Patent Document

BACKGROUND OF THE INVENTION  
         [0001]    (a) Field of the Invention  
           [0002]    The invention relates to the identification of three genes: the gene clk-2, the gene cex-7 that is located in the same operon as clk-2, and the gene coq-4. The invention shows that these genes regulate the timing of development and behavior, and determine life span and that clk-2 regulates the length of telomeres.  
           [0003]    (b) Description of Prior Art  
           [0004]    A class of genes was identified in the nematode  Caenorhabditis elegans , the clk (‘clock’) genes, whose activity controls how fast the worms live and die. Mutations in these genes result in an alteration of developmental and behavioral timing, including an average slow down of the animal&#39;s embryonic and post-embryonic development and of their rhythmic behaviors, as well as an increase in the animal&#39;s life span. In addition, mutations in these genes display a maternal effect, namely, homozygous mutants (clk/clk) derived from a heterozygous mother (clk/+), appear phenotypically wild-type.  
           [0005]    We isolated the mutations that define the genes clk-1, clk-2, clk-3 in a screen for viable maternal-effect mutations in the nematode  Caenorhabditis elegans  (Hekimi, S. et al.,  Genetics  141, 1351 (1995)). gro-1 was originally identified by a spontaneous mutation isolated from a strain that had been recently established from a wild isolate (Hodgkin, J. and Doniach, T.  Genetics  146, 149 (1997)). Our subsequent reappraisal of this mutation revealed that it shares the characteristics of the clk genes (Wong, A. et al.,  Genetics  139, 1247 (1995)).  
           [0006]    We have molecularly identified two of these genes, clk-1 and gro-1. clk-1 encodes a protein that is highly conserved from proteobacteria to humans which is structurally similar to the yeast metabolic regulator Cat5p/Coq7p (Ewbank, J. J. et al,  Science  275, 980 (1997); WO98/17823). gro-1 encodes a highly conserved cellular enzyme, the dimethylallyltransferase:tRNA dimethylallyltransferase (WO99/10482).  
           [0007]    To date, clk-1 is the gene that has been characterized in greatest detail. In addition to the phenotypic and molecular characterization, it was found that clk-1 is ubiquitously expressed in the worm&#39;s body where it localizes to the mitochondria, the energy generating organelle of the cell (Felkai, S. et al,  EMBO Journal  18, 1783 (1999)). clk-1 thus controls timing by regulating physiological rates (Branicky R, C. Benard, S. Hekimi,  Bioessays  22, 48 (2000)).  
           [0008]    The gene clk-2 is defined by one allele that was isolated in a screen for viable maternal-effect mutations in  Caenorhabditis elegans  (Hekimi, S. et al.,  Genetics  141, 1351 (1995)). The mutations in the gene clk-2 were shown to result in an alteration of the timing of several developmental and behavioral events (Hekimi, S. et al.,  Genetics  141, 1351 (1995)) and that the activity of the gene clk-2 controls how fast the worms live and how soon they die (Lakowski, B. and Hekimi,  S. Science  272, 1010 (1996). We have also noticed other phenotypes of the clk-2 mutants such as the temperature sensitivity of the clk-2 (qm37) allele. Overall, these phenotypes are similar to those of mutations in the three clk genes (Hekimi, S. et al.,  Genetics  141, 1351 (1995)).  
           [0009]    Results to date suggest that the effect of clk genes on the rate of aging is due to an effect on the rate of living. First, clk-1 mutations which lead to a decrease of clk-1 activity result in a slow down of development and behavior and in an increase in life span. On the other hand, overexpression of clk-1 in transgenic animals accelerates the rate of living as revealed by the absence of a characteristic behavioral slow down with age. Second, the effect of the different clk genes is additive. We have shown that double clk mutants develop more slowly and live longer than the single clk mutants. Third, clk genes are distinct from dauer formation genes (daf genes) which are involved in stress resistance and also prolong life span. Daf genes affect life span through a separate mechanism from that of clk. In fact, clk mutants are neither dauer constitutive nor dauer defective and daf-16 mutations cannot suppress the long life of clk-1, -2, -3 mutants.  
           [0010]    The gene coq-4 is similar to the gene clk-1 in that both genes are required for normal ubiquinone biosynthesis in yeast and both genes have no homologues in  E. coli . The gene cex-7 that will be described below has been found to be a pseudoautosomal gene named XE7 in humans.  
           [0011]    It would be highly desirable to be provided with a detailed phenotypic and molecular characterization of the gene clk-2, as well as with a characterization of the gene coq-4 in an animal.  
         SUMMARY OF THE INVENTION  
         [0012]    One aim of the present invention is to provide with a clk-2 gene which has a function at the level of cellular physiology involved in developmental rate, telomere length and longevity, wherein clk-2 mutations cause a longer life, an altered cellular metabolism and an altered telomere length relative to the wild type, wherein clk-2 gene has the identifying characteristics of nucleotide sequence described in FIG. 1.  
           [0013]    In accordance with the present invention there is provided the use of a clk-2 gene to alter a function at the level of cellular physiology involved in the regulation of developmental rates, telomere length and longevity, wherein clk-2 mutations cause a longer life, an altered cellular metabolism and physiological rates and an altered telomere length relative to the wild type, wherein clk-2 gene has the identifying characteristics of nucleotide sequences described in FIGS.  1 ,  4 - 7 ,  15 ,  16 , and  20 - 24 , or wherein the gene codes for a protein sequence as described in FIGS. 2, 3,  8 - 14 ,  17 - 19 , and  25 - 32  as deduced from FIGS.  1 ,  4 - 7 ,  15 ,  16 ,  20 - 24 .  
           [0014]    Also is provided with the invention the use of a clk-2 gene to alter function at the level of cellular physiology involved in the regulation of developmental rate, telomere length and longevity, wherein clk-2 mutations cause a longer life and altered cellular metabolism and physiological rates and an altered telomere length relative to the wild type, wherein the gene codes for a protein having a sequence as set forth in FIG. 32.  
           [0015]    In accordance with the invention there is provided a CLK-2 protein that has a function at the level of cellular physiology involved in the regulation of developmental rate, telomere length and longevity.  
           [0016]    There is also provided with the invention a mutant CLK-2 protein which has the amino acid sequence described in FIG. 31, and the use of CLK-2 protein to alter a function at the level of cellular physiology involved in the regulation of developmental rates, telomere length and longevity, wherein the CLK-2 protein has the amino acid sequence as described in FIGS. 2, 3,  8 - 14 ,  17 - 19 , and  25 - 32 .  
           [0017]    In accordance with the invention, there is provided a clk-2 gene which has the nucleotide sequence described in FIG. 1, and the use of clk-2 gene and homologues thereof, to manipulate the physiological rates and/or telomere biology, whereby life span of an organism is altered.  
           [0018]    There is also provided a mouse which comprises a gene knockout of the murine clk-2 gene homologue to a clk-2 gene.  
           [0019]    There is provided with the present invention a method to increase the life span of multicellular organism and metazoan which comprises altering the function of telomeres and mechanisms of sub-telomeric silencing.  
           [0020]    The invention also provides the use of clk-2 gene, CLK-2 protein, and homologues thereof, for screening drugs which decrease or increase the life span of a multicellular organism, wherein the drug enhances or suppresses the expression of the clk-2 gene or activity of the protein CLK-2, and homologues thereof.  
           [0021]    The use of a compound is provided with the invention for the manufacture of a medicament for increasing and/or decreasing physiological rates of tissues, organ, and/or whole organism of a host; wherein the compound is interfering with activity of CLK-2 protein and homologues thereof.  
           [0022]    The use of a compound is also provided to promote tissue and/or organ specific reduction or increase of clk-2 activity for the manufacture of a medicament for the treatment of pathological conditions causing increase or decrease of physiological rate of tissue and/or organ in an individual, wherein the compound is interfering with activity of CLK-2 protein and homologues thereof.  
           [0023]    In accordance with the invention there is provided a clk-2 co-expressed gene which comprises a cex-7 gene having the nucleotide sequence as described in FIG. 33, and which codes for a CEX-7 protein having the amino acid sequence described in FIG. 34 wherein the gene is located in the clk-2 operon and the cex-7 gene is transcriptionally co-expressed with clk-2 gene present in the same operon.  
           [0024]    A human homologue of cex-7 gene is also provided with the invention, wherein the gene codes for a protein having a sequence as described in FIG. 35.  
           [0025]    There is provided with the invention the use of a human homologue of cex-7 gene and homologues thereof to alter a function at the level of cellular level physiology involved in the regulation of developmental rates and longevity wherein the gene codes for a protein having a sequence as described in FIG. 35.  
           [0026]    The invention provides with a mouse which comprises a gene knock out of the murine cex-7 gene homologue of the human gene described in FIG. 35.  
           [0027]    There is also provided with the invention the use of a compound for the manufacture of a medicament for increasing and/or decreasing physiological rates of tissues, organ, and/or whole organism of a host; wherein the compound is interfering with activity of CEX-7 and homologues thereof.  
           [0028]    Another aim of the invention is to provide with the use of a compound which promotes tissue and/or organ specific reduction or increase of cex-7 activity for the manufacture of a medicament for the treatment of pathological conditions causing increase or decrease of physiological rate of tissue and/or organ in an individual, wherein the compound is interfering with activity of CEX-7 and homologues thereof.  
           [0029]    There is provided with the invention a coq-4 gene which has a function at the level of cellular physiology involved in the regulation of developmental rate and longevity, wherein coq-4 mutations cause altered cellular metabolism and physiological relative to the wild type, wherein coq-4 gene has the identifying characteristics of nucleotide sequence as described in FIG. 36.  
           [0030]    A coq-4 gene provided with the invention has a function at the level of cellular physiology involved in the regulation of developmental rate and longevity, wherein coq-4 mutations cause altered cellular metabolism and physiological relative to the wild type, wherein coq-4 gene has the identifying characteristics of nucleotide sequence as described in FIG. 36, and the gene codes for a protein having a sequence as described in FIG. 37.  
           [0031]    In accordance with the invention, there is provided with the use of coq-4 gene to alter a function at the level of cellular physiology involved in the regulation of developmental rates, wherein coq-4 mutations cause an altered cellular metabolism and physiological rates relative to the wild type, wherein the gene codes for a protein having a sequence as described in FIGS.  43  to  54  and homologues thereof.  
           [0032]    There is also provided with the invention a mouse which comprises a gene knock out of the murine coq-4 gene as described in FIG. 47.  
           [0033]    There is provided also with the invention the use of a compound for the manufacture of a medicament for increasing and/or decreasing physiological rates of tissues, organs and/or whole organism of a host; wherein the compound is interfering with activity of COQ-4 and homologues thereof.  
           [0034]    A compound in accordance with the invention is provided to promote tissue and/or organ specific reduction or increase of coq-4 activity for the manufacture of a medicament for the treatment of pathological conditions causing increase or decrease of physiological rate of tissue and/or organ in an individual, wherein the compound is interfering with activity of COQ-4 and homologues thereof.  
           [0035]    Having the clk genes in hand can serve to manipulate the rate of development, the cell cycle, the rate of behavior and the rate of aging. Another way to look at it is that it can help to control physiological rates including for medical and industrial purposes. Slowing down the rate of aging of individual organs or tissues to slow down their rate of deterioration is one medical example; accelerating the growth of farm animals or crops is an example of industrial utilization.  
           [0036]    Here we describe our analysis of clk-2 and cex-7 and the inventions that result from this analysis, including the molecular characterization of clk-2 and cex-7 and the identification of homologues in several species, including humans. We also describe our identification of a new clk gene: coq-4. We have obtained a mutation in the worm coq-4 locus and have shown that the mutant animals display several of the most important characteristics of clk mutations. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0037]    [0037]FIGS. 1A and 1B illustrate the  Caenorhabditis elegans  clk-2 cDNA sequence.  
         [0038]    [0038]FIG. 2 illustrates the  Caenorhabditis elegans  CLK-2 protein sequence.  
         [0039]    [0039]FIG. 3 illustrates the  Homo sapiens  CLK-2 protein sequence(derived from clone KIAA0683).  
         [0040]    [0040]FIGS. 4A and 4B illustrate the  Homo sapiens  clk-2 homologue nucleotide sequence (derived from AL080126).  
         [0041]    [0041]FIG. 5 illustrates part of  Mus musculus  clk-2 cDNA sequence (derived from AA671905 vl11b10.r1).  
         [0042]    [0042]FIG. 6 illustrates part of  Mus musculus  clk-2 cDNA sequence (derived from AA031108 mi40f03.r1).  
         [0043]    [0043]FIG. 7 illustrates part of  Mus musculus  clk-2 cDNA sequence (derived from AA230994 mw30h11.r1).  
         [0044]    [0044]FIG. 8 illustrates part of  Mus musculus  CLK-2 protein sequence (derived from gb|AA671905.1|AA671905.)  
         [0045]    [0045]FIG. 9 illustrates part of  Mus musculus  CLK-2 protein sequence (derived from gb|AA230994.1|AA230994).  
         [0046]    [0046]FIG. 10 illustrates part of  Mus musculus  CLK-2 protein sequence (derived from gb|AA031108.1|AA031108).  
         [0047]    [0047]FIG. 11 illustrates  Mus musculus  composite CLK-2 protein sequence.  
         [0048]    [0048]FIG. 12 illustrates part of  Sus scrofa  CLK-2 protein sequence (derived from gb|AW429611.1|AW429611).  
         [0049]    [0049]FIG. 13 illustrates the  Drosophila melanogaster  CLK-2 protein sequence.  
         [0050]    [0050]FIG. 14 illustrates the putative  Arabidopsis thaliana  CLK-2 protein sequence (derived from 7630034|emb|CAB88328.1|).  
         [0051]    [0051]FIG. 15 illustrates part of  Oryza sativa  clk-2 cDNA sequence (derived from AU031811).  
         [0052]    [0052]FIG. 16 illustrates part of  Oryza sativa  clk-2 cDNA sequence (derived from D24238).  
         [0053]    [0053]FIG. 17 illustrates part of  Oryza sativa  CLK-2 protein sequence (derived from dbj|D24422.1|D24422).  
         [0054]    [0054]FIG. 18 illustrates part of  Oryza sativa  CLK-2 protein sequence (derived from dbj|AU031811.1|AU031811).  
         [0055]    [0055]FIG. 19 illustrates  Oryza sativa  composite CLK-2 protein.  
         [0056]    [0056]FIG. 20 illustrates part of  Glycine max  clk-2 cDNA sequence (derived from AI461201 sa76d07.y1 Gm-c1004).  
         [0057]    [0057]FIG. 21 illustrates part of  Glycine max  clk-2 cDNA sequence (derived from AW185029 se85g06.y1 Gm-c1023).  
         [0058]    [0058]FIG. 22 illustrates part of  Glycine max  clk-2 cDNA sequence (derived from AW350166 GM210007A10F4R Gm-r1021).  
         [0059]    [0059]FIG. 23 illustrates part of  Glycine max  clk-2 cDNA sequence (derived from AW397826 sg68g12.y1 Gm-c1007).  
         [0060]    [0060]FIG. 24 illustrates part of  Glycine max  clk-2 cDNA sequence (derived from AW567713 si54a01.y1 Gm-r1030).  
         [0061]    [0061]FIG. 25 illustrates part of  Glycine max  CLK-2 protein sequence (derived from gb|AW350166.1|AW350166).  
         [0062]    [0062]FIG. 26 illustrates part of  Glycine max  CLK-2 protein sequence (derived from gb|AI461201.1|AI461201).  
         [0063]    [0063]FIG. 27 illustrates part of  Glycine max  CLK-2 protein sequence (derived from gb|AW|85029.1|AW185029).  
         [0064]    [0064]FIG. 28 illustrates part of  Glycine max  CLK-2 protein sequence (derived from gb|AW567713.1|AW567713).  
         [0065]    [0065]FIG. 29 illustrates part of  Glycine max  CLK-2 protein sequence (derived from gb|AW397826.1|AW397826).  
         [0066]    [0066]FIG. 30 illustrates  Glycine max  CLK-2 composite protein sequence.  
         [0067]    [0067]FIG. 31 illustrates the  Caenorhabditis elegans  CLK-2 (QM37) mutant protein, with C to Y substitution at position 772.  
         [0068]    [0068]FIG. 32 illustrates Tel2p, the  Saccharomyces cerevisiae  CLK-2 protein.  
         [0069]    [0069]FIG. 33 illustrates the  Caenorhabditis elegans  cex-7 cDNA sequence.  
         [0070]    [0070]FIG. 34 illustrates the  Caenorhabditis elegans  CEX-7 protein sequence.  
         [0071]    [0071]FIG. 35 illustrates the  Homo sapiens  CEX-7 protein sequence (XE7).  
         [0072]    [0072]FIG. 36 illustrates the  Caenorhabditis elegans  coq-4 cDNA sequence.  
         [0073]    [0073]FIG. 37 illustrates the  Caenorhabditis elegans  COQ-4 protein sequence.  
         [0074]    [0074]FIGS. 38A and 38B illustrate the comparison of CLK-2 eukaryotic homologues (hCLK-2:  Homo sapiens  CLK-2:  Caenorhabditis elegans  Tel2p:  Saccharomyces cerevisiae  AtCLK-2:  Arabidopsis thaliana ).  
         [0075]    [0075]FIG. 39 illustrates the comparison of CLK-2 animal homologues (D.m.:  Drosophila melanogaster , H.s.:  Homo sapiens  C.e.:  Caenorhabditis elegans ).  
         [0076]    [0076]FIG. 40 illustrates the comparison of CLK-2 vertebrate homologues (H.s.:  Homo sapiens,  M.m.:  Mus musculus,  S.s.: Sus scrofa).  
         [0077]    [0077]FIG. 41 illustrates the comparison of CLK-2 plant homologues (A.t.:  Arabidopsis thaliana , G.m.:  Glycine max , O.s.:  Oryza sativa ).  
         [0078]    [0078]FIG. 42 illustrates the comparison of COQ-4 homologous proteins.  
         [0079]    [0079]FIG. 43 illustrates  Drosophila melanogaster  COQ-4 protein (derived from gi|7293987|gb|AAF49344.1|CG3877).  
         [0080]    [0080]FIG. 44 illustrates  Homo sapiens  COQ-4 protein (derived from gi|7705807|ref|NP — 057119.1|CGI-92).  
         [0081]    [0081]FIG. 45 illustrates  Schizosaccharomyces pombe  COQ-4 protein (derived from gi|7493130|pir||T37755).  
         [0082]    [0082]FIG. 46 illustrates  Arabidopsis thaliana  COQ-4 protein (derived from gi|4406761|gb|AAD20072.1|).  
         [0083]    [0083]FIG. 47A illustrates part of  Mus musculus  COQ-4 protein (derived from gb|AA274683.1|AA274683); FIG. 47B part of  Mus musculus  COQ-4 protein (derived from dbj|AU051632.1|AU051632); FIG. 47C part of  Mus musculus  COQ-4 protein (derived from gb|AI157531.1|AI157531); and FIG. 47D  Mus musculus  COQ-4 consensus protein.  
         [0084]    [0084]FIG. 48 illustrates  Glycine max  COQ-4 protein (derived from gb|AW201157.1|AW201157).  
         [0085]    [0085]FIG. 49 illustrates  Bos taurus  COQ-4 protein (derived from gb|AW660771.1|AW660771).  
         [0086]    [0086]FIG. 50 illustrates  Medicago truncatula  COQ-4 protein (derived from gb|AW696025.1|AW696025).  
         [0087]    [0087]FIG. 51 illustrates  Ancylostoma caninum  COQ-4 protein (derived from gb|AW870537.1|AW870537).  
         [0088]    [0088]FIG. 52 illustrates  Trypanosoma cruzi  COQ-4 Protein (derived from gb|AW330043.1|AW330043).  
         [0089]    [0089]FIG. 53 illustrates Rattus rattus COQ-4 protein (derived from gb|AA800046.1|AA800046).  
         [0090]    [0090]FIG. 54 illustrates  Gossypium hirsutum  COQ-4 protein (derived from gb|A|731097.1|AI731097).  
         [0091]    FIGS.  55 A-C illustrate the expression pattern of clk-2.  
         [0092]    FIGS.  56 A-E illustrate the telomere-lengthening phenotype of clk-2(qm37) mutants at different temperatures. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0093]    For the first time, there is provided with the present invention a new method of increasing life span by modulating the biology of telomeres.  
         [0094]    The Clk Phenotype of clk-2 Mutants  
         [0095]    We had shown previously that clk-2 mutants have a phenotype similar to that of clk-1 mutants, including the maternal rescue effect, their slow development and behavior, and their increased life span (Hekimi, et al.,  Genetics  141, 1351 (1995); Lakowski, B. and Hekimi, S.  Science  272, 1010 (1996). We have characterized the defects of clk-2 mutants in much further detail, the results of which follow. From 15° C. to 20° C. the phenotype of clk-2 mutants is similar to that of clk-1 mutants. The average developmental, reproductive and behavioral rates are dramatically slower, and the mean and maximum life span longer, than those of the wild type as summarized in Table 1. In particular, the embryonic development of clk-2(qm37) mutants lasts 17.0±1.5 hours (n=97) at 20° C., while the wild type lasts 13.2±0.7 hours (n=80). The post-embryonic development of clk-2 (qm37) mutants is also slower lasting 95.7±1.3 hours at 20° C. (n=73), while the wild-type worms take only 53.6±8.7 hours (n=184).  
         [0096]    The defecation cycles are slowed down as well, occurring every 105.7±15.2 seconds in clk-2 mutants at 20° C. (n=10) and every 54.9±0.6 seconds in the wild type (n=70). The pumping rate is lower, 180.9±24.8 pumps per minute occurring in the clk-2 mutants at 20° C. (n=25), and 265.3±64.4 pumps per minute in the wild type (n=25).  
                                                       TABLE 1                           Phenotypic characterization of clk-2(qm37)       animals at 20° C.                        Maternally           Wild Type       rescue clk-           (N2)   clk-2(qm37)   2(qm37)                            Embryonic   13.2 ± 0.7   17.0 ± 1.5   13.3 ± 1.6           Development   n = 80   n = 97   n = 40           (hours)           Post-embryonic   53.6 ± 8.7   95.7 ± 1.3    53.9 ± 12.4           Development    n = 184   n = 73   n = 98           (hours)           Self-brood   302.4 ± 30.5   83.4   113.9 ± 30.3           Size   n = 20   n = 10   n = 24           (eggs)           Peak Egg-   5.3   1.3    3.6 ± 0.9           laying Rate   n = 10   n = 10   n = 24           (eggs per           hour)           Defecation   54.9 ± 0.6   105.7 ± 15.2   60.3 ± 9.0           (seconds)   n = 70   n = 10   n = 8            Pumping   265.3 ± 64.4   180.9 ± 24.8   245.2 ± 24.6           (pumps per   n = 25   n = 25   n = 11           minute)                      
 
