                 hsa239370 
                 hsa241344 
                 hsa244968 
               
               
                 hs202g3 
                 hsa131921 
                 hsa234197 
                 hsa234298 
                 hsa239371 
                 hsa241345 
                 hsa244969 
               
               
                 hs202g9 
                 hsa132847 
                 hsa234199 
                 hsa235649 
                 hsa239372 
                 hsa241346 
                 hsa244970 
               
               
                 hs202m3 
                 hsa132849 
                 hsa234202 
                 hsa235658 
                 hsa239373 
                 hsa241347 
                 hsa244971 
               
               
                 hs203e1 
                 hsa132850 
                 hsa234203 
                 hsa235662 
                 hsa239375 
                 hsa241348 
                 hsa244972 
               
               
                 hs203g1 
                 hsa132851 
                 hsa234205 
                 hsa235664 
                 hsa239376 
                 hsa241349 
                 hsa244973 
               
               
                 hs203m5 
                 hsa132852 
                 hsa234206 
                 hsa235665 
                 hsa239377 
                 hsa241350 
                 hsa244974 
               
               
                 hs204e1 
                 hsa224746 
                 hsa234207 
                 hsa235667 
                 hsa239378 
                 hsa241351 
                 hsa244975 
               
               
                 hs204g1 
                 hsa225092 
                 hsa234208 
                 hsa235671 
                 hsa239379 
                 hsa241353 
                 hsa244976 
               
               
                 hs3d6hcv 
                 hsa225093 
                 hsa234209 
                 hsa235675 
                 hsa239380 
                 hsa241354 
                 hsa244977 
               
               
                 hs6d4xa7 
                 hsa230634 
                 hsa234211 
                 hsa235677 
                 hsa239381 
                 hsa241355 
                 hsa244978 
               
               
                 hs6d4xb7 
                 hsa230635 
                 hsa234212 
                 hsa238036 
                 hsa239382 
                 hsa241356 
                 hsa244979 
               
               
                 hs6d4xf1 
                 hsa230636 
                 hsa234214 
                 hsa238037 
                 hsa239383 
                 hsa241357 
                 hsa244980 
               
               
                 hs6d4xf2 
                 hsa230637 
                 hsa234217 
                 hsa238038 
                 hsa239384 
                 hsa241420 
                 hsa244981 
               
               
                 hs6d4xg3 
                 hsa230638 
                 hsa234221 
                 hsa238039 
                 hsa239385 
                 hsa241421 
                 hsa244982 
               
               
                 hs6d4xh5 
                 hsa230639 
                 hsa234224 
                 hsa238040 
                 hsa239386 
                 hsa242555 
                 hsa244983 
               
               
                 hs83x6b2 
                 hsa230640 
                 hsa234227 
                 hsa238326 
                 hsa239387 
                 hsa242556 
                 hsa244984 
               
               
                 hs83x6b5 
                 hsa230641 
                 hsa234229 
                 hsa238327 
                 hsa239388 
                 hsa243108 
                 hsa244985 
               
               
                 hs83x6c3 
                 hsa230643 
                 hsa234230 
                 hsa238328 
                 hsa239390 
                 hsa243110 
                 hsa244986 
               
               
                 hs83x6c4 
                 hsa230644 
                 hsa234232 
                 hsa239330 
                 hsa239391 
                 hsa244928 
                 hsa244987 
               
               
                 hs83x6c5 
                 hsa230645 
                 hsa234235 
                 hsa239331 
                 hsa240553 
                 hsa244929 
                 hsa244988 
               
               
                 hs83x6d4 
                 hsa230646 
                 hsa234238 
                 hsa239332 
                 hsa240554 
                 hsa244930 
                 hsa244989 
               
               
                 hs83x6f1 
                 hsa230647 
                 hsa234239 
                 hsa239333 
                 hsa240555 
                 hsa244931 
                 hsa244990 
               
               
                 hs83x6f2 
                 hsa230648 
                 hsa234242 
                 hsa239334 
                 hsa240556 
                 hsa244932 
                 hsa244991 
               
               
                 hs83x6f3 
                 hsa230649 
                 hsa234245 
                 hsa239335 
                 hsa240557 
                 hsa244933 
                 hsa244992 
               
               
                 hs83x6f5 
                 hsa230650 
                 hsa234248 
                 hsa239336 
                 hsa240558 
                 hsa244934 
                 hsa244993 
               
               
                 hs83x6h3 
                 hsa230651 
                 hsa234249 
                 hsa239337 
                 hsa240559 
                 hsa244935 
                 hsa244994 
               
               
                 hs83x9a6 
                 hsa230652 
                 hsa234251 
                 hsa239338 
                 hsa240560 
                 hsa244936 
                 hsa244995 
               
               
                 hs83x9b6 
                 hsa230653 
                 hsa234252 
                 hsa239339 
                 hsa240561 
                 hsa244937 
                 hsa244996 
               
               
                 hs83x9b9 
                 hsa230654 
                 hsa234255 
                 hsa239340 
                 hsa240562 
                 hsa244938 
                 hsa244997 
               
               
                 hs83x9c8 
                 hsa230655 
                 hsa234256 
                 hsa239341 
                 hsa240563 
                 hsa244939 
                 hsa244998 
               
               
                 hs83x9d6 
                 hsa230656 
                 hsa234257 
                 hsa239342 
                 hsa240564 
                 hsa244940 
                 hsa244999 
               
               
                 hs83x9d7 
                 hsa230657 
                 hsa234258 
                 hsa239343 
                 hsa240565 
                 hsa244941 
                 hsa245000 
               
               
                 hs83x9e6 
                 hsa230658 
                 hsa234259 
                 hsa239344 
                 hsa240566 
                 hsa244942 
                 hsa245001 
               
               
                 hs83x9e8 
                 hsa234156 
                 hsa234260 
                 hsa239345 
                 hsa240567 
                 hsa244943 
                 hsa245002 
               
               
                 hs83x9e9 
                 hsa234158 
                 hsa234262 
                 hsa239346 
                 hsa240568 
                 hsa244944 
                 hsa245003 
               
               
                 hs83x9f6 
                 hsa234160 
                 hsa234263 
                 hsa239347 
                 hsa240569 
                 hsa244945 
                 hsa245004 
               
               
                 hs83x9g6 
                 hsa234161 
                 hsa234264 
                 hsa239348 
                 hsa240570 
                 hsa244946 
                 hsa245005 
               
               
                 hs9d4x10 
                 hsa234163 
                 hsa234266 
                 hsa239349 
                 hsa240571 
                 hsa244947 
                 hsa245006 
               
               
                 hs9d4x7 
                 hsa234164 
                 hsa234268 
                 hsa239350 
                 hsa240572 
                 hsa244948 
                 hsa245007 
               
               
                 hs9d4x8 
                 hsa234166 
                 hsa234269 
                 hsa239351 
                 hsa240573 
                 hsa244949 
                 hsa245008 
               
               
                 hs9d4x9 
                 hsa234168 
                 hsa234270 
                 hsa239353 
                 hsa240575 
                 hsa244950 
                 hsa245009 
               
               
                 hs9d4xa6 
                 hsa234169 
                 hsa234272 
                 hsa239354 
                 hsa240576 
                 hsa244951 
                 hsa245010 
               
               
                 hs9d4xa7 
                 hsa234171 
                 hsa234273 
                 hsa239355 
                 hsa240578 
                 hsa244952 
                 hsa245011 
               
               
                 hs9d4xb6 
                 hsa234172 
                 hsa234274 
                 hsa239356 
                 hsa240580 
                 hsa244953 
                 hsa245012 
               
               
                 hs9d4xc2 
                 hsa234175 
                 hsa234276 
                 hsa239357 
                 hsa240581 
                 hsa244954 
                 hsa245013 
               
               
                 hs9d4xd6 
                 hsa234178 
                 hsa234277 
                 hsa239358 
                 hsa240582 
                 hsa244955 
                 hsa245014 
               
               
                 hs9d4xe6 
                 hsa234180 
                 hsa234279 
                 hsa239359 
                 hsa240585 
                 hsa244956 
                 hsa245015 
               
               
                 hs9d4xf3 
                 hsa234181 
                 hsa234281 
                 hsa239360 
                 hsa240586 
                 hsa244957 
                 hsa245016 
               
               
                 hs9d4xh4 
                 hsa234183 
                 hsa234282 
                 hsa239361 
                 hsa240588 
                 hsa244958 
                 hsa245017 
               
               
                 hs9d4xh5 
                 hsa234184 
                 hsa234283 
                 hsa239362 
                 hsa240589 
                 hsa244959 
                 hsa245018 
               
               
                 hsa005975 
                 hsa234186 
                 hsa234284 
                 hsa239363 
                 hsa240590 
                 hsa244960 
                 hsa245019 
               
               
                 hsa005977 
                 hsa234187 
                 hsa234286 
                 hsa239364 
                 hsa240592 
                 hsa244961 
                 hsa245020 
               
               
                 hsa006161 
                 hsa234189 
                 hsa234287 
                 hsa239365 
                 hsa240593 
                 hsa244962 
                 hsa245021 
               
               
                 hsa245022 
                 hsa245217 
                 hsa245305 
                 hsa279524 
                 hsabhiv8 
                 hsb8g2g08 
                 hsevh52a1 
               
               
                 hsa245023 
                 hsa245218 
                 hsa245307 
                 hsa279526 
                 hsadeigvh 
                 hsb8g3b07 
                 hsevh52a2 
               
               
                 hsa245024 
                 hsa245219 
                 hsa245309 
                 hsa279527 
                 hsaj2768 
                 hsb8g3c07 
                 hsevh52a3 
               
               
                 hsa245025 
                 hsa245220 
                 hsa245311 
                 hsa279528 
                 hsaj2769 
                 hsb8g3c08 
                 hsevh52a4 
               
               
                 hsa245026 
                 hsa245221 
                 hsa245312 
                 hsa279529 
                 hsaj2771 
                 hsb8g3c12 
                 hsevh52a5 
               
               
                 hsa245027 
                 hsa245222 
                 hsa245313 
                 hsa279530 
                 hsaj2772 
                 hsb8g3d03 
                 hsevh52b1 
               
               
                 hsa245028 
                 hsa245223 
                 hsa245315 
                 hsa279531 
                 hsaj2773 
                 hsb8g3d04 
                 hsevh53a1 
               
               
                 hsa245029 
                 hsa245224 
                 hsa245317 
                 hsa279532 
                 hsaj2776 
                 hsb8g3d07 
                 hsevh53a2 
               
               
                 hsa245030 
                 hsa245225 
                 hsa245318 
                 hsa279533 
                 hsaj2777 
                 hsb8g3d08 
                 hsfog1h 
               
               
                 hsa245031 
                 hsa245226 
                 hsa245319 
                 hsa279535 
                 hsaj4083 
                 hsb8g3e02 
                 hsfog3h 
               
               
                 hsa245032 
                 hsa245228 
                 hsa245320 
                 hsa279536 
                 hsaj4899 
                 hsb8g3e03 
                 hsfogbh 
               
               
                 hsa245033 
                 hsa245229 
                 hsa245321 
                 hsa279537 
                 hsasighc 
                 hsb8g3f03 
                 hsfom1h 
               
               
                 hsa245034 
                 hsa245230 
                 hsa245322 
                 hsa279543 
                 hsavh510 
                 hsb8g3g01 
                 hsfs10hc 
               
               
                 hsa245035 
                 hsa245231 
                 hsa245323 
                 hsa279544 
                 hsavh512 
                 hsb8g3g03 
                 hsfs11hc 
               
               
                 hsa245036 
                 hsa245232 
                 hsa245325 
                 hsa279545 
                 hsavh513 
                 hsb8g3g05 
                 hsfs9whc 
               
               
                 hsa245037 
                 hsa245233 
                 hsa245326 
                 hsa279552 
                 hsavh514 
                 hsb8g3g10 
                 hsgad2h 
               
               
                 hsa245039 
                 hsa245234 
                 hsa245338 
                 hsa389169 
                 hsavh515 
                 hsb8g3h01 
                 hsgvh0117 
               
               
                 hsa245040 
                 hsa245235 
                 hsa245342 
                 hsa389170 
                 hsavh516 
                 hsb8g4c02 
                 hsgvh0118 
               
               
                 hsa245041 
                 hsa245236 
                 hsa245343 
                 hsa389171 
                 hsavh517 
                 hsb8g4e01 
                 hsgvh0119 
               
               
                 hsa245042 
                 hsa245237 
                 hsa245345 
                 hsa389172 
                 hsavh519 
                 hsb8g4e05 
                 hsgvh0120 
               
               
                 hsa245043 
                 hsa245238 
                 hsa245346 
                 hsa389173 
                 hsavh520 
                 hsb8g4f11 
                 hsgvh0121 
               
               
                 hsa245044 
                 hsa245239 
                 hsa245347 
                 hsa389174 
                 hsavh523 
                 hsb8g4h09 
                 hsgvh0122 
               
               
                 hsa245045 
                 hsa245240 
                 hsa245348 
                 hsa389175 
                 hsavh524 
                 hsb8g4h10 
                 hsgvh0123 
               
               
                 hsa245046 
                 hsa245241 
                 hsa245349 
                 hsa389176 
                 hsavh526 
                 hsb8g5d10 
                 hsgvh0124 
               
               
                 hsa245047 
                 hsa245246 
                 hsa245350 
                 hsa389177 
                 hsavh529 
                 hsb8g5h08 
                 hsgvh0201 
               
               
                 hsa245048 
                 hsa245251 
                 hsa245352 
                 hsa389178 
                 hsavh53 
                 hsbel1 
                 hsgvh0202 
               
               
                 hsa245049 
                 hsa245255 
                 hsa245353 
                 hsa389179 
                 hsavh56 
                 hsbel14 
                 hsgvh0203 
               
               
                 hsa245050 
                 hsa245258 
                 hsa245355 
                 hsa389180 
                 hsb3g4a07 
                 hsbel28 
                 hsgvh0204 
               
               
                 hsa245051 
                 hsa245260 
                 hsa245356 
                 hsa389181 
                 hsb73g04n 
                 hsbel29 
                 hsgvh0205 
               
               
                 hsa245052 
                 hsa245261 
                 hsa245357 
                 hsa389182 
                 hsb74a08n 
                 hsbel3 
                 hsgvh0206 
               
               
                 hsa245053 
                 hsa245262 
                 hsa245358 
                 hsa389183 
                 hsb7g1a11 
                 hsbel34 
                 hsgvh0207 
               
               
                 hsa245054 
                 hsa245263 
                 hsa245359 
                 hsa389184 
                 hsb7g2b01 
                 hsbel43 
                 hsgvh0208 
               
               
                 hsa245055 
                 hsa245265 
                 hsa249378 
                 hsa389185 
                 hsb7g3a01 
                 hsbel45 
                 hsgvh0209 
               
               
                 hsa245056 
                 hsa245266 
                 hsa249628 
                 hsa389186 
                 hsb7g3a05 
                 hsbel5 
                 hsgvh0210 
               
               
                 hsa245057 
                 hsa245268 
                 hsa249629 
                 hsa389187 
                 hsb7g3a10 
                 bsbel54 
                 hsgvh0211 
               
               
                 hsa245058 
                 hsa245272 
                 hsa249630 
                 hsa389188 
                 hsb7g3b02 
                 bsbel69 
                 hsgvh0213 
               
               
                 hsa245059 
                 hsa245273 
                 hsa249631 
                 hsa389190 
                 hsb7g3b03 
                 hsbo1vhig 
                 hsgvh0214 
               
               
                 hsa245060 
                 hsa245275 
                 hsa249632 
                 hsa389191 
                 hsb7g3b05 
                 hsbo3vhig 
                 hsgvh0215 
               
               
                 hsa245061 
                 hsa245277 
                 hsa249633 
                 hsa389192 
                 hsb7g3c03 
                 hsbr1vhig 
                 hsgvh0216 
               
               
                 hsa245062 
                 hsa245278 
                 hsa249634 
                 hsa389193 
                 hsb7g3c12 
                 hsbradh3 
                 hsgvh0217 
               
               
                 hsa245063 
                 hsa245279 
                 hsa249635 
                 hsa389194 
                 hsb7g3d07 
                 hscal4ghc 
                 hsgvh0218 
               
               
                 hsa245064 
                 hsa245280 
                 hsa249636 
                 hsa389195 
                 hsb7g3e01 
                 hsd4xd10 
                 hsgvh0219 
               
               
                 hsa245065 
                 hsa245281 
                 hsa249637 
                 hsa389927 
                 hsb7g3f02 
                 hsd4xf21 
                 hsgvh0220 
               
               
                 hsa245066 
                 hsa245282 
                 hsa271600 
                 hsa389929 
                 hsb7g3f10 
                 hsd4xg2 
                 hsgvh0221 
               
               
                 hsa245067 
                 hsa245283 
                 hsa271601 
                 hsa6351 
                 hsb7g3g02 
                 hsd4xi10 
                 hsgvh0222 
               
               
                 hsa245068 
                 hsa245284 
                 hsa271602 
                 hsa7321 
                 hsb7g3g04 
                 hsd4xi4 
                 hsgvh0223 
               
               
                 hsa245069 
                 hsa245285 
                 hsa271603 
                 hsa7322 
                 hsb7g4a08 
                 hsd4xk9 
                 hsgvh0224 
               
               
                 hsa245071 
                 hsa245286 
                 hsa271604 
                 hsa7323 
                 hsb7g4c05 
                 hsd4xl3 
                 hsgvh0302 
               
               
                 hsa245072 
                 hsa245287 
                 hsa279513 
                 hsa7325 
                 hsb7g4d09 
                 hsd5hc 
                 hsgvh0304 
               
               
                 hsa245073 
                 hsa245288 
                 hsa279514 
                 hsa7326 
                 hsb7g4f08 
                 hsdo1vhig 
                 hsgvh0306 
               
               
                 hsa245201 
                 hsa245289 
                 hsa279515 
                 hsa7328 
                 hsb7g4g07 
                 hseliepa1 
                 hsgvh0307 
               
               
                 hsa245203 
                 hsa245290 
                 hsa279516 
                 hsa7438 
                 hsb7g5g03 
                 hseliepa3 
                 hsgvh0308 
               