         [0097]    In addition, we have also examined the self-brood size at 20° C. and found that is reduced in clk-2 mutants where it is 83.4 (n=10), while it is 302.4±30.5 in the wild type (n=20). The peak egg-laying rate is 1.3 (n=10) in clk-2 mutants at 20° C., and 5.3 (n=10) in the wild type. We have also examined the life span. clk-2(qm37) mutants live longer than the wild type, living on average 22.4±7.4 days (n=100) at 20° C. and having a maximum life span of 40 days, which is longer that the average life span of 19.3±5.3 days (n=100) and maximum life span of 32 days of wild-type N2 worms.  
         [0098]    The developmental and behavioral phenotypes are fully maternally rescued, that is to say that homozygous clk-2/clk-2 mutants derived from a clk-2(qm37)/+heterozygous mother display wild-type phenotypes. In fact, the embryonic development of homozygous mutants derived from a heterozygous mother takes only 13.3±1.6 hours (n=40) and their post-embryonic development lasts only 53.9±12.4 hours (n=98) at 20° C. Also maternally rescued are both defecation, which occurs every 60.3±9.1 seconds at 20° C. (n=8) and pumping, which occurs at a rate of 245.2±24.6 pumps per minute at 20 C. (n=11). However, the reproductive phenotypes are only partially rescued by a wild-type copy of the gene clk-2 in the mother. The self-brood size is 113.9±30.3 at 20° C. (n=24), and the peak egg-laying rate is 3.6±0.9 (n=24). This indicates that the wild-type clk-2 gene in the mother induces an epigenetic state that lasts for only one generation. Erasure of the epigenetic state in the germ-line prevents the animal from having a wild-type rate of reproduction. In addition, the life span of maternally rescued homozygous mutants is dramatically shortened vs. both the mutant and the wild-type life span. Indeed, homozygous mutants derived from a heterozygous mother live only 14.9±4.1 days on average (n=106) and have a maximum life span of 27 days at 20° C. Interestingly, wild-type siblings of maternally rescued clk-2 live slightly shorter than wild-type N2 worms, 17.3±4.1 days (n=206). This observation indicates that wild-type physiological rates imposed by a maternal epigenetic setting are deleterious to animals that are partially incapable of regulating their physiological rates in response to environmental conditions.  
                                 TABLE 2                           Life span of mutants and double mutant       combinations at 20° C. indicated in days                        Maximum Life           Genotype   Mean Life Span   Span                       Wild type (N2)   19.3 ± 5.3   32               n = 100           clk-2(qm37)   22.4 ± 7.4   40               n = 100           Maternally   14.9 ± 4.1   27           rescued   n = 106           clk-2 (qm37)           Wild type (N2)   18.4 ± 4.6   31               n = 260           clk-2(qm37)   22.9 ± 7.3   45               n = 260           daf-16(m26)   18.1 ± 2.6   25               n = 260           daf-16(m26) clk-   21.7 ± 5.8   41           2(qm37)   n = 260           daf-2 (e1370)    29.3 ± 10.3   51               n = 50           daf-2(e1370) clk-    54.5 ± 21.4   101            2(qm37)   n = 50           eat-2 (ad465)    30.0 ± 7.0   42               n = 34           eat-2(ad465) clk-   26.6 ± 6.3   45           2(qm37)   n = 50                      
 
         [0099]    We characterized the life span increase produced by clk-2 (qm37) by comparing it to that produced by other aging genes as summarized in table 2. Among the other genes that affect life span in worms, the best understood are the daf genes. Mutations in the eat genes prolong life span through caloric restriction by reducing the food intake of the animals, a process that also prolongs life span in vertebrates. Mutations in daf genes prolong life span by partial activation of the dauer formation pathway. The dauer stage is a dormant, long-lived, alternative developmental stage which is induced by adverse environmental conditions. The increased life span of all dauer formation mutants that have been tested is suppressed by loss of function mutations in daf-16.  
         [0100]    In fact, we found that while daf-16(m26) lives 18.1±2.6 days on average with a maximum life span of 25 days, the double mutants daf-16(m26) clk-2(qm37) lives an average life span of 21.7±5.8 days with a maximum life span of 41 days. Furthermore, although double mutants with two long-lived dauer formation mutations do not live longer than mutants carrying only one of the component mutations, daf-2(e1370) clk-2(qm37) double mutants live substantially longer than daf-2, almost three times longer than the wild type. We have shown that while daf-2(e1370) lives 29.3±10.3 days on average with a maximum life span of 51 days, the double mutants daf-2(e1370) clk-2(qm37) lives an average life span of 54.5±21.4 days with a maximum life span of 101 days. In contrast to these observations, the effects of clk-2 and eat-2 are not additive. In fact, the double mutants live somewhat shorter than eat-2 mutants. We have shown that eat-2(ad465) lives 30.0±7.0 days on average with a maximum life span of 42 days, and that the double mutants daf-2(e1370) clk-2(qm37) live 26.6±6.3 days on average with a maximum life span of 45 days. These observations are also consistent with the finding that daf-2 eat-2 double mutants live longer than daf-2 or eat-2 mutants in isolation (Lakowski, B. and Hekimi, S.  Science  272, 1010 (1996)). Together, these results show that daf-2 and clk-2 prolong life span by distinct mechanisms but that clk-2 works in a way that resembles caloric restriction.  
         [0101]    The Strict Maternal Effect of the clk-2(qm37) Mutation  
         [0102]    In addition to the Clk phenotype displayed by clk-2(qm37) mutants, they exhibit a temperature-sensitive embryonic lethal and sterile phenotypes at 25° C. We knew that qm37 is a temperature sensitive mutation and that the mutants lay dead embryos when they are transferred to 25° C. (Hekimi, S. et al.,  Genetics  141, 1351 (1995)). These findings have now been extended, and the phenotype of clk-2 mutants at 25° C. has been examined after a number of temperature shift experiments at different stages of development, from permissive to restrictive temperature and vice versa.  
         [0103]    At the permissive temperatures (15 to 20° C.), clk-2 embryos all develop normally and grow up to become long-lived adults. However, when hermaphrodites that have developed at a permissive temperature are transferred to 25° C. before egg-laying begins, they produce only progeny that dies during embryogenesis at various stages of development. When these hermaphrodites, that have been producing dead embryos at 25° C., are transferred back to 18° C., they lay only dead eggs at first, but start to lay live eggs that develop into adults after having been 5-6 hours at 18° C. When hermaphrodites that are kept at 18° C., and that lay only live eggs, are transferred to 25° C. it also takes 5-6 hours before they lay only dead eggs. Both conditions (laying live or dead progeny) are fully reversible upon temperature shift even when the animal&#39;s entire post-embryonic development was carried out at a single temperature (permissive or non-permissive). In addition, when larvae that developed at the permissive temperature are shifted to 25° C., some arrest development and others reach a sterile and sick adulthood. These phenotypes are fully reversible as well. Finally, all these lethality and sterility phenotypes displayed by clk-2(qm37) mutants at 25° C. can be fully maternally rescued: heterozygous animals produce only live progeny at any temperature.  
         [0104]    We have also found that the embryonic lethality at 25° C. is a strict maternal phenotype. That is to say that despite qm37 behaving as a recessive mutation, a wild-type allele in the genome of the embryo is not sufficient for survival if the mother was clk-2/clk-2 homozygous mutant. When clk-2 hermaphrodites are mated to wild-type males at 25° C. they nonetheless produce only dead embryos. When shifted to 18° C. at various times after mating they produce live males, indicating that the mating was successful. The strictly maternal lethal action of clk-2 indicates a very early focus of action, before activation of the zygotic genome.  
         [0105]    To establish how early clk-2 acts during the development of the worm, we dissected embryos at the 2-4 cell stage from wild-type N2 and clk-2 mutant hermaphrodites kept at either permissive (20° C.) or non-permissive (25° C.) temperature and transferred them to the other temperature (or not, as a control). As summarized in table 3, we found that when development up to the 2-4 cell stage proceeded at the permissive temperature, almost all eggs hatched and carried out further embryonic and post-embryonic development at 20° C. {100% of dissected N2 eggs (n=35) hatched and 87% of dissected clk-2 eggs hatched (n=91)} or 25° C. {97% of dissected N2 eggs (n=36) hatched and 91% of dissected clk-2 eggs hatched (n=93)}. In contrast, when eggs had carried out development up to the 2-4 cell stage at 25° C. and were then transferred to 20° C., only very few clk-2 eggs hatched and succeeded in completing development at 20° C. {12% of dissected clk-2 eggs hatched (n=136)}. As a control, when N2 eggs had carried out development up to the 2-4 cell stage at 25° C. and were then transferred to 20° C., almost all hatched and succeeded in completing development at 20° C. {98%, n=45}, or at 25° C. {96%, n=45}. These results indicate that clk-2 is required for viability before the 2-4 cell stage. clk-2 is required in a narrow window between the very end of oogenesis and the initiation of embryonic development.  
                                 TABLE 3                           Survival of eggs at the 2-4 cell stage, dissected from       mothers raised at 20 or 25° C. and transferred or not to       another temperature                    % of eggs that   % of eggs that               hatch when   hatch when               developing at   developing at           Mothers   20° C.   25° C.                       N2 at 20° C.   100    97               n = 35   n = 36           clk-2 at 20° C.   87    91*               n = 91   n = 93           N2 at 25° C.   98   96               n = 45   n = 45           clk-2 at 25° C.    12*   n.d.               n = 136                                              
 