               
                 hsa245204 
                 hsa245291 
                 hsa279517 
                 hsa7440 
                 hsb8g1c04 
                 hseliepa4 
                 hsgvh0309 
               
               
                 hsa245208 
                 hsa245292 
                 hsa279519 
                 hsa7441 
                 hsb8g1e04 
                 hseliepb2 
                 hsgvh0310 
               
               
                 hsa245209 
                 hsa245294 
                 hsa279520 
                 hsa7442 
                 hsb8g1f03 
                 hseliepd2 
                 hsgvh0311 
               
               
                 hsa245210 
                 hsa245298 
                 hsa279521 
                 hsa7443 
                 hsb8g1g04 
                 hselilpb1 
                 hsgvh0312 
               
               
                 hsa245214 
                 hsa245299 
                 hsa279522 
                 hsa7444 
                 hsb8g1h02 
                 hsevh51a1 
                 hsgvh0314 
               
               
                 hsa245215 
                 hsa245301 
                 hsa279523 
                 hsaarma1 
                 hsb8g2f09 
                 hsevh51b1 
                 hsgvh0315 
               
               
                 hsgvh0318 
                 hsig001vh 
                 hsighpat5 
                 hsigvhc07 
                 hsimghc1 
                 hsmvh0401 
                 hsrou233 
               
               
                 hsgvh0320 
                 hsig030vh 
                 hsighpat6 
                 hsigvhc08 
                 hsimghc2 
                 hsmvh0403 
                 hsrt792hc 
               
               
                 hsgvh0321 
                 hsig033vh 
                 hsighpat7 
                 hsigvhc09 
                 hsimghc3 
                 hsmvh0404 
                 hsrt79hc 
               
               
                 hsgvh0322 
                 hsig039vh 
                 hsighpat8 
                 hsigvhc10 
                 hsimghc4 
                 hsmvh0405 
                 hssm1vhig 
               
               
                 hsgvh0323 
                 hsig040vh 
                 hsighpat9 
                 hsigvhc11 
                 hsimghcS 
                 hsmvh0406 
                 hssp46a 
               
               
                 hsgvh0324 
                 hsig055vh 
                 hsighpt11 
                 hsigvhc12 
                 hsin42p5 
                 hsmvh0501 
                 hst14vh 
               
               
                 hsgvh0325 
                 hsig057vh 
                 hsighpt12 
                 hsigvhc14 
                 hsin51p7 
                 hsmvh0502 
                 hst14x1 
               
               
                 hsgvh0326 
                 hsig1059 
                 hsighpta1 
                 hsigvhc16 
                 hsin51p8 
                 hsmvh0503 
                 hst14x10 
               
               
                 hsgvh0327 
                 hsig10610 
                 hsighvb5 
                 hsigvhc17 
                 hsin78 
                 hsmvh0504 
                 hst14x11 
               
               
                 hsgvh0328 
                 hsig13g10 
                 hsighvca 
                 hsigvhc18 
                 hsin87 
                 hsmvh0505 
                 hst14x12 
               
               
                 hsgvh0329 
                 hsig473 
                 hsighvcb 
                 hsigvhc19 
                 hsin89p2 
                 hsmvh0506 
                 hst14x13 
               
               
                 hsgvh0330 
                 hsig7sa11 
                 hsighvcc 
                 hsigvhc20 
                 hsin92 
                 hsmvh0507 
                 hst14x14 
               
               
                 hsgvh0331 
                 hsigaehc 
                 hsighvcd 
                 hsigvhc21 
                 hsin98p1 
                 hsmvh0508 
                 hst14x15 
               
               
                 hsgvh0332 
                 hsigaf2h2 
                 hsighvce 
                 hsigvhc22 
                 hsjac10h 
                 hsmvh0509 
                 hst14x16 
               
               
                 hsgvh0333 
                 hsigashc 
                 hsighvm 
                 hsigvhc23 
                 hsjhba1f 
                 hsmvh0510 
                 hst14x17 
               
               
                 hsgvh0334 
                 hsigathc 
                 hsighxx1 
                 hsigvhc24 
                 hsjhbr2f 
                 hsmvh0511 
                 hst14x18 
               
               
                 hsgvh0335 
                 hsigdvrhc 
                 hsighxx10 
                 hsigvhc25 
                 hsjhej1f 
                 hsmvh0513 
                 hst14x19 
               
               
                 hsgvh0336 
                 hsigg1kh 
                 hsighxx11 
                 hsigvhc26 
                 hsld1110 
                 hsmvh0515 
                 hst14x20 
               
               
                 hsgvh0419 
                 hsigg1kl 
                 hsighxx12 
                 hsigvhc27 
                 hsld1117 
                 hsmvh0529 
                 hst14x21 
               
               
                 hsgvh0420 
                 hsigg1lh 
                 hsighxx14 
                 hsigvhc28 
                 hsld152 
                 hsmvh51 
                 hst14x22 
               
               
                 hsgvh0421 
                 hsigghc85 
                 hsighxx16 
                 hsigvhc29 
                 hsld21 
                 hsmvh510 
                 hst14x23 
               
               
                 hsgvh0422 
                 hsigghcv3 
                 hsighxx18 
                 hsigvhc30 
                 hsld217 
                 hsmvh511 
                 hst14x24 
               
               
                 hsgvh0423 
                 hsigghevr 
                 hsighxx2 
                 hsigvhc31 
                 hsld218 
                 hsmvh512 
                 hst14x25 
               
               
                 hsgvh0424 
                 hsiggvdj1 
                 hsighxx20 
                 hsigvhc32 
                 hsld25 
                 hsmvh515 
                 hst14x3 
               
               
                 hsgvh0428 
                 hsiggvdj2 
                 hsighxx21 
                 hsigvhc33 
                 hsmad2h 
                 hsmvh516 
                 hst14x6 
               
               
                 hsgvh0429 
                 hsiggvhb 
                 hsighxx22 
                 hsigvhc35 
                 hsmbcl5h4 
                 hsmvh517 
                 hst14x7 
               
               
                 hsgvh0430 
                 hsiggvhc 
                 hsighxx23 
                 hsigvhc36 
                 hsmica1h 
                 hsmvh53 
                 hst14x8 
               
               
                 hsgvh0517 
                 hsigh10g1 
                 hsighxx25 
                 hsigvhc37 
                 hsmica3h 
                 hsmvh54 
                 hst14x9 
               
               
                 hsgvh0519 
                 hsigh10g2 
                 hsighxx26 
                 hsigvhc38 
                 hsmica4h 
                 hsmvh55 
                 hst22x1 
               
               
                 hsgvh0522 
                 hsigh10g3 
                 hsighxx28 
                 hsigvhc39 
                 hsmica5h 
                 hsmvh56 
                 hst22x11 
               
               
                 hsgvh0523 
                 hsigh10g4 
                 hsighxx29 
                 hsigvhc40 
                 hsmica6h 
                 hsmvh57 
                 hst22x12 
               
               
                 hsgvh0526 
                 hsigh10g5 
                 hsighxx3 
                 hsigvhc41 
                 hsmica7h 
                 hsmvh58 
                 hst22x13 
               
               
                 hsgvh0527 
                 hsigh10g7 
                 hsighxx30 
                 hsigvhc42 
                 hsmt11ige 
                 hsmvh59 
                 hst22x14 
               
               
                 hsgvh0531 
                 hsigh10g8 
                 hsighxx31 
                 hsigvhc43 
                 hsmt12ige 
                 hsnamembo 
                 hst22x15 
               
               
                 hsgvh511 
                 hsigh10g9 
                 hsighxx32 
                 hsigvhls 
                 hsmt13ige 
                 hsnpb346e 
                 hst22x18 
               
               
                 hsgvh512 
                 hsigh13g1 
                 hsighxx34 
                 hsigvhttd 
                 hsmt14ige 
                 hsoak3h 
                 hst22x20 
               
               
                 hsgvh513 
                 hsigh13g7 
                 hsighxx36 
                 hsigvp151 
                 hsmt15ige 
                 hsog31h 
                 hst22x21 
               
               
                 hsgvh515 
                 hsigh14g1 
                 hsighxx37 
                 hsigvp152 
                 hsmt16ige 
                 hspag1h 
                 hst22x22 
               
               
                 hsgvh519 
                 hsigh14g2 
                 hsighxx38 
                 hsigvp153 
                 hsmt17ige 
                 hsrael 
                 hst22x23 
               
               
                 hsgvh521 
                 hsigh2f2 
                 hsighxx5 
                 hsigvp154 
                 hsmt21ige 
                 hsregah 
                 hst22x25 
               
               
                 hsgvh526 
                 hsigh3135 
                 hsighxx6 
                 hsigvp155 
                 hsmt22ige 
                 hsrfabh37 
                 hst22x26 
               
               
                 hsgvh530 
                 hsigh35 
                 hsighxx7 
                 hsigvp156 
                 hsmt23ige 
                 hsrighvja 
                 hst22x27 
               
               
                 hsgvh533 
                 hsigh44 
                 hsighxx8 
                 hsigvp157 
                 hsmt24ige 
                 hsrighvjb 
                 hst22x28 
               
               
                 hsgvh534 
                 hsigh4c2 
                 hsighxx9 
                 hsigvp158 
                 hsmt25ige 
                 hsrou10 
                 hst22x30 
               
               
                 hsgvh535 
                 hsigh9e1 
                 hsigkrf 
                 hsigvp251 
                 hsmt26ige 
                 hsrou11 
                 hst22x9 
               
               
                 hsgvh536 
                 hsighadi2 
                 hsigmhavh 
                 hsigvp255 
                 hsmt27ige 
                 hsrou111 
                 hsu24687 
               
               
                 hsgvh55 
                 hsighadi3 
                 hsigrhe15 
                 hsigvp256 
                 hsmutuiem 
                 hsrou112 
                 hsu24688 
               
               
                 hsh217e 
                 hsighcvr 
                 hsigtgk1h 
                 hsigvp257 
                 hsmvh0001 
                 hsrou119 
                 hsu24690 
               
               
                 hsh241e 
                 hsighcza 
                 hsigtgk4h 
                 hsigvp360 
                 hsmvh0002 
                 hsrou122 
                 hsu24691 
               
               
                 hsh28e 
                 hsighczb 
                 hsigtgl9h 
                 hsigvp363 
                 hsmvh0003 
                 hsrou126 
                 hsv52a512 
               
               
                 hsha3d1ig 
                 hsighczc 
                 hsigvarh1 
                 hsigvp369 
                 hsmvh0004 
                 hsrou127 
                 hsvdj10h 
               
               
                 hshambh 
                 hsighczd 
                 hsigvhc 
                 hsigvp39 
                 hsmvh0005 
                 hsrou129 
                 hsvdj12h 
               
               
                 hshcmg42 
                 hsighczf 
                 hsigvhc01 
                 hsihr8 
                 hsmvh0006 
                 hsrou13 
                 hsvgcg1 
               
               
                 hshcmg43 
                 hsighczg 
                 hsigvhc02 
                 hsihr9 
                 hsmvh0007 
                 hsrou131 
                 hsvgcm1 
               
               
                 hshcmg44 
                 hsigheavy 
                 hsigvhc03 
                 hsihv1 
                 hsmvh0009 
                 hsrou18 
                 hsvgcm2 
               
               
                 hshcmg46 
                 hsighpat2 
                 hsigvhc04 
                 hsihv11 
                 hsmvh0010 
                 hsrou219 
                 hsvh1djh6 
               
               
                 hshcmt42 
                 hsighpat3 
                 hsigvhc05 
                 hsihv18 
                 hsmvh0011 
                 hsrou221 
                 hsvh3djh4 
               
               
                 hshcmt47 
                 hsighpat4 
                 hsigvhc06 
                 hsim9vch 
                 hsmvh0012 
                 hsrou222 
                 hsvh4dj 
               
               
                 hsvh4djh6 
                 hsvhic11 
                 hsww1p10e 
                 hsy14935 
                 hsz80377 
                 hsz80424 
                 hsz80482 
               
               
                 hsvh4r 
                 hsvhic2 
                 hsx98932 
                 hsy14936 
                 hsz80378 
                 hsz80426 
                 hsz80483 
               
               
                 hsvh52a43 
                 hsvhic3 
                 hsx98933 
                 hsy14937 
                 hsz80383 
                 hsz80427 
                 hsz80487 
               
               
                 hsvh52a55 
                 hsvhid1 
                 hsx98934 
                 hsy14938 
                 hsz80385 
                 hsz80429 
                 hsz80489 
               
               
                 hsvh5dj 
                 hsvhid5 
                 hsx98935 
                 hsy14939 
                 hsz80386 
                 hsz80433 
                 hsz80492 
               
               
                 hsvh5djh5 
                 hsvhid7 
                 hsx98936 
                 hsy14940 
                 hsz80388 
                 hsz80436 
                 hsz80495 
               
               
                 hsvh710p1 
                 hsvhid9 
                 hsx98938 
                 hsy14943 
                 hsz80390 
                 hsz80438 
                 hsz80496 
               
               
                 hsvheg7 
                 hsvhie4 
                 hsx98939 
                 hsy14945 
                 hsz80391 
                 hsz80439 
                 hsz80499 
               
               
                 hsvhfa2 
                 hsvhif10 
                 hsx98940 
                 hsy18120 
                 hsz80392 
                 hsz80441 
                 hsz80500 
               
               
                 hsvhfa7 
                 hsvhif3 
                 hsx98941 
                 hsz74663 
                 hsz80393 
                 hsz80442 
                 hsz80502 
               
               
                 hsvhfb5 
                 hsvhif7 
                 hsx98943 
                 hsz74665 
                 hsz80394 
                 hsz80443 
                 hsz80504 
               
               
                 hsvhfc2 
                 hsvhig2 
                 hsx98944 
                 hsz74668 
                 hsz80397 
                 hsz80445 
                 hsz80507 
               
               
                 hsvhfd7 
                 hsvhp2 
                 hsx98945 
                 hsz74671 
                 hsz80400 
                 hsz80458 
                 hsz80509 
               
               
                 hsvhfe5 
                 hsvhp29 
                 hsx98946 
                 hsz74672 
                 hsz80403 
                 hsz80459 
                 hsz80512 
               
               
                 hsvhfg9 
                 hsvhp30 
                 hsx98947 
                 hsz74682 
                 hsz80406 
                 hsz80460 
                 hsz80513 
               
               
                 hsvhgd8 
                 hsvhp32 
                 hsx98948 
                 hsz74688 
                 hsz80407 
                 hsz80461 
                 hsz80517 
               
               
                 hsvhgd9 
                 hsvhp34 
                 hsx98950 
                 hsz74690 
                 hsz80409 
                 hsz80462 
                 hsz80519 
               
               
                 hsvhgh7 
                 hsvhp4 
                 hsx98951 
                 hsz74693 
                 hsz80411 
                 hsz80463 
                 hsz80520 
               
               
                 hsvhha10 
                 hsvhp46 
                 hsx98952 
                 hsz74695 
                 hsz80412 
                 hsz80465 
                 hsz80527 
               
               
                 hsvhia2 
                 hsvhp48 
                 hsx98953 
                 hsz80363 
                 hsz80414 
                 hsz80466 
                 hsz80534 
               
               
                 hsvhia5 
                 hsvhp53 
                 hsx98954 
                 hsz80364 
                 hsz80415 
                 hsz80473 
                 hsz80538 
               
               
                 hsvhib12 
                 hsvhp7 
                 hsx98955 
                 hsz80365 
                 hsz80416 
                 hsz80474 
                 hsz80544 
               
               
                 hsvhib6 
                 hsvigd9 
                 hsx98956 
                 hsz80367 
                 hsz80417 
                 hsz80475 
                 hsz80545 
               
               
                 hsvhib8 
                 hswad35vh 
                 hsx98958 
                 hsz80368 
                 hsz80418 
                 hsz80476 
                   
               
               
                 hsvhic1 
                 hswanembo 
                 hsx98963 
                 hsz80372 
                 hsz80421 
                 hsz80477 
                   
               
               
                 hsvhic10 
                 hswo1vhig 
                 hsy14934 
                 hsz80375 
                 hsz80422 
                 hsz80480 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 20P 
               
               
                   
               
             
             
               
                 Human GLG CDR1 &amp; CDR2 AA seqs 
               
             
          
           
               
                   
                 CDR1 
                   
                          1    1   1 
                   
               
               
                 Name 
                 1234567 
                 CDR2 
                 1234567890123456789 
               
               
                   
               
               
                 1-02 
                 GYY-MH 
                 (SEQ ID NO: 230) 
                 WINPNSGG--TNYAQKFQG 
                 (SEQ ID NO: 231) 
               
               
                 1-03 
                 SYA--MH 
                 (SEQ ID NO: 232) 
                 WINAGNGN--TKYSQKFQG 
                 (SEQ ID NO: 233) 
               
               
                 1-08 
                 SYD--IN 
                 (SEQ ID NO: 234) 
                 WMNPNSGN--TGYAQKFQG 
                 (SEQ ID NO: 235) 
               
               
                 1-18 
                 SYG--IS 
                 (SEQ ID NO: 236) 
                 WISAYNGN--TNYAQKLQG 
                 (SEQ ID NO: 237) 
               
               
                 1-24 
                 ELS--MH 
                 (SEQ ID NO: 238) 
                 GFDPEDGE--TIYAQKFQG 
                 (SEQ ID NO: 239) 
               
               
                 1-45 
                 YRY--LH 
                 (SEQ ID NO: 240) 
                 WITPFNGN--TNYAQKFQD 
                 (SEQ ID NO: 241) 
               
               
                 1-46 
                 SYY--MH 
                 (SEQ ID NO: 242) 
                 IINPSGGS--TSYAQKFQG 
                 (SEQ ID NO: 243) 
               
               
                 1-58 
                 SSA--VQ 
                 (SEQ ID NO: 244) 
                 WIVVGSGN--TNYAQKFQE 
                 (SEQ ID NO: 245) 
               
               
                 1-69 
                 SYA--IS 
                 (SEQ ID NO: 246) 
                 GIIPIFGT--ANYAQKFQG 
                 (SEQ ID NO: 247) 
               
               
                 1-e 
                 SYA--IS 
                 (SEQ ID NO: 248) 
                 GIIPIFGT--ANYAQKFQG 
                 (SEQ ID NO: 249) 
               
               
                 1-f 
                 DYY--MH 
                 (SEQ ID NO: 250) 
                 LVDPEDGE--TIYAEKFQG 
                 (SEQ ID NO: 251) 
               
               
                 2-05 
                 TSGVGVG 
                 (SEQ ID NO: 252) 
                 LIYWNDDK---RYSPSLKS 
                 (SEQ ID NO: 253) 
               
               
                 2-26 
                 NARMGVS 
                 (SEQ ID NO: 254) 
                 HIFSNDEK---SYSTSLKS 
                 (SEQ ID NO: 255) 
               
               
                 2-70 
                 TSGMRVS 
                 (SEQ ID NO: 256) 
                 RIDWDDDK---FYSTSLKT 
                 (SEQ ID NO: 257) 
               
               
                 3-07 
                 SYW--MS 
                 (SEQ ID NO: 258) 
                 NIKQDGSE--KYYVDSVKG 
                 (SEQ ID NO: 259) 
               
               
                 3-09 
                 DYA--MH 
                 (SEQ ID NO: 260) 
                 GISWNSGS--IGYADSVKG 
                 (SEQ ID NO: 261) 
               
               
                 3-11 
                 DYY--MS 
                 (SEQ ID NO: 262) 
                 YISSSGST--IYYADSVKG 
                 (SEQ ID NO: 263) 
               
               
                 3-13 
                 SYD--MH 
                 (SEQ ID NO: 264) 
                 AIGTAGD---TYYPGSVKG 
                 (SEQ ID NO: 265) 
               
               
                 3-15 
                 NAW--MS 
                 (SEQ ID NO: 266) 
                 RIKSKTDGGTTDYAAPVKG 
                 (SEQ ID NO: 267) 
               
               
                 3-20 
                 DYG--MS 
                 (SEQ ID NO: 268) 
                 GINWNGGS--TGYADSVKG 
                 (SEQ ID NO: 269) 
               
               
                 3-21 
                 SYS--MN 
                 (SEQ ID NO: 270) 
                 SISSSSSY--IYYADSVKG 
                 (SEQ ID NO: 271) 
               
               
                 3-23 
                 SYA--MS 
                 (SEQ ID NO: 272) 
                 AISGSGGS--TYYADSVKG 
                 (SEQ ID NO: 273) 
               
               
                 3-30 
                 SYG--MH 
                 (SEQ ID NO: 274) 
                 VISYDGSN--KYYADSVKG 
                 (SEQ ID NO: 275) 
               
               
                 3303 
                 SYA--MH 
                 (SEQ ID NO: 276) 
                 VISYDGSN--KYYADSVKG 
                 (SEQ ID NO: 277) 
               
               
                 3305 
                 SYG--MH 
                 (SEQ ID NO: 278) 
                 VISYDGSN--KYYADSVKG 
                 (SEQ ID NO: 279) 
               
               
                 3-33 
                 SYG--MH 
                 (SEQ ID NO: 280) 
                 VIWYDGSN--KYYADSVKG 
                 (SEQ ID NO: 281) 
               
               
                 3-43 
                 DYT--MH 
                 (SEQ ID NO: 282) 
                 LISWDGGS--TYYADSVKG 
                 (SEQ ID NO: 283) 
               
               
                 3-48 
                 SYS--MN 
                 (SEQ ID NO: 284) 
                 YISSSSST--IYYADSVKG 
                 (SEQ ID NO: 285) 
               
               
                 3-49 
                 DYA--MS 
                 (SEQ ID NO: 286) 
                 FIRSKAYGGTTEYTASVKG 
                 (SEQ ID NO: 287) 
               
               
                 3-53 
                 SNY--MS 
                 (SEQ ID NO: 288) 
                 VIYSGGS---TYYADSVKG 
                 (SEQ ID NO: 289) 
               
               
                 3-64 
                 SYA--MH 
                 (SEQ ID NO: 290) 
                 AISSNGGS--TYYANSVKG 
                 (SEQ ID NO: 291) 
               
               
                 3-66 
                 SNY--MS 
                 (SEQ ID NO: 292) 
                 VIYSGGS---TYYADSVKG 
                 (SEQ ID NO: 293) 
               
               
                 3-72 
                 DHY--MD 
                 (SEQ ID NO: 294) 
                 RTRNKANSYTTEYAASVKG 
                 (SEQ ID NO: 295) 
               
               
                 3-73 
                 GSA--MH 
                 (SEQ ID NO: 296) 
                 RIRSKANSYATAYAASVKG 
                 (SEQ ID NO: 297) 
               
               
                 3-74 
                 SYW--MH 
                 (SEQ ID NO: 298) 
                 RINSDGSS--TSYADSVKG 
                 (SEQ ID NO: 299) 
               
               
                 3-d 
                 SNE--MS 
                 (SEQ ID NO: 300) 
                 SISGGS----TYYADSRKG 
                 (SEQ ID NO: 301) 
               
               
                 4-04 
                 SSNW-WS 
                 (SEQ ID NO: 302) 
                 EIYHSGS---TNYNPSLKS 
                 (SEQ ID NO: 303) 
               
               
                 4-28 
                 SSNW-WG 
                 (SEQ ID NO: 304) 
                 YIYYSGS---TYYNPSLKS 
                 (SEQ ID NO: 305) 
               
               
                 4301 
                 SGGYYWS 
                 (SEQ ID NO: 306) 
                 YIYYSGS---TYYNPSLKS 
                 (SEQ ID NO: 307) 
               
               
                 4302 
                 SGGYSWS 
                 (SEQ ID NO: 308) 
                 YIYHSGS---TYYNPSLKS 
                 (SEQ ID NO: 309) 
               
               
                 4304 
                 SGDYYWS 
                 (SEQ ID NO: 310) 
                 YIYYSGS---TYYNPSLKS 
                 (SEQ ID NO: 311) 
               
               
                 4-31 
                 SGGYYWS 
                 (SEQ ID NO: 312) 
                 YIYYSGS---TYYNPSLKS 
                 (SEQ ID NO: 313) 
               
               
                 4-34 
                 GYY--WS 
                 (SEQ ID NO: 314) 
                 EINHSGS---TNYNPSLKS 
                 (SEQ ID NO: 315) 
               
               
                 4-39 
                 SSSYYWG 
                 (SEQ ID NO: 316) 
                 SIYYSGS---TYYNPSLKS 
                 (SEQ ID NO: 317) 
               
               
                 4-59 
                 SYY--WS 
                 (SEQ ID NO: 318) 
                 YIYYSGS---TNYNPSLKS 
                 (SEQ ID NO: 319) 
               
               
                 4-61 
                 SGSYYWS 
                 (SEQ ID NO: 320) 
                 YIYYSGS---TNYNPSLKS 
                 (SEQ ID NO: 321) 
               
               
                 4-b 
                 SGYY-WG 
                 (SEQ ID NO: 322) 
                 SIYHSGS---TYYNPSLKS 
                 (SEQ ID NO: 323) 
               
               
                 5-51 
                 SYW--IG 
                 (SEQ ID NO: 324) 
                 IIYPGDSD--TRYSPSFQG 
                 (SEQ ID NO: 325) 
               
               
                 5-a 
                 SYW--IS 
                 (SEQ ID NO: 326) 
                 RIDPSDSY--TNYSPSFQG 
                 (SEQ ID NO: 327) 
               
               
                 6-1 
                 SNSAAWN 
                 (SEQ ID NO: 328) 
                 RTYYRSKWY-NDYAVSVKS 
                 (SEQ ID NO: 329) 
               
               
                 74.1 
                 SYA--MN 
                 (SEQ ID NO: 330) 
                 WINTNTGN--PTYAQGFTG 
                 (SEQ ID NO: 331) 
               
               
                   
               
             
          
           
               
                 CDR1 of human GLGs 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 — 
                 Consens. 
               
               
                   
               
               
                 1 
                   
                   
                 7 
                 1 
                   
                 3 
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                 
                   35 
                 
                 2 
                   
                   
                 1 
                   
                 Sd x 
               
               
                 2 
                 2 
                   
                   
                   
                   
                 6 
                 1 
                   
                   
                 1 
                   
                 4 
                   
                   
                 1 
                 7 
                   
                   
                   
                 
                   29 
                 
                   
                 Ysg x 
               
               
                 3 
                 
                   11 
                 
                   
                 3 
                 1 
                   
                 
                   10 
                 
                   
                   
                   
                   
                   
                 2 
                   
                   
                 1 
                 6 
                 1 
                   
                 5 
                 
                   11 
                 
                   
                 YAGS x 
               
               
                 4 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                 1 
                 2 
                 7 
                 
                   38 
                 
                 — 
               
               
                 5 
                 1 
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                 5 
                 
                   41 
                 
                 — 
               
               
                 6 
                   
                   
                   
                   
                   
                   
                   
                 6 
                   
                 1 
                 
                   28 
                 
                   
                   
                   
                   
                   
                   
                 4 
                 
                   12 
                 
                   
                   
                 Mwi 
               
               
                 7 
                   
                   
                 1 
                   
                   
                 5 
                 
                   16 
                 
                   
                   
                   
                   
                 5 
                   
                 1 
                   
                 
                   23 
                 
                   
                   
                   
                   
                   
                 SHng 
               
               
                   
               
             
          
           
               
                 CDR2 of human GLGs 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 — 
                 Consens. 
               
               
                   
               
               
                 1 
                 3 
                   
                   
                 2 
                 1 
                 5 
                 1 
                 2 
                   
                 3 
                   
                 1 
                   
                   
                 7 
                 4 
                   
                 6 
                 7 
                 9 
                   
                 X 
               
               
                 2 
                   
                   
                   
                   
                 1 
                   
                   
                 
                   46 
                 
                   
                   
                 1 
                   
                   
                   
                   
                   
                 2 
                 1 
                   
                   
                   
                 I 
               
               
                 3 
                   
                   
                 4 
                   
                 1 
                 1 
                   
                 2 
                 2 
                   
                   
                 8 
                   
                   
                 3 
                 
                   12 
                 
                 1 
                 1 
                 1 
                 
                   15 
                 
                   
                 ysn x 
               
               
                 4 
                 2 
                   
                   
                   
                   
                 2 
                 4 
                   
                   
                   
                   
                 1 
                 
                   10 
                 
                 1 
                   
                 
                   11 
                 
                 2 
                 1 
                 5 
                 
                   12 
                 
                   
                 ysp x 
               
               
                 5 
                 1 
                   
                 8 
                 2 
                 1 
                 6 
                   
                 2 
                 4 
                   
                   
                 8 
                   
                   
                 1 
                 
                   17 
                 
                   
                   
                   
                 1 
                   
                 sd x 
               
               
                 6 
                 3 
                   
                 7 
                   
                 2 
                 
                   26 
                 
                   
                   
                   
                   
                   
                 3 
                   
                   
                   
                 8 
                 2 
                   
                   
                   
                   
                 Gsd x 
               
               
                 7 
                   
                   
                 4 
                 1 
                   
                 
                   17 
                 
                   
                   
                 1 
                   
                   
                 2 
                   
                   
                   
                 
                   24 
                 
                   
                   
                   
                 1 
                 1 
                 SG x 
               
               
                 8 
                   
                   
                 1 
                 3 
                   
                 3 
                   
                   
                 3 
                   
                   
                 
                   10 
                 
                   
                   
                   
                 9 
                 4 
                   
                 1 
                 2 
                 
                   15 
                 
                 -ns 
               
               
                 9 
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                 
                   46 
                 
                 — 
               
               
                 10 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3 
                   
                   
                   
                 
                   47 
                 
                 — 
               
               
                 11 
                 2 
                   
                   
                   
                   
                   
                   
                 4 
                 5 
                   
                   
                 1 
                 1 
                   
                   
                   
                 
                   35 
                 
                   
                   
                   
                 3 
                 T 
               
               
                 12 
                 1 
                   
                 2 
                 2 
                 1 
                 3 
                   
                 2 
                 1 
                   
                   
                 
                   11 
                 
                   
                   
                 2 
                 3 
                 1 
                   
                   
                 
                   22 
                 
                   
                 Yn x 
               
               
                 13 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   51 
                 
                   
                 Y 
               
               
                 14 
                 
                   31 
                 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   11 
                 
                 1 
                   
                   
                 6 
                 1 
                 1 
                   
                   
                   
                 An x 
               
               
                 15 
                 4 
                   
                 
                   16 
                 
                 1 
                   
                 1 
                   
                   
                   
                   
                   
                 1 
                 
                   14 
                 
                 
                   11 
                 
                   
                   
                 2 
                 1 
                   
                   
                   
                 dpq x 
               
               
                 16 
                   
                   
                   
                   
                   
                 1 
                   
                   
                 11 
                   
                   
                   
                 1 
                   
                   
                 
                   38 
                 
                   
                   
                   
                   
                   
                 Sk 
               
               
                 17 
                   
                   
                   
                   
                 
                   13 
                 
                   
                   
                   
                   
                 
                   15 
                 
                   
                   
                   
                   
                 1 
                   
                   
                 
                   22 
                 
                   
                   
                   
                 Vlf 
               
               
                 18 
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   37 
                 
                   
                   
                   
                   
                 
                   13 
                 
                   
                   
                 1 
                   
                   
                   
                   
                 Kq 
               
               
                 19 
                   
                   
                 1 
                 1 
                   
                 
                   34 
                 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   14 
                 
                 1 
                   
                   
                   
                   
                 GS 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 21P 
               
               
                   
               
               
                 Tallies of Amino-acid frequencies in mature CDR1 and CDR2 
               
               
                   
               
             
             
               
                 Tally of 23 examples with length 14 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
               
               
                   
               
               
                 1 
                   
                 8 
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                 13 
                   
                   
                   
                   
               
               
                 2 
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 15 
                 3 
                 2 
                   
                   
                   
                   
               
               
                 3 
                 2 
                   
                   
                 1 
                   
                 14 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                 5 
                   
                   
                   
                   
               
               
                 4 
                   
                   
                 2 
                   
                 2 
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 5 
                   
                   
                   
                 3 
                   
                   
               
               
                 5 
                   
                   
                   
                   
                   
                 7 
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                 13 
                   
                   
                   
                 1 
                   
                   
               
               
                 6 
                 1 
                   
                   
                   
                 4 
                 3 
                   
                 12 
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
               
               
                 7 
                   
                   
                   
                   
                   
                 3 
                   
                 1 
                 1 
                   
                   
                 2 
                 1 
                   
                 5 
                 10 
                   
                   
                   
                   
                   
                   
               
               
                 8 
                   
                   
                   
                   
                 6 
                 1 
                   
                   
                   
                 1 
                   
                 2 
                   
                   
                 1 
                 6 
                 4 
                 2 
                   
                   
                   
                   
               
               
                 9 
                   
                   
                   
                   
                 1 
                 5 
                   
                 1 
                   
                   
                   
                 3 
                 1 
                   
                 4 
                 7 
                 1 
                   
                   
                   
                   
                   
               
               
                 10 
                 1 
                   
                 8 
                   
                   
                 3 
                   
                   
                   
                   
                   
                 1 
                 2 
                   
                 1 
                 4 
                 1 
                   
                   
                 2 
                   
                   
               
               
                 11 
                 1 
                   
                   
                   
                 1 
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                 1 
                   
                 16 
                   
                   
               
               
                 12 
                 1 
                   
                 2 
                 1 
                   
                 1 
                 1 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                   
                 1 
                 14 
                   
                   
               
               
                 13 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 4 
                   
                   
                   
                   
                   
                   
                 2 
                 17 
                   
                   
                   
               
               
                 14 
                 4 
                   
                 1 
                   
                   
                 5 
                   
                   
                   
                   
                   
                 4 
                   
                   
                   
                 5 
                 4 
               
               
                   
               
             
          
           
               
                 Tally of 11 examples with length 12 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
               
               
                   
               
               
                 1 
                   
                   
                   
                   
                   
                 4 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 7 
                   
                   
                   
                   
               
               
                 2 
                   
                   
                   
                   
                 1 
                 4 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 4 
                   
                   
                   
                 2 
                   
                   
               
               
                 3 
                   
                   
                   
                   
                   
                 7 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 4 
                   
                   
                   
                   
                   
                   
               
               
                 4 
                 1 
                   
                 1 
                   
                 1 
                 5 
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
               
               
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 9 
                 1 
                   
                   
                   
                   
                   
               
               
                 6 
                   
                   
                   
                   
                 2 
                 1 
                   
                 3 
                   
                 2 
                   
                   
                   
                   
                   
                 3 
                   
                   
                   
                   
                   
                   
               
               
                 7 
                   
                   
                   
                   
                   
                 3 
                   
                 1 
                   
                   
                   
                 3 
                   
                   
                 1 
                 3 
                   
                   
                   
                   
                   
                   
               
               
                 8 
                 1 
                   
                 3 
                   
                   
                 2 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                 2 
                   
                   
                   
                   
                   
               
               
                 9 
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 9 
                   
                   
               
               
                 10 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 10 
                   
                   
               
               
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 11 
                   
                   
                   
               
               
                 12 
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 7 
                 1 
               
               
                   
               
             
          
           
               
                 Tally of 175 examples with length 7 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
               
               
                   
               
               
                 1 
                 2 
                   
                   
                 1 
                 1 
                 2 
                   
                   
                   
                 1 
                   
                 3 
                   
                   
                 2 
                 
                   153 
                 
                 10 
                   
                   
                   
                   
                   
               
               
                 2 
                 3 
                   
                 2 
                   
                 1 
                 
                   87 
                 
                   
                   
                   
                   
                 1 
                 10 
                 1 
                   
                 5 
                 
                   61 
                 
                 2 
                   
                   
                 2 
                   
                   
               
               
                 3 
                 3 
                   
                 
                   26 
                 
                 1 
                   
                 
                   54 
                 
                   
                 1 
                   
                   
                   
                 5 
                 1 
                   
                 2 
                 
                   76 
                 
                 3 
                 1 
                   
                 2 
                   
                   
               
               
                 4 
                 6 
                 1 
                 1 
                   
                 6 
                   
                 1 
                   
                   
                   
                 2 
                 1 
                   
                   
                   
                   
                   
                 11 
                 1 
                 
                   145 
                 
                   
                   
               
               