         [0106]    Indeed, clk-2 hermaphrodites that have spent 26 hours of adulthood at 25° C., carry on average 9.9 developing eggs in the uterus (n=125), but produce on average 10.7 dead eggs (n=133) when shifted down to permissive temperature. This observation indicates that, upon transfer from the lethal temperature, only one oocyte or embryo dies on average in addition to those that have already formed an eggshell. This corresponds to the time at which fertilization, oocyte meiosis, pronuclear formation and eggshell formation occurs. We observed early embryonic development using DIC microscopy but did not detect any obvious abnormality in the events which follow fertilization. The early embryos look invariably normal and healthy with cells and nuclei of normal size and shape. We also visualized DNA using Dapi in oocyte and early embryos and did not detect abnormal patterns of chromosome segregation or any other defects. Finally, meiosis per se is not affected as clk-2 homozygous males can sire abundant cross-progeny at 25° C. when mated to wild-type hermaphrodites.  
         [0107]    clk-2 Positional Cloning, Gene Structure and Operon  
         [0108]    We have molecularly identified the gene clk-2 by positional cloning. The gene was localized on the genetic map within an interval of 0.84 cM on the left cluster of linkage group III of  Caenorhabditis elegans , between the genetic markers sma-4 and mab-5 (Hekimi, S. et al.,  Genetics  141, 1351 (1995)). We refined this genetic position by a series of additional mapping experiments involving the genetic markers sma-3, unc-36, lin-13, and lin-39 by multi- and two-point crosses. The following multi-point results were obtained (the genotypes whose progeny was scored is given in brackets): dpy-17 14 clk-2 18 unc-32 (clk-2/dpy-17 unc-32); lon-1 47 clk-2 23 unc-36 (clk-2/lon-1 unc-36); sma-4 35 clk-2 3 mab-5 14 unc-36 (clk-2/sma-4 mab-5 unc-36); sma-3 18 clk-2 0 lin-13 10 unc-36 (sma-3 clk-2 unc-36/lin-13); clk-2 3 lin-13 49 unc-32 (lin-13/clk-2 unc-32); sma-3 40 lin-39 0 clk-2 33 unc-36 (sma-3 clk-2 unc-36/lin-39). In addition, a two-point cross was carried out (clk-2 unc-36/++) and 5/630 Uncs were found to develop quickly (p=0.4 cM). We also found that the deletion nDf2O does not delete clk-2 and that the duplication qDp3 does include clk-2. We thus placed the gene clk-2 within an interval of 0.3 cM, between sma-3 (at −0.9 cM on LGIII) and lin-13 (at −0.6 cM on LGIII), and lying very close to the gene lin-39 (at −0.65 cM).  
         [0109]    By aligning the genetic and physical maps, we predicted the physical region which likely would contain the clk-2 gene. Groups of cosmids from this region were tested for their ability to rescue the clk-2 mutant by DNA microinjection. clk-2 was rescued by a pool of 4 cosmids (H14A12, K07D8, C34A5, C07H6). Individual injection of cosmids C07H6 and C34A5 also rescued the clk-2 phenotype, narrowing the physical position of clk-2 to within approximately 15 kb. Fragments of cosmid C07H6 (obtained by restriction digests from base pair 31,528 to base pair 36,545 of cosmid C07H6 [Accession: AC006605]) were then tested for rescue and a short region of approximately 5 kb was shown to fully rescue the phenotype, indicating that this 5 kb fragment contains the clk-2 gene.  
         [0110]    The identity of the gene was further confirmed by phenocopying the clk-2 phenotype with RNA interference (RNAi) experiments, that is the injection of double stranded RNA corresponding to the coding mRNA sequence of a gene of interest to fully abolish the function of this gene. Double stranded RNA was produced by in vitro transcription from a cDNA (EST 447b4, gift of Y. Kohara) that mapped to this region, and injected into wild-type as well as into clk-2(qm37) worms. All wild-type and clk-2 animals injected with clk-2 dsRNA initially produced embryos that hatched and developed into worms phenotypically resembling clk-2(qm37), that is, slow development, slow defecation and sterility. After 24 hours, the injected animals started laying only dead eggs. These results confirmed the identity of clk-2. The observation that RNAi-treated mothers produce dead eggs, a phenotype more severe than the weak embryonic lethality normally present in the clk-2(qm37) strain, indicated that qm37 is a partial loss-of-function mutation that displays the null phenotype only at 25° C. We further confirmed the identity of the gene by characterizing the molecular lesion underlying the clk-2 mutation. Genomic DNA from the clk-2(qm37) strain was isolated and the nucleotide sequence of the clk-2 region determined. The qm37 mutation is a G-&gt;A transition at in base 2321 of the cDNA.  
         [0111]    The structure of the gene was established experimentally by determining the nucleotide sequence of the EST yk447b4 cDNA, thus defining the actual intron/exon boundaries in vivo and allowing to predict the encoded protein. The gene clk-2 is SL2 transpliced. We have further established the gene structure by RT-PCR experiments, which not only showed that clk-2 is SL2 transpliced, but also that the gene just upstream to clk-2, which we called cex-7, is expressed and is SL1 transpliced. The transplicing by SL1 of a gene placed upstream, and by SL2 of a gene downstream constitutes a hallmark of genes which are in an operon, and are transcriptionally co-expressed. Therefore, clk-2 and cex-7 are transcriptionally co-expressed, and thus play functionally related roles. The cDNA (yk215f6) that corresponds to cex-7 was also sequenced. The gene cex-7 encodes a predicted protein of 481 amino acid residues in length (FIG. 34), that is similar to a human polypeptide of 550 amino acids (FIG. 35).  
         [0112]    clk-2 encodes a predicted protein of 877 amino acids and the clk-2(qm37) mutation is a cysteine to tyrosine substitution at residue 772 of the predicted protein. We have been able to detect the expressed protein by western blot analysis of protein extracted from both mutant and wild-type worms at different temperatures. CLK-2 is similar to unique predicted proteins in human (FIG. 3), Drosophila (FIG. 13), rice (FIG. 19), soybean (FIGS.  26 - 30 ) and to  Saccharomyces cerevisiae  Tel2p (FIG. 32) and in other species (FIGS.  7 - 12 ,  14 ,  17 - 19 ). The structural conservation among these proteins is illustrated by the alignment presented in FIGS. 38, 39,  40  and  41 . No homologue of Tel2p had previously been recognized because aligning multiple sequences is necessary to reveal the homology. Tel2p has been shown to bind yeast telomeric DNA in a sequence-specific manner (Kota, R. S. Runge, K. W.  Chromosoma  108, 278 (1999); Kota, R. S., Runge, K. W.  Nucleic Acids Research  26, 1528 (1998)) and to affect the length of telomeres.  
         [0113]    Expression Pattern of clk-2  
         [0114]    We determined the spatial and temporal expression pattern of the gene clk-2 by analyzing transcript and protein levels (FIG. 55) and by examining transgenic worms carrying reporter fusions. Panel A of FIG. 55 illustrates Northern and Western (37) analyses of clk-2 at all developmental stages. The level of ck-2 mRNA appears uniform throughout pre-adult development (E, embryos; L1-L4, larval stages; A, adult; glp-4, adult glp-4 (bn2ts) mutants at 25° C.). The low level of clk-2 expression in L4 larvae and in glp-4 mutants that lack a germline at 25° C. suggest that most clk-2 RNA in adults is located in gametes. In contrast to the finding with mRNA, the level of CLK-2 protein is similar at all stages including adults (lower panel of A). Panel B of FIG. 55, clk-2 mRNA and protein levels (lower panel) in mutant backgrounds (glp-4 (bn2ts), fem-3 (q20ts), which produces only sperm at 25° C., and fem-2 (b245ts), which produces only oocytes at 25° C.). The mRNA and protein levels of clk-2 expression are similar to the wild type in fem-3 and elevated in fem-2 mutants. glp-4 mutants have wild type protein levels but reduced mRNA levels. clk-2 mRNA appears strongly elevated in clk-2 mutants. Panel C of FIG. 55, CLK-2 protein levels in wild type and clk-2 mutants at three temperatures. clk-2(qm37) is a missense (C772Y) and temperature-sensitive mutation. The level of CLK-2 is greatly reduced in the mutant, but does not change as a function of temperature in either the wild type or the mutant. Worms were raised at 20° C. except when specified otherwise.  
         [0115]    We grew populations of worms synchronized at different developmental stages and extracted total or polyA+ selected RNA from them. The highest level of clk-2 mRNA is detected in young adults. We used several mutants to determine the origin of the transcript level in young adults. Since clk-2 mRNA level is highly reduced in glp-4(bn2ts) mutants that do not develop a germline at the non-permissive temperature, most of the RNA present in wild-type young adults is in the germline. Given the low abundance of RNA in L4 larvae which possess an already large germline but only a few male gametes, most of the clk-2 mRNA in wild-type adults is localized to meiotic gametes, in particular to oocytes.  
         [0116]    We have analyzed the CLK-2 protein level in different genetic backgrounds and in worms grown at different temperatures. We immunodetected CLK-2 protein on western blots by using two different polyclonal antibodies, MG19 and MG20. We obtained these antibodies by injecting rabbits with a bacterially expressed His 10 -CLK-2 protein. We found that the content of CLK-2 protein is uniform across developmental stages in wild type and in clk-2 animals. Furthermore, the concentration of CLK-2 is not different from the wild type in, glp-4 mutants which have no germline, nor in fem-3 and fem-2 mutants that contain only sperm and only oocytes, respectively. Taken together these results indicate that gametes specifically accumulate high levels of clk-2 mRNA, presumably as a store to be used by the embryo. Finally, we observed that in qm37 mutants, while the level of clk-2 mRNA appears slightly elevated, the level of CLK-2 protein is greatly reduced.  
         [0117]    We constructed three reporter constructs of the clk-2 gene that comprised different upstream promoter regions and/or the coding region of the clk-2 gene fused to the green fluorescent protein. Two of the constructs are transcriptional fusions, one containing bases 36932 to 37319 and the other containing bases 36932 to 40010 of cosmid C07H6 [Accession: AC006605]. A third reporter construct (pMQ251) is a translational fusion that contains bases 30501 to 37319, except bases 35078 to 36545 which are part of the gene cex-7. We microinjected these reporter genes into wild type and clk-2(qm37) mutant worms, and analyzed numerous worms from several transgenic lines carrying these reporters. We observed that the clk-2 promoter region directs expression in all somatic tissues, including hypodermis, muscles, neurons, excretory system, gut, pharynx, somatic gonad, vulva, and presumably all cells. No expression was visible in the germline, despite the use of both standard and complex array mixes. This is commonly the case for transgenes in  C. elegans  and does not indicate an absence of expression in the germline tissue. A full length fusion protein between CLK-2 and GFP (encoded by the construct pMQ251) that complements the mutant phenotype for development, behavior and viability at 25° C., is localized exclusively into the cytoplasm, which is consistent with the absence of an obvious nuclear localization signal in the predicted protein. The pattern observed is not a consequence of overexpression as very small transgene concentrations have been used in complex arrays (Kelly et al.,  Genetics  146:227-238, 1997). However, although the nucleus appears dark in the fluorescent images, it still may contains very small amounts of the fusion protein. This analysis of expression indicates that CLK-2 protein is indeed produced in the nematode, as shown by western analysis on total  C. elegans  extracts using anti-CLK-2 antibodies.  
         [0118]    Yeast Tel2p has been found to bind telomeric repeats in vitro, and thus is expected to be nuclear in vivo. However, it was found that CLK-2::GFP is excluded from the nucleus. Subtelomeric silencing and telomere length regulation can also be affected by events in the cytosol. For example, Hst2p, a cytosolic NAD+-dependent deacetylase homologous to Sir2p, can modulate nucleolar and telomeric silencing in yeast Perrod et al.,  EMBO J.,  20(Nos 1 &amp; 2), 197-209, 2001), and the nonsense-mediated mRNA decay pathway appears to affect both telomeric silencing and telomere length regulation (Lew et al.,  Molecular and Cellular Biology,  18(10):6121-6130, 1998). Other proteins that affect telomere length, like tankyrase Smith, S. and De Lange, Titia,  J. of cell Science,  112:3649-3656, 1999), are mostly extranuclear Chi, N.-W., and Lodish, H. F.,  J. of Biological Chemistry,  275(49):38437-38444, 2000), with only a very small amount of protein localized to the telomeres Smith et al.,  Science  282:1484-1487, 1998).  
         [0119]    The Role of clk-2  
         [0120]    Telomere function has been found to affect replicative life span in yeast and in vertebrate cells. It also has also been shown to affect the immortality of the germline in  C. elegans . However, an involvement of telomere function in determining the life span of muiticellular organisms has not been established prior to this work. Here we have shown that the maternal-effect clk-2 gene of  C. elegans  regulates telomere length, and prolongs life span by a mechanism that is distinct from the regulation of dauer formation but resembles caloric restriction, and encodes a protein that is similar to the yeast telomere binding protein Tel2p.  
         [0121]    The timing of the lethal action of clk-2 (qm37) indicates a function for clk-2 during the events that immediately follow fertilization, including oocyte meiosis, pronuclei formation and karyogamy, and this would be consistent with the known importance of telomeres in meiosis. However, our examination of the morphology of chromosomes in oocytes and early embryos did not reveal any abnormalities. Similarly, although telomere function appears linked to double strand break repair and chromosome stability, including in worms, clk-2 mutants appear only moderately sensitive to ionizing radiation and do not display signs of chromosome instability. In fact, we examined the response of clk-2 (qm37) mutants to gamma-radiation and found that among the progeny of irradiated animals, the proportion of dead eggs and larvae was about 10 times higher than among the progeny of irradiated wild-type animals. There is also no report of a function of Tel2p in the response to ionizing radiation in yeast.  
         [0122]    The null phenotype of tel2 is lethal but a hypomorphic mutation of tel2 results in short telomeres and slow growth (Runge, K. W. and Zakian, V. A.  Molecular  &amp;  Cellular Biology  16, 3094 (1996). Tel2p has been shown to be involved in telomere position effect (TPE) and thus contributes to silencing of sub-telomeric regions (Runge, K. W. and Zakian, V. A.  Molecular  &amp;  Cellular Biology  16, 3094 (1996), one of the best studied examples of epigenesis. Mutations in other genes, such as tell, that also result in telomere shortening do not result in abnormal TPE, indicating that the TPE defect in tel2 mutants is not a simple consequence of short telomeres. Furthermore, the rapid death and abnormal cellular morphology of cells fully lacking Tel2p suggests that Tel2p, like Rap1p and the Sir proteins, also functions at non-telomeric sites (Zakian, V. A.  Ann. Rev. Genet.  30, 141 (1996)). In light of this, the absolute requirement for maternal clk-2 in embryogenesis suggests a function for CLK-2 in silencing genes that-are needed during some part of the worm&#39;s life cycle but that are deleterious when expressed during early development. The study of the mes genes which are required for the specification of the germline in  C. elegans  and can confer maternal-effect sterile phenotype has shown that mechanisms of silencing are part of the normal development of worms. Indeed, some of the mes genes have been found to encode proteins that resemble Polycomb group proteins and appear generally to be involved in the regulation of chromatin structure.  
         [0123]    Mutations in clk-1 and clk-2(qm37) at the permissive temperature confer a similar CLK phenotype and in particular an increase of life span of similar magnitude (Lakowski, B. and Hekimi, S.  Science  272, 1010 (1996) and show similar pattern of interactions with other aging genes (Lakowski, B. Hekimi, S.  Proc. Nat. Acad. Sci. US  95, 13091 (1998)). CLK-1 is a mitochondrial protein of unknown function (Felkai, S. et al,  EMBO Journal  18, 1783 (1999).). In an attempt to explain many puzzling features of the clk-1 phenotype, including the maternal effect, we have suggested that the action of CLK-1 is to indirectly, but specifically, regulate nuclear gene expression (Branicky R, C. Benard, S. Hekimi,  Bioessays  22:48, 2000). One possibility might be that CLK-2 might be one of the molecules that implements changes in gene expression in response to alteration of CLK-1 activity. clk-1 clk-2 double mutants have a phenotype that is more severe than either of the single mutants (Lakowski, B. and Hekimi, S. Science 272, 1010 (1996). However, the phenotype of a double mutants containing the null allele clk-1 (qm3O) is not more severe than a double mutant containing the much weaker allele clk-1 (e2519), in contrast to the situation with clk-3, for which double mutants with clk-l(qm30) are much more severe than with clk-1 (e2519) (Lakowski, B. and Hekimi, S.  Science  272, 1010 (1996). These observations indicate that at least part of the activity of clk-1 requires clk-2. Furthermore, clk-1 clk-2 double mutant embryos resemble clk-1 mutant in that the interphases of the embyronic cell cycles are slowed down, but mitoses appear unaltered. This indicates that clk-2 as well as clk-1 is involved in determining the rate of cellular multiplication, and thus affects mechanisms which are known to lead to cancer when deregulated.  
         [0124]    Telomere function has also been implicated in the replicative life span of yeast, where Sir proteins mediate silencing at the telomeres and the HM loci. When displaced from the telomeres by mutation or by shortage of telomeric DNA, part of the Sir complex can move to the nucleolus where its action appears to prolong replicative life span. These and other studies indicate that telomeres are a reserve compartment for silencing factors and participate in regulating silencing in other parts of the genome. It has been suggested that the effect on cellular senescence of expressing telomerase in cultured human cells might be mediated by an effect on silencing rather than by preventing chromosome erosion. Therefore, clk-2 must be involved in determining cellular senescence, including in vertebrates, and affect in this manner aging and diseases linked to cellular senescence such as cancer.  
         [0125]    As mentioned earlier, CLK-2 is similar to predicted proteins in vertebrates and plants as well as to  Saccharomyces cerevisiae  Tel2p. Tel2p has been shown to bind yeast telomeric DNA in a sequence-specific manner, and to affect the length of telomeres. We found that clk-2 also affected the length of telomeres in worms (FIG. 56). In worms, genomic DNA hybridization to telomeric probes after restriction digestion with HinfI reveals the end fragments of the chromosomes carrying the telomeres, which appear as smears, as well as fragments carrying tracts of telomeric repeats that are internal to the chromosome, which appear as discrete bands. The regions where the telomeric smears are the most intense are indicated by stippled lines. Two lanes are shown for each genotype and each temperature.  
         [0126]    The length of telomeres in wild-type and clk-2 mutants was examined by Southern blotting at three temperatures, including the lethal temperature. For 18 and 20° C., worms were grown for numerous generations at each temperature before DNA extraction. Since clk-2(qm37) is lethal at 25° C., mixed stage worms from 20° C. were transferred to and grown at 25° C. for 3-4 days. Genomic DNA was prepared, HinfI digested and separated on a 0.6% agarose gel at 1.2Vcm −1 . Southern blots were hybridized with gamma  32 P DATP end-labelled TTAGGCTTAGGCTTAGGCTTAGGCTTAGGCTTAGGCTTAGGCTTAGG oligo-nucleotide. Use of a second type of probe, made by direct incorporation of alpha  32 P DATP during PCR amplification of telomeric repeats from the plasmid cTel55X with primers T7 and SHP1617 (GAATAATGAGAATTTTCAGGC), gave identical results. The extrachromosomal array in MQ691 clk-2(qm37); qmEx159 contains a clone with the entire coding sequence of clk-2 as well as the promoter of the operon but excluding cux-7 (bases 37319 to 31528 of cosmid C07H6, except bases 36544 to 35077) and rescues clk-2 mutant phenotypes. In clk-2 mutants, telomeres are two to three times longer than in the wild type on average (FIG. 56). However, the chromosomes are of wild-type length in strain MQ691, which carries an extrachromsomal array expressing wild-type CLK-2 in a clk-2(qm37) chromosomal background (FIG. 56) indicating that the alteration of telomere length clk-2 (qm37) mutants is indeed due to abnormal function of clk-2 in these mutants.  
         [0127]    The length of terminal telomeric fragments in the animals of the strain MQ691, which carries an extrachromosomal array (qmEx159) containing functional wild-type CLK-2 that rescues development and behavior at 25° C. in a clk-2(qm37) chromosomal background, was further analyzed. A similar clone containing the qm37 mutation fails to rescue the Clk-2 phenotypes. In MQ691 animals, the length of terminal telomeric fragments appear very similar to the wild-type, and even shorter, indicating that the lengthened telomere phenotype of qm37 mutants is rescued by the expression of clk-2(+). The telomere length of non-transgenic animals of the strain MQ931, derived from MQ691, which have lost the extrachromosomal array and thus again lack clk-2(+) has been further examined. The terminal telomeric repeats in this strain are long again. Thus, the lengthened telomere phenotype of clk-2(qm37) can be rescued by clk-2(+) and reverses back to mutant length after the loss of the transgene.  
         [0128]    In  C. elegans , tracks of numerous TTAGGC telomeric repeats are present at the ends of the 6 chromosomes (Wicky C., et al.,  Proc. Natl. Acad. Sci. USA,  93:8983-8988, 1996). In addition, numerous interstitial blocks of perfect and degenerate telomeric repeats are located more internally to the chromosomes ( C. elegans  II. Edited by Riddel D et al. Published by Plainview, N.Y.: Cold Spring Harbor Laboratory Press (1997), pp 56-59, Chapter 3). Analysis of genomic DNA after restriction digestion with a frequent cutter that does not cleave within the telomeric repeats (HinfI), electrophoresis, and hybridization to telomeric probes, reveals the telomere-carrying end fragments of the chromosomes (Wicky C., et al.,  Proc. Natl. Acad. Sci. USA,  93:8983-8988, 1996). Telomeres, and thus the restriction fragments containing them, are heterogeneous in size and appear as smears. On the other hand, restriction fragments carrying tracts of internal telomeric repeats are of fixed size and appear as discrete bands in the 0.5-3 kb range (Ahmed S, Hodgkin J.  Nature,  403(6766):159-64, 2000; and Wicky C., et al.,  Proc. Natl. Acad. Sci. USA,  93:8983-8988, 1996). The quality of visualization of the length of telomeres in  C. elegans  with a hybridization probe that detects telomeric repeats is marred by the numerous internal repeats that also hybridize to the probe. In particular, they can mask the detection of the telomeres of chromosomes that have small HinfI terminal telomeric fragments. To further describe the telomere phenotype of clk-2(qm37) mutants, the length of individual telomeres has been characterized. The subtelomeric regions just adjacent to the terminal telomeric repeats share no sequence homology among the chromosomes (Wicky C., et al.,  Proc. Natl. Acad. Sci. USA,  93:8983-8988, 1996). Taking advantage of this sequence diversity, probes specific to particular telomeres were designed. The size of a given HinfI terminal fragment is related to the fixed distance between the most exterior HinfI site of the chromosome and the beginning of the telomeric repeats, and by the variable number of terminal telomeric repeats. Upon genomic DNA digestion with HinfI and Southern blotting with a probe specific to a particular telomere, the terminal fragments, which are heterogeneous in size, again appear as a smear. Detailed results obtained for two individual telomeres are illustrated in FIG. 56.  
         [0129]    The length of the terminal fragment of the left telomere of chromosome X is ˜1 kb longer in qm37 than in the wild type, ranging from 2.4 to 4.2 kb and from 1.7 to 2.8 kb, respectively. This telomere is of wild-type length in MQ691, which carries the rescuing transgene, and lengthens again to the clk-2(qm37) values in the non-rescued MQ931 strain. The length of another terminal fragment (left telomere of chromome IV) is also ˜1 kb longer in qm37 than in the wild type, ranging from 2.2 to 3.9 kb and from 1.8 to 2.8 kb respectively. This telomere becomes shorter than the wild type in MQ691, ranging from 1.3 to 2 kb only. This telomere acquires the mutant length again after loss of the transgene in MQ931. Thus, the overexpression of clk-2 can shorten the tracks of telomeric repeats, but not at each telomere.  
         [0130]    Identity of the Gene cog-4 and the cog-4 (qm143) Mutants  
         [0131]    The gene COQ7/CAT5 of the yeast  S. cerevisiae  is the homologous gene to clk-1 (Ewbank, J. J. et al, Science 275, 980 (1997); PCT/CA97/00768). While Coq7p does not structurally resemble an enzyme, it is required for ubiquinone biosynthesis in yeast. A second gene, COQ4 (Marbois, B. N. and Clark, C.  J Biol Chem,  271, 2995 (1996) (Accession: NP — 010490), that is also required for ubiquinone biosynthesis in yeast, does not code for an enzyme, and like COQ7, has no homologue in bacteria. We have generated a deletion mutant worm to describe the role of the gene coq-4 and its functional relationships with the clk genes we have identified and described, including clk-1, clk-2, and gro-1.  
         [0132]    The gene coq-4 in  C. elegans  largely corresponds to the predicted gene T03F1.2 of the cosmid T03F1 (Accession U88169). It is localized on LGI, between unc-73 and unc-11. coq-4 is less than 100 kb away from the characterized gene, unc-73, and less than 40 kb away from the other characterized gene, unc-11. coq-4 is 843 bp long and has four exons. We experimentally established the structure of the gene coq-4 by sequencing a cDNA clone, yk140a2. A second gene, T03F1.3, which is highly similar to phosphoglycerate kinase (PGK), is 264 bp upstream of coq-4 and, as we have shown, forms an operon with coq-4 and is thus transcriptionally co-expressed. We showed that Coq-4 is in the same operon as T03F1.3 by RT-PCR, that coq-4 is SL2 trans-spliced and that T03F1.3 is SL1 trans-spliced.  
         [0133]    We have generated a coq-4-(qm143) deletion mutant by carrying out PCR-based mutant screen following a large scale EMS mutagenesis wild-type worm. coq-4 (qm143) has a 1469 bp deletion, which starts from 44 bp downstream of T03F1-3, and ends 406 bp downstream of coq-4. The predicted gene downstream is 1521 bp away from coq-4 and 1115 bp away from the deletion. Therefore, coq-4 (qm143) is a null mutant and it does not affect the coding sequence of any gene other than coq-4.  
         [0134]    The Phenotype of cog-4 Mutants  
         [0135]    cog-4(qm143) is a non-strict maternal-effect lethal mutation. Most of the progeny, from a homozygous coq-4 hermaphrodite, dies during embryogenesis. Very few eggs hatch, and those which do hatch fail to complete development and die as young larvae. We have also shown that maternal cog-4 product is sufficient for homozygous coq-4 to develop normally until adulthood. However, homozygous coq-4 adult worms from a heterozygous hermaphrodite (coq-4/+) are paralytic and are defective in egg-laying. Moreover, coq-4 homozygous mutants can be mated by N2 males and produce progeny, which grow normally. Taken together, these results indicate that either maternal or zygotic coq-4 product is sufficient for coq-4 mutant to go through embryonic and post-embryonic development. coq-4 deletion (qm143) is kept as a balanced strain, coq-4(qm143)/unc-73(e936). We demonstrated that the phenotypes of the coq-4 mutants, in particular the sterility, can be rescued by an extrachromosomal wild-type copy of coq-4 DNA fragment.  
         [0136]    Expression Pattern of cog-4  
         [0137]    The spatial expression pattern of coq-4 was determined by using translational reporter fusion to the green fluorescence protein, containing 2.2 kb of upstream promoter region. These constructs were injected into both N2 and heterozygous coq-4 (coq-4/unc-73), and animals of several transgenic lines were examined. We found that a functional coq-4::gfp is expressed in the hypodermis, muscles, the gut, the excretory canal and embryos. In addition, we detected that the reporter fusion localizes to the mitochondria, in particular, in muscle cells.  
         [0138]    While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.  
     
       
       
         1 
         
           
             52  
           
           
             1  
             2814  
             DNA  
             C. elegans clk-2 cDNA  
           
            1 

ctcaagatga atttacgaag tcgcctggta aatgccacgg aacgtgctgt gctttttcaa     60 

attttcaaag atgtgcagaa tgatccggaa aagtacgaca atgcagttga ggcgatctgt    120 

gaatcaatcg actattttgg caaatttttg accgatagcg agtatcttac acaaatcaag    180 

ccgattcttg atacacagtg cccaacaaag tcgataattt gcttctcgaa atgtttgaca    240 

aaagtgagca cagatataaa tactaccaca tttcgagatg tgatcaccat gctcgactgg    300 

ttgaagtatg tcgttgaaaa atcgctgaca agtgctattt gtagcagtct gaaagttaaa    360 

gaaactgatg tcagtgcagt tcagttgtat cgagaattcg catcagcatg ttcaaatatt    420 

ccggagaaag tttcgaattg ttgtgcaaag gcattgtctg gcgagcatgt caaatatatc    480 

aacacggtta agtggatatt caaaatgaat ctggtgcaag gaattcaaaa ggctatgctt    540 

cttgctcacg acgacattgt aactgctgcc ccgttcactt cattctacgg atccggtggt    600 

ccttatatga agactgtcgc agaaattatt tcatctggaa gaaacataga tatcaccaac    660 

aaggatgggc ttctagttca aatgattgaa tggattggtt cactaaacaa ttttgattct    720 

caatggcgtc ggatgatgtt tctcatcttc caagagccca catatcaggg aattcaagtt    780 

catgaatcac tactgacaac attgttccta atttcgaaaa gtgaccaaat cttgaaacga    840 

tgtatcgaag ccactgatct gactggaaca ctgaagcgtg tagtgatggt taagctcccg    900 

tttcagcgag ttctcaaacg aaagaccatc gagattctta tcaattttgt ttatcgaact    960 

aaggaacaat ttgccatcca gctattagag acttctgtga aaatctggag tgatctcaat   1020 

tacgcaaaaa gtgctccaga atcacaagaa cgacacatag tcagaatgat attatacttg   1080 

gttcatcttt tcagaacatg ttcttcaatc gattgggagt cactcttcct gaactctatg   1140 

gatggagttc attgtcgaat gagcatgttg cctatgtacg tccaaagtgg tatttttgtt   1200 

aatcaagcac tgtgcaagca agcgacaaag catcgatcga aaacgcacgg atcagatgag   1260 

caacctccag agactctaga agaaaacaaa ttcgtttcaa gtgaagtggg aaaaatatgg   1320 

tttgaagaga tgacgtcaat tttggaacat ggatttaatt cttctacagt gaaagattct   1380 

gagcgagttc gagaaaccgc caacgaaata accaaagacg attcgggtga agaatttgaa   1440 

gaaaccaatg cacagcgtct tcaaaacaac aaagattcgg cagcaatcac atcgaaaaac   1500 

aatctacgtt tagattctga tgatgacgaa gactttcctg actatcaagt taatgaatca   1560 

gaaaagatct tcaagaattt agaaattgga gaagaaccga aaaataaagt gacacctcca   1620 

gcatacattg cagatgcttt cgaaatgcta ttagagaaag aaaaatacga ggtttttgaa   1680 

gcagctttct ttaatattac gaatttgatc aatcgccggc caattggatt tccacaaatc   1740 

gctgagaagt tgttcatccg aatcctccat cttcaaaaca attttggaac gcctaaattc   1800 

aaggaaactg ttgatgaaat tgcagttgca tgtatcactc agcgtccaga aattgtccca   1860 

tctgtagtgc gtctgatcat tgcaccaggt caaggtttca gtatcaaaca acgtcttctt   1920 

cattacattc acaatgctgc tgatggaatg ggtgcattgg ataagaaact tgaagagtgt   1980 

gtaatggcgc aacaattgag aattggtggt ccaacgttaa gtattattct tcatcgaact   2040 

ataaacactg attatgacga tgaggatgaa gatccccaca gacttttagt tcctgaatgg   2100 

cgacgaatgg tggatgctcg cattgctgca aataccagaa gaattggaac gacgcgagag   2160 

ccaccaagag ccggagttgt caatcgtctc gcacaagctg ccaaatatat gttttatcct   2220 

ttgttggttt tgccacgtgg tgagaacgca agtcttttgg gcaaggactc cgatctactc   2280 

gcctcactca tcatggttgc atcgatggtt tatgtgagat gtggcgtatg tcctcaaatt   2340 

catcgaatgt caagtgagct tatatcatat gcaacgcctc atcgattctc tgaaaacgca   2400 

aaactacgga ctgcctgcat cattgcccat ctgaatgtga cgactttgtt gcctggagat   2460 

cttatggatg aactgtttga tgtaccggca cttattggat ggtttgattg ggccaattct   2520 

gtactggtta atgcatcttc atcacaattg gaaaaggata tgactcgcca gtttggtcat   2580 

agtgttacaa aacaccttca acgttatcat ccagctgtac tgcaacacca agacgtttaa   2640 

atagttacta ttcacttgtt ttccttcttt tcaagtactg tatcatttct tactatcttg   2700 

ccaacacttt gatctctacc tcgttcactt cttgctttgc cacccgttga tatcacctgt   2760 

ctcattcatt tatcagcatg ttcataatat caaaaataaa atcttatcaa atgt         2814 

 
           