                 5 
                 5 
                 2 
                   
                   
                   
                 13 
                 2 
                   
                   
                 2 
                   
                 3 
                   
                   
                   
                 6 
                 2 
                   
                   
                 
                   140 
                 
                   
                   
               
               
                 6 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                   
                 13 
                 
                   159 
                 
                   
                   
                   
               
               
                 7 
                 2 
                   
                 1 
                   
                   
                 
                   67 
                 
                 1 
                   
                   
                   
                   
                 10 
                   
                   
                   
                 
                   88 
                 
                 5 
                 1 
               
               
                   
               
             
          
           
               
                 Tally of 38 examples with length 6 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 | 
                 X 
               
               
                   
               
               
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                 
                   34 
                 
                 2 
                   
                   
                   
                   
                   
               
               
                 2 
                 1 
                   
                 2 
                   
                 1 
                 8 
                   
                   
                   
                   
                   
                 4 
                   
                   
                   
                 
                   22 
                 
                   
                   
                   
                   
                   
                   
               
               
                 3 
                   
                   
                   
                   
                   
                   
                 3 
                   
                   
                   
                   
                 
                   26 
                 
                   
                   
                   
                   
                   
                   
                   
                 9 
                   
                   
               
               
                 4 
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   29 
                 
                 7 
                   
                   
               
               
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 
                   38 
                 
                   
                   
                   
               
               
                 6 
                   
                   
                   
                   
                   
                 10 
                   
                   
                   
                   
                   
                 3 
                   
                   
                   
                 
                   22 
                 
                 3 
               
               
                   
               
             
          
           
               
                 Tally of 820 examples with length 5 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
                 Seen 
               
               
                   
               
               
                 1 
                 8 
                   
                 
                   81 
                 
                 10 
                   
                 
                   151 
                 
                 4 
                 8 
                 5 
                 3 
                   
                 
                   100 
                 
                   
                 4 
                 15 
                 
                   364 
                 
                 
                   55 
                 
                 8 
                   
                 4 
                 SGNDT x 
                 15 
               
               
                 2 
                 7 
                 5 
                 12 
                   
                 24 
                 1 
                 30 
                 1 
                 1 
                 5 
                   
                 26 
                   
                 1 
                 1 
                 23 
                 2 
                   
                   
                 
                   681 
                 
                 Y 
                 15 
               
               
                 3 
                 
                   202 
                 
                 4 
                 24 
                 13 
                 13 
                 
                   133 
                 
                 10 
                   
                   
                 2 
                   
                 7 
                 5 
                 2 
                 3 
                 32 
                 14 
                 13 
                 
                   112 
                 
                 
                   231 
                 
                 YAGW x 
                 17 
               
               
                 4 
                   
                   
                   
                   
                 6 
                   
                   
                 
                   172 
                 
                 2 
                 7 
                 
                   409 
                 
                   
                   
                   
                   
                   
                 3 
                 16 
                 
                   205 
                 
                   
                 MWI 
                 8 
               
               
                 5 
                 8 
                   
                 6 
                 1 
                 1 
                 49 
                 
                   241 
                 
                 2 
                   
                   
                   
                 
                   79 
                 
                 1 
                 3 
                   
                 
                   367 
                 
                 
                   56 
                 
                 2 
                   
                 4 
                 SHNT x 
                 14 
               
               
                 CDR2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
             
          
           
               
                 Tally of 31 examples with CDR2 of length 19 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 X 
                   
               
               
                   
               
               
                 1 
                   
                   
                   
                   
                 11 
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                 1 
                 15 
                 1 
                 1 
                   
                   
                   
                   
                 RF x 
               
               
                 2 
                 1 
                   
                   
                   
                   
                   
                   
                 28 
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                 I 
               
               
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                 9 
                 1 
                   
                   
                   
                   
                 18 
                 1 
                 1 
                   
                   
                 1 
                   
                 Rk 
               
               
                 4 
                   
                   
                   
                   
                   
                 1 
                   
                   
                 2 
                   
                   
                 6 
                   
                   
                   
                 21 
                 1 
                   
                   
                   
                   
                 S 
               
               
                 5 
                   
                   
                 1 
                 1 
                   
                 1 
                   
                   
                 22 
                   
                 1 
                   
                   
                 1 
                 1 
                 1 
                 1 
                   
                   
                 1 
                   
                 K x 
               
               
                 6 
                 16 
                   
                 1 
                   
                   
                 1 
                   
                 1 
                 1 
                   
                   
                   
                 3 
                   
                   
                 1 
                 6 
                 1 
                   
                   
                   
                 A x 
               
               
                 7 
                 1 
                   
                 9 
                   
                   
                   
                   
                   
                   
                   
                   
                 7 
                   
                   
                   
                 3 
                 1 
                   
                   
                 10 
                   
                 y x 
               
               
                 8 
                   
                   
                   
                   
                   
                 23 
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                 5 
                 1 
                   
                   
                   
                   
                 G 
               
               
                 9 
                 2 
                   
                   
                   
                   
                 18 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                 1 
                   
                 7 
                 1 
                 G 
               
               
                 10 
                 4 
                   
                   
                   
                   
                 1 
                   
                 1 
                 1 
                   
                   
                 1 
                   
                   
                   
                 1 
                 21 
                   
                   
                 1 
                   
                 T 
               
               
                 11 
                 1 
                   
                   
                   
                   
                   
                   
                 3 
                   
                 1 
                   
                   
                   
                   
                   
                   
                 26 
                   
                   
                   
                   
                 T 
               
               
                 12 
                 2 
                   
                 11 
                 9 
                   
                 1 
                 1 
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                 2 
                 1 
                   
                   
                 2 
                   
                 x 
               
               
                 13 
                   
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 29 
                   
                 Y 
               
               
                 14 
                 29 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 1 
                   
                   
                   
                   
                 A 
               
               
                 15 
                 25 
                   
                 3 
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                 A 
               
               
                 16 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 10 
                   
                   
                 20 
                   
                   
                   
                   
                   
                 Sp 
               
               
                 17 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                   
                   
                 29 
                   
                   
                   
                 V 
               
               
                 18 
                   
                   
                   
                 1 
                   
                   
                   
                   
                 27 
                   
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                   
                   
                   
                 K 
               
               
                 19 
                   
                   
                 1 
                   
                   
                 30 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 G 
               
               
                   
               
             
          
           
               
                 Tally of 579 ( n &gt; 50, bold;  over 400, underscored) examples with length 17 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 X 
                   
               
               
                   
               
               
                 1 
                 44 
                 1 
                 1 
                 2 
                 11 
                 
                   81 
                 
                 5 
                 
                   69 
                 
                 1 
                 14 
                 6 
                 41 
                 1 
                 4 
                 34 
                 30 
                 19 
                 
                   118 
                 
                 
                   66 
                 
                 31 
                   
                 VGIW x 
               
               
                 2 
                   
                   
                   
                   
                 7 
                   
                   
                 
                   522 
                 
                 1 
                 10 
                 17 
                 1 
                   
                   
                   
                 3 
                 8 
                 10 
                   
                   
                   
                 I 
               
               
                 3 
                 3 
                 1 
                 22 
                   
                 5 
                 7 
                 6 
                 
                   51 
                 
                 25 
                 1 
                   
                 
                   76 
                 
                   
                   
                 8 
                 
                   262 
                 
                 19 
                 1 
                 46 
                 46 
                   
                 SNI x 
               
               
                 4 
                 39 
                 2 
                 8 
                 6 
                 16 
                 
                   64 
                 
                 9 
                 3 
                 2 
                 3 
                   
                 15 
                 
                   178 
                 
                 23 
                 6 
                 50 
                 11 
                 8 
                 16 
                 
                   120 
                 
                   
                 PYG x 
               
               
                 5 
                 3 
                   
                 
                   194 
                 
                 6 
                 1 
                 
                   70 
                 
                 6 
                 44 
                 6 
                 4 
                 1 
                 
                   55 
                 
                   
                 4 
                 8 
                 
                   133 
                 
                 9 
                 7 
                 1 
                 27 
                   
                 DSGN x 
               
               
                 6 
                 3 
                 1 
                 
                   75 
                 
                 4 
                 45 
                 
                   326 
                 
                 1 
                   
                   
                 6 
                   
                 43 
                   
                   
                 1 
                 
                   63 
                 
                 8 
                 1 
                   
                 2 
                   
                 GDS x 
               
               
                 7 
                 8 
                   
                 24 
                 5 
                   
                 
                   226 
                 
                 3 
                 3 
                 3 
                 4 
                   
                 24 
                   
                 2 
                 11 
                 
                   245 
                 
                 14 
                 6 
                   
                 1 
                   
                 SG x 
               
               
                 8 
                 4 
                 2 
                 
                   57 
                 
                 37 
                 5 
                 22 
                 4 
                 18 
                 18 
                 2 
                 2 
                 
                   161 
                 
                 1 
                 4 
                 11 
                 
                   106 
                 
                 
                   90 
                 
                 2 
                 1 
                 32 
                   
                 NST X 
               
               
                 9 
                 
                   56 
                 
                   
                   
                 11 
                   
                 2 
                   
                 
                   63 
                 
                 
                   157 
                 
                 1 
                 3 
                 3 
                 11 
                 5 
                 13 
                 4 
                 
                   242 
                 
                 8 
                   
                   
                   
                 TKIA x 
               
               
                 10 
                 1 
                   
                 14 
                 2 
                 13 
                 30 
                 23 
                 6 
                 29 
                 2 
                 3 
                 
                   110 
                 
                   
                 3 
                 
                   52 
                 
                 20 
                 10 
                 1 
                 1 
                 
                   259 
                 
                   
                 YNR x 
               
               
                 11 
                   
                 1 
                 2 
                   
                 7 
                   
                 5 
                   
                 1 
                 4 
                   
                 3 
                   
                   
                   
                 5 
                   
                   
                   
                 
                   551 
                 
                   
                 Y 
               
               
                 12 
                 
                   405 
                 
                   
                   
                 2 
                   
                 18 
                   
                 1 
                   
                 6 
                   
                 2 
                 3 
                   
                 1 
                 89 
                 8 
                 44 
                   
                   
                   
                 A 
               
               
                 13 
                 7 
                   
                 
                   323 
                 
                 22 
                   
                 7 
                 4 
                   
                   
                 1 
                   
                 4 
                 
                   66 
                 
                 
                   138 
                 
                 3 
                   
                   
                 1 
                   
                 3 
                   
                 DQP x 
               
               
                 14 
                 2 
                   
                   
                 5 
                 6 
                 3 
                   
                   
                 
                   123 
                 
                   
                 1 
                 4 
                   
                 2 
                 7 
                 
                   421 
                 
                 1 
                 2 
                   
                 2 
                   
                 SK x 
               
               
                 15 
                 1 
                   
                   
                 1 
                 
                   188 
                 
                 2 
                   
                 1 
                   
                 22 
                 3 
                   
                   
                   
                   
                 1 
                   
                 
                   357 
                 
                   
                 2 
                 1 
                 VF 
               
               
                 16 
                 1 
                   
                   
                 13 
                   
                 1 
                 1 
                   
                 
                   332 
                 
                 3 
                 2 
                 1 
                 1 
                 
                   199 
                 
                 21 
                   
                 4 
                   
                   
                   
                   
                 KQ x 
               
               
                 17 
                   
                   
                 11 
                 1 
                   
                 
                   565 
                 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                 G 
               
               
                   
               
             
          
           
               
                 Tally of 464 ( over 50, bold;  over 400, underscored) 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                 X 
                   
               
               
                   
               
               
                 1 
                 5 
                   
                 13 
                 
                   184 
                 
                 8 
                 1 
                 7 
                 1 
                 2 
                 15 
                   
                 6 
                   
                 3 
                 26 
                 
                   65 
                 
                 9 
                 14 
                   
                 
                   105 
                 
                   
                 EYSL x 
               
               
                 2 
                   
                   
                   
                   
                 6 
                   
                   
                 
                   429 
                 
                   
                 3 
                 4 
                   
                   
                   
                   
                 1 
                 2 
                 19 
                   
                   
                   
                 I 
               
               
                 3 
                   
                 1 
                 13 
                   
                 13 
                 4 
                 10 
                 5 
                   
                   
                   
                 
                   154 
                 
                   
                   
                 1 
                 12 
                 1 
                   
                   
                 
                   250 
                 
                   
                 YN x 
               
               
                 4 
                 1 
                   
                 12 
                 2 
                 6 
                   
                 
                   199 
                 
                 2 
                   
                 1 
                   
                 3 
                 4 
                 5 
                 2 
                 19 
                 28 
                   
                 15 
                 
                   165 
                 
                   
                 YH x 
               
               
                 5 
                 5 
                   
                 20 
                 1 
                 1 
                 18 
                   
                 4 
                   
                   
                   
                 9 
                 1 
                   
                 22 
                 
                   365 
                 
                 16 
                 1 
                   
                 1 
                   
                 S x 
               
               
                 6 
                   
                   
                 13 
                 8 
                   
                 
                   439 
                 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                 1 
                 1 
                 1 
                   
                   
                 G 
               
               
                 7 
                   
                   
                 20 
                 2 
                   
                 14 
                 2 
                 4 
                 2 
                   
                   
                 26 
                 1 
                   
                 12 
                 
                   357 
                 
                 20 
                 1 
                   
                 2 
                 1 
                 S x 
               
               
                 8 
                 13 
                   
                   
                   
                   
                 2 
                   
                 4 
                 8 
                 1 
                 2 
                   
                 4 
                   
                 3 
                 6 
                 
                   420 
                 
                   
                   
                   
                 1 
                 T 
               
               
                 9 
                   
                   
                 10 
                   
                 4 
                 1 
                 10 
                 1 
                 8 
                 1 
                   
                 
                   245 
                 
                   
                   
                 13 
                 9 
                 3 
                 1 
                 1 
                 
                   157 
                 
                   
                 NY x 
               
               
                 10 
                   
                 6 
                   
                   
                 2 
                   
                 2 
                   
                   
                   
                   
                 2 
                   
                 1 
                   
                 7 
                   
                   
                   
                 
                   444 
                 
                   
                 Y 
               
               
                 11 
                 14 
                   
                 3 
                   
                   
                   
                 1 
                 1 
                 8 
                   
                   
                 
                   408 
                 
                 4 
                   
                   
                 21 
                 2 
                   
                   
                 2 
                   
                 N 
               
               
                 12 
                 4 
                   
                 13 
                   
                   
                 4 
                   
                   
                   
                 2 
                   
                 1 
                 
                   418 
                 
                   
                   
                 14 
                 7 
                 1 
                   
                   
                   
                 P 
               
               
                 13 
                 2 
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                 6 
                   
                   
                 
                   452 
                 
                 1 
                   
                   
                 1 
                   
                 S 
               
               
                 14 
                   
                   
                   
                   
                 2 
                   
                   
                 2 
                   
                 
                   441 
                 
                   
                   
                   
                   
                 1 
                   
                   
                 18 
                   
                   
                   
                 L 
               
               
                 15 
                   
                   
                   
                 18 
                   
                   
                   
                   
                 
                   413 
                 
                   
                 3 
                 5 
                   
                 11 
                 10 
                 1 
                 2 
                 1 
                   
                   
                   
                 K 
               
               
                 16 
                 1 
                   
                 1 
                   
                   
                 31 
                   
                 2 
                   
                   
                   
                 2 
                   
                   
                 3 
                 
                   419 
                 
                 5 
                   
                   
                   
                   
                 S 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 22P 
               
               
                   
               
               
                 Tally of VH types 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1-02 
                 16 
                 1-03 
                 16 
                 1-08 
                 13 
                 1-18 
                 27 
                 1-24 
                 5 
               
               
                 1-45 
                 0 
                 1-46 
                 14 
                 1-58 
                 1 
                 1-69 
                 37 
                 1-e 
                 16 
               
               
                 1-f 
                 1 
                 2-05 
                 13 
                 2-26 
                 1 
                 2-70 
                 2 
                 3-07 
                 33 
               
               
                 3-09 
                 13 
                 3-11 
                 15 
                 3-13 
                 4 
                 3-15 
                 10 
                 3-20 
                 4 
               
               
                 3-21 
                 25 
                 3-23 
                 85 
                 3-30 
                 55 
                 3303 
                 59 
                 3305 
                 0 
               
               
                 3-33 
                 42 
                 3-43 
                 1 
                 3-48 
                 24 
                 3-49 
                 11 
                 3-53 
                 12 
               
               
                 3-64 
                 4 
                 3-66 
                 4 
                 3-72 
                 3 
                 3-73 
                 3 
                 3-74 
                 12 
               
               
                 3-d 
                 0 
                 4-04 
                 29 
                 4-28 
                 3 
                 4301 
                 46 
                 4302 
                 7 
               
               
                 4304 
                 37 
                 4-31 
                 0 
                 4-34 
                 184 
                 4-39 
                 65 
                 4-59 
                 45 
               
               
                 4-61 
                 9 
                 4-b 
                 11 
                 5-51 
                 55 
                 5-a 
                 13 
                 6-1 
                 7 
               
               
                 74.1 
                 3 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 23P 
               
               
                   
               
               
                 Oligonucleotides used to variegate CDR1 and CDR2 of human HC 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 !(name) 5′-....DNA sequence....-3′ 
               
               
                 !everything to right of an exclamation point is commentary 
               
               
                 ![RC] means “reverse complement” of sequence shown 
               
               
                 ! If last non-comment and non-blank character is “-”, then continue 
               
               
                 ! on next line. 
               
               
                 ! Ignore case, “a” = “A”, “c” = “C”, etc. 
               
               
                 ! Ignore “|” and blanks. 
               
               
                 ! &lt;number&gt; means incorporate trinucleotide mixtue of given number. 
               
               
                 !------------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 ! CDR1 
               
               
                 (ON-R1V1vg) 5′-       ct|TCC|GGA|ttc|act|ttc|tct|- 
               
               
                        &lt;1&gt;|tac|&lt;1&gt;|atg|&lt;1&gt;|-              ! CDR1 of length 5, ON = 55 bases 
               
               
                                   tgg|gtt|cgC|CAa|gct|ccT|GG-3′ (SEQ ID NO: 27) 
               
               
                 ! &lt;1&gt; = ADEFGHIKLMNPQRSTVWY no C 
               
               
                 ! 
               