             2  
             876  
             PRT  
             C. elegans  
             
               clk-2 protein  
             
           
            2 

Met Asn Leu Arg Ser Arg Leu Val Asn Ala Thr Glu Arg Ala Val Leu 
 1               5                  10                  15 

Phe Gln Ile Phe Lys Asp Val Gln Asn Asp Pro Glu Lys Tyr Asp Asn 
            20                  25                  30 

Ala Val Glu Ala Ile Cys Glu Ser Ile Asp Tyr Phe Gly Lys Phe Leu 
        35                  40                  45 

Thr Asp Ser Glu Tyr Leu Thr Gln Ile Lys Pro Ile Leu Asp Thr Gln 
    50                  55                  60 

Cys Pro Thr Lys Ser Ile Ile Cys Phe Ser Lys Cys Leu Thr Lys Val 
65                  70                  75                  80 

Ser Thr Asp Ile Asn Thr Thr Thr Phe Arg Asp Val Ile Thr Met Leu 
                85                  90                  95 

Asp Trp Leu Lys Tyr Val Val Glu Lys Ser Leu Thr Ser Ala Ile Cys 
            100                 105                 110 

Ser Ser Leu Lys Val Lys Glu Thr Asp Val Ser Ala Val Gln Leu Tyr 
        115                 120                 125 

Arg Glu Phe Ala Ser Ala Cys Ser Asn Ile Pro Glu Lys Val Ser Asn 
    130                 135                 140 

Cys Cys Ala Lys Ala Leu Ser Gly Glu His Val Lys Tyr Ile Asn Thr 
145                 150                 155                 160 

Val Lys Trp Ile Phe Lys Met Asn Leu Val Gln Gly Ile Gln Lys Ala 
                165                 170                 175 

Met Leu Leu Ala His Asp Asp Ile Val Thr Ala Ala Pro Phe Thr Ser 
            180                 185                 190 

Phe Tyr Gly Ser Gly Gly Pro Tyr Met Lys Thr Val Ala Glu Ile Ile 
        195                 200                 205 

Ser Ser Gly Arg Ile Asp Ile Thr Asn Lys Asp Gly Leu Leu Val Gln 
    210                 215                 220 

Met Ile Glu Trp Ile Gly Ser Leu Asn Asn Phe Asp Ser Gln Trp Arg 
225                 230                 235                 240 

Arg Met Met Phe Leu Ile Phe Gln Glu Pro Thr Tyr Gln Gly Ile Gln 
                245                 250                 255 

Val His Glu Ser Leu Leu Thr Thr Leu Phe Leu Ile Ser Lys Ser Asp 
            260                 265                 270 

Gln Ile Leu Lys Arg Cys Ile Glu Ala Thr Asp Leu Thr Gly Thr Leu 
        275                 280                 285 

Lys Arg Val Val Met Val Lys Leu Pro Phe Gln Arg Val Leu Lys Arg 
    290                 295                 300 

Lys Thr Ile Glu Ile Leu Ile Asn Phe Val Tyr Arg Thr Lys Glu Gln 
305                 310                 315                 320 

Phe Ala Ile Gln Leu Leu Glu Thr Ser Val Lys Ile Trp Ser Asp Leu 
                325                 330                 335 

Asn Tyr Ala Lys Ser Ala Pro Glu Ser Gln Glu Arg His Ile Val Arg 
            340                 345                 350 

Met Ile Leu Tyr Leu Val His Leu Phe Arg Thr Cys Ser Ser Ile Asp 
        355                 360                 365 

Trp Glu Ser Leu Phe Leu Asn Ser Met Asp Gly Val His Cys Arg Met 
    370                 375                 380 

Ser Met Leu Pro Met Tyr Val Gln Ser Gly Ile Phe Val Asn Gln Ala 
385                 390                 395                 400 

Leu Cys Lys Gln Ala Thr Lys His Arg Ser Lys Thr His Gly Ser Asp 
                405                 410                 415 

Glu Gln Pro Pro Glu Thr Leu Glu Glu Asn Lys Phe Val Ser Ser Glu 
            420                 425                 430 

Val Gly Lys Ile Trp Phe Glu Glu Met Thr Ser Ile Leu Glu His Gly 
        435                 440                 445 

Phe Asn Ser Ser Thr Val Lys Asp Ser Glu Arg Val Arg Glu Thr Ala 
    450                 455                 460 

Asn Glu Ile Thr Lys Asp Asp Ser Gly Glu Glu Phe Glu Glu Thr Asn 
465                 470                 475                 480 

Ala Gln Arg Leu Gln Asn Asn Lys Asp Ser Ala Ala Ile Thr Ser Lys 
                485                 490                 495 

Asn Asn Leu Arg Leu Asp Ser Asp Asp Asp Glu Asp Phe Pro Asp Tyr 
            500                 505                 510 

Gln Val Asn Glu Ser Glu Lys Ile Phe Lys Asn Leu Glu Ile Gly Glu 
        515                 520                 525 

Glu Pro Lys Asn Lys Val Thr Pro Pro Ala Tyr Ile Ala Asp Ala Phe 
    530                 535                 540 

Glu Met Leu Leu Glu Lys Glu Lys Tyr Glu Val Phe Glu Ala Ala Phe 
545                 550                 555                 560 

Phe Asn Ile Thr Asn Leu Ile Asn Arg Arg Pro Ile Gly Phe Pro Gln 
                565                 570                 575 

Ile Ala Glu Lys Leu Phe Ile Arg Ile Leu His Leu Gln Asn Asn Phe 
            580                 585                 590 

Gly Thr Pro Lys Phe Lys Glu Thr Val Asp Glu Ile Ala Val Ala Cys 
        595                 600                 605 

Ile Thr Gln Arg Pro Glu Ile Val Pro Ser Val Val Arg Leu Ile Ile 
    610                 615                 620 

Ala Pro Gly Gln Gly Phe Ser Ile Lys Gln Arg Leu Leu His Tyr Ile 
625                 630                 635                 640 

His Asn Ala Ala Asp Gly Met Gly Ala Leu Asp Lys Lys Leu Glu Glu 
                645                 650                 655 

Cys Val Met Ala Gln Gln Leu Arg Ile Gly Gly Pro Thr Leu Ser Ile 
            660                 665                 670 

Ile Leu His Arg Thr Ile Asn Thr Asp Tyr Asp Asp Glu Asp Glu Asp 
        675                 680                 685 

Pro His Arg Leu Leu Val Pro Glu Trp Arg Arg Met Val Asp Ala Arg 
    690                 695                 700 

Ile Ala Ala Asn Thr Arg Arg Ile Gly Thr Thr Arg Glu Pro Pro Arg 
705                 710                 715                 720 

Ala Gly Val Val Asn Arg Leu Ala Gln Ala Ala Lys Tyr Met Phe Tyr 
                725                 730                 735 

Pro Leu Leu Val Leu Pro Arg Gly Glu Asn Ala Ser Leu Leu Gly Lys 
            740                 745                 750 

Asp Ser Asp Leu Leu Ala Ser Leu Ile Met Val Ala Ser Met Val Tyr 
        755                 760                 765 

Val Arg Cys Gly Val Cys Pro Gln Ile His Arg Met Ser Ser Glu Leu 
    770                 775                 780 

Ile Ser Tyr Ala Thr Pro His Arg Phe Ser Glu Asn Ala Lys Leu Arg 
785                 790                 795                 800 

Thr Ala Cys Ile Ile Ala His Leu Asn Val Thr Thr Leu Leu Pro Gly 
                805                 810                 815 

Asp Leu Met Asp Glu Leu Phe Asp Val Pro Ala Leu Ile Gly Trp Phe 
            820                 825                 830 

Asp Trp Ala Asn Ser Val Leu Val Asn Ala Ser Ser Ser Gln Leu Glu 
        835                 840                 845 

Lys Asp Met Thr Arg Gln Phe Gly His Ser Val Thr Lys His Leu Gln 
    850                 855                 860 

Arg His His Pro Ala Val Leu Gln His Gln Asp Val 
865                 870                 875 

 
           
             3  
             836  
             PRT  
             Homo sapiens  
             
               clk-2 protein  
             
           
            3 

Met Glu Pro Ala Pro Ser Glu Val Arg Leu Ala Val Arg Glu Ala Ile 
 1               5                  10                  15 

His Ala Leu Ser Ser Ser Glu Asp Gly Gly His Ile Phe Cys Thr Leu 
            20                  25                  30 

Glu Ser Leu Lys Arg Tyr Leu Gly Glu Met Glu Pro Pro Ala Leu Pro 
        35                  40                  45 

Arg Glu Lys Glu Glu Phe Ala Ser Ala His Phe Ser Pro Val Leu Arg 
    50                  55                  60 

Cys Leu Ala Ser Arg Leu Ser Pro Ala Trp Leu Glu Leu Leu Pro His 
65                  70                  75                  80 

Gly Arg Leu Glu Glu Leu Trp Ala Ser Phe Phe Leu Glu Gly Pro Ala 
                85                  90                  95 

Asp Gln Ala Phe Leu Val Leu Met Glu Thr Ile Glu Gly Ala Ala Gly 
            100                 105                 110 

Pro Ser Phe Arg Leu Met Lys Met Ala Arg Leu Leu Ala Arg Phe Leu 
        115                 120                 125 

Arg Glu Gly Arg Leu Ala Val Leu Met Glu Ala Gln Cys Arg Gln Gln 
    130                 135                 140 

Thr Gln Pro Gly Phe Ile Leu Leu Arg Glu Thr Leu Leu Gly Lys Val 
145                 150                 155                 160 

Val Ala Leu Pro Asp His Leu Gly Asn Arg Leu Gln Gln Glu Asn Leu 
                165                 170                 175 

Ala Glu Phe Phe Pro Gln Asn Tyr Phe Arg Leu Leu Gly Glu Glu Val 
            180                 185                 190 

Val Arg Val Leu Gln Ala Val Val Asp Ser Leu Gln Gly Gly Leu Asp 
        195                 200                 205 

Ser Ser Val Ser Phe Val Ser Gln Val Leu Gly Lys Ala Cys Val His 
    210                 215                 220 

Gly Arg Gln Gln Glu Ile Leu Gly Val Leu Val Pro Arg Leu Ala Ala 
225                 230                 235                 240 

Leu Thr Gln Gly Ser Tyr Leu His Gln Arg Val Cys Trp Arg Leu Val 
                245                 250                 255 

Glu Gln Val Pro Asp Arg Ala Met Glu Ala Val Leu Thr Gly Leu Val 
            260                 265                 270 

Glu Ala Ala Leu Gly Pro Glu Val Leu Ser Arg Leu Leu Gly Asn Leu 
        275                 280                 285 

Val Val Lys Asn Lys Lys Ala Gln Phe Val Met Thr Gln Lys Leu Leu 
    290                 295                 300 

Phe Leu Gln Ser Arg Leu Thr Thr Pro Met Leu Gln Ser Leu Leu Gly 
305                 310                 315                 320 

His Leu Ala Met Asp Ser Gln Arg Arg Pro Leu Leu Leu Gln Val Leu 
                325                 330                 335 

Lys Glu Leu Leu Glu Thr Trp Gly Ser Ser Ser Ala Ile Arg His Thr 
            340                 345                 350 

Pro Leu Pro Gln Gln Arg His Val Ser Lys Ala Val Leu Ile Cys Leu 
        355                 360                 365 

Ala Gln Leu Gly Glu Pro Glu Leu Arg Asp Ser Arg Asp Glu Leu Leu 
    370                 375                 380 

Ala Ser Met Met Ala Gly Val Lys Cys Arg Leu Asp Ser Ser Leu Pro 
385                 390                 395                 400 

Pro Val Arg Arg Leu Gly Met Ile Val Ala Glu Val Val Ser Ala Arg 
                405                 410                 415 

Ile His Pro Glu Gly Pro Pro Leu Lys Phe Gln Tyr Glu Glu Asp Glu 
            420                 425                 430 

Leu Ser Leu Glu Leu Leu Ala Leu Ala Ser Pro Gln Pro Ala Gly Asp 
        435                 440                 445 

Gly Ala Ser Glu Ala Gly Thr Ser Leu Val Pro Ala Thr Ala Glu Pro 
    450                 455                 460 

Pro Ala Glu Thr Pro Ala Glu Ile Val Asp Gly Gly Val Pro Gln Ala 
465                 470                 475                 480 

Gln Leu Ala Gly Ser Asp Ser Asp Leu Asp Ser Asp Asp Glu Phe Val 
                485                 490                 495 

Pro Tyr Asp Met Ser Gly Asp Arg Glu Leu Lys Ser Ser Lys Ala Pro 
            500                 505                 510 

Ala Tyr Val Arg Asp Cys Val Glu Ala Leu Thr Thr Ser Glu Asp Ile 
        515                 520                 525 

Glu Arg Trp Glu Ala Ala Leu Arg Ala Leu Glu Gly Leu Val Tyr Arg 
    530                 535                 540 

Ser Pro Thr Ala Thr Arg Glu Val Ser Val Glu Leu Ala Lys Val Leu 
545                 550                 555                 560 

Leu His Leu Glu Glu Lys Thr Cys Val Val Gly Phe Ala Gly Leu Arg 
                565                 570                 575 

Gln Arg Ala Leu Val Ala Val Thr Val Thr Asp Pro Ala Pro Val Ala 
            580                 585                 590 

Asp Tyr Leu Thr Ser Gln Phe Tyr Ala Leu Asn Tyr Ser Leu Arg Gln 
        595                 600                 605 

Arg Met Asp Ile Leu Asp Val Leu Thr Leu Ala Ala Gln Glu Leu Ser 
    610                 615                 620 

Arg Pro Gly Cys Leu Gly Arg Thr Pro Gln Pro Gly Ser Pro Ser Pro 
625                 630                 635                 640 

Asn Thr Pro Cys Leu Pro Glu Ala Ala Val Ser Gln Pro Gly Ser Ala 
                645                 650                 655 

Val Ala Ser Asp Trp Arg Val Val Val Glu Glu Arg Ile Arg Ser Lys 
            660                 665                 670 

Thr Gln Arg Leu Ser Lys Gly Gly Pro Arg Gln Gly Pro Ala Gly Ser 
        675                 680                 685 

Pro Ser Arg Phe Asn Ser Val Ala Gly His Phe Phe Phe Pro Leu Leu 
    690                 695                 700 

Gln Arg Phe Asp Arg Pro Leu Val Thr Phe Asp Leu Leu Gly Glu Asp 
705                 710                 715                 720 

Gln Leu Val Leu Gly Arg Leu Ala His Thr Leu Gly Ala Leu Met Cys 
                725                 730                 735 

Leu Ala Val Asn Thr Thr Val Ala Val Ala Met Gly Lys Ala Leu Leu 
            740                 745                 750 

Glu Phe Val Trp Ala Leu Arg Phe His Ile Asp Ala Tyr Val Arg Gln 
        755                 760                 765 

Gly Leu Leu Ser Ala Val Ser Ser Val Leu Leu Ser Leu Pro Ala Ala 
    770                 775                 780 

Leu Leu Glu Asp Leu Met Asp Glu Leu Leu Glu Ala Arg Ser Trp Leu 
785                 790                 795                 800 

Ala Asp Val Ala Glu Lys Asp Pro Asp Glu Asp Cys Arg Thr Leu Ala 
                805                 810                 815 

Leu Arg Ala Leu Leu Leu Leu Gln Arg Leu Lys Asn Arg Leu Leu Pro 
            820                 825                 830 

Pro Ala Ser Pro 
        835 

 
           
             4  
             3320  
             DNA  
             Homo sapiens clk-2  
           
            4 

gcgccccaga ggctcaagaa aacccgcggg agcctcgccc ggacccagga actcgtgctc     60 

ggggccaacc ggctgggccg cgatcgcgtt tcgtccgggg ccgcggcggc cgtggggaat    120 

cggctgcagc gaatcggtgg cgcgcggcgc ctgagcgcgc tgcagtcacc cgggagccgg    180 

gtccaggtcg tcttcccgtg acgcccagat ctgtcctgca ggatggagcc agcaccctca    240 

gaggttcgac tcgccgtccg ggaagccatt catgccctct cgtcttcgga ggatggcggc    300 

cacatcttct gcaccctgga gtccctgaag cggtatctcg gtgagatgga gcctccagcg    360 

ctcccgaggg agaaggagga gtttgcctcg gcccacttct cgcctgtcct cagatgtctt    420 

gccagcaggc tgagcccagc ctggctggag ctgctgcccc atggccgcct ggaggagctg    480 

tgggccagct tcttcctgga gggcccggcg gaccaagcct tcctggtgtt gatggagacc    540 

atcgagggtg ctgcgggccc cagcttccgg ctgatgaaga tggcgcggct gctggccaga    600 

ttcctgcgcg agggccggct ggcagtgctg atggaggcgc agtgtcggca gcagacgcgg    660 

cccggcttca tcctgctccg ggagacgctg ctgggcaagg tggtggccct gcccgatcac    720 

ctgggcaacc gcctgcagca ggagaacttg gccgagttct tcccccagaa ctacttccgc    780 

ctgctcggcg aggaggtcgt ccgggtgctg caggcggttg tggactctct ccaaggtggc    840 

ctggattcct ccgtgtcctt cgtgtctcag gtccttggga aagcctgtgt ccacgggagg    900 

cagcaggaga tcctgggcgt gctggtaccc cggctggcag cgctcaccca gggcagctac    960 

ctgcaccagc gcgtctgctg gcgcctggtg gagcaagtgc cggaccgggc catggaggct   1020 

gtgctgaccg ggctggtgga ggccgcactg gggcctgagg tcctttcgag actgctgggg   1080 

aacctggtgg tgaagaacaa gaaggcccag tttgtgatga cccagaagct tctgttctta   1140 

cagtcccggc tcacgacgcc catgctgcag agcctgctgg gccatctggc catggacagc   1200 

cagcggcgcc cgctcctgct gcaggtgctg aaggagctgt tggagacgtg gggcagcagc   1260 

agtgccatcc gccacactcc cctgccgcag cagcgccacg tcagcaaggc tgtcctcatc   1320 

tgcctggcgc aactcgggga gccggaactg cgggacagcc gggatgaact gctggccagc   1380 

atgatggcgg gcgtgaagtg ccgcctggac agtagcctgc cccccgtgcg acgcctgggc   1440 

atgatcgtgg cagaggtcgt tagtgcccgg atccaccccg aggggcctcc cctgaaattc   1500 

cagtacgaag aggatgaact gagcctcgag ctgctggcct tggcctcccc ccagcctgcg   1560 

ggtgacggcg cctcggaggc gggcacgtcc ctcgttccag ccacggcaga gccccctgca   1620 

gagacccccg cagagatcgt ggatggcggc gtcccccaag cacagctggc gggctctgac   1680 

tcggacctgg acagcgatga tgagtttgtc ccctacgaca tgtcggggga cagagagctg   1740 

aagagcagca aggctcctgc ctacgtccgg gactgcgtgg aagccctgac cacgtctgag   1800 

gacatagagc gctgggaggc agccctgcgg gcccttgagg gcctggtcta caggagcccc   1860 

acagccactc gggaggtgag cgtggagctg gccaaggtgc ttctgcatct ggaggagaag   1920 

acctgtgtgg tgggatttgc agggctgcgc cagagagccc tggtggccgt cacggtcaca   1980 

gacccggccc cggtggccga ctatctgacc tcacagttct atgccctcaa ctacagcctc   2040 

cggcagcgca tggacatcct ggatgtgctg actctggctg cccaggagct gtctaggcct   2100 

gggtgcctcg ggaggactcc ccaacctggc tccccaagtc ccaacacccc gtgcctgcca   2160 

gaggcagccg tctctcagcc tggcagtgcc gtggcgtctg actggcgggt ggtggtggag   2220 

gagcggatca gaagcaagac ccagcggctc tccaagggtg gcccgaggca gggcccggca   2280 

ggcagcccca gcagattcaa ctccgtggcc ggccacttct tcttccccct ccttcagcgc   2340 

tttgacaggc ctctggtgac cttcgacctc ttgggagaag accagctggt tctcggaagg   2400 

ctggcgcaca ccttaggggc cctgatgtgc ctggctgtta acaccacggt ggctgtggcc   2460 

atgggcaagg ccctgctgga attcgtgtgg gcccttcgct tccacatcga tgcctacgtg   2520 

cgccaggggc tgttgtcggc cgtctcctcc gtcctgctca gcctgcctgc tgcgcgcctg   2580 

ctggaggacc tgatggacga gctgctggaa gcccggtcct ggctggcgga cgtggctgag   2640 

aaagacccgg acgaggactg caggacgctg gcactgaggg ccctgctgct tctgcagaga   2700 

ctcaagaaca ggctcctccc acccgcgtct ccctagtccc tggaggcctc cccaggacca   2760 

ccctcgccga cagcaaggca ggcggctgag cagcggcctg gagcagcaga gccaggcttt   2820 

gtagcgaggc caggtcttcg gccgcatccg gtacggagag tgcagatgca ggaaggcccg   2880 

gcctgccgct atttatagtg cagccagtcc gctaaaaata cactgggcct gggcactgcc   2940 

cgccgggaca tggcagcctg gacgtggggc tggggctgtg ggcgctgctg gcggggttga   3000 

ctcttccagt gagggcagaa ccaggctggc aggaggggag gacggtgtac ctgctgctca   3060 

gagcccccaa ggctctcctc tgagagccac caagcaggac agagcagctc ttgtcccagg   3120 

tccctcgggc tgagcgccgt gtcaccagga gaatagtgct cacagcccag gcagggtgtg   3180 

tggctcctgg atgggctcgt ggggcgggat gggacagggc acgggctctc agaaaataaa   3240 

ctgctttatt ggaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa   3300 

aaaaaaaaaa aaaaaaaaaa                                               3320 

 
           
             5  
             466  
             DNA  
             Mus musculus clk-2 cDNA  
           
            5 

gtgacccgca agctcctgct cctgcagtac cagcacacga cacccatggt gcagagcctg     60 

ttggggtact tggctctaga cagtcagcgg cggccactcc tcatacaggt gcttaaggag    120 

ctgctggaga cctggggctg cagcagtgct gtccgacaca cacccctgga gcagcagtgt    180 

tacatcagca aggccatcct tgtctgcctg gcacacctcg gggagccgga gctgcaggac    240 

atccgggatg aattgctggc cagcatgatg gcaggcgtga agtgccgcct ggatagcagc    300 

ctgccccctg tgcgccgctt gggcatgatt gtggccgagg tcatcagctc caggatccac    360 

cctgaggggc ctctcctgaa attccaatat gaagatgacg agatgagccg tgagttgctg    420 

gccttggcta ccccagagcc tgcgggtgac tgctcctcgg tgtcac                   466 

 
           
             6  
             267  
             DNA  
             Artificial Sequence  
             
               part of Mus musculus cDNA  
             
           
            6 

tgtcccatgt gctgacttct gaggtggctg tgctagtggg taaggccctg ctggagtttg     60 

tatgggccct tcgcttccac gttgacattt acgtgcgccg gggcttgctg tctgctgtgt    120 

cctctgtcct cctcagtgta cccacagagc ggctgctggg ggacctgcca gatgagctac    180 

tggaagccag atcctggttg gcagatgtgg ctgagaagga tgtggacgag gactgtaggg    240 

agctggcagt aagggctctg ctgcttc                                        267 

 
           
             7  
             337  
             DNA  
             Artificial Sequence  
             
               part of Mus musculus cDNA  
             
           
            7 

tcacagttct atggcctaaa ctatagcctc cgccagcgca tggacatcct ggacgtcctt     60 

gttctggctg cccaggcact gtctcggcca aagagcctgc agagacgttc ccagcacggt    120 

ccccccgttc ctggcaccat gtgttcacca gcactagccg tttctcagac tggcaatgtc    180 

gctgctcctg actggcaggt ggttgtggag gagcggatca gaagcaagac ccggaggttc    240 

tcgaagggct gtcctcagcg ggacgtgtca ggcgtcccca atgaattcag ctctgtggct    300 

ggctacttct tcttccccct ccttcagcac tttgaca                             337 

 
           
             8  
             153  
             PRT  
             unknown  
             
               part of Mus musculus clk-2 protein  
             
           
            8 

Val Thr Arg Lys Leu Leu Leu Leu Gln Tyr Gln His Thr Thr Pro Met 
 1               5                  10                  15 

Val Gln Ser Leu Leu Gly Tyr Leu Ala Leu Asp Ser Gln Arg Arg Pro 
            20                  25                  30 

Leu Leu Ile Gln Val Leu Lys Glu Leu Leu Glu Thr Trp Gly Cys Ser 
        35                  40                  45 

Ser Ala Val Arg His Thr Pro Leu Glu Gln Gln Cys Tyr Ile Ser Lys 
    50                  55                  60 

Ala Ile Leu Val Cys Leu Ala His Leu Gly Glu Pro Glu Leu Gln Asp 
65                  70                  75                  80 

Ile Arg Asp Glu Leu Leu Ala Ser Met Met Ala Gly Val Lys Cys Arg 
                85                  90                  95 

Leu Asp Ser Ser Leu Pro Pro Val Arg Arg Leu Gly Met Ile Val Ala 
            100                 105                 110 

Glu Val Ile Ser Ser Arg Ile His Pro Glu Gly Pro Leu Leu Lys Phe 
        115                 120                 125 

Gln Tyr Glu Asp Asp Glu Met Ser Arg Glu Leu Leu Ala Leu Ala Thr 
    130                 135                 140 

Pro Glu Pro Ala Gly Asp Cys Ser Ser 
145                 150 

 
           
             9  
             112  
             PRT  
             unknown  
             
               part of Mus musculus clk-2 protein  
             
           
            9 

Ser Gln Phe Tyr Gly Leu Asn Tyr Ser Leu Arg Gln Arg Met Asp Ile 
 1               5                  10                  15 

Leu Asp Val Leu Val Leu Ala Ala Gln Ala Leu Ser Arg Pro Lys Ser 
            20                  25                  30 

Leu Gln Arg Arg Ser Gln His Gly Pro Pro Val Pro Gly Thr Met Cys 
        35                  40                  45 

Ser Pro Ala Leu Ala Val Ser Gln Thr Gly Asn Val Ala Ala Pro Asp 
    50                  55                  60 

Trp Gln Val Val Val Glu Glu Arg Ile Arg Ser Lys Thr Arg Arg Phe 
65                  70                  75                  80 

Ser Lys Gly Cys Pro Gln Arg Asp Val Ser Gly Val Pro Asn Glu Phe 
                85                  90                  95 

Ser Ser Val Ala Gly Tyr Phe Phe Phe Pro Leu Leu Gln His Phe Asp 
            100                 105                 110 

 
           
             10  
             85  
             PRT  
             unknown  
             
               part of Mus musculus clk-2 protein  
             
           
            10 

Leu Thr Ser Glu Val Ala Val Leu Val Gly Lys Ala Leu Leu Glu Phe 
 1               5                  10                  15 

Val Trp Ala Leu Arg Phe His Val Asp Ile Tyr Val Arg Arg Gly Leu 
            20                  25                  30 

Leu Ser Ala Val Ser Ser Val Leu Leu Ser Val Pro Thr Glu Arg Leu 
        35                  40                  45 

Leu Gly Asp Leu Pro Asp Glu Leu Leu Glu Ala Arg Ser Trp Leu Ala 
    50                  55                  60 

Asp Val Ala Glu Lys Asp Val Asp Glu Asp Cys Arg Glu Leu Ala Val 
65                  70                  75                  80 

Arg Ala Leu Leu Leu 
                85 

 
           
             11  
             350  
             PRT  
             unknown  
             
               composite protein sequence of Mus musculus 
      clk-2  
             
           
            11 

Val Thr Arg Lys Leu Leu Leu Leu Gln Tyr Gln His Thr Thr Pro Met 
 1               5                  10                  15 

Val Gln Ser Leu Leu Gly Tyr Leu Ala Leu Asp Ser Gln Arg Arg Pro 
            20                  25                  30 

Leu Leu Ile Gln Val Leu Lys Glu Leu Leu Glu Thr Trp Gly Cys Ser 
        35                  40                  45 

Ser Ala Val Arg His Thr Pro Leu Glu Gln Gln Cys Tyr Ile Ser Lys 
    50                  55                  60 

Ala Ile Leu Val Cys Leu Ala His Leu Gly Glu Pro Glu Leu Gln Asp 
65                  70                  75                  80 

Ile Arg Asp Glu Leu Leu Ala Ser Met Met Ala Gly Val Lys Cys Arg 
                85                  90                  95 

Leu Asp Ser Ser Leu Pro Pro Val Arg Arg Leu Gly Met Ile Val Ala 
            100                 105                 110 

Glu Val Ile Ser Ser Arg Ile His Pro Glu Gly Pro Leu Leu Lys Phe 
        115                 120                 125 

Gln Tyr Glu Asp Asp Glu Met Ser Arg Glu Leu Leu Ala Leu Ala Thr 
    130                 135                 140 

Pro Glu Pro Ala Gly Asp Cys Ser Ser Ser Gln Phe Tyr Gly Leu Asn 
145                 150                 155                 160 

Tyr Ser Leu Arg Gln Arg Met Asp Ile Leu Asp Val Leu Val Leu Ala 
                165                 170                 175 

Ala Gln Ala Leu Ser Arg Pro Lys Ser Leu Gln Arg Arg Ser Gln His 
            180                 185                 190 

Gly Pro Pro Val Pro Gly Thr Met Cys Ser Pro Ala Leu Ala Val Ser 
        195                 200                 205 

Gln Thr Gly Asn Val Ala Ala Pro Asp Trp Gln Val Val Val Glu Glu 
    210                 215                 220 

Arg Ile Arg Ser Lys Thr Arg Arg Phe Ser Lys Gly Cys Pro Gln Arg 
225                 230                 235                 240 

Asp Val Ser Gly Val Pro Asn Glu Phe Ser Ser Val Ala Gly Tyr Phe 
                245                 250                 255 

Phe Phe Pro Leu Leu Gln His Phe Asp Leu Thr Ser Glu Val Ala Val 
            260                 265                 270 

Leu Val Gly Lys Ala Leu Leu Glu Phe Val Trp Ala Leu Arg Phe His 
        275                 280                 285 

Val Asp Ile Tyr Val Arg Arg Gly Leu Leu Ser Ala Val Ser Ser Val 
    290                 295                 300 

Leu Leu Ser Val Pro Thr Glu Arg Leu Leu Gly Asp Leu Pro Asp Glu 
305                 310                 315                 320 

Leu Leu Glu Ala Arg Ser Trp Leu Ala Asp Val Ala Glu Lys Asp Val 
                325                 330                 335 

Asp Glu Asp Cys Arg Glu Leu Ala Val Arg Ala Leu Leu Leu 
            340                 345                 350 

 
           
             12  
             122  
             PRT  
             unknown  
             
               part of Sus Scrofa clk-2 protein  
             
           
            12 

Lys Ala Pro Val Tyr Val Arg Asp Cys Val Glu Ala Leu Thr Ala Ser 
 1               5                  10                  15 

Glu Asp Trp Glu Arg Trp Glu Ala Ala Leu Arg Ala Leu Glu Gly Leu 
            20                  25                  30 

Val Phe Arg Ser Pro Ala Ala Ala Arg Glu Val Ser Val Glu Leu Ala 
        35                  40                  45 

Lys Val Leu Leu His Leu Glu Glu Lys Thr Ala Val Ala Gly Phe Glu 
    50                  55                  60 

Gly Leu Arg Gln Arg Ala Leu Val Ala Val Thr Val Thr Asp Pro Ala 
65                  70                  75                  80 

Arg Val Ala Glu Tyr Leu Thr Ala Gln Phe Tyr Ala Leu Asn Tyr Ser 
                85                  90                  95 

Leu Arg Gln Arg Met Asp Ile Leu Asp Val Leu Thr Leu Ala Ala Gln 
            100                 105                 110 

Glu Leu Ser Arg Pro Gly Arg Leu Gly Arg 
        115                 120 

 
           
             13  
             554  
             PRT  
             D. melanogaster clk-2  
           
            13 

Leu Ile Ser Leu Pro Ala Gln Val Ala Asn Arg Leu Gly Arg Arg Leu 
 1               5                  10                  15 

Pro Glu Thr Phe Ala Pro Val Ser Tyr Gln Lys Leu Leu Leu Arg Gln 
            20                  25                  30 

Trp Leu Lys Ser Leu His Phe Val Leu Gln Cys Asp Asp Asn Arg Glu 
        35                  40                  45 

Tyr Phe Asp Leu Glu Pro Tyr Ser Trp Leu Leu Ser Gln Ala Ile Asn 
    50                  55                  60 

Leu Ile Tyr Asp Val Ser Thr Leu Glu Ser Leu Leu Arg Val Leu Lys 
65                  70                  75                  80 

Asp Tyr Ala Val Ala Pro Arg Gly Arg Lys Val Val His Thr Ile Leu 
                85                  90                  95 

Lys Glu Leu Asp Pro Ala Ala Cys Leu Lys Thr Ala Gln Ser Ala Leu 
            100                 105                 110 

Ser Ala Gly Leu Asn Leu Tyr Val Leu Ile Gly Ala Ala Thr Leu Glu 
        115                 120                 125 

Thr Pro His Trp Lys His Cys Leu Leu Gln Lys Leu Pro Leu Gln Arg 
    130                 135                 140 

Thr Pro Val Asp Asn Lys Gln Leu Ile Thr Leu Ala Ser Tyr Leu Asn 
145                 150                 155                 160 

Ala Val Ala Pro Ala Gln Leu Gln Val Leu Leu Asn Gln Leu Leu Gly 
                165                 170                 175 

Ile Trp Ser Lys Arg Ile Ser Leu Gln Lys Leu Gly Ser Gln Glu His 
            180                 185                 190 

Leu Ala Ile Ser Lys Leu Leu Val Leu Ala Gln Leu Asp Ser Asp Asp 
        195                 200                 205 

Asp Glu Pro Leu Asp Glu Asp Asp Asp Glu Leu Lys Pro Tyr Asp Met 
    210                 215                 220 

Ser Asn Asp Thr Thr Thr Thr Ile Asp Gln Arg Pro Lys Phe Val Ile 
225                 230                 235                 240 

Asp Leu Leu His Leu Leu Arg Glu Lys Val Glu Asn Tyr Gln Val Phe 
                245                 250                 255 

Glu Gly Ala Leu Gly Thr Ala Glu Gln Leu Ile Arg Gly Gln Leu Ala 
            260                 265                 270 

Lys His Asp Thr Gln Leu Ala Leu Asp Leu Leu Gln Leu Phe Leu Val 
        275                 280                 285 

Met Glu Met Gln Phe Tyr Tyr Glu Gln Phe Glu Arg Thr Gln Phe Lys 
    290                 295                 300 

Cys Cys Val Ala Ile Cys Val Ala His Pro Gly Pro Cys Ala Glu Tyr 
305                 310                 315                 320 

Leu Cys Arg Gln Phe His Thr Asp Asn Ser Phe Tyr Ser Ala Ser Val 
                325                 330                 335 

Arg Ile Leu Ile Leu Gln Val Leu Ala Ala Thr Ala Lys Glu Leu Ser 
            340                 345                 350 

Gly Asp Glu Asn Met Gln Asn Glu Met Glu Ile Val Asp Val Ile Pro 
        355                 360                 365 

Pro Ala Ala Lys His Pro Arg Lys Phe Glu Phe Gln Gln Glu Glu Glu 
    370                 375                 380 

Ser Pro Ala Ala Arg Leu Ala Ala Ala Gln Arg Ile Ile Arg Asp Arg 
385                 390                 395                 400 

Leu Arg Ala Lys Thr Lys Arg Tyr Phe Ser Lys Pro Lys Ala Gly Asp 
                405                 410                 415 

Gln Met Glu Lys Ala Asn Pro Phe His Pro Val Ala Gly Thr Phe Phe 
            420                 425                 430 

Phe Ser Leu Val Arg Gly Gln Arg Thr Arg Gln Met Leu Tyr Val Lys 
        435                 440                 445 

Tyr Glu Ile Asp Thr Gln Leu Leu Val Asn Leu Leu Asn Thr Met Ser 
    450                 455                 460 

Val Leu Val Met Cys Ser Gln Asn Cys Pro Leu Leu Pro Ala Met Thr 
465                 470                 475                 480 

Arg Glu Ile Phe Asp Leu Cys Ala Phe Val Arg Phe Asn Ala Glu Ala 
                485                 490                 495 

Arg Val Arg Ala Ala Thr Leu Gln Leu Ile Gly Ile Ala Leu Val Thr 
            500                 505                 510 

Thr Pro Ala His Val Leu Ala Gln His Phe Ala Glu Ser Leu Asn Glu 
        515                 520                 525 

Leu Gln Arg Trp Leu Asn Asp Phe Ile Arg Ser Pro Leu Val Gly Gly 
    530                 535                 540 

Glu Thr Ser Glu Glu Cys Arg Glu Leu Ala 
545                 550 

 
           
             14  
             1017  
             PRT  
             unknown  
             
               A. thaliana clk-2 putative protein  
             
           
            14 

Met Ala Glu Gly Thr Lys Gln Glu Arg Thr Leu Glu Asn Asn Leu Leu 
 1               5                  10                  15 

His Lys Val Gly Glu Ala Val Ser Ala Ile Ser Asp Ala Lys His Val 
            20                  25                  30 

Asp Gln Val Ile Ser Ala Ile His Ser Val Ala Val Leu Leu Phe Pro 
        35                  40                  45 

Val Asp Pro Ser Leu Phe Ser Gly Asn Phe Glu Met Leu His Ile Val 
    50                  55                  60 

Arg Gly Ser Gly Thr Phe Gly Leu Leu Met Ile Leu Tyr Leu Gly Ser 
65                  70                  75                  80 

Ala Gln Val Cys Ser Ser Val Val Pro Ser Ala Asp Glu Arg Asn Glu 
                85                  90                  95 

Trp Leu Glu Thr Phe Tyr Arg Gly Val Ala Phe Pro Thr Phe Ala Arg 
            100                 105                 110 

Val Leu Leu Leu Asp Val Ala Ser Asp Trp Leu Ser Cys Phe Pro Ile 
        115                 120                 125 

Ser Val Gln Lys His Leu Tyr Asp Lys Phe Phe Leu Asp Gly Ser Val 
    130                 135                 140 

Ile Glu Val Val Gln Val Leu Val Pro Phe Leu His His Val Gly Asp 
145                 150                 155                 160 

Gly Gly Val Asn Ala Asn Ser Val Gln Thr Asn Val Glu Arg Leu Leu 
                165                 170                 175 

Ile Leu Cys Leu Leu Glu Asn Asp Gly Val Leu Lys Ile Thr Lys Glu 
            180                 185                 190 

Ile Gly Asn Ile Tyr Gln Gly His Asn Ser Ser Asn Gly Ser Leu Lys 
        195                 200                 205 

Pro Leu Leu Ser Arg Leu Ser Gln Ile Leu Thr Ser Ile Pro Asp Lys 
    210                 215                 220 

Ala Arg Ala Ser Cys Thr Glu Ala Asn Cys Thr Val Ile Val Leu Ser 
225                 230                 235                 240 

Phe Val Gly Glu Val Phe Ser Arg Ile Cys Arg Arg Gly Leu Ser Asp 
                245                 250                 255 

Leu Leu Leu Ser Glu Val Thr Pro His Val Leu Ala Gln Val Arg Arg 
            260                 265                 270 

Leu Leu Asn Ser Lys Ile Gly Ala Ile Glu Val Asp Thr Phe Gln Leu 
        275                 280                 285 

Asp Pro Thr Thr Arg Ile Trp Ser Lys Thr Met Glu Ala Val Thr Asp 
    290                 295                 300 

Pro Tyr Ala Val Glu Lys Met Ala Glu Gln Leu Leu His Gln Leu Tyr 
305                 310                 315                 320 

Ala Glu His Pro Ser Asp Val Glu Ala Phe Trp Thr Ile Trp Thr Leu 
                325                 330                 335 

Phe His Arg Asn Val Ile His Gln Ala Ser Val Arg Gln Ala Lys Cys 
            340                 345                 350 

Phe Leu Trp Gln Leu Asp Ser Phe Phe Arg Tyr Pro Phe Phe Phe Phe 
        355                 360                 365 

His Phe His Pro Asn Ala Val Lys Gln Cys Val Leu Glu Cys Pro Pro 
    370                 375                 380 

Val Thr Asn Thr Leu Ala Lys Gly Asp Val Thr Gln Gly Leu Leu Glu 
385                 390                 395                 400 

Thr Thr Gln Arg Leu Ala Ser Val Trp Ser Lys Arg Glu Phe Leu Gln 
                405                 410                 415 

Ser Val Gln Leu Glu Gln Gln Ala Tyr Leu Gln Phe Leu Phe Pro Val 
            420                 425                 430 

Thr Asp Ile Ser Asp Ile Thr Ala Ala Leu Gly Leu Cys Leu Glu Asn 
        435                 440                 445 

Met Ser Arg Glu Glu Leu Asp Arg Thr Lys Asp Val Met His Ser Ile 
    450                 455                 460 

Leu Gln Gly Val Ser Cys Arg Leu Glu Asn Pro Gly Asp Leu Val Arg 
465                 470                 475                 480 

Lys Met Ala Ser Ser Ile Ala Phe Met Phe Ser Lys Val Ile Asp Pro 
                485                 490                 495 

Lys Asn Pro Leu Tyr Leu Asp Asp Ser Ile Thr Asp Asn Ala Ile Asp 
            500                 505                 510 

Trp Glu Phe Gly Leu Gln Thr Ala Ser Ile Thr Asn Thr Met Glu Asn 
        515                 520                 525 

Gly Asp Gly Glu Asn Lys Arg Ser Ala Ser Leu Thr Glu Val Asn Glu 
    530                 535                 540 

Ser Ser Arg Arg Asn Lys Gln Lys Glu Asn Arg Lys Ser Lys Asn Ile 
545                 550                 555                 560 

Ser Ala Phe Val Leu Ala Asp Pro Asn Glu Ile Val Asp Leu Ala Thr 
                565                 570                 575 

Leu Asn Cys Asp Thr Glu Ser Asp Lys Asp Asp Gly Asp Asp Asp Ala 
            580                 585                 590 

Ser Val Ser Ser Asp Asn Ser Ser Val Thr Ser Leu Glu Pro Tyr Asp 
        595                 600                 605 

Leu Met Asp Asp Asp Lys Asp Leu Gly Lys Gln Phe Thr His Leu Val 
    610                 615                 620 

Asp Val Val Gly Ala Leu Arg Lys Thr Asp Asp Ala Asp Gly Val Glu 
625                 630                 635                 640 

Lys Ala Ile Tyr Val Ala Glu Lys Leu Val Arg Ala Ser Pro Asp Glu 
                645                 650                 655 

Leu Thr His Ile Ala Gly Asp Leu Ala Arg Thr Leu Val Gln Val Arg 
            660                 665                 670 

Cys Ser Asp Ile Ala Ile Glu Gly Glu Glu Asp Ser Ala Glu Glu Lys 
        675                 680                 685 