               
                 (ON-R1top) 5′-cctactgtct |TCC|GGA|ttc|act|ttc|tct-3′ (SEQ ID NO: 28) 
               
               
                 (ON-R1bot)[RC] 5′-tgg|gtt|cgC|CAa|gct|ccT|GG ttgctcactc-3′ (SEQ ID NO: 29) 
               
               
                 (ON-R1V2vg) 5′-       ct|TCC|GGA|ttc|act|ttc|tct|- 
               
               
                        &lt;6&gt;|&lt;7&gt;|&lt;7&gt;|tac|tac|tgg|&lt;7&gt;|-      ! CDR1 of length 7, ON = 61 bases 
               
               
                                   tgg|gtt|cgC|CAa|gct|ccT|GG-3′ (SEQ ID NO: 30) 
               
               
                 ! &lt;6&gt; = ST, 1:1 
               
               
                 ! &lt;7&gt; = 0.2025(SG) + 0.035(ADEFHIKLMNPQRTVWY) no C 
               
               
                 (ON-R1V3vg) 5′-ct|TCC|GGA|ttc|act|ttc|tct|- 
               
               
                       |atc|agc|ggt|ggt|tct|atc|tcc|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|tac|tac|tgg|&lt;1&gt;|- ! CDR1, L = 14 
               
               
                                   tgg|gtt|cgC|CAa|gct|ccT|GG-3′(SEQ ID NO: 31) ! ON = 82 bases 
               
               
                 ! CDR2 
               
               
                 (ON-R2V1vg)                                   5′-ggt|ttg|gag|tgg|gtt|tct|- 
               
               
                           &lt;2&gt;|atc|&lt;2&gt;|&lt;3&gt;|tct|ggt|ggc|&lt;1&gt;|act|&lt;1&gt;|- 
               
               
                                   tat|gct|gac|tcc|gtt|aaa|gg-3′ (SEQ ID NO: 32)! ON = 68 
               
               
                 bases, CDR2 = 17 AA 
               
               
                 (ON-R2top) 5′-ct|tgg|gtt|cgC|CAa|gct|ccT|GGt|aaa|ggt|ttg|gag|tgg|gtt|tct-3′ 
               
               
                            (SEQ ID NO: 33) 
               
               
                 (ON-R2bot)[RC] 5′-tat|gct|gac|tcc|gtt|aaa|ggt|- 
               
               
                            cgc|ttc|act|atc|TCT|AGA|ttcctgtcac-3′ (SEQ ID NO: 34)! XbaI plus 10 
               
               
                 bases of scab 
               
               
                 (ON-R2V2vg)                                   5′-ggt|ttg|gag|tgg|gtt|tct|- 
               
               
                           &lt;1&gt;|atc|&lt;4&gt;|&lt;1&gt;|&lt;1&gt;|ggt|&lt;5&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|- 
               
               
                                   tat|gct|gac|tcc|gtt|aaa|gg-3′ (SEQ ID NO: 35)! ON = 68 
               
               
                 bases, CDR2 = 17 AA 
               
               
                 ! &lt;4&gt; = DINSWY, equimolar ! &lt;5&gt; = SGDN, equimolar 
               
               
                 (ON-R2V3vg)                                   5′-ggt|ttg|gag|tgg|gtt|tct|- 
               
               
                           &lt;1&gt;|atc|&lt;4&gt;|&lt;1&gt;|&lt;1&gt;|ggt|&lt;5&gt;|&lt;l&gt;|&lt;1&gt;|- 
               
               
                                   tat|aac|cct|tcc|ctt|aag|gg-3′ (SEQ ID NO: 36)! ON = 65 
               
               
                 bases, CDR2 = 16 AA 
               
               
                 (ON-R2bo3)[RC] 5′-tat|aac|cct|tcc|ctt|aag|ggt|- 
               
               
                            cgc|ttc|act|atc|TCT|AGA|ttcctgtcac-3′ (SEQ ID NO: 37)! XbaI plus 10 
               
               
                 bases of scab 
               
               
                 (ON-R2V4vg)                                   5′-ggt|ttg|gag|tgg|gtt|tct|- 
               
               
                           &lt;1&gt;|atc|&lt;8&gt;|agt|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|ggt|ggt|act|act|&lt;1&gt; 
               
               
                                   tat|gcc|gct|tcc|gtt|aag|gg-3′ (SEQ ID NO: 38)! ON = 74 
               
               
                 bases, CDR2 = 19 AA 
               
               
                 (ON-R2bo4)[RC] 5′-tat|gcc|gct|tcc|gtt|aag|ggt|- 
               
               
                            cgc|ttc|act|atc|TCT|AGA|ttcctgtcac-3′ (SEQ ID NO: 39) ! XbaI plus 
               
               
                 10 bases of scab 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 25P 
               
             
             
               
                   
               
               
                 Lengths of CDRs in 285 human kappa chains 
               
             
          
           
               
                   
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
               
               
                   
               
             
          
           
               
                 CDR1 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 154 
                 73 
                 3 
                 0 
                 0 
                 28 
                 27 
                 0 
                 0 
               
               
                 CDR2 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 285 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 CDR3 
                 0 
                 5 
                 0 
                 0 
                 1 
                 0 
                 3 
                 2 
                 28 
                 166 
                 63 
                 12 
                 1 
                 1 
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 26P 
               
               
                   
               
               
                 Tally of kappa types: V and J 
               
               
                   
               
             
             
               
                 V genes: 
               
               
                   
               
             
          
           
               
                 O12 
                 59 
                 O2 
                 0 
                 O18 
                 0 
                 O8 
                 0 
                 A20 
                 0 
               
               
                 A30 
                 0 
                 L14 
                 0 
                 L1 
                 2 
                 L15 
                 0 
                 L4 
                 2 
               
               
                 L18 
                 0 
                 L5 
                 4 
                 L19 
                 0 
                 L8 
                 4 
                 L23 
                 0 
               
               
                 L9 
                 1 
                 L24 
                 0 
                 L11 
                 4 
                 L12 
                 8 
                 O11 
                 10 
               
               
                 O1 
                 0 
                 A17 
                 5 
                 A1 
                 0 
                 A18 
                 3 
                 A2 
                 0 
               
               
                 A19 
                 13 
                 A3 
                 0 
                 A23 
                 4 
                 A27 
                 79 
                 A11 
                 26 
               
               
                 L2 
                 28 
                 L16 
                 0 
                 L6 
                 11 
                 L20 
                 0 
                 L25 
                 0 
               
               
                 B3 
                 22 
                 B2 
                 0 
                 A26 
                 0 
                 A10 
                 0 
                 A14 
                 0 
               
               
                   
               
             
          
           
               
                   
                 JH# 
                 1 
                 2 
                 3 
                 4 
                 5 
               
               
                   
               
               
                   
                 tally 
                 105 
                 64 
                 29 
                 78 
                 9 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 27P 
               
               
                   
               
               
                 Names of Kappa chains analyzed 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 AB022651 
               
               
                   
                 AB022653 
               
               
                   
                 AB022654 
               
               
                   
                 AB022656 
               
               
                   
                 AF007572 
               
               
                   
                 AF021036 
               
               
                   
                 AF103499 
               
               
                   
                 AF103500 
               
               
                   
                 AF103527 
               
               
                   
                 AF103873 
               
               
                   
                 AF107244 
               
               
                   
                 AF107245 
               
               
                   
                 AF107246 
               
               
                   
                 AF107247 
               
               
                   
                 AF115361 
               
               
                   
                 AF165099 
               
               
                   
                 AF165101 
               
               
                   
                 AF165103 
               
               
                   
                 AF165108 
               
               
                   
                 AF165110 
               
               
                   
                 AF165111 
               
               
                   
                 AF184763 
               
               
                   
                 AF184767 
               
               
                   
                 hsa004955 
               
               
                   
                 hsa004956 
               
               
                   
                 hsa011133 
               
               
                   
                 HSA241367 
               
               
                   
                 HSA241375 
               
               
                   
                 HSA388639 
               
               
                   
                 HSA388640 
               
               
                   
                 HSA388641 
               
               
                   
                 HSA388642 
               
               
                   
                 HSA388643 
               
               
                   
                 HSA388644 
               
               
                   
                 HSA388645 
               
               
                   
                 HSA388646 
               
               
                   
                 HSA388647 
               
               
                   
                 HSA388648 
               
               
                   
                 HSA388650 
               
               
                   
                 HSA388651 
               
               
                   
                 HSA388652 
               
               
                   
                 HSA388653 
               
               
                   
                 HSA388654 
               
               
                   
                 HSA388655 
               
               
                   
                 HSA388656 
               
               
                   
                 HSA388657 
               
               
                   
                 hsew1vk 
               
               
                   
                 hsew3vk 
               
               
                   
                 hsew4vk 
               
               
                   
                 hsigdpk13 
               
               
                   
                 hsigg1kl 
               
               
                   
                 HSIGGVKA 
               
               
                   
                 hsigk123 
               
               
                   
                 hsigk319 
               
               
                   
                 hsigklc14 
               
               
                   
                 hsigklc28 
               
               
                   
                 hsigklc5 
               
               
                   
                 hsigklg31 
               
               
                   
                 hsigklv01 
               
               
                   
                 hsigklv02 
               
               
                   
                 hsigklv03 
               
               
                   
                 hsigklv04 
               
               
                   
                 hsigklv05 
               
               
                   
                 hsigklv06 
               
               
                   
                 hsigklv07 
               
               
                   
                 hsigklv09 
               
               
                   
                 hsigklv10 
               
               
                   
                 hsigklv12 
               
               
                   
                 hsigklv13 
               
               
                   
                 hsigklv14 
               
               
                   
                 hsigklv15 
               
               
                   
                 hsigklv16 
               
               
                   
                 hsigklv17 
               
               
                   
                 hsigklv18 
               
               
                   
                 hsigklv19 
               
               
                   
                 hsigklv20 
               
               
                   
                 hsigklv21 
               
               
                   
                 hsigklv22 
               
               
                   
                 hsigklv23 
               
               
                   
                 hsigklv24 
               
               
                   
                 hsigklv25 
               
               
                   
                 hsigklv27 
               
               
                   
                 hsigklv28 
               
               
                   
                 hsigklv29 
               
               
                   
                 hsigklv31 
               
               
                   
                 hsigklv32 
               
               
                   
                 hsigklv33 
               
               
                   
                 hsigklv34 
               
               
                   
                 hsigklv35 
               
               
                   
                 hsigklv36 
               
               
                   
                 hsigklv37 
               
               
                   
                 hsigklv38 
               
               
                   
                 hsigklv39 
               
               
                   
                 hsigklv40 
               
               
                   
                 hsigklv41 
               
               
                   
                 hsigklv42 
               
               
                   
                 hsigklv43 
               
               
                   
                 hsigklv44 
               
               
                   
                 hsigklv45 
               
               
                   
                 hsigklv46 
               
               
                   
                 hsigklv49 
               
               
                   
                 hsigklv50 
               
               
                   
                 hsigklv51 
               
               
                   
                 hsigklv52 
               
               
                   
                 hsigklv53 
               
               
                   
                 hsigklv54a 
               
               
                   
                 hsigklv56 
               
               
                   
                 hsigklv57 
               
               
                   
                 hsigklv58 
               
               
                   
                 hsigklv59 
               
               
                   
                 hsigklv60 
               
               
                   
                 hsigklv61 
               
               
                   
                 hsigklv62 
               
               
                   
                 hsigklv63 
               
               
                   
                 hsigklv65 
               
               
                   
                 hsigklv66 
               
               
                   
                 hsigklv68 
               
               
                   
                 hsigklv69 
               
               
                   
                 hsigklv71 
               
               
                   
                 hsigkvba 
               
               
                   
                 hsigkvbb 
               
               
                   
                 hsigkvbc 
               
               
                   
                 hsigkvbd 
               
               
                   
                 hsigkvbe 
               
               
                   
                 hsigkvbf 
               
               
                   
                 hsigkvc01 
               
               
                   
                 hsigkvc03 
               
               
                   
                 hsigkvc06 
               
               
                   
                 hsigkvc11 
               
               
                   
                 hsigkvc12 
               
               
                   
                 hsigkvc20 
               
               
                   
                 hsigkvc23 
               
               
                   
                 hsigkvc27 
               
               
                   
                 hsigkvc29 
               
               
                   
                 hsigrklc 
               
               
                   
                 hsikcvjp1 
               
               
                   
                 hsikcvjp2 
               
               
                   
                 hsikcvjp3 
               
               
                   
                 hsikcvjp6 
               
               
                   
                 hsikcvjp7 
               
               
                   
                 hsld110vl 
               
               
                   
                 hsld117vl 
               
               
                   
                 hsld128vl 
               
               
                   
                 hsld140vl 
               
               
                   
                 hsld152vl 
               
               
                   
                 hsld184vl 
               
               
                   
                 hsld198vl 
               
               
                   
                 hsld24vl 
               
               
                   
                 hsmbcl1k1 
               
               
                   
                 hsmbcl1k2 
               
               
                   
                 hsmbcl2k2 
               
               
                   
                 hsmbcl5k4 
               
               
                   
                 hss10avl 
               
               
                   
                 hss17bvl 
               
               
                   
                 hss1a15vl 
               
               
                   
                 HSU44792 
               
               
                   
                 HSU44794 
               
               
                   
                 HSU94422 
               
               
                   
                 hsz84852 
               
               
                   
                 hsz84853 
               
               
                   
                 humigk1dm 
               
               
                   
                 humigk3am 
               
               
                   
                 humigk3bm 
               
               
                   
                 humigk3dm 
               
               
                   
                 humigkacoa 
               
               
                   
                 humigkacob 
               
               
                   
                 humigkacoc 
               
               
                   
                 humigkacoe 
               
               
                   
                 humigkacof 
               
               
                   
                 humigkb1aa 
               
               
                   
                 humigkb1ab 
               
               
                   
                 humigkb1ac 
               
               
                   
                 humigkvra 
               
               
                   
                 humigkvrb 
               
               
                   
                 humigkvrc 
               
               
                   
                 humigkvrd 
               
               
                   
                 humigkvre 
               
               
                   
                 humigkvrg 
               
               
                   
                 humigkvrh 
               
               
                   
                 humigkvri 
               
               
                   
                 humigkx 
               
               
                   
                 humigky1 
               
               
                   
                 humigky2 
               
               
                   
                 humigky4 
               
               
                   
                 humigky5 
               
               
                   
                 humigky6 
               
               
                   
                 humigl3ac 
               
               
                   
                 humikc 
               
               
                   
                 humikca 
               
               
                   
                 humikcad 
               
               
                   
                 humikcaf 
               
               
                   
                 humikcag 
               
               
                   
                 humikcah 
               
               
                   
                 humikcai 
               
               
                   
                 humikcaj 
               
               
                   
                 humikcal 
               
               
                   
                 humikcam 
               
               
                   
                 humikcan 
               
               
                   
                 humikcas 
               
               
                   
                 humikcau 
               
               
                   
                 humikcav 
               
               
                   
                 humikcaw 
               
               
                   
                 humikcax 
               
               
                   
                 humikcay 
               
               
                   
                 humikcaz 
               
               
                   
                 humikcb 
               
               
                   
                 humikcba 
               
               
                   
                 humikcbb 
               
               
                   
                 humikcbc 
               
               
                   
                 humikcbd 
               
               
                   
                 humikcbe 
               
               
                   
                 humikcbf 
               
               
                   
                 humikcbg 
               
               
                   
                 humikcbh 
               
               
                   
                 humikcbi 
               
               
                   
                 humikcbj 
               
               
                   
                 humikcbl 
               
               
                   
                 humikcbm 
               
               
                   
                 humikcbn 
               
               
                   
                 humikcbo 
               
               
                   
                 humikcbp 
               
               
                   
                 humikcbq 
               
               
                   
                 humikcbs 
               
               
                   
                 humikcbt 
               
               
                   
                 humikcbu 
               
               
                   
                 humikcbv 
               
               
                   
                 humikcbw 
               
               
                   
                 humikcbx 
               
               
                   
                 humikcbz 
               
               
                   
                 humikcc 
               
               
                   
                 humikcca 
               
               
                   
                 humikccb 
               
               
                   
                 humikccc 
               
               
                   
                 humikccd 
               
               
                   
                 humikcce 
               
               
                   
                 humikccf 
               
               
                   
                 humikccg 
               
               
                   
                 humikcch 
               
               
                   
                 humikcci 
               
               
                   
                 humikccj 
               
               
                   
                 humikcck 
               
               
                   
                 humikcco 
               
               
                   
                 humikccp 
               
               
                   
                 humikccq 
               
               
                   
                 humikccr 
               
               
                   
                 humikccs 
               
               
                   
                 humikcct 
               
               
                   
                 humikccu 
               
               
                   
                 humikccv 
               
               
                   
                 humikccw 
               
               
                   
                 humikcd 
               
               
                   
                 humikcf 
               
               
                   
                 humikcg 
               
               
                   
                 humikch 
               
               
                   
                 humikci 
               
               
                   
                 humikck 
               
               
                   
                 humikcm 
               
               
                   
                 humikcn 
               
               
                   
                 humikco 
               
               
                   
                 humikcp 
               
               
                   
                 humikcq 
               
               
                   
                 humikcr 
               
               
                   
                 humikcs 
               
               
                   
                 humikct 
               
               
                   
                 humikcu 
               
               
                   
                 humikcv 
               
               
                   
                 humikcva 
               
               
                   
                 humikcvb 
               
               
                   
                 humikcvc 
               
               
                   
                 humikcvd 
               
               
                   
                 humikcve 
               
               
                   
                 humikcvf 
               
               
                   
                 humikcvg 
               
               
                   
                 humikcvh 
               
               
                   
                 humikcvi 
               
               
                   
                 humikcvj 
               
               
                   
                 humikcw 
               
               
                   
                 humikcx 
               
               
                   
                 humikcy 
               
               
                   
                 humikcz 
               
               
                   
                 S46248 
               
               
                   
                 S82746 
               
               
                   
                 S82747 
               
               
                   
                 SU96396 
               
               
                   
                 SU96397 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 28P 
               
             
             
               
                   
               
               
                 AA types seen in 154 kappa sequences having CDR1 of length 11 Tally 
               
             
          
           
               
                   
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 11 
                 143 
                   
                   
                   
                   
                   
                 R 
               
               
                 2 
                 148 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 2 
                 2 
                 1 
                   
                   
                 A 
               
               
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 152 
                 2 
                   
                   
                   
                 S 
               
               
                 4 
                   
                   
                 1 
                 3 
                   
                   
                 3 
                   
                   
                   
                   
                   
                   
                 147 
                   
                   
                   
                   
                   
                   
                 Q 
               
               
                 5 
                   
                   
                 12 
                 1 
                   
                 27 
                   
                   
                   
                   
                   
                 7 
                   
                   
                 3 
                 99 
                 4 
                 1 
                   
                   
                 S 
               
               
                 6 
                 1 
                   
                   
                   
                   
                   
                   
                 81 
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                 71 
                   
                   
                 V 
               
               
                 7 
                 2 
                   
                 4 
                   
                   
                 18 
                   
                 5 
                 1 
                 2 
                   
                 9 
                   
                   
                 12 
                 97 
                 3 
                   
                   
                 1 
                 S 
               
               
                 8 
                   
                   
                 3 
                   
                   
                 5 
                 1 
                 2 
                 1 
                   
                   
                 31 
                 1 
                   
                 10 
                 87 
                 12 
                   
                   
                 1 
                 S 
               
               
                 9 
                 2 
                   
                 7 
                   
                 10 
                 1 
                 6 
                   
                   
                   
                   
                 29 
                   
                   
                 1 
                 8 
                   
                   
                 13 
                 77 
                 Y 
               
               
                 10 
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                 150 
                   
                   
                   
                   
                   
                 1 
                   
                 1 
                   
                   
                 L 
               
               
                 11 
                 96 
                   
                   
                   
                   
                 4 
                 2 
                   
                   
                   
                   
                 46 
                   
                   
                   
                 2 
                 1 
                 3 
                   
                   
                 A 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 30P 
               
               
                   
               
               
                 Synthetic Kappa light chain gene 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ! 
               