Arg Gln Arg Ala Leu Ile Ala Leu Leu Val Thr Arg Pro Phe Glu Ser 
    690                 695                 700 

Leu Glu Thr Leu Asn Asn Ile Leu Tyr Ser Pro Asn Val Asp Val Ser 
705                 710                 715                 720 

Gln Arg Ile Met Ile Leu Asp Val Met Ala Glu Ala Ala Arg Glu Leu 
                725                 730                 735 

Ala Asn Ser Lys Thr Leu Lys Pro Lys His Glu Ala Arg Gly Pro Leu 
            740                 745                 750 

Ile Ser Asn Ile Ser Asp Pro Gln Pro Trp Tyr Leu Pro Ser Asn Ala 
        755                 760                 765 

Ser Thr Pro Trp Lys Lys Val Ser Glu Thr Gly Ser Phe His Leu Asn 
    770                 775                 780 

Trp Ala Asn Arg Phe Glu Arg Glu Leu Gln Ser Lys Pro Gly Gln Thr 
785                 790                 795                 800 

Lys Lys Gly Lys Ser Arg Arg Trp Ser Leu Lys Ser Ala Asp Arg Asp 
                805                 810                 815 

Gln Asn Ser Thr Asp Trp Ser Gln Asn Arg Phe Pro Leu Tyr Ala Ala 
            820                 825                 830 

Ala Phe Met Leu Pro Ala Met Lys Glu Phe Asp Lys Lys Arg His Gly 
        835                 840                 845 

Val Asp Leu Leu Gly Arg Asp Phe Val Val Leu Gly Lys Leu Val His 
    850                 855                 860 

Met Leu Gly Val Cys Met Gln Cys Ala Ser Met His Pro Glu Ala Ser 
865                 870                 875                 880 

Ala Leu Ala Ile Ser Leu Leu Asp Met Leu Gln Arg Arg Glu Val Cys 
                885                 890                 895 

Asn His Pro Glu Ala Tyr Val Arg Arg Ala Val Leu Phe Ala Ala Ser 
            900                 905                 910 

Ser Val Leu Val Ser Leu His Pro Ser Tyr Ile Val Ser Thr Leu Val 
        915                 920                 925 

Glu Gly Asn Leu Asp Leu Ser Arg Ala Leu Glu Trp Ile Arg Thr Trp 
    930                 935                 940 

Ala Leu Gln Ile Ala Asp Ser Asp Ile Asp Arg Asp Cys Tyr Thr Met 
945                 950                 955                 960 

Ala Leu Ser Cys Leu Gln Leu His Ala Glu Met Ala Leu Gln Thr Ser 
                965                 970                 975 

Arg Ala Leu Glu Ser Thr Gly Gly Ser Ser Ser Ser Ser Ser Ile Arg 
            980                 985                 990 

Pro Met Asn Ile Ser Leu Pro Ser Gly Ile Ser Lys Leu Thr Ser Ile 
        995                 1000                1005 

Lys Leu Pro Ser Ser Asn Val His Leu 
    1010                1015 

 
           
             15  
             469  
             DNA  
             Artificial Sequence  
             
               part of Oryza sativa clk-2 cDNA  
             
           
            15 

gtttctactg ggtttggaat ggatacgcac atgggctctt ccatgttgca gaaacagatc     60 

ctgatacaga atgcacatca atggctatga ccctccctgc ggctttcatt ctgagatggc    120 

ccttcagaca tcacgagcac tggaatcggc ggatcacagc aaggccagca gcagcagcag    180 

caggtcgcta ccttctaagc ttgataacat catcatacca tttgccaaca tgatgtgatc    240 

gatgtactag attaagttgt aaataagcat atattatctt gccatgtaat attagaaatt    300 

ccaggtcagc taattctgat taggcttgat attgtcatat tacagggttt tttaatctgg    360 

gatttgaaaa tgctagaatt tttgtcgatt cgtgtggaga ttgtatggaa gttgtcctga    420 

tccagattaa agagaattga tgaaaattgt acccaaaaaa aaaaaaaaa                469 

 
           
             16  
             376  
             DNA  
             Artificial Sequence  
             
               part of Oryza sativa clk-2 cDNA  
             
           
            16 

agttcctagt gatcagggac ctgctggtgc aggtctntgg agggaagtct cagaatcagg     60 

aacacttctg aattggtcac accggtatga aagagaagtt ccatctagat ctggtcaagt    120 

taaatcagga aaatctcgta aatggggtct tggaaaagct aaagatttgc agacagagtg    180 

gtcaaaaaac agatttcctt tatatgctgc tgcttttatg ctccctgtta tgcaaggata    240 

tgataaaaga tcacatggtg ttgacttgct caatcgggac tttgttgtcc taggtaaatt    300 

gatatacatg cttggtgtct gtatgaagtg catggcaatg catccagaag catcagctgt    360 

tgccccagct cttctt                                                    376 

 
           
             17  
             122  
             PRT  
             unknown  
             
               part of Oryza sativa clk-2 protein  
             
           
            17 

Pro Trp Arg Glu Val Ser Glu Ser Gly Thr Leu Leu Asn Trp Ser His 
 1               5                  10                  15 

Arg Tyr Glu Arg Glu Val Pro Ser Arg Ser Gly Gln Val Lys Ser Gly 
            20                  25                  30 

Lys Ser Arg Lys Trp Gly Leu Gly Lys Ala Lys Asp Leu Gln Thr Glu 
        35                  40                  45 

Trp Ser Lys Asn Arg Phe Pro Leu Tyr Ala Ala Ala Phe Met Leu Pro 
    50                  55                  60 

Val Met Gln Gly Tyr Asp Lys Arg Ser His Gly Val Asp Leu Leu Asn 
65                  70                  75                  80 

Arg Asp Phe Val Val Leu Gly Lys Leu Ile Tyr Met Leu Gly Val Cys 
                85                  90                  95 

Met Lys Cys Met Ala Met His Pro Glu Ala Ser Ala Val Ala Pro Ala 
            100                 105                 110 

Leu Leu Asp Met Ile Arg Ser Arg Ala Val 
        115                 120 

 
           
             18  
             70  
             PRT  
             unknown  
             
               part of Oryza sativa clk-2 protein  
             
           
            18 

Leu Glu Trp Ile Arg Thr Trp Ala Leu Pro Cys Cys Arg Asn Tyr Arg 
 1               5                  10                  15 

Met His Ile Asn Gly Tyr Asp Pro Pro Cys Gly Phe His Ser Glu Met 
            20                  25                  30 

Ala Leu Gln Thr Ser Arg Ala Leu Glu Ser Ala Asp His Ser Lys Ala 
        35                  40                  45 

Ser Ser Ser Ser Ser Arg Ser Leu Pro Ser Lys Leu Asp Asn Ile Ile 
    50                  55                  60 

Ile Pro Phe Ala Asn Met 
65                  70 

 
           
             19  
             192  
             PRT  
             unknown  
             
               composite protein sequence of Oryza sativa 
      clk-2 protein  
             
           
            19 

Pro Trp Arg Glu Val Ser Glu Ser Gly Thr Leu Leu Asn Trp Ser His 
 1               5                  10                  15 

Arg Tyr Glu Arg Glu Val Pro Ser Arg Ser Gly Gln Val Lys Ser Gly 
            20                  25                  30 

Lys Ser Arg Lys Trp Gly Leu Gly Lys Ala Lys Asp Leu Gln Thr Glu 
        35                  40                  45 

Trp Ser Lys Asn Arg Phe Pro Leu Tyr Ala Ala Ala Phe Met Leu Pro 
    50                  55                  60 

Val Met Gln Gly Tyr Asp Lys Arg Ser His Gly Val Asp Leu Leu Asn 
65                  70                  75                  80 

Arg Asp Phe Val Val Leu Gly Lys Leu Ile Tyr Met Leu Gly Val Cys 
                85                  90                  95 

Met Lys Cys Met Ala Met His Pro Glu Ala Ser Ala Val Ala Pro Ala 
            100                 105                 110 

Leu Leu Asp Met Ile Arg Ser Arg Ala Val Leu Glu Trp Ile Arg Thr 
        115                 120                 125 

Trp Ala Leu Pro Cys Cys Arg Asn Tyr Arg Met His Ile Asn Gly Tyr 
    130                 135                 140 

Asp Pro Pro Cys Gly Phe His Ser Glu Met Ala Leu Gln Thr Ser Arg 
145                 150                 155                 160 

Ala Leu Glu Ser Ala Asp His Ser Lys Ala Ser Ser Ser Ser Ser Arg 
                165                 170                 175 

Ser Leu Pro Ser Lys Leu Asp Asn Ile Ile Ile Pro Phe Ala Asn Met 
            180                 185                 190 

 
           
             20  
             464  
             DNA  
             Artificial Sequence  
             
               part of Glycine max clk-2 cDNA  
             
           
            20 

ttttaggaat tggtcaaata gctatgagag ggaacttccc ccaaaaccta atcaggtcaa     60 

gaaagggaaa acacgccggt ggagcctaca atctcccaca caacaaaacc agatggagta    120 

ttctcataat aagttaccca tgtatgctgc tgcattcatg cttcctgcca tggagggata    180 

tgataaaaaa aggcaaggtg ttgacttgct tggaagagat tttattgtct tggggaaact    240 

catttatatg cttggggtct gtatgaaatc tgtagccatg catccagaag cttctatgct    300 

ggctccttcc ctcctaaata tgttaagatc cagggaggta tgccatcacc aggaagcata    360 

tgtgagaaga gccgtgcttt ttgcagctgc atgtgtattg gttgcccttc atcctactta    420 

catttcatcc accttactcg aaggaaatgc tgaaatttcg actg                     464 

 
           
             21  
             521  
             DNA  
             Artificial Sequence  
             
               part of Glycine max clk-2 cDNA  
             
           
            21 

tccggagaag gactctgatt ccccttccaa taaagagaaa agtatttgtt taaagggtaa     60 

aaagaagtta ttggacttta atgcgcttga tccagatgag attattgatc cagcatcact    120 

gaatcttgaa tcagacgata gcgatgagga tgctgacgat ggtgctagtg agaattcata    180 

ttcttcaagt gattcatctt tacggccata tgatttgtca gatgatgact cagatttgaa    240 

aagaaaaatt tcacagttgg ctgatgtagt tgcagctctt agaaaatcca atgatgccga    300 

tggggtggaa agggctattg atgtagctga aaagctcata agagcatccc ccgatgaact    360 

aaaacatgca gcaagggata tgaccagaac tcttgttcag gttcggtgct ctgatatagc    420 

tttagaaggt gcagaagaat caactgaaga caaaagacaa agatcattag ttgccttagt    480 

agttacctgc ccatttgaat cacttgagtc actaaacaac c                        521 

 
           
             22  
             741  
             DNA  
             Artificial Sequence  
             
               part of Glycine max clk-2 cDNA  
             
           
            22 

atnnatnnnn nntagcagaa ataattagca gtttagcacg tttagaattt atattctggg     60 

ctagaagcta ttcacaatag ctagaagcat cactaatccc cattttagta gggaatttta    120 

atggtcactt tggatgcatc agaaggaaga acaggacctg ccttgagtga acttcttact    180 

gactccaatg ctcgggaagt ttgaagagcc atctcggcat ggagttgtat acatgtcata    240 

gccatcgtat agcattcttt atctgtgtct gactcggcta tgtcaagtgc ccatgtgcga    300 

atccattcaa ggccagtcga aatttcagca tttccttcga gtaaggtgga tgaaatgtaa    360 

gtaggatgaa gggcaaccaa tacacatgca gctgcaaaaa gcacggctct tctcacatat    420 

gcttcctggt gatggcatac ctccctggat cttaacatat ttaggaggga aggagccagc    480 

atagaagctt ctggatgcat ggctacagat ttcatacaga ccccaagcat ataaatgagt    540 

ttccccaaga caataaaatc tcttccaagc aagtcaacac cttgcctttt tttatcatat    600 

ccctccatgg caggaagcat gaatgcagca gcatacatgg gtaacttatt atgagaatac    660 

tccatctggt tttgttgtgt gggnnnnngt nnncnccacn nncgtgtttt ccctttcttg    720 

acctgattng nttttgnnng a                                              741 

 
           
             23  
             456  
             DNA  
             Artificial Sequence  
             
               part of Glycine max clk-2 cDNA  
             
           
            23 

ttgaaatttc aactggcctt gaatggattc gcacatgggc acttgatgta gccgagtcgg     60 

acacagataa agaatgctat acgatggcta tgacatgtat acagctccat gttgagatgg    120 

ctcttcaaac ttcccgagca ttggagtcag taagaaattc actcaaggca ggtcctgttc    180 

ttccttctga tgcatccaaa gtgaccatta aaattcccca cttaaatggg gattagtgat    240 

gcttctagct attgtggatg gattctagcc cagaatacaa attctatatc atgctaaact    300 

gctaattatt tctgctactc tattaattta atgttttatg gggtccttgt tttcgtaaga    360 

aattgtatat tttaggattg tatatattct cacaagggga cgaggttgat gtcaatgctc    420 

ccctacacac ccacccttga tgtagcacgt gttact                              456 

 
           
             24  
             455  
             DNA  
             Artificial Sequence  
             
               part of Glycine max clk-2 cDNA  
             
           
            24 

aaactcgcgg cggaaggcag cagagtggcg ccgatggagg agggtttaga gaagagagaa     60 

ttggaaggcg aagtagttac caaggttgtc gaagtggttt cggctataaa gaatgcgaag    120 

cacgtcgatc aagtcattcg cgcgcttcat tccttagtca cccttctttt cccctttgac    180 

tcttcactcc tatcagatag cattgaccag agttaccgag accaggtcga agttccttct    240 

gcagaaaaac gacatgcttg gtggcgtgcg ttttatcgag gagctgcttt tcctacactg    300 

gctaggtttt tattacttga tgttgcctcg aactggttgg gttgttttcc ctttatggcg    360 

cagaagtaca tttatgatgt tttctttgtt cgtggattgg tcactgacgt tctgcagatt    420 

ctggttcctt ttcttcagct gagtgcgagt gatgg                               455 

 
           
             25  
             208  
             PRT  
             unknown  
             
               part of Glycine max clk-2 protein  
             
           
            25 

Lys Xaa Asn Gln Val Lys Lys Gly Lys Thr Arg Xaa Trp Xaa Xaa Xaa 
 1               5                  10                  15 

Xaa Pro Thr Gln Gln Asn Gln Met Glu Tyr Ser His Asn Lys Leu Pro 
            20                  25                  30 

Met Tyr Ala Ala Ala Phe Met Leu Pro Ala Met Glu Gly Tyr Asp Lys 
        35                  40                  45 

Lys Arg Gln Gly Val Asp Leu Leu Gly Arg Asp Phe Ile Val Leu Gly 
    50                  55                  60 

Lys Leu Ile Tyr Met Leu Gly Val Cys Met Lys Ser Val Ala Met His 
65                  70                  75                  80 

Pro Glu Ala Ser Met Leu Ala Pro Ser Leu Leu Asn Met Leu Arg Ser 
                85                  90                  95 

Arg Glu Val Cys His His Gln Glu Ala Tyr Val Arg Arg Ala Val Leu 
            100                 105                 110 

Phe Ala Ala Ala Cys Val Leu Val Ala Leu His Pro Thr Tyr Ile Ser 
        115                 120                 125 

Ser Thr Leu Leu Glu Gly Asn Ala Glu Ile Ser Thr Gly Leu Glu Trp 
    130                 135                 140 

Ile Arg Thr Trp Ala Leu Asp Ile Ala Glu Ser Asp Thr Asp Lys Glu 
145                 150                 155                 160 

Cys Tyr Thr Met Ala Met Thr Cys Ile Gln Leu His Ala Glu Met Ala 
                165                 170                 175 

Leu Gln Thr Ser Arg Ala Leu Glu Ser Val Arg Ser Ser Leu Lys Ala 
            180                 185                 190 

Gly Pro Val Leu Pro Ser Asp Ala Ser Lys Val Thr Ile Lys Ile Pro 
        195                 200                 205 

 
           
             26  
             151  
             PRT  
             unknown  
             
               part of Glycine max clk-2 protein  
             
           
            26 

Asn Trp Ser Asn Ser Tyr Glu Arg Glu Leu Pro Pro Lys Pro Asn Gln 
 1               5                  10                  15 

Val Lys Lys Gly Lys Thr Arg Arg Trp Ser Leu Gln Ser Pro Thr Gln 
            20                  25                  30 

Gln Asn Gln Met Glu Tyr Ser His Asn Lys Leu Pro Met Tyr Ala Ala 
        35                  40                  45 

Ala Phe Met Leu Pro Ala Met Glu Gly Tyr Asp Lys Lys Arg Gln Gly 
    50                  55                  60 

Val Asp Leu Leu Gly Arg Asp Phe Ile Val Leu Gly Lys Leu Ile Tyr 
65                  70                  75                  80 

Met Leu Gly Val Cys Met Lys Ser Val Ala Met His Pro Glu Ala Ser 
                85                  90                  95 

Met Leu Ala Pro Ser Leu Leu Asn Met Leu Arg Ser Arg Glu Val Cys 
            100                 105                 110 

His His Gln Glu Ala Tyr Val Arg Arg Ala Val Leu Phe Ala Ala Ala 
        115                 120                 125 

Cys Val Leu Val Ala Leu His Pro Thr Tyr Ile Ser Ser Thr Leu Leu 
    130                 135                 140 

Glu Gly Asn Ala Glu Ile Ser 
145                 150 

 
           
             27  
             172  
             PRT  
             unknown  
             
               part of Glycine max clk-2 protein  
             
           
            27 

Glu Lys Asp Ser Asp Ser Pro Ser Asn Lys Glu Lys Ser Ile Cys Leu 
 1               5                  10                  15 

Lys Gly Lys Lys Lys Leu Leu Asp Phe Asn Ala Leu Asp Pro Asp Glu 
            20                  25                  30 

Ile Ile Asp Pro Ala Ser Leu Asn Leu Glu Ser Asp Asp Ser Asp Glu 
        35                  40                  45 

Asp Ala Asp Asp Gly Ala Ser Glu Asn Ser Tyr Ser Ser Ser Asp Ser 
    50                  55                  60 

Ser Leu Arg Pro Tyr Asp Leu Ser Asp Asp Asp Ser Asp Leu Lys Arg 
65                  70                  75                  80 

Lys Ile Ser Gln Leu Ala Asp Val Val Ala Ala Leu Arg Lys Ser Asn 
                85                  90                  95 

Asp Ala Asp Gly Val Glu Arg Ala Ile Asp Val Ala Glu Lys Leu Ile 
            100                 105                 110 

Arg Ala Ser Pro Asp Glu Leu Lys His Ala Ala Arg Asp Met Thr Arg 
        115                 120                 125 

Thr Leu Val Gln Val Arg Cys Ser Asp Ile Ala Leu Glu Gly Ala Glu 
    130                 135                 140 

Glu Ser Thr Glu Asp Lys Arg Gln Arg Ser Leu Val Ala Leu Val Val 
145                 150                 155                 160 

Thr Cys Pro Phe Glu Ser Leu Glu Ser Leu Asn Asn 
                165                 170 

 
           
             28  
             134  
             PRT  
             unknown  
             
               part of Glycine max clk-2 protein  
             
           
            28 

Met Glu Glu Gly Leu Glu Lys Arg Glu Leu Glu Gly Glu Val Val Thr 
 1               5                  10                  15 

Lys Val Val Glu Val Val Ser Ala Ile Lys Asn Ala Lys His Val Asp 
            20                  25                  30 

Gln Val Ile Arg Ala Leu His Ser Leu Val Thr Leu Leu Phe Pro Phe 
        35                  40                  45 

Asp Ser Ser Leu Leu Ser Asp Ser Ile Asp Gln Ser Tyr Arg Asp Gln 
    50                  55                  60 

Val Glu Val Pro Ser Ala Glu Lys Arg His Ala Trp Trp Arg Ala Phe 
65                  70                  75                  80 

Tyr Arg Gly Ala Ala Phe Pro Thr Leu Ala Arg Phe Leu Leu Leu Asp 
                85                  90                  95 

Val Ala Ser Asn Trp Leu Gly Cys Phe Pro Phe Met Ala Gln Lys Tyr 
            100                 105                 110 

Ile Tyr Asp Val Phe Phe Val Arg Gly Leu Val Thr Asp Val Leu Gln 
        115                 120                 125 

Ile Leu Val Pro Phe Leu 
    130 

 
           
             29  
             75  
             PRT  
             unknown  
             
               part of Glycine max clk-2 protein  
             
           
            29 

Glu Ile Ser Thr Gly Leu Glu Trp Ile Arg Thr Trp Ala Leu Asp Val 
 1               5                  10                  15 

Ala Glu Ser Asp Thr Asp Lys Glu Cys Tyr Thr Met Ala Met Thr Cys 
            20                  25                  30 

Ile Gln Leu His Val Glu Met Ala Leu Gln Thr Ser Arg Ala Leu Glu 
        35                  40                  45 

Ser Val Arg Asn Ser Leu Lys Ala Gly Pro Val Leu Pro Ser Asp Ala 
    50                  55                  60 

Ser Lys Val Thr Ile Lys Ile Pro His Leu Asn 
65                  70                  75 

 
           
             30  
             528  
             PRT  
             unknown  
             
               composite of Glycine max clk-2 protein  
             
           
            30 

Met Glu Glu Gly Leu Glu Lys Arg Glu Leu Glu Gly Glu Val Val Thr 
 1               5                  10                  15 

Lys Val Val Glu Val Val Ser Ala Ile Lys Asn Ala Lys His Val Asp 
            20                  25                  30 