               
                 ! 
               
               
                 ! A27:: JH1 with all CDRs replaced by stuffers. 
               
               
                 ! Each stuffer contains at least one stop codon and a 
               
               
                 ! restriction site that will be unique within the diversity vector. 
               
               
                 ! 
               
               
                     1 GAGGACCATt GGGCCCC                 ctccgagact 
               
               
                 !     Scab...... Eco0109I 
               
               
                 !                ApaI. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                    28         CTCGAG cgca 
               
               
                 !             XhoI.. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                    38 acgcaatTAA TGTgagttag ctcactcatt aggcacccca ggcTTTACAc tttatgcttc 
               
               
                 !            ..−35..         Plac                    ..−10. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                    98 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tc 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                   140 acacagga aacagctatgac 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                   160 catgatta cgCCAAGCTT TGGagccttt tttttggaga ttttcaac (SEQ ID NO: 54) 
               
               
                 !                PflMI....... 
               
               
                 !                    Hind3. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !        M13 III signal sequence (AA seq)---------------------------&gt; 
               
               
                 !          1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                 !          M   K   K   L   L   F   A   I   P   L   V   V   P   F   Y 
               
               
                   206     gtg aag aag ctc cta ttt gct atc ccg ctt gtc gtt ccg ttt tac 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !        --Signal--&gt;  FR1-------------------------------------------&gt; 
               
               
                 !         16  17  18  19  20  21  22  23  24  25  26  27  28  29  30 
               
               
                 !          S   H   S   A   Q   S   V   L   T   Q   S   P   G   T   L 
               
               
                   251    |agc|cat|aGT|GCA|Caa|tcc|gtc|ctt|act|caa|tct|cct|ggc|act|ctt| 
               
               
                 !                  ApaLI... 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !        ----- FR1 -------------------------------------&gt;| CDR1------ &gt; 
               
               
                 !         31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                 !          S   L   S   P   G   E   R   A   T   L   S   C   R   A   S (SEQ ID NO: 55) 
               
               
                          |tcG|CTA|AGC|CCG|GGt|gaa|cgt|gct|acC|TTA|AGt|tgc|cgt|gct|tcc| (SEQ ID NO: 54; Cont&#39;d)) 
               
               
                 !           EspI.....                       AflII... 
               
               
                 !                   XmaI.... 
               
               
                 ! 
               
               
                 !----------------------------------- 
               
               
                 ! For CDR1: 
               
               
                 ! &lt;1&gt; ADEFGHIKLMNPQRSTVWY equimolar 
               
               
                 ! &lt;2&gt; S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each) 
               
               
                 ! &lt;3&gt; Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each) 
               
               
                 ! In a preferred embodiment, we omit codon 52 in vgDNA for CDR1. 
               
               
                 ! 
               
               
                 !          ------- CDR1 ---------------------&gt;|--- FR2 ---------------&gt; 
               
               
                 !              &lt;1&gt;     &lt;2&gt; &lt;2&gt; xxx &lt;3&gt; 
               
               
                 !          46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                 !           Q   S   V   S   S   S   Y   L   A   W   Y   Q   Q   K   P 
               
               
                           |cag|tct|gtt|tcc|tct|tct|tat|ctt|gct|tgg|tat|caa|cag|aaA|CCT| 
               
               
                 !                                                                SexAI... 
               
               
                 !----------------------------------- 
               
               
                 ! For CDR2: 
               
               
                 ! &lt;1&gt; ADEFGHIKLMNPQRSTVWY equimolar 
               
               
                 ! &lt;2&gt; S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each) 
               
               
                 ! &lt;4&gt; A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each) 
               
               
                 !         ----- FR2 -------------------------&gt;|------- CDR2 ----------&gt; 
               
               
                 !                                              &lt;1&gt;         &lt;2&gt;     &lt;4&gt; 
               
               
                 !          61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                 !           G   Q   A   P   R   L   L   I   Y   G   A   S   S   R   A 
               
               
                           |GGT|caG|GCG|CCg|cgt|tta|ctt|att|tat|ggt|gct|tct|tcc|cgc|gct| 
               
               
                 !    SexAI....   KasI.... (CDR1 installed as AflII-(SexAI or KasI) cassette.) 
               
               
                 ! 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !      CDR2--&gt;|--- FR3 -----------------------------------------------&gt; 
               
               
                 !          &lt;1&gt; 
               
               
                 !          76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                 !           T   G   I   P   D   R   F   S   G   S   G   S   G   T   D 
               
               
                           |act|gGG|ATC|CCG|GAC|CGt|ttc|tct|ggc|tct|ggt|tca|ggt|act|gac| 
               
               
                 !               BamHI... 
               
               
                 !                      RsrII... 
               
               
                 ! (CDR2 installed as (SexAI or KasI) to (BamHI or RsrII) cassette.) 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         ------ FR3 -------------------------------------------------&gt; 
               
               
                 !          91  92  93  94  95  96  97  98  99 100 101 102 103 104 105 
               
               
                 !           F   T   L   T   I   S   R   L   E  P   E   D   F   A   V 
               
               
                   477     |ttt|acc|ctt|act|att|TCT|AGA|ttg|gaa|cct|gaa|gac|ttc|gct|gtt| 
               
               
                 !                              XbaI... 
               
               
                 ! 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         -----------&gt;|----CDR3--------------------------&gt;|-----FR4---&gt; 
               
               
                 !                              &lt;3&gt; &lt;1&gt; &lt;1&gt; &lt;1&gt;     &lt;1&gt; 
               
               
                 !         106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                 !          Y   Y   C   Q   Q   Y   G   S   S   P   E   T   F   G   Q 
               
               
                          |tat|tat|tgC|CAa|cag|taT|GGt|tct|tct|cct|gaa|act|ttc|ggt|caa| 
               
               
                 !                   BstXI........... 
               
               
                 ! 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !        -----FR4-------------------&gt;|      &lt;------- Ckappa ------------ 
               
               
                 !        121 122 123 124 125 126 127        128 129 130 131 132 133 134 
               
               
                 !         G   T   K   V   E   I   K          R   T   V   A   A   P   S 
               
               
                   510   |ggt|aCC|AAG|Gtt|gaa|atc|aag|      |CGT|ACG|gtt|gcc|gct|cct|agt| 
               
               
                 !             StyI....                      BsiWI.. 
               
               
                 ! 
               
               
                 ! (CDR3 installed as XbaI to (StyI or BsiWI) cassette.) 
               
               
                 ! 
               
               
                 !        135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 
               
               
                 !         V   F   I   F   P   P   S   D   E   Q   L   K   S   G   T 
               
               
                   552   |gtg|ttt|atc|ttt|cct|cct|tct|gac|gaa|CAA|TTG|aag|tca|ggt|act| 
               
               
                 !                                            MfeI... 
               
               
                 ! 
               
               
                 !        150 151 152 153 154 155 156 157 156 159 160 161 162 163 164 
               
               
                 !         A   S   V   V   C   L   L   N   N   F   Y   P   R   E   A 
               
               
                   597   |gct|tct|gtc|gta|tgt|ttg|ctc|aac|aat|ttc|tac|cCT|CGT|Gaa|gct| 
               
               
                 !                                                     BssSI... 
               
               
                 ! 
               
               
                 !        165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 
               
               
                 !         K   V   Q   W   K   V   D   N   A   L   Q   S   G   N   S 
               
               
                   642   |aaa|gtt|cag|tgg|aaa|gtc|gat|aAC|GCG|Ttg|cag|tcg|ggt|aac|agt| 
               
               
                 !                                     MluI.... 
               
               
                 ! 
               
               
                 !        180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 
               
               
                 !         Q   E   S   V   T   E   Q   D   S   K   D   S   T   Y   S 
               
               
                   687   |caa|gaa|tcc|gtc|act|gaa|cag|gat|agt|aag|gac|tct|acc|tac|tct| 
               
               
                 ! 
               
               
                 !        195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 
               
               
                 !         L   S   S   T   L   T   L   S   K   A   D   Y   E   K   H 
               
               
                   732   |ttg|tcc|tct|act|ctt|act|tta|tca|aag|gct|gat|tat|gag|aag|cat| 
               
               
                 ! 
               
               
                 !        210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 
               
               
                 !         K   V   Y   A   C   E   V   T   H   Q   G   L   S   S   P 
               
               
                   777   |aag|gtc|tat|GCt|TGC|gaa|gtt|acc|cac|cag|ggt|ctG|AGC|TCc|cct| 
               
               
                 !                                                      SacI.... 
               
               
                 ! 
               
               
                 !       225 226 227 228 229 230 231 232 233 234 
               
               
                 !        V   T   K   S   F   N   R   G   E   C   .   . (SEQ ID NO: 332) 
               
               
                   822  |gtt|acc|aaa|agt|ttc|aaC|CGT|GGt|gaa|tgc|taa|tag GGCGCGCC 
               
               
                 !                             DsaI....                  AscI.... 
               
               
                 !                                                        BssHII 
               
               
                 ! 
               
               
                   866 acgcatctctaa GCGGCCGC aacaggaggag (SEQ ID NO: 333) 
               
               
                 !                  NotI.... 
               
               
                 !                   EagI.. 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 31P 
               
             
             
               
                   
               
               
                 Tally of 285 CDR2s of length 7 in human kappa 
               
             
          
           
               
                 Tally 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                 51 
                   
                 62 
                 7 
                   
                 95 
                 1 
                   
                 11 
                 15 
                 2 
                 1 
                   
                   
                 2 
                 6 
                 6 
                 3 
                 22 
                 1 
                 x 
               
               
                 2 
                 225 
                   
                   
                   
                   
                 18 
                   
                 5 
                   
                 5 
                   
                 2 
                 1 
                   
                 1 
                 3 
                 16 
                 9 
                   
                   
                 A 
               
               
                 3 
                 2 
                   
                   
                   
                 9 
                   
                   
                 1 
                   
                   
                   
                 2 
                   
                   
                   
                 267 
                 2 
                   
                 1 
                 1 
                 S 
               
               
                 4 
                 2 
                   
                 1 
                   
                   
                   
                 5 
                 4 
                 9 
                 1 
                   
                 77 
                   
                   
                 4 
                 93 
                 80 
                   
                 2 
                 7 
                 Sx 
               
               
                 5 
                   
                 1 
                   
                   
                 2 
                   
                   
                   
                   
                 80 
                   
                   
                   
                   
                 200 
                 2 
                   
                   
                   
                   
                 R 
               
               
                 6 
                 162 
                   
                 7 
                 36 
                 4 
                   
                 4 
                   
                 1 
                 3 
                   
                   
                 3 
                 63 
                   
                   
                   
                 2 
                   
                   
                 Ax 
               
               
                 7 
                 5 
                   
                 1 
                   
                   
                 3 
                   
                 1 
                 1 
                   
                   
                 2 
                 2 
                   
                 1 
                 125 
                 144 
                   
                   
                   
                 x 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 32P 
               
             
             
               
                   
               
               
                 Tally of 166 CDR3s of length 9 from human kappa. 
               
             
          
           
               
                 Tally 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                   
                   
                   
                   
                   
                   
                 4 
                   
                   
                 8 
                 21 
                   
                   
                 131 
                 1 
                   
                   
                 1 
                   
                   
                 Q 
               
               
                 2 
                   
                   
                   
                 1 
                   
                   
                 9 
                   
                 2 
                 1 
                   
                   
                   
                 153 
                   
                   
                   
                   
                   
                   
                 Q 
               
               
                 3 
                 14 
                 4 
                 4 
                   
                 3 
                 6 
                 4 
                   
                   
                 1 
                   
                 1 
                 3 
                   
                 21 
                 16 
                 3 
                 4 
                   
                 82 
                 Yx 
               
               
                 4 
                 1 
                   
                 9 
                 1 
                 2 
                 37 
                 4 
                 2 
                 2 
                 15 
                 1 
                 33 
                   
                   
                 2 
                 20 
                 7 
                 1 
                   
                 29 
                 x 
               
               
                 5 
                 2 
                   
                 2 
                 6 
                   
                 3 
                 4 
                 5 
                 3 
                   
                   
                 28 
                   
                 17 
                 7 
                 65 
                 19 
                 1 
                 1 
                 3 
                 x 
               
               
                 6 
                 7 
                   
                 1 
                   
                 11 
                 2 
                   
                 3 
                   
                 8 
                   
                 1 
                 4 
                   
                 3 
                 41 
                 33 
                 5 
                 28 
                 19 
                 x 
               
               
                 7 
                   
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                 6 
                   
                   
                 146 
                 2 
                 2 
                 5 
                   
                 2 
                   
                   
                 P 
               
               
                 8 
                 2 
                 4 
                 1 
                 2 
                 21 
                 7 
                 3 
                 5 
                 1 
                 38 
                   
                   
                 7 
                 4 
                 25 
                 1 
                 3 
                 1 
                 16 
                 25 
                 x 
               
               
                 9 
                 3 
                   
                   
                   
                   
                   
                 2 
                 1 
                   
                   
                   
                 1 
                   
                   
                   
                 2 
                 157 
                   
                   
                   
                 T 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 33P 
               
             
             
               
                   
               
               
                 lengths of CDRs in 93 human lambda chains 
               
             
          
           
               
                   
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18+ 
               
               
                   
               
             
          
           
               
                 CDR1 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 23 
                 7 
                 15 
                 46 
                 0 
                 0 
                 0 
                 2 
               
               
                 CDR2 
                 5 
                 0 
                 0 
                 1 
                 0 
                 0 
                 0 
                 80 
                 2 
                 0 
                 0 
                 1 
                 4 
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                 CDR3 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 1 
                 16 
                 28 
                 27 
                 6 
                 1 
                 0 
                 4 
                 6 
                 4 
                 0 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 34P 
               
             
             
               
                   
               
               
                 Tally of 46 CDR1s of length 14 from human lambda chains 
               
             
          
           
               
                 Tally 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                 2 
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 41 
                   
                   
                   
                 T 
               
               
                 2 
                   
                   
                   
                   
                   
                 43 
                   
                   
                   
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 G 
               
               
                 3 
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 1 
                 6 
                 36 
                   
                   
                   
                 TGx 
               
               
                 4 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 45 
                   
                   
                   
                   
                 S 
               
               
                 5 
                   
                   
                   
                   
                   
                 5 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 40 
                   
                   
                   
                   
                 S 
               
               
                 6 
                   
                   
                 39 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 4 
                   
                   
                   
                 2 
                   
                   
                   
                   
                 DNx 
               
               
                 7 
                   
                   
                   
                   
                   
                   
                   
                 8 
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                 37 
                   
                   
                 V 
               
               
                 8 
                   
                   
                 1 
                   
                   
                 42 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                 1 
                   
                   
                 G 
               
               
                 9 
                 4 
                   
                 1 
                   
                   
                 35 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 2 
                 3 
                   
                   
                   
                 TGx 
               
               
                 10 
                 1 
                   
                   
                   
                 1 
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                 38 
                 Yx 
               
               
                 11 
                   
                   
                 4 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 35 
                   
                   
                   
                   
                   
                   
                   
                 6 
                 DNx 
               
               
                 12 
                   
                   
                 3 
                   
                 1 
                   
                 2 
                   
                   
                 1 
                   
                   
                   
                   
                 1 
                 2 
                   
                   
                   
                 36 
                 Yx 
               
               
                 13 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                 43 
                   
                   
                 V 
               
               
                 14 
                   
                   
                   
                   
                 1 
                   
                 4 
                   
                   
                   
                   
                   
                   
                   
                   
                 41 
                   
                   
                   
                   
                 S 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 35P 
               
               
                   
               
               
                 Synthtic human lambda-chain gene 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ! Lambda 14-7(A) 2a2 :: JH2:: Clambda 
               
               
                 ! AA sequence tested 
               
               
                 ! 
               
               
                      1 GAGGACCATt GGGCCCC ttactccgtgac 
               
               
                 !      Scab...... Eco0109I 
               
               
                 !                 ApaI.. 
               
               
                 !----------------------------------------------- 
               
               
                 ! 
               
               
                 !              -----------FR1--------------------------------------------&gt; 
               
               
                 !               1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                 !       S   A   Q   S   A   L   T   Q   P   A   S   V   S   G   S   P   G 
               
               
                     30 aGT|GCA|Caa|tcc|gct|ctc|act|cag|cct|GCT|AGC|gtt|tcc|gGG|TcA|CCt|GGT| 
               
               
                 !       ApaLI...                           NheI...          BstEII... 
               
               
                 !                                                                SexAI.... 
               
               
                 !----------------------------------------------- 
               
               
                 ! 
               
               
                 ! For CDR1, 
               
               
                 ! &lt;1&gt; = 0.27 T, 0.27 G, 0.027 {ADEFHIKLMNPQRSVWY} no C 
               
               
                 ! &lt;2&gt; = 0.27 D, 0.27 N, 0.027 {AEFGHIKLMPQRSTVWY} no C 
               
               
                 ! &lt;3&gt; = 0.36 Y, 0.0355{ADEFGHIKLMNPQRSTVW} no C 
               
               
                 !                                    T   G  &lt;1&gt;  S   S  &lt;2&gt;  V   G 
               
               
                 !      ------FR1------------------&gt; |-----CDR1--------------------- 
               
               
                 !       16  17  18  19  20  21  22  23  24  25  26  27  28  29  30 
               
               
                 !        Q   S   I   T   I   S   C   T   G   T   S   S   D   V   G 
               
               
                        |caa|agt|atc|act|att|tct|TGT|ACA|ggt|act|tct|tct|gat|gtt|ggc| 
               
               
                 !                               BsrGI.. 
               
               
                 ! 
               
               
                 ! a second vg scheme for CDR1 gives segments of length 11: 
               
               
                 ! G 23 &lt;2&gt;&lt;4&gt;L&lt;4&gt;&lt;4&gt;&lt;4&gt;&lt;3&gt;&lt;4&gt;&lt;4&gt; where 
               
               
                 ! &lt;4&gt; = equimolar {ADEFGHIKLMNPQRSTVWY} no C 
               
               
                 !------------------------------------------------------- 
               
               
                 ! 
               
               
                 !       &lt;1&gt; &lt;3&gt; &lt;2&gt; &lt;3&gt;  V   S = vg Scheme #1, length = 14 
               
               
                 !       -----CDR1-------------&gt;|--------FR2------------------------- 
               
               
                 !       31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                 !        G   Y   N   Y   V   S   W   Y   Q   Q   H   P   G   K   A 
               
               
                        |ggt|tac|aat|tac|gtt|tct|tgg|tat|caa|caa|caC|CCG|GGc|aaG|GCG| 
               
               
                 !                                                 XmaI....    KasI..... 
               
               
                 !                                                 AvaI.... 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !                               &lt;4&gt; &lt;4&gt; &lt;4&gt; &lt;2&gt;  R   P   S 
               
               
                 !       --FR2-----------------&gt; |------CDR2---------------&gt;|-----FR3-- 
               
               
                 !       46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                 !        P   K   L   M   I   Y   E   V   S   N   R   P   S  G   V 
               
               
                        |CCg|aag|ttg|atg|atc|tac|gaa|gtt|tcc|aat|cgt|cct|tct|ggt|gtt| 
               
               
                 ! KasI.... 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !      -------FR3---------------------------------------------------- 
               
               
                 !       61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                 !        S   N   R   F   S   G   S   K   S   G   N   T   A   S   L 
               
               
                        |agc|aat|cgt|ttc|TCC|GGA|tct|aaa|tcc|ggt|aat|acc|gcA|AGC|TTa| 
               
               
                 !                       BspEI..           |               HindIII. 
               
               
                 !                            BsaBI........(blunt) 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !      -------FR3--------------------------------------------------&gt;| 
               
               
                 !       76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                 !        T   I   S   G   L   Q   A   E   D   E   A   D   Y   Y   C 
               
               
                        |act|atc|tct|ggt|CTG|CAG|gct|gaa|gac|gag|gct|gac|tac|tat|tgt| 
               
               
                 !                       PstI... 
               
               
                 ! 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 ! &lt;5&gt; = 0.36 S, 0.0355{ADEFGHIKLMNPQRTVWY} no C 
               
               
                 ! 
               
               
                 !       &lt;4&gt; &lt;5&gt; &lt;4&gt; &lt;2&gt; &lt;4&gt;  S  &lt;4&gt; &lt;4&gt; &lt;4&gt; &lt;4&gt;  V 
               
               
                 !      -----CDR3----------------------------------&gt;|---FR4--------- 
               
               
                 !       91  92  93  94  95  96  97  98  99 100 101 102 103 104 105 
               
               
                 !        S   S   Y   T   S   S   S   T   L  V   V   F   G   G   G 
               
               
                        |tct|tct|tac|act|tct|tct|agt|acc|ctt|gtt|gtc|ttc|ggc|ggt|GGT| 
               
               
                 !                                                               KpnI... 
               
               
                 ! 
               
               
                 !------------------------------------------------------------------------ 
               
               
                 ! 
               
               
                 !      -------FR4--------------&gt; 
               
               
                 !       106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                 !        T   K   L   T   V   L   G   Q   P   K   A   A   P   S   V 
               
               
                    279 |ACC|aaa|ctt|act|gtc|ctc|gGT|CAA|CCT|aAG|Gct|gct|cct|tcc|gtt| 
               
               
                 !   KpnI...                      HincII.. 
               
               
                 !                                       Bsu36I... 
               
               
                 ! 
               
               
                 !       121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 
               
               
                 !        T   L   F   P   P   S   S   E   E   L   Q   A   N   K   A 
               
               
                    324 |act|ctc|ttc|cct|cct|agt|tct|GAA|GAG|Ctt|caa|gct|aac|aag|gct| 
               
               
                 !                                   SapI..... 
               
               
                 ! 
               
               
                 !       136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 
               
               
                 !        T   L   V   C   L   I   S   D   F   Y   P   G   A   V   T 
               
               
                    369 |act|ctt|gtt|tgc|tTG|ATC|Agt|gac|ttt|tat|cct|ggt|gct|gtt|act| 
               
               
                 !                        BclI.... 
               
               
                 ! 
               
               
                 !       151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 
               
               
                 !        V   A   W   K   A   D   S   S   P   V   K   A   G   V   E 
               
               
                    414 |gtc|gct|tgg|aaa|gcc|gat|tct|tct|cct|gtt|aaa|gct|ggt|gtt|GAG| 
               
               
                 !                                                               BsmBI... 
               
               
                 ! 
               
               
                 !       166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 
               
               
                 !        T   T   T   P   S   K   Q   S   N   N   K   Y   A   A   S 
               
               
                    459 |ACG|acc|act|cct|tct|aaa|caa|tct|aac|aat|aag|tac|gct|gcG|AGC| 
               
               
                 ! BsmBI....                                                   SacI.... 
               
               
                 ! 
               
               
                 !       181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 
               
               
                 !        S   Y   L   S   L   T   P   E   Q   W   K   S   H   K   S 
               
               
                    504 |TCt|tat|ctt|tct|ctc|acc|cct|gaa|caa|tgg|aag|tct|cat|aaa|tcc| 
               
               
                 !  SacI... 
               
               
                 ! 
               
               
                 !       196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 
               
               
                 !        Y   S   C   Q   V   T   H   E   G   S   T   V   E   K   T 
               
               
                    549 |tat|tcc|tgt|caa|gtt|acT|CAT|GAa|ggt|tct|acc|gtt|gaa|aag|act| 
               
               
                 !                             BspHI... 
               
               
                 ! 
               
               
                 !       211 212 213 214 215 216 217 218 219 
               
               
                 !        V   A   P   T   E   C   S   .   . (SEQ ID NO: 57) 
               
               
                    594 |gtt|gcc|cct|act|gag|tgt|tct|tag|tga|GGCGCGCC 
               
               
                 !                                           AscI.... 
               
               
                 !                                            BssHII 
               
               
                 ! 
               
               
                    629 aacgatgttcaag GCGGCCGC aacaggaggag (SEQ ID NO: 56) 
               
               
                 !                    NotI.... Scab....... 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 36P 
               
             
             
               
                   
               
               
                 Tally of 23 CDR1s of length 11 from human lambda chains 
               
             
          
           
               
                 Tally 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                 1 
                   
                   
                   
                   
                 6 
                   
                   
                   
                   
                   
                   
                   
                 10 
                   
                 6 
                   
                   
                   
                   
                 x 
               
               
                 2 
                 1 
                   
                   
                 1 
                   
                 21 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 G 
               
               
                 3 
                   
                   
                 15 
                   
                   
                 1 
                   
                   
                   
                   
                   
                 7 
                   
                   
                   
                   
                   
                   
                   
                   
                 DNx 
               
               
                 4 
                 2 
                   
                   
                 1 
                   
                 1 
                   
                   
                 3 
                   
                   
                 7 
                   
                   
                 1 
                 8 
                   
                   
                   
                   
                 X 
               
               
                 5 
                   
                   
                   
                   
                   
                   
                   
                 7 
                   
                 16 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 L 
               
               
                 6 
                   
                   
                   
                   
                   
                 11 
                   
                   
                 1 
                   
                   
                   
                 2 
                   
                 8 
                   
                 1 
                   
                   
                   
                 X 
               
               
                 7 
                   
                   
                 1 
                 1 
                   
                 1 
                   
                   
                 2 
                   
                   
                 2 
                   
                   
                 1 
                 14 
                 1 
                   
                   
                   
                 X 
               
               
                 8 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 10 
                   
                   
                 1 
                   
                 1 
                 1 
                 2 
                   
                   
                   
                 7 
                 X 
               
               
                 9 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                 6 
                   
                   
                   
                 15 
                 Yx 
               
               
                 10 
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                 11 
                   
                   
                 X 
               
               
                 11 
                   
                 3 
                   
                   
                   
                   
                 7 
                   
                   
                   
                   
                   
                   
                   
                   
                 9 
                 2 
                   
                   
                 2 
                 X 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 37P 
               
             
             
               
                   
               
               
                 Tally of 80 CDR2s of length 7 from human lambda chains 
               
             
          
           
               
                 Tally 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                 1 
                   
                 14 
                 32 
                 1 
                 13 
                   
                   
                 3 
                   
                   
                 1 
                   
                 4 
                 5 
                 1 
                 2 
                   
                   
                 3 
                 X 
               
               
                 2 
                   
                   
                 18 
                 2 
                   
                   
                   
                   
                 8 
                   
                   
                 16 
                   
                   
                   
                   
                 2 
                 34 
                   
                   
                 X 
               
               
                 3 
                 1 
                   
                 2 
                   
                   
                   
                   
                 1 
                   
                   
                   
                 31 
                   
                   
                   
                 39 
                 4 
                   
                   
                 2 
                 X 
               
               
                 4 
                   
                   
                 6 
                 4 
                   
                   
                 1 
                   
                 14 
                 1 
                   
                 41 
                   
                 8 
                 1 
                 1 
                 2 
                   
                   
                 1 
                 DNx 
               
               
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                 1 
                   
                   
                   
                   
                 78 
                   
                   
                   
                   
                   
                 R 
               
               
                 6 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                 77 
                   
                   
                 2 
                   
                   
                   
                   
                 P 
               
               
                 7 
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 78 
                   
                   
                   
                   
                 S 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 38P 
               
             
             
               
                   
               
               
                 Tally of 27 CDR3s of length 11 from human lambda chains 
               
             
          
           
               
                 Tally 
                 A 
                 C 
                 D 
                 E 
                 F 
                 G 
                 H 
                 I 
                 K 
                 L 
                 M 
                 N 
                 P 
                 Q 
                 R 
                 S 
                 T 
                 V 
                 W 
                 Y 
                   
               
               
                   
               
             
          
           
               
                 1 
                 4 
                   
                   
                   
                   
                 5 
                   
                   
                   
                   
                   
                 6 
                   
                 5 
                   
                 4 
                 3 
                   
                   
                   
                 X 
               
               
                 2 
                 3 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                 14 
                 5 
                 2 
                   
                   
                 Sx 
               
               
                 3 
                   
                   
                   
                   
                 1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 7 
                   
                   
                   
                 13 
                 6 
                 X 
               
               
                 4 
                   
                   
                 19 
                   
                   
                 2 
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 1 
                 4 
                   
                   
                   
                 DNx 
               
               
                 5 
                 1 
                   
                 4 
                   
                   
                 2 
                   
                 2 
                   
                   
                   
                 2 
                   
                   
                 1 
                 13 
                 2 
                   
                   
                   
                 X 
               
               
                 6 
                   
                   
                   
                   
                   
                   
                   
                 1 
                   
                   
                   
                 3 
                   
                   
                 1 
                 21 
                 1 
                   
                   
                   
                 S 
               
               
                 7 
                   
                   
                 1 
                   
                   
                 7 
                   
                   
                   
                 12 
                   
                 1 
                   
                   
                   
                 4 
                 2 
                   
                   
                   
                 X 
               
               
                 8 
                   
                   
                 2 
                   
                   
                 1 
                   
                   
                   
                   
                   
                 10 
                 1 
                   
                   
                 6 
                 6 
                 1 
                   
                   
                 X 
               
               
                 9 
                 3 
                   
                   
                   
                 1 
                 8 
                 10 
                   
                   
                 3 
                   
                   
                 1 
                   
                   
                 1 
                   
                   
                   
                   
                 X 
               
               
                 10 
                 1 
                   
                   
                   
                   
                 4 
                 1 
                   
                 1 
                 1 
                   
                   
                 3 
                   
                 1 
                 1 
                   
                 6 
                 5 
                 3 
                 X 
               
               
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 2 
                   
                   
                   
                   
                   
                   
                   
                 25 
                   
                   
                 V 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 40P 
               
               
                   
               
               
                 Synthetic Kappa light chain gene with stuffers 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ! 
               
               
                 !  A27:: JH1 with all CDRs replaced by stuffers. 
               
               
                 !  Each stuffer contains at least one stop codon and a 
               
               
                 !  restriction site that will be unique within the diversity vector. 
               
               
                 ! 
               
               
                      1 GAGGACCATt GGGCCCC                 ctccgagact 
               
               
                 !      Scab...... Eco0109I 
               
               
                 !                 ApaI. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                     28         CTCGAG cgca 
               
               
                 !              XhoI.. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                     38 acgcaatTAA TGTgagttag ctcactcatt aggcacccca ggcTTTACAc tttatgcttc 
               
               
                 !             ..−35..         Plac                    ..−10. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                     98 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tc 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                    140 acacagga aacagctatgac 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                    160 catgatta cgCCAAGCTT TGGagccttt tttttggaga ttttcaac 
               
               
                 !                 PflMI....... 
               
               
                 !                   Hind3. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         M13 III signal sequence (AA seq)---------------------------&gt; 
               
               
                 !           1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                 !           M   K   K   L   L   F   A   I   P   L   V   V   P   F   Y 
               
               
                    206     gtg aag aag ctc cta ttt gct atc ccg ctt gtc gtt ccg ttt tac 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         --Signal--&gt;  FR1-------------------------------------------&gt; 
               
               
                 !          16  17  18  19  20  21  22  23  24  25  26  27  28  29  30 
               
               
                 !           S   H   S   A   Q   S   V   L   T   Q   S   P   G   T   L 
               
               
                    251    |agc|cat|aGT|GCA|Caa|tcc|gtc|ctt|act|caa|tct|cct|ggc|act|ctt| 
               
               
                 !                   ApaLI... 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         ----- FR1 ---------------------------------&gt;|-------Stuffer-&gt; 
               
               
                 !          31  32  33  34  35  36  37  38  39  40  41  42  43 
               
               
                 !           S   L   S   P   G   E   R   A   T   L   S   |   | 
               
               
                    296    |tcG|CTA|AGC|CCG|GGt|gaa|cgt|gct|acC|TTA|AGt|TAG|TAA|gct|ccc| 
               
               
                 !            EspI.....                       AflII... 
               
               
                 !                    XmaI.... 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !          ------- Stuffer for CDR1-------------------------&gt;|- FR2 --&gt; 
               
               
                 !                                                              59  60 
               
               
                 !                                                               K   P 
               
               
                    341    |AGG|CCT|ctt|TGA|tct|                              g|aaA|CCT| 
               
               
                 !          StuI...                                               SexAI... 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         ----- FR2 ------|-----------Stuffer for CDR2----------------&gt; 
               
               
                 !          61  62  63  64  65  66 
               
               
                 !           G   Q   A   P   R   |   | 
               
               
                    363    |GGT|caG|GCG|CCg|cgt|TAA|TGA|a AGCGCT aa TGGCCA aca gtg 
               
               
                 !    SexAI....   KasI....                AfeI..    MscI.. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !   Stuffer--&gt;|--- FR3 -----------------------------------------------&gt; 
               
               
                 !          &lt;1&gt; 
               
               
                 !          76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                 !           T   G   I   P   D   R   F   S   G   S   G   S   G   T   D 
               
               
                    405    |act|gGG|ATC|CCG|GAC|CGt|ttc|tct|ggc|tct|ggt|tca|ggt|act|gac| 
               
               
                 !               BamHI... 
               
               
                 !                      RsrII..... 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         ------FR3 ----------------------STUFFER for CDR3------------------&gt; 
               
               
                 !          91  92  93  94  95  96  97 
               
               
                 !           F   T   L   T   I   S   R   |   | 
               
               
                    450    |ttt|acc|ctt|act|att|TCT|AGA|TAA|TGA| GTTAAC TAG acc TACGTA acc tag 
               
               
                 !                              XbaI...          HpaI..         SnaBI. 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 ! 
               
               
                 !         -----------------CDR3 stuffer------------------&gt;|-----FR4---&gt; 
               
               
                 !                                                         118 119 120 
               
               
                 !                                                           F   G   Q 
               
               
                    501                                                    |ttc|ggt|caa| 
               
               
                 !----------------------------------- 
               
               
                 ! 
               
               
                 !         -----FR4-------------------&gt;|      &lt;------- Ckappa ------------ 
               
               
                 !         121 122 123 124 125 126 127        128 129 130 131 132 133 134 
               
               
                 !           G   T   K   V   E   I   K         R   T   V   A   A   P   S 
               
               
                    510    |ggt|aCC|AAG|Gtt|gaa|atc|aag|     |CGT|ACG|gtt|gcc|gct|cct|agt| 
               
               
                 !               StyI....                     BsiWI.. 
               
               
                 ! 
               