Gln Val Ile Arg Ala Leu His Ser Leu Val Thr Leu Leu Phe Pro Phe 
        35                  40                  45 

Asp Ser Ser Leu Leu Ser Asp Ser Ile Asp Gln Ser Tyr Arg Asp Gln 
    50                  55                  60 

Val Glu Val Pro Ser Ala Glu Lys Arg His Ala Trp Trp Arg Ala Phe 
65                  70                  75                  80 

Tyr Arg Gly Ala Ala Phe Pro Thr Leu Ala Arg Phe Leu Leu Leu Asp 
                85                  90                  95 

Val Ala Ser Asn Trp Leu Gly Cys Phe Pro Phe Met Ala Gln Lys Tyr 
            100                 105                 110 

Ile Tyr Asp Val Phe Phe Val Arg Gly Leu Val Thr Asp Val Leu Gln 
        115                 120                 125 

Ile Leu Val Pro Phe Leu Glu Lys Asp Ser Asp Ser Pro Ser Asn Lys 
    130                 135                 140 

Glu Lys Ser Ile Cys Leu Lys Gly Lys Lys Lys Leu Leu Asp Phe Asn 
145                 150                 155                 160 

Ala Leu Asp Pro Asp Glu Ile Ile Asp Pro Ala Ser Leu Asn Leu Glu 
                165                 170                 175 

Ser Asp Asp Ser Asp Glu Asp Ala Asp Asp Gly Ala Ser Glu Asn Ser 
            180                 185                 190 

Tyr Ser Ser Ser Asp Ser Ser Leu Arg Pro Tyr Asp Leu Ser Asp Asp 
        195                 200                 205 

Asp Ser Asp Leu Lys Arg Lys Ile Ser Gln Leu Ala Asp Val Val Ala 
    210                 215                 220 

Ala Leu Arg Lys Ser Asn Asp Ala Asp Gly Val Glu Arg Ala Ile Asp 
225                 230                 235                 240 

Val Ala Glu Lys Leu Ile Arg Ala Ser Pro Asp Glu Leu Lys His Ala 
                245                 250                 255 

Ala Arg Asp Met Thr Arg Thr Leu Val Gln Val Arg Cys Ser Asp Ile 
            260                 265                 270 

Ala Leu Glu Gly Ala Glu Glu Ser Thr Glu Asp Lys Arg Gln Arg Ser 
        275                 280                 285 

Leu Val Ala Leu Val Val Thr Cys Pro Phe Glu Ser Leu Glu Ser Leu 
    290                 295                 300 

Asn Asn Glu Ile Ser Thr Gly Leu Glu Trp Ile Arg Thr Trp Ala Leu 
305                 310                 315                 320 

Asp Val Ala Glu Ser Asp Thr Asp Lys Glu Cys Tyr Thr Met Ala Met 
                325                 330                 335 

Thr Cys Ile Gln Leu His Val Glu Met Ala Leu Gln Thr Ser Arg Ala 
            340                 345                 350 

Leu Glu Ser Val Arg Asn Ser Leu Lys Ala Gly Pro Val Leu Pro Ser 
        355                 360                 365 

Asp Ala Ser Lys Val Thr Ile Lys Ile Pro His Leu Asn Asn Trp Ser 
    370                 375                 380 

Asn Ser Tyr Glu Arg Glu Leu Pro Pro Lys Pro Asn Gln Val Lys Lys 
385                 390                 395                 400 

Gly Lys Thr Arg Arg Trp Ser Leu Gln Ser Pro Thr Gln Gln Asn Gln 
                405                 410                 415 

Met Glu Tyr Ser His Asn Lys Leu Pro Met Tyr Ala Ala Ala Phe Met 
            420                 425                 430 

Leu Pro Ala Met Glu Gly Tyr Asp Lys Lys Arg Gln Gly Val Asp Leu 
        435                 440                 445 

Leu Gly Arg Asp Phe Ile Val Leu Gly Lys Leu Ile Tyr Met Leu Gly 
    450                 455                 460 

Val Cys Met Lys Ser Val Ala Met His Pro Glu Ala Ser Met Leu Ala 
465                 470                 475                 480 

Pro Ser Leu Leu Asn Met Leu Arg Ser Arg Glu Val Cys His His Gln 
                485                 490                 495 

Glu Ala Tyr Val Arg Arg Ala Val Leu Phe Ala Ala Ala Cys Val Leu 
            500                 505                 510 

Val Ala Leu His Pro Thr Tyr Ile Ser Ser Thr Leu Leu Glu Gly Asn 
        515                 520                 525 

 
           
             31  
             876  
             PRT  
             unknown  
             
               C. elegans clk-2 (QM37) mutant protein, with C 
      to Y substitution at position 772  
             
           
            31 

Met Asn Leu Arg Ser Arg Leu Val Asn Ala Thr Glu Arg Ala Val Leu 
 1               5                  10                  15 

Phe Gln Ile Phe Lys Asp Val Gln Asn Asp Pro Glu Lys Tyr Asp Asn 
            20                  25                  30 

Ala Val Glu Ala Ile Cys Glu Ser Ile Asp Tyr Phe Gly Lys Phe Leu 
        35                  40                  45 

Thr Asp Ser Glu Tyr Leu Thr Gln Ile Lys Pro Ile Leu Asp Thr Gln 
    50                  55                  60 

Cys Pro Thr Lys Ser Ile Ile Cys Phe Ser Lys Cys Leu Thr Lys Val 
65                  70                  75                  80 

Ser Thr Asp Ile Asn Thr Thr Thr Phe Arg Asp Val Ile Thr Met Leu 
                85                  90                  95 

Asp Trp Leu Lys Tyr Val Val Glu Lys Ser Leu Thr Ser Ala Ile Cys 
            100                 105                 110 

Ser Ser Leu Lys Val Lys Glu Thr Asp Val Ser Ala Val Gln Leu Tyr 
        115                 120                 125 

Arg Glu Phe Ala Ser Ala Cys Ser Asn Ile Pro Glu Lys Val Ser Asn 
    130                 135                 140 

Cys Cys Ala Lys Ala Leu Ser Gly Glu His Val Lys Tyr Ile Asn Thr 
145                 150                 155                 160 

Val Lys Trp Ile Phe Lys Met Asn Leu Val Gln Gly Ile Gln Lys Ala 
                165                 170                 175 

Met Leu Leu Ala His Asp Asp Ile Val Thr Ala Ala Pro Phe Thr Ser 
            180                 185                 190 

Phe Tyr Gly Ser Gly Gly Pro Tyr Met Lys Thr Val Ala Glu Ile Ile 
        195                 200                 205 

Ser Ser Gly Arg Ile Asp Ile Thr Asn Lys Asp Gly Leu Leu Val Gln 
    210                 215                 220 

Met Ile Glu Trp Ile Gly Ser Leu Asn Asn Phe Asp Ser Gln Trp Arg 
225                 230                 235                 240 

Arg Met Met Phe Leu Ile Phe Gln Glu Pro Thr Tyr Gln Gly Ile Gln 
                245                 250                 255 

Val His Glu Ser Leu Leu Thr Thr Leu Phe Leu Ile Ser Lys Ser Asp 
            260                 265                 270 

Gln Ile Leu Lys Arg Cys Ile Glu Ala Thr Asp Leu Thr Gly Thr Leu 
        275                 280                 285 

Lys Arg Val Val Met Val Lys Leu Pro Phe Gln Arg Val Leu Lys Arg 
    290                 295                 300 

Lys Thr Ile Glu Ile Leu Ile Asn Phe Val Tyr Arg Thr Lys Glu Gln 
305                 310                 315                 320 

Phe Ala Ile Gln Leu Leu Glu Thr Ser Val Lys Ile Trp Ser Asp Leu 
                325                 330                 335 

Asn Tyr Ala Lys Ser Ala Pro Glu Ser Gln Glu Arg His Ile Val Arg 
            340                 345                 350 

Met Ile Leu Tyr Leu Val His Leu Phe Arg Thr Cys Ser Ser Ile Asp 
        355                 360                 365 

Trp Glu Ser Leu Phe Leu Asn Ser Met Asp Gly Val His Cys Arg Met 
    370                 375                 380 

Ser Met Leu Pro Met Tyr Val Gln Ser Gly Ile Phe Val Asn Gln Ala 
385                 390                 395                 400 

Leu Cys Lys Gln Ala Thr Lys His Arg Ser Lys Thr His Gly Ser Asp 
                405                 410                 415 

Glu Gln Pro Pro Glu Thr Leu Glu Glu Asn Lys Phe Val Ser Ser Glu 
            420                 425                 430 

Val Gly Lys Ile Trp Phe Glu Glu Met Thr Ser Ile Leu Glu His Gly 
        435                 440                 445 

Phe Asn Ser Ser Thr Val Lys Asp Ser Glu Arg Val Arg Glu Thr Ala 
    450                 455                 460 

Asn Glu Ile Thr Lys Asp Asp Ser Gly Glu Glu Phe Glu Glu Thr Asn 
465                 470                 475                 480 

Ala Gln Arg Leu Gln Asn Asn Lys Asp Ser Ala Ala Ile Thr Ser Lys 
                485                 490                 495 

Asn Asn Leu Arg Leu Asp Ser Asp Asp Asp Glu Asp Phe Pro Asp Tyr 
            500                 505                 510 

Gln Val Asn Glu Ser Glu Lys Ile Phe Lys Asn Leu Glu Ile Gly Glu 
        515                 520                 525 

Glu Pro Lys Asn Lys Val Thr Pro Pro Ala Tyr Ile Ala Asp Ala Phe 
    530                 535                 540 

Glu Met Leu Leu Glu Lys Glu Lys Tyr Glu Val Phe Glu Ala Ala Phe 
545                 550                 555                 560 

Phe Asn Ile Thr Asn Leu Ile Asn Arg Arg Pro Ile Gly Phe Pro Gln 
                565                 570                 575 

Ile Ala Glu Lys Leu Phe Ile Arg Ile Leu His Leu Gln Asn Asn Phe 
            580                 585                 590 

Gly Thr Pro Lys Phe Lys Glu Thr Val Asp Glu Ile Ala Val Ala Cys 
        595                 600                 605 

Ile Thr Gln Arg Pro Glu Ile Val Pro Ser Val Val Arg Leu Ile Ile 
    610                 615                 620 

Ala Pro Gly Gln Gly Phe Ser Ile Lys Gln Arg Leu Leu His Tyr Ile 
625                 630                 635                 640 

His Asn Ala Ala Asp Gly Met Gly Ala Leu Asp Lys Lys Leu Glu Glu 
                645                 650                 655 

Cys Val Met Ala Gln Gln Leu Arg Ile Gly Gly Pro Thr Leu Ser Ile 
            660                 665                 670 

Ile Leu His Arg Thr Ile Asn Thr Asp Tyr Asp Asp Glu Asp Glu Asp 
        675                 680                 685 

Pro His Arg Leu Leu Val Pro Glu Trp Arg Arg Met Val Asp Ala Arg 
    690                 695                 700 

Ile Ala Ala Asn Thr Arg Arg Ile Gly Thr Thr Arg Glu Pro Pro Arg 
705                 710                 715                 720 

Ala Gly Val Val Asn Arg Leu Ala Gln Ala Ala Lys Tyr Met Phe Tyr 
                725                 730                 735 

Pro Leu Leu Val Leu Pro Arg Gly Glu Asn Ala Ser Leu Leu Gly Lys 
            740                 745                 750 

Asp Ser Asp Leu Leu Ala Ser Leu Ile Met Val Ala Ser Met Val Tyr 
        755                 760                 765 

Val Arg Tyr Gly Val Cys Pro Gln Ile His Arg Met Ser Ser Glu Leu 
    770                 775                 780 

Ile Ser Tyr Ala Thr Pro His Arg Phe Ser Glu Asn Ala Lys Leu Arg 
785                 790                 795                 800 

Thr Ala Cys Ile Ile Ala His Leu Asn Val Thr Thr Leu Leu Pro Gly 
                805                 810                 815 

Asp Leu Met Asp Glu Leu Phe Asp Val Pro Ala Leu Ile Gly Trp Phe 
            820                 825                 830 

Asp Trp Ala Asn Ser Val Leu Val Asn Ala Ser Ser Ser Gln Leu Glu 
        835                 840                 845 

Lys Asp Met Thr Arg Gln Phe Gly His Ser Val Thr Lys His Leu Gln 
    850                 855                 860 

Arg His His Pro Ala Val Leu Gln His Gln Asp Val 
865                 870                 875 

 
           
             32  
             688  
             PRT  
             unknown  
             
               Tel2p, S. cerevisiae clk-2 protein  
             
           
            32 

Met Val Leu Glu Thr Leu Lys Gln Gly Leu Asp Ser Ser Gln Ile His 
 1               5                  10                  15 

Glu Ala Leu Ile Gln Leu Asp Ser Tyr Pro Arg Glu Pro Val Asp Leu 
            20                  25                  30 

Asp Ala Ser Met Val Leu Ile Lys Phe Val Ile Pro Val Tyr Pro Ser 
        35                  40                  45 

Leu Pro Glu Arg Ser Lys Val Ile Leu Arg Arg Leu Ala Ser Lys Ser 
    50                  55                  60 

Phe Thr Phe Leu Cys Gln Ile Val Thr Phe Ser Arg Thr Ile Ser Gly 
65                  70                  75                  80 

Arg Asp Gly Leu Gln Glu Ile Arg Ile Tyr Gln Glu Ile Leu Glu Asp 
                85                  90                  95 

Ile Ile Ser Phe Glu Pro Gly Cys Leu Thr Phe Tyr Leu Lys Ala Ser 
            100                 105                 110 

Thr Thr Ser Lys Ala Asp Arg Asp Ser Ile Lys Ala Leu Phe Phe Gly 
        115                 120                 125 

Ser Lys Leu Phe Asn Val Leu Ala Asn Arg Ile Asp Met Ala Lys Tyr 
    130                 135                 140 

Leu Gly Tyr Leu Arg Leu Gln Trp Lys Phe Leu Leu Glu Ser Asn Glu 
145                 150                 155                 160 

Thr Asp Pro Pro Gly Phe Leu Gly Glu Trp Leu Val Ser Ser Phe Leu 
                165                 170                 175 

Leu Asn Pro Val Leu Ala Ala Asp Met Leu Leu Gly Glu Leu Phe Leu 
            180                 185                 190 

Leu Lys Glu Ser Tyr Phe Phe Ser Phe Gln Lys Ile Ile Ser Ala Ser 
        195                 200                 205 

Ser Leu Ile Asp Gln Lys Arg Leu Ile Ala Lys Phe Leu Leu Pro Tyr 
    210                 215                 220 

Ile Gln Val Ile Val Thr Leu Glu Asn Leu Asn Asp Val Arg Lys Ile 
225                 230                 235                 240 

Leu Arg Arg Phe Asp Leu Asp Lys Ile Ile Ser Leu Ser Val Leu Phe 
                245                 250                 255 

Glu Ile Gln Ser Leu Pro Leu Lys Glu Val Ile Val Arg Leu Met Ser 
            260                 265                 270 

Asn His Ser Ser Thr Lys Phe Val Ser Ala Leu Val Ser Lys Phe Ala 
        275                 280                 285 

Asp Phe Thr Asp Glu Glu Val Asp Thr Lys Thr Cys Glu Leu Leu Val 
    290                 295                 300 

Leu Phe Ala Val His Asn Leu Asn His Ser Gln Arg Glu Glu Ile Ala 
305                 310                 315                 320 

His Asp Glu Arg Phe Leu Asn Gly Val Thr Lys His Leu Gly Ser Asn 
                325                 330                 335 

Glu Arg Glu Ala Arg Glu Arg Ala Met Phe Ile Ala Lys Leu Leu Ser 
            340                 345                 350 

Gly Gly His Leu Lys Tyr Glu Ser Asp Phe Lys Ile Asn Ile Pro Asn 
        355                 360                 365 

Val Lys Phe Glu Ser Asn Ser Asp Asp Lys Ile Ile Asp Phe Gln Ser 
    370                 375                 380 

Leu Lys Asn Pro Ser Ile Cys Asn Thr Gln Thr Asp Val Gly Lys Asp 
385                 390                 395                 400 

Lys Ile Thr Glu Val Ser Gly His Val Gln Ser Leu Thr Leu Asp Cys 
                405                 410                 415 

Ser Asp Ser Asp Asp Glu Asp Glu Asn Asp Glu Arg Glu Ile Val Lys 
            420                 425                 430 

Arg Ile Val Phe Leu Lys Asp Leu Met Lys Glu Tyr Glu Lys Thr Gly 
        435                 440                 445 

Glu Ser Arg Lys Ala Pro Leu Ile Pro Leu Leu Lys Gln Thr Val Lys 
    450                 455                 460 

Leu Ile Arg Gln Lys Ala Asp Phe Gln Leu Glu Val Gly Tyr Tyr Ala 
465                 470                 475                 480 

Gln Gly Ile Leu Ser Ser Ile Val Cys Leu Asn Asn Glu Phe Asp Glu 
                485                 490                 495 

Pro Leu Phe Glu Gln Trp Arg Ile Asn Ala Leu Thr Ser Ile Leu Val 
            500                 505                 510 

Val Leu Pro Glu Lys Val Asn Gly Ala Ile Asn Ile Leu Phe Asn Ser 
        515                 520                 525 

Glu Leu Ser Leu Gln Gln Arg Met Ser Leu Leu Ser Ala Leu Gly Leu 
    530                 535                 540 

Ser Ala Arg Glu Leu Arg Gly Leu Asp Asp Pro Thr Ile Val Lys Pro 
545                 550                 555                 560 

Lys Phe Asp Phe Pro Thr Asn Arg Leu Pro Trp Asp Asp Gln Ser His 
                565                 570                 575 

His Asn Ser Arg Leu Val Glu Val Gln Glu Ser Thr Ser Met Ile Lys 
            580                 585                 590 

Lys Thr Lys Thr Val Trp Lys Ser Arg Lys Leu Gly Lys Asp Arg Glu 
        595                 600                 605 

Lys Gly Thr Gln Asn Arg Phe Arg Lys Tyr Ala Gly Leu Phe Phe Tyr 
    610                 615                 620 

Pro Leu Ala His Gly Trp Leu Asn Gly Ile Asp Val Gly Thr Tyr Asn 
625                 630                 635                 640 

Gln Leu Phe Lys Ser His Tyr Leu Thr Thr Leu Arg Ile Ile Tyr Ser 
                645                 650                 655 

Cys Ala Asn Pro Val His Asp Phe Glu Ser Met Thr Glu Leu Met Asn 
            660                 665                 670 

His Ile Ile Ser Ser Ala Ile Glu Glu Gly Ile Ser Leu Asn Lys Gly 
        675                 680                 685 

 
           
             33  
             1520  
             DNA  
             C. elegans cex-7 cDNA  
           
            33 

tcgaacttca atttatatcg atgtttcttc tattttagtg caaattttaa tcaaaaaaat     60 

taaacctttt gtcaacatgg cgcgaaattt tcccactgct ctcgattacc tgggatcaga    120 

agctgaagat tttaacaagg cgcaacactt gtatctgaaa ccgatggctg ttataaaaat    180 

taccgtagtg ctgcctcgga tgacgatccc gggacaatca atatctaatt gggatctcat    240 

ggaaagacta aaacgtgcaa ttgatccaat tcaaatggat tcttgcaaag ttcgtgagag    300 

caatatcgac agtgttattt ttgaagcgga acttctttcg ctaggaatca tgcagaaaac    360 

gatgaagatt ctcgatggat tctctatgaa agtgtctgga tttgctgagc ccttgaaagt    420 

taaaacaaaa gaggcaaagc ttgattttcc aagtcgtcat gattgggatg attggtttat    480 

gaaacataag atggacgaga tgaaacccgg agaacgtcct gatacagttt atttggcaag    540 

aattccagtg aaatggttct gcgatggtta caatgatctt ccttctgaac gacgtcttcg    600 

cgttgcaatg gaagcgttcg gatctgttag agttgtcgac attccaattt gtgacccact    660 

ccgatctcga atgaattcaa aaatctctgg tattcagcaa aaaggtttcg gattagggca    720 

ggatgtattt tttgaagcat atgtgcaatt tatggagtat aaaggtttcg ccactgccat    780 

ggattccctg agaaatcgta aatgggcaaa acgaattgat ggacggttct ttcaggctaa    840 

tgtcaaggtg gatttcgatc gatcacgtca tctcagcgaa gttcaaattg caaagcgagc    900 

ggaagaacga cgtcaaattg aaacggaacg actgcggcaa gaagaagagg agttgaatat    960 

cagacgtcaa gaagaactga aagttaaaca agaactcgat gataaagata gaagacgaga   1020 

agatagagaa cggaaacgcc gcgaaaagag ggaactcgaa cgaatggctg aagaagagaa   1080 

aaaacgcctt gaaaaggaac gacttgaagc agagcaacga tcacgagcca ctcgccgttt   1140 

gcaaggtgtt cgtcttttga agtttctgtt tgaaaaaatt gaagcacgag aagagagacg   1200 

aaagagaaaa gaagaagaaa agttgaaaga tgagctgagc aaaatcaaag aacttgaaga   1260 

acaacctgta gaacaagaag acgcattgag gcaagctcta cttcagcaga gggaaattcg   1320 

aatgcgagaa cgcttgaaag agaagatgaa agcttcagga gcagagaagg ataagaagag   1380 

agataaaaat aagacttcta gaagaagacg aactaataga catgacactt catcctcttc   1440 

atccgaagat tctgattctc catctgattc tccccactct cgtcgacaaa gaaaacgtca   1500 

aagtgaagga gatgatttcc                                               1520 

 
           