               
                 ! (CDR3 installed as XbaI to (StyI or BsiWI) cassette.) 
               
               
                 ! 
               
               
                 !            135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 
               
               
                 !             V   F   I   F   P   P   S   D   E   Q   L   K   S   G   T (SEQ ID NO: 96) 
               
               
                    552      |gtg|ttt|atc|ttt|cct|cct|tct|gac|gaa|CAA|TTG|aag|tca|ggt|act| 
               
               
                 !                                                MfeI... 
               
               
                 ! 
               
               
                 ! 
               
               
                    866 acgcatctctaa GCGGCCGC aacaggaggag (SEQ ID NO: 95) 
               
               
                 !                   NotI.... 
               
               
                 !                    EagI.. 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 41P 
               
               
                   
               
               
                 Variegated DNA for kappa chains 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 !---------------------------------------------------------------- 
               
               
                 ! Kappa chains 
               
               
                 ! For CDR1: 
               
               
                 ! &lt;1&gt; ADEFGHIKLMNPQRSTVWY equimolar 
               
               
                 ! &lt;2&gt; S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each) 
               
               
                 ! &lt;3&gt; Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each) 
               
               
                 ! &lt;4&gt; A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each) 
               
               
                 (Ka1vg600)                         5′-gct|acC|TTA|AGt|tgc|cgt|gct|tcc|cag- 
               
               
                       |&lt;1&gt;|gtt|&lt;2&gt;|&lt;2&gt;|    &lt;3&gt;|ctt|gct|tgg|tat|caa|cag|aaA|CC-3′ (SEQ ID NO: 66) 
               
               
                 (Ka2vg650)      5′-caG|GCG|CCg|cgt|tta|ctt|att|tat|&lt;1&gt;|gct|tct|&lt;2&gt;|cgc|&lt;4&gt;|- 
               
               
                                   |&lt;1&gt;|gGG|ATC|CCG|GAC|CGt|ttc|tct|ggt|tctcacc-3′ (SEQ ID NO: 71) 
               
               
                 (Ka3vg670) 5′-                                            gac|ttc|gct|gtt|- 
               
               
                               |tat|tat|tgC|CAa|cag|&lt;3&gt;|&lt;1&gt;|&lt;1&gt;|&lt;1&gt;|cct|&lt;1&gt;|act|ttc|ggt|caa|- 
               
               
                               |ggt|aCC|AAG|Gtt|g-3′ (SEQ ID NO: 77) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 42P 
               
               
                   
               
               
                 Variegated DNA for lambda chains 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 !------------------------ 
               
               
                 ! For CDR1, 
               
               
                 ! &lt;1&gt; = 0.27 T, 0.27 G, 0.027 {ADEFHIKLMNPQRSVWY} no C 
               
               
                 ! &lt;2&gt; = 0.27 D, 0.27 N, 0.027 {AEFGHIKLMPQRSTVWY} no C 
               
               
                 ! &lt;3&gt; = 0.36 Y, 0.0355{ADEFGHIKLMNPQRSTVW} no C 
               
               
                 ! &lt;4&gt; = equimolar {ADEFGHIKLMNPQRSTVWY} no C 
               
               
                 ! &lt;5&gt; = 0.36 S, 0.0355{ADEFGHIKLMNPQRTVWY} no C 
               
               
                 (Lm1vg710) 5′-gt|atc|act|att|tct|TGT|ACA|ggt|&lt;1&gt;|tct|tct|&lt;2&gt;|gtt|ggc|- 
               
               
                        |&lt;1&gt;|&lt;3&gt;|&lt;2&gt;|&lt;3&gt;|gtt|tct|tgg|tat|caa|caa|caC|CC-3′ (SEQ ID NO: 83) 
               
               
                 !------------------------------------------------- 
               
               
                 (Lm2vg750)                              5′-G|CCg|aag|ttg|atg|atc|tac|- 
               
               
                    &lt;4&gt;|&lt;4&gt;|&lt;4&gt;|&lt;2&gt;|cgt|cct|tct|ggt|gtc|agc|aat|c-3′ (SEQ ID NO: 88) 
               
               
                 (Lm3vg817) 5′-                         gac|gag|gct|gac|tac|tat|tgt|- 
               
               
                        |&lt;4&gt;|&lt;5&gt;|&lt;4&gt;|&lt;2&gt;|&lt;4&gt;|tct|&lt;4&gt;|&lt;4&gt;|&lt;4&gt;|&lt;4&gt;|gtc|ttc|ggc|ggt|GGT|- 
               
               
                       |ACC|aaa|ctt|ac-3′ (SEQ ID NO: 93) 
               
               
                 !---------------------------------------------------------------- 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 43P 
               
               
                   
               
               
                 Constant DNA for Synthetic Library 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ! CDR3 library components 
               
               
                 (Ctop25) 5′-gctctggtcaa  C|TTA|AG g|gct|gag|g-3′ (SEQ ID NO: 58) 
               
               
                 (CtprmA) 5′-gctctggtcaa  C|TTA|AG g|gct|gag|gac- 
               
               
                 !                       AflII... 
               
               
                             |a cc|gct|gtc|tac|tac|tgc|gcc -3′ (SEQ ID NO: 59) 
               
               
                 ! 
               
               
                 (CBprmB)[RC] 5′- |tac|ttc|gat|tac|ttg|ggc|caa|GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′ (SEQ ID NO: 60) 
               
               
                 !                                                      BstEII... 
               
               
                 (CBot25)[RC]                             5′- |GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′ (SEQ ID NO: 61) 
               
               
                 !---------------------------------------------------------------- 
               
               
                 ! Kappa chains 
               
               
                 (Ka1Top610) 5′-ggtctcagtt- 
               
               
                             G|CTA|AGC|CCG|GGt|gaa|cgt|gct|acC|TTA|AGt|tgc|cgt|gct|tcc|cag-3′ (SEQ ID NO: 62) 
               
               
                 (Ka1STp615) 5′-ggtctcagtt- 
               
               
                             G|CTA|AGC|CCG|GGt|g-3′ (SEQ ID NO: 63) 
               
               
                 (Ka1Bot620) [RC]            5′-ctt|gct|tgg|tat|caa|cag|aaA|- 
               
               
                                     CCt|GGT|caG|GCG|CC aagtcgtgtc-3′ (SEQ ID NO: 64) 
               
               
                 (Ka1SB625)  [RC] 5′-cct |GGT|caG|GCG|CC aagtcgtgtc-3′ (SEQ ID NO: 65) 
               
               
                 ! 
               
               
                 (Ka2Tshort657) 5′-cacgagtcctA|CCT|GGT|- 
               
               
                                    caG|GC-3′ (SEQ ID NO: 68) 
               
               
                 (Ka2Tlong655)  5′-cacgagtcctA|CCT|GGT|- 
               
               
                                    caG|GCG|CCg|cgt|tta|ctt|att|tat-3′ (SEQ ID NO: 69) 
               
               
                 (Ka2Bshort660) [RC] 5′-           |GAC|CGt|ttc|tct|ggt|tctcacc-3′ (SEQ ID NO: 70) 
               
               
                 !---------------------------------------------------------------- 
               
               
                 (Ka3Tlon672)5′-       gacgagtcct  TCT|AGA|ttg|gaa|cct|gaa|gac|ttc|gct|gtt|- 
               
               
                              |tat|tat|tgC|CAa|c -3′ (SEQ ID NO: 72) 
               
               
                 (Ka3BotL682)                                      [RC] 5′-act|ttc|ggt|caa|- 
               
               
                              |ggt|aCC|AAG|Gtt|gaa|atc|aag|     |CGT|ACG| tcacaggtgag-3′ (SEQ ID NO: 73) 
               
               
                 (Ka3Bsho694) [RC]5′-          gaa|atc|aag|     |CGT|ACG| tcacaggtgag-3′ (SEQ ID NO: 74) 
               
               
                 !----------------------------------------------------------------- 
               
               
                 (Lm1TPri75) 5′-gacgagtcct GG|TcA|CCt|GGT|-3′ (SEQ ID NO: 78) 
               
               
                 (Lm1TLo715) 5′-gacgagtcct GG|TcA|CCt|GGT|- 
               
               
                          caa|agt|atc|act|att|tct|TGT|ACA|ggt-3′ (SEQ ID NO: 79) 
               
               
                 (Lm1BLo724)[RC] 5′-gtt|tct|tgg|tat|caa|caa|caC|CCG|GGc|aaG|GCG|- 
               
               
                          AGA TCT  tcacaggtgag-3′ (SEQ ID NO: 80) 
               
               
                 (Lm1BSh737)[RC] 5′-                                 Gc|aaG|GCG|- 
               
               
                          AGA TCT tcacaggtgag-3′ (SEQ ID NO: 81) 
               
               
                 !------------------------------------------------- 
               
               
                 (Lm2TSh757)  5′-gagcagagga C|CCG|GGc|aaG|GC-3′ (SEQ ID NO: 84) 
               
               
                 (Lm2TLo753)  5′-gagcagagga C|CCG|GGc|aaG|GCG|CCg|aag|ttg|atg|atc|tac|-3′ (SEQ ID NO: 85) 
               
               
                 (Lm2BLo762)[RC] 5′-cgt|cct|tct|ggt|gtc|agc|aat|cgt|ttc|TCC|GGA|tcacaggtgag-3′ (SEQ ID NO: 86) 
               
               
                 (Lm2BSh765)[RC] 5′-                            cgt|ttc|TCC|GGA|tcacaggtgag-3′ (SEQ ID NO: 87) 
               
               
                 !------------------------------------------------- 
               
               
                 (Lm3TSh822)         5′-CTG|CAG|gct|gaa|gac|gag|gct|gac -3′ (SEQ ID NO: 89) 
               
               
                 (Lm3TLo819)         5′-CTG|CAG|gct|gaa|gac|gag|gct|gac|tac|tat|tgt|-3′ (SEQ ID NO: 90) 
               
               
                 (Lm3BLo825) [RC]                             5′-gtc|ttc|ggc|ggt|GGT|- 
               
               
                       |ACC|aaa|ctt|act|gtc|ctc|gGT|CAA| CCT|aAG|G  acacaggtgag-3′ (SEQ ID NO: 91) 
               
               
                 (Lm3BSh832) [RC]   5′-       c|gGT|CAA| CCT|aAG|G  acacaggtgag-3′ (SEQ ID NO: 92) 
               
               
                 !--------------------------------------------------------------- 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 48P 
               
               
                   
               
               
                 Synthtic human lambda-chain gene with stuffers in place of CDRs 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 ! Lambda 14-7(A)    2a2 ::JH2::Clambda 
               
               
                 ! AA sequence tested 
               
               
                 ! 
               
               
                      1 GAGGACCATt GGGCCCC   ttactccgtgac 
               
               
                 !      Scab...... EcoO109I 
               
               
                 !                 ApaI.. 
               
               
                 !----------------------------------------------- 
               
               
                 ! 
               
               
                 !              -----------FR1--------------------------------------------&gt; 
               
               
                 !               1   2   3   4   5   6   7   8   9  10  11  12  13  14  15 
               
               
                 !       S   A   Q   S   A   L   T   Q   P   A   S   V   S   G   S   P   G 
               
               
                     30 aGT|GCA|Caa|tcc|gct|ctc|act|cag|cct|GCT|AGC|gtt|tcc|gGG|TcA|CCt|GGT| 
               
               
                 !       ApaLI...                           NheI...          BstEII... 
               
               
                 !                                                                SexAI.... 
               
               
                 !----------------------------------------------- 
               
               
                 ! 
               
               
                 !      ------FR1------------------&gt; |-----stuffer for CDR1--------- 
               
               
                 !       16  17  18  19  20  21  22  23 
               
               
                 !        Q   S   I   T   I   S   C   T 
               
               
                     81 |caa|agt|atc|act|att|tct|TGT|ACA|tct TAG TGA ctc 
               
               
                 !                               BsrGI.. 
               
               
                 !------------------------------------------------------- 
               
               
                 ! 
               
               
                 !       -----Stuffer---------------------------&gt;-------------------- 
               
               
                 !       31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                 !        R   S   |   |   P   |                   H   P   G   K   A 
               
               
                    117  AGA TCT TAA TGA ccg tag                 caC|CCG|GGc|aaG|GCG| 
               
               
                 !       BglII                                     XmaI....    KasI..... 
               
               
                 !                                                  AvaI.... 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !       --|-------------Stuffer -------------------------------------&gt; 
               
               
                 !        P 
               
               
                    150 |CCg|TAA|TGA|atc tCG TAC G                        ct|ggt|gtt| 
               
               
                 ! KasI....               BsiWI... 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !      -------FR3---------------------------------------------------- 
               
               
                 !       61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                 !        S   N   R   F   S   G   S   K   S   G   N   T   A   S   L 
               
               
                    177 |agc|aat|cgt|ttc|TCC|GGA|tct|aaa|tcc|ggt|aat|acc|gcA|AGC|TTa| 
               
               
                 !                       BspEI..          |                HindIII. 
               
               
                 !                            BsaBI........(blunt) 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !      -------FR3-------------&gt;|--Stuffer--------------------------&gt;| 
               
               
                 !       76  77  78  79  80  81  82  83  84  85  86  87  88  89  90 
               
               
                 !        T   I   S   G   L   Q 
               
               
                    222 |act|atc|tct|ggt|CTG|CAG|gtt ctg tag ttc CAATTG ctt tag tga ccc 
               
               
                 !                       PstI...                 MfeI.. 
               
               
                 !------------------------------------------------------------------- 
               
               
                 ! 
               
               
                 !      -----Stuffer-------------------------------&gt;|---FR4--------- 
               
               
                 !                                                      103 104 105 
               
               
                 !                                                        G   G   G 
               
               
                    270                                                 |ggc|ggt|GGT| 
               
               
                 !                                                               KpnI... 
               
               
                 !------------------------------------------------------------------------ 
               
               
                 ! 
               
               
                 !      -------FR4--------------&gt; 
               
               
                 !       106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 
               
               
                 !        T   K   L   T   V   L   G   Q   P   K   A   A   P   S   V 
               
               
                    279 |ACC|aaa|ctt|act|gtc|ctc|gGT|CAA|CCT|aAG|Gct|gct|cct|tcc|gtt| 
               
               
                 !   KpnI...                      HincII.. 
               
               
                 !                                       Bsu36I... 
               
               
                 ! 
               
               
                 !       121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 
               
               
                 !        T   L   F   P   P   S   S   E   E   L   Q   A   N   K   A 
               
               
                    324 |act|ctc|ttc|cct|cct|agt|tct|GAA|GAG|Ctt|caa|gct|aac|aag|gct| 
               
               
                 !                                   SapI..... 
               
               
                 ! 
               
               
                 !       136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 
               
               
                 !        T   L   V   C   L   I   S   D   F   Y   P   G   A   V   T   (SEQ ID NO: 98) 
               
               
                    369 |act|ctt|gtt|tgc|tTG|ATC|Agt|gac|ttt|tat|cct|ggt|gct|gtt|act| (SEQ ID NO: 97) 
               
               
                 !                      BclI.... 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
             
           
               
                 TABLE 50P 
               
               
                   
               
               
                 3-23:: CDR3:: JH4 Stuffers in place of CDRs 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                                                   FR1(DP47/V3-23)--------------- 
               
               
                           20  21  22              23  24  25  26  27  28  29  30 
               
               
                            A   M   A               E   V   Q   L   L   E   S   G 
               
               
                 ctgtctgaac CC atg gcc             gaa|gtt|CAA|TTG|tta|gag|tct|ggt| 
               
               
                 Scab...... NcoI....                      | MfeI  | 
               
               
                   
               
               
                       --------------FR1-------------------------------------------- 
               
               
                        31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 
               
               
                         G   G   L   V   Q   P   G   G   S   L   R   L   S   C   A 
               
               
                       |ggc|ggt|ctt|gtt|cag|cct|ggt|ggt|tct|tta|cgt|ctt|tct|tgc|gct| 
               
               
                   
               
               
                       ----FR1--------------------&gt;|...CDR1 stuffer....|---FR2------ 
               
               
                        46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 
               
               
                         A   S   G   F   T   F   S   S   Y   A   |   |   W   V   R 
               
               
                       |gct|TCC|GGA|ttc|act|ttc|tct|tCG|TAC|Gct| TAG|TAA |tgg|gtt|cgC| 
               
               
                           | BspEI |                 | BsiWI|                     |BstXI. 
               
               
                   
               
               
                        -------FR2--------------------------------&gt;|...CDR2 stuffer. 
               
               
                        61  62  63  64  65  66  67  68  69  70  71  72  73  74  75 
               
               
                         Q   A   P   G   K   G   L   E   W   V   S   |   p   r   | 
               
               
                       |CAa|gct|ccT|GGt|aaa|ggt|ttg|gag|tgg|gtt|tct|TAA|CCT|AGG|TAG| 
               
               
                   ...BstXI          |                                  AvrII.. 
               
               
                   
               
               
                      .....CDR2 stuffer....................................|---FR3--- 
               
               
                       --------FR3-------------------------------------------------- 
               
               
                         91  92  93  94  95  96  97  98  99 100 101 102 103 104 105 
               
               
                         T   I   S   R   D   N   S   K   N   T   L   Y   L   Q   M 
               
               
                       |act|atc|TCT|AGA|gac|aac|tct|aag|aat|act|ctc|tac|ttg|cag|atg| 
               
               
                               | XbaI  | 
               
               
                   
               
               
                       ---FR3-----------..&gt; Stuffer-------------&gt;| 
               
               
                        106 107 108 109 110 
               
               
                         N   S   L   R   A (SEQ ID NO: 53) 
               
               
                       |aac|agC|TTA|AGg|gct|TAG TAA AGG cct TAA (SEQ ID NO: 52) 
               
               
                              |AflII |              StuI... 
               
               
                   
               
               
                       |----- FR4 ---(JH4)----------------------------------------- 
               
               
                        Y   F   D   Y   W   G   Q   G   T   L   V   T   V   S   S (SEQ ID NO: 26) 
               
               
                      |tat|ttc|gat|tat|tgg|ggt|caa|GGT|ACC|ctG|GTC|ACC|gtc|tct|agt|... (SEQ ID NO: 25) 
               
               
                                              | KpnI  |  | BstEII |