             34  
             478  
             PRT  
             unknown  
             
               C. elegans cex-7 protein  
             
           
            34 

Met Ala Arg Asn Phe Pro Leu Tyr Leu Gly Ser Glu Ala Glu Asp Phe 
 1               5                  10                  15 

Asn Lys Ala Gln His Leu Tyr Leu Lys Pro Met Ala Val Ile Lys Ile 
            20                  25                  30 

Thr Val Val Leu Pro Arg Met Thr Ile Pro Gly Gln Ser Ile Ser Asn 
        35                  40                  45 

Trp Asp Leu Met Glu Arg Leu Lys Arg Ala Ile Asp Pro Ile Gln Met 
    50                  55                  60 

Asp Ser Cys Lys Val Arg Glu Ser Asn Ile Asp Ser Val Ile Phe Glu 
65                  70                  75                  80 

Ala Glu Leu Leu Ser Leu Gly Ile Met Gln Lys Thr Met Lys Ile Leu 
                85                  90                  95 

Asp Gly Phe Ser Met Lys Val Ser Gly Phe Ala Glu Pro Leu Lys Val 
            100                 105                 110 

Lys Thr Lys Glu Ala Lys Leu Asp Phe Pro Ser Arg His Asp Trp Asp 
        115                 120                 125 

Asp Trp Phe Met Lys His Lys Met Asp Glu Met Lys Pro Gly Glu Arg 
    130                 135                 140 

Pro Asp Thr Val Tyr Leu Ala Arg Ile Pro Val Lys Trp Phe Cys Asp 
145                 150                 155                 160 

Gly Tyr Asn Asp Leu Pro Ser Glu Arg Arg Leu Arg Val Ala Met Glu 
                165                 170                 175 

Ala Phe Gly Ser Val Arg Val Val Asp Ile Pro Ile Cys Asp Pro Leu 
            180                 185                 190 

Arg Ser Arg Met Asn Ser Lys Ile Ser Gly Ile Gln Gln Lys Gly Phe 
        195                 200                 205 

Gly Leu Gly Gln Asp Val Phe Phe Glu Ala Tyr Val Gln Phe Met Glu 
    210                 215                 220 

Tyr Lys Gly Phe Ala Thr Ala Met Asp Ser Leu Arg Asn Arg Lys Trp 
225                 230                 235                 240 

Ala Lys Arg Ile Asp Gly Arg Phe Phe Gln Ala Asn Val Lys Val Asp 
                245                 250                 255 

Phe Asp Arg Ser Arg His Leu Ser Glu Val Gln Ile Ala Lys Arg Ala 
            260                 265                 270 

Glu Glu Arg Arg Gln Ile Glu Thr Glu Arg Leu Arg Gln Glu Glu Glu 
        275                 280                 285 

Glu Leu Asn Ile Arg Arg Gln Glu Glu Leu Lys Val Lys Gln Glu Leu 
    290                 295                 300 

Asp Asp Lys Asp Arg Arg Arg Glu Asp Arg Glu Arg Lys Arg Arg Glu 
305                 310                 315                 320 

Lys Arg Glu Leu Glu Arg Met Ala Glu Glu Glu Lys Lys Arg Leu Glu 
                325                 330                 335 

Lys Glu Arg Leu Glu Ala Glu Gln Arg Ser Arg Ala Thr Arg Arg Leu 
            340                 345                 350 

Gln Gly Val Arg Leu Leu Lys Phe Leu Phe Glu Lys Ile Glu Ala Arg 
        355                 360                 365 

Glu Glu Arg Arg Lys Arg Lys Glu Glu Glu Lys Leu Lys Asp Glu Leu 
    370                 375                 380 

Ser Lys Ile Lys Glu Leu Glu Glu Gln Pro Val Glu Gln Glu Asp Ala 
385                 390                 395                 400 

Leu Arg Gln Ala Leu Leu Gln Gln Arg Glu Ile Arg Met Arg Glu Arg 
                405                 410                 415 

Leu Lys Glu Lys Met Lys Ala Ser Gly Ala Glu Lys Asp Lys Lys Arg 
            420                 425                 430 

Asp Lys Asn Lys Thr Ser Arg Arg Arg Arg Thr Asn Arg His Asp Thr 
        435                 440                 445 

Ser Ser Ser Ser Ser Glu Asp Ser Asp Ser Pro Ser Asp Ser Pro His 
    450                 455                 460 

Ser Arg Arg Gln Arg Lys Arg Gln Ser Glu Gly Asp Asp Phe 
465                 470                 475 

 
           
             35  
             550  
             PRT  
             unknown  
             
               XE7, Homo sapiens cex-7 protein  
             
           
            35 

Met Ala Ala Ala Thr Ile Val His Asp Thr Ser Glu Ala Val Glu Leu 
 1               5                  10                  15 

Cys Pro Ala Tyr Gly Leu Tyr Leu Lys Pro Ile Thr Lys Met Thr Ile 
            20                  25                  30 

Ser Val Ala Leu Pro Gln Leu Lys Gln Pro Gly Lys Ser Ile Ser Asn 
        35                  40                  45 

Trp Glu Val Met Glu Arg Leu Lys Gly Met Val Gln Asn His Gln Phe 
    50                  55                  60 

Ser Thr Leu Arg Ile Ser Lys Ser Thr Met Asp Phe Ile Arg Phe Glu 
65                  70                  75                  80 

Gly Glu Val Glu Asn Lys Ser Leu Val Lys Ser Phe Leu Ala Cys Leu 
                85                  90                  95 

Asp Gly Lys Thr Ile Lys Leu Ser Gly Phe Ser Asp Ile Leu Lys Val 
            100                 105                 110 

Arg Ala Ala Glu Phe Lys Ile Asp Phe Pro Thr Arg His Asp Trp Asp 
        115                 120                 125 

Ser Phe Phe Arg Asp Ala Lys Asp Met Asn Glu Thr Leu Pro Gly Glu 
    130                 135                 140 

Arg Pro Asp Thr Ile His Leu Glu Gly Leu Pro Cys Lys Trp Phe Ala 
145                 150                 155                 160 

Leu Lys Glu Ser Gly Ser Glu Lys Pro Ser Glu Asp Val Leu Val Lys 
                165                 170                 175 

Val Phe Glu Lys Phe Gly Glu Ile Arg Asn Val Asp Ile Pro Met Leu 
            180                 185                 190 

Asp Pro Tyr Arg Glu Glu Met Thr Gly Arg Asn Phe His Thr Phe Ser 
        195                 200                 205 

Phe Gly Gly His Leu Asn Phe Glu Ala Tyr Val Gln Tyr Arg Glu Tyr 
    210                 215                 220 

Met Gly Phe Ile Gln Ala Met Ser Ala Leu Arg Gly Met Lys Leu Met 
225                 230                 235                 240 

Tyr Lys Gly Glu Asp Gly Lys Ala Val Ala Cys Asn Ile Lys Val Ser 
                245                 250                 255 

Phe Asp Ser Thr Lys His Leu Ser Asp Ala Ser Ile Lys Lys Arg Gln 
            260                 265                 270 

Leu Glu Arg Gln Lys Leu Gln Glu Leu Glu Gln Gln Arg Glu Glu Gln 
        275                 280                 285 

Lys Arg Arg Glu Lys Glu Ala Glu Glu Arg Gln Arg Ala Glu Glu Arg 
    290                 295                 300 

Lys Gln Lys Glu Leu Glu Glu Leu Glu Arg Glu Arg Lys Arg Glu Glu 
305                 310                 315                 320 

Lys Leu Arg Lys Arg Glu Gln Lys Gln Arg Asp Arg Glu Leu Arg Arg 
                325                 330                 335 

Asn Gln Lys Lys Leu Glu Lys Leu Gln Ala Glu Glu Gln Lys Gln Leu 
            340                 345                 350 

Gln Glu Lys Ile Lys Leu Glu Glu Arg Lys Leu Leu Leu Ala Gln Arg 
        355                 360                 365 

Asn Leu Gln Ser Ile Arg Leu Ile Ala Glu Leu Leu Ser Arg Ala Lys 
    370                 375                 380 

Ala Val Lys Leu Arg Glu Gln Glu Gln Lys Glu Glu Lys Leu Arg Leu 
385                 390                 395                 400 

Gln Gln Gln Glu Glu Arg Arg Arg Leu Gln Glu Ala Glu Leu Arg Arg 
                405                 410                 415 

Val Glu Glu Glu Lys Glu Arg Ala Leu Gly Leu Gln Arg Lys Glu Arg 
            420                 425                 430 

Glu Leu Arg Glu Arg Leu Leu Ser Ile Leu Gln Ser Lys Lys Pro Asp 
        435                 440                 445 

Asp Ser His Thr His Asp Glu Leu Gly Val Ala His Gly Pro Ala Ala 
    450                 455                 460 

Ala Arg Pro Gly His Pro Ala Asp Arg Val Val Arg Leu Cys Glu Arg 
465                 470                 475                 480 

His His Ala Ala Pro Pro Arg Gly Pro Ala Pro Gly Arg Cys Pro Gln 
                485                 490                 495 

Gly Glu Pro Gly Pro Pro Arg Gly Arg Arg Arg Ser Gln Lys Arg Glu 
            500                 505                 510 

Arg Glu Arg Gly Arg Gly Gly Pro Met Gln Gly Gly Ser Glu Leu Leu 
        515                 520                 525 

Ser Cys Gly Pro Arg Gly Trp Leu Ser Arg Glu Glu Val Pro Gly Arg 
    530                 535                 540 

Arg Pro Leu Leu His Ser 
545                 550 

 
           
             36  
             696  
             DNA  
             C. elegans coq-4 cDNA  
             
               clk  
             
           
            36 

atgtctgctc aaaagctata cgcatcgcat gttcccttgg caccgctgtc tcggatgctt     60 

ctcgggattg gatcagcagt aacagcgatc tcggatccaa aaagaggaga tatggtggca    120 

gcgatgggcg aaactactgc aattggacca gttttagaaa atattcgaaa aagaatggaa    180 

tctgatgttg ttggaaagcg acttcttctc gaaaaaccaa gaatttcaaa tggaacaatt    240 

gatagaaagt ggctaagaca gttaccggat ggaacattag gaaaattgta ttcaaacttt    300 

ctcgatcgtt tgaacacatc tccagatgct cggcccactg tcaagtatat cgataatttg    360 

gagcatcttt atgttatgca aaggtatcgc gaaacacacg acttcaccca catcgcattg    420 

gagcagaaaa cgaacatgct cggcgaggta acagtcaaat atttcgaagg aattcaatat    480 

gggcttccaa tgtgtgtcac tggtggaata tttggaggtg ccaggctttt aacaaaaaat    540 

cgccaagaac ttgtcgaccg gaacctccct tgggttgtgg agcaggccac gaatgcacga    600 

ttcttcatgg ctttcgactg ggaaaatcac tttgaaaagc agctcagcga ggtgcagaag    660 

gagctaaata taacgccatt atctgtgaat atgtga                              696 

 
           
             37  
             263  
             PRT  
             unknown  
             
               C. elegans COQ-4 protein  
             
           
            37 

Met Ser Ala Gln Lys Leu Tyr Ala Ser His Val Pro Leu Ala Pro Leu 
 1               5                  10                  15 

Ser Arg Met Leu Leu Gly Ile Gly Ser Ala Val Thr Ala Ile Ser Asp 
            20                  25                  30 

Pro Lys Arg Gly Asp Met Val Ala Ala Met Gly Glu Thr Thr Ala Ile 
        35                  40                  45 

Gly Pro Val Leu Glu Asn Ile Arg Lys Arg Met Glu Ser Asp Val Val 
    50                  55                  60 

Gly Lys Arg Leu Leu Leu Glu Lys Pro Arg Ile Ser Asn Gly Thr Ile 
65                  70                  75                  80 

Asp Arg Lys Trp Leu Arg Gln Leu Pro Asp Gly Thr Leu Gly Lys Leu 
                85                  90                  95 

Tyr Ser Asn Phe Leu Asp Arg Leu Asn Thr Ser Pro Asp Ala Arg Pro 
            100                 105                 110 

Thr Val Lys Tyr Ile Asp Asn Leu Glu His Leu Tyr Val Met Gln Arg 
        115                 120                 125 

Tyr Arg Glu Thr His Asp Phe Thr His Ile Ala Leu Glu Gln Lys Thr 
    130                 135                 140 

Asn Met Leu Gly Glu Val Thr Val Lys Tyr Phe Glu Gly Ile Gln Tyr 
145                 150                 155                 160 

Gly Leu Pro Met Cys Val Thr Gly Gly Ile Phe Gly Gly Ala Arg Leu 
                165                 170                 175 

Leu Thr Lys Asn Arg Gln Glu Leu Val Asp Arg Asn Leu Pro Trp Val 
            180                 185                 190 

Val Glu Gln Ala Thr Asn Ala Arg Phe Phe Met Ala Phe Asp Trp Glu 
        195                 200                 205 

Asn His Phe Glu Lys Gln Leu Ser Glu Val Gln Lys Glu Leu Asn Ile 
    210                 215                 220 

Thr Pro Leu Ser Glu Leu Leu Asp Leu Pro Glu Met Glu Pro Asp Val 
225                 230                 235                 240 

Pro Asp Ile Leu Phe Ser Lys Gly His Pro Gly Phe Trp Arg Val Leu 
                245                 250                 255 

Gln Ala Val Asp Met Met Ile 
            260 

 
           
             38  
             268  
             PRT  
             D. melanogaster COQ-4  
           
            38 

Met Met Gln Arg Cys Leu Arg Leu Gln Lys Pro Leu Ala Leu Arg Arg 
 1               5                  10                  15 

Gly Leu Arg Leu Ala Gln Ala Asn Ser Gln Ala Val Ala Thr Glu Ala 
            20                  25                  30 

Pro Glu Ala Glu Pro Leu Asp Ala Phe Glu Arg Gln Tyr Leu Lys Glu 
        35                  40                  45 

Arg Ile Glu Ile Ser Pro Phe Gln Arg Leu Phe Leu Gly Ala Gly Ser 
    50                  55                  60 

Ser Ile Ala Ala Leu Leu Asn Pro Arg Arg His Asp Met Ile Ala Cys 
65                  70                  75                  80 

Leu Gly Glu Thr Thr Gly Glu Asp Ala Leu Trp Thr Ile Leu Asp Thr 
                85                  90                  95 

Met Gln Ala Ser Glu Glu Gly Gln Arg Ile Met Ala Asp Lys Pro Arg 
            100                 105                 110 

Ile His Thr Ser Thr Ile Asp Phe Lys Tyr Leu Glu Thr Leu Pro Pro 
        115                 120                 125 

Asp Thr Phe Gly Ala Ala Tyr Val Lys Phe Leu Lys Asp Asn Gln Val 
    130                 135                 140 

Thr Pro Asp Ser Arg Met Ala Val Arg Phe Leu Glu Asp Pro Lys Leu 
145                 150                 155                 160 

Ala Tyr Leu Met Thr Arg Tyr Arg Glu Cys His Asp Leu Ile His Thr 
                165                 170                 175 

Val Leu Asp Met Pro Thr Asn Met Leu Gly Glu Val Ala Val Lys Trp 
            180                 185                 190 

Val Glu Ala Leu Asn Thr Gly Leu Pro Met Cys Tyr Gly Gly Ala Val 
        195                 200                 205 

Phe Gly Ala Val Arg Leu Arg Pro Lys Gln Arg Arg Ala Tyr Leu Lys 
    210                 215                 220 

His Tyr Leu Pro Trp Ala Leu Glu Asn Gly Lys Arg Thr Lys Pro Leu 
225                 230                 235                 240 

Met Pro Val Tyr Trp Glu Lys Arg Trp Glu Gln Asn Ile His Glu Leu 
                245                 250                 255 

Arg Ser Glu Leu Gly Ile Thr Val Leu Asn Lys Ala 
            260                 265 

 
           
             39  
             265  
             PRT  
             Homo Sapiens COQ-4  
           
            39 

Met Ala Thr Leu Leu Arg Pro Val Leu Arg Arg Leu Cys Gly Leu Pro 
 1               5                  10                  15 

Gly Leu Gln Arg Pro Ala Ala Glu Met Pro Leu Arg Ala Arg Ser Asp 
            20                  25                  30 

Gly Ala Gly Pro Leu Tyr Ser His His Leu Pro Thr Ser Pro Leu Gln 
        35                  40                  45 

Lys Ala Leu Leu Ala Ala Gly Ser Ala Ala Met Ala Leu Tyr Asn Pro 
    50                  55                  60 

Tyr Arg His Asp Met Val Ala Val Leu Gly Glu Thr Thr Gly His Arg 
65                  70                  75                  80 

Thr Leu Lys Val Leu Arg Asp Gln Met Arg Arg Asp Pro Glu Gly Ala 
                85                  90                  95 

Gln Ile Leu Gln Glu Arg Pro Arg Ile Ser Thr Ser Thr Leu Asp Leu 
            100                 105                 110 

Gly Lys Leu Gln Ser Leu Pro Glu Gly Ser Leu Gly Arg Glu Tyr Leu 
        115                 120                 125 

Arg Phe Leu Asp Val Asn Arg Val Ser Pro Asp Thr Arg Ala Pro Thr 
    130                 135                 140 

Arg Phe Val Asp Asp Glu Glu Leu Ala Tyr Val Ile Gln Arg Tyr Arg 
145                 150                 155                 160 

Glu Val His Asp Met Leu His Thr Leu Leu Gly Met Pro Thr Asn Ile 
                165                 170                 175 

Leu Gly Glu Ile Val Val Lys Trp Phe Glu Ala Val Gln Thr Gly Leu 
            180                 185                 190 

Pro Met Cys Ile Leu Gly Ala Phe Phe Gly Pro Ile Arg Leu Gly Ala 
        195                 200                 205 

Gln Ser Leu Gln Val Leu Val Ser Glu Leu Ile Pro Trp Ala Val Gln 
    210                 215                 220 

Asn Gly Arg Arg Ala His Cys Val Leu Asn Leu Tyr Tyr Glu Arg Arg 
225                 230                 235                 240 

Trp Glu Gln Ser Leu Arg Ala Leu Arg Glu Glu Leu Gly Ile Thr Ala 
                245                 250                 255 

Pro Pro Met His Val Gln Gly Leu Ala 
            260                 265 

 
           
             40  
             272  
             PRT  
             S. cerevisiae COQ-4  
           
            40 

Met Phe Tyr Leu Asn Ala His Leu Glu Ile Asn Lys Val Val Asp Val 
 1               5                  10                  15 

Val Met Ser Leu Ser Lys Lys Phe Leu Lys Pro Ser Val Ala Ser Asn 
            20                  25                  30 

Gln Leu Arg Leu Leu Phe Thr Ala Ala Glu Arg Lys Val Asn Tyr Pro 
        35                  40                  45 

Gly His Val Pro Leu Ser Pro Leu Gln Arg Ile Phe Leu Val Ala Gly 
    50                  55                  60 

Ser Ala Ile Met Gly Leu Lys Ala Pro Trp Arg Gly Gly Asp Met Ile 
65                  70                  75                  80 

Ser Val Leu Gly Asp Ala Ser Gly Gln Pro Phe Phe Leu His Arg Leu 
                85                  90                  95 

Leu Asn Lys Met Leu Val Asp Lys Thr Gly Arg Glu Ile Leu Lys Asp 
            100                 105                 110 

Lys Pro Arg Met Thr Ser Lys Ser Leu Asn Leu Pro Phe Leu Arg Thr 
        115                 120                 125 

Leu Pro Pro Asn Thr Leu Gly Lys Ile Tyr Val Asp Trp Ile Asp Lys 
    130                 135                 140 

Glu His Val Gly Pro Asp Thr Arg Ser Pro Thr Arg Phe Val Asp Asp 
145                 150                 155                 160 

Pro Glu Glu Ala Tyr Val Met Gln Arg Tyr Arg Glu Ser His Asp Phe 
                165                 170                 175 

Tyr His Ala Ile Cys Asn Met Pro Thr Asn Ile Glu Gly Glu Leu Ala 
            180                 185                 190 

Ile Lys Trp Leu Glu Phe Val Asn Met Gly Leu Pro Val Gly Ala Leu 
        195                 200                 205 

Ser Ala Leu Phe Gly Pro Leu Arg Leu Asn Cys Glu Gln Ala Ser Arg 
    210                 215                 220 

Phe Arg Arg Val Tyr Ile Pro Trp Ser Ile Arg Asn Gly Leu Asn Ala 
225                 230                 235                 240 

Lys Thr Leu Ile Asn Val Tyr Trp Glu Lys Glu Leu Thr Asn Asp Ile 
                245                 250                 255 

Glu Asp Val Arg Arg Arg Ile Arg Ile Glu Ala Ala Pro Pro Leu Val 
            260                 265                 270 

 
           
             41  
             226  
             PRT  
             Arabidopsis thaliana COQ-4  
           
            41 

Met Ile Ile Glu Arg Ala Arg Val Pro Leu Ser Arg Trp Gln Gln Ala 
 1               5                  10                  15 

Ala Val Ala Met Gly Ser Ala Leu Gly Ala Leu Val Asp Pro Arg Arg 
            20                  25                  30 

Ala Asp Leu Ile Ala Ala Leu Gly Glu Thr Thr Gly Lys Pro Ala Phe 
        35                  40                  45 

Glu Met Val Leu Glu Arg Met Lys Lys Ser Glu Glu Gly Arg Ala Ile 
    50                  55                  60 

Leu Leu Glu Arg Pro Arg Val Val Ser Glu Gln Val Gly His Ala Trp 
65                  70                  75                  80 

Asp Leu Pro Glu Asn Thr Phe Gly Ala Ala Tyr Ala Lys Phe Met Gly 
                85                  90                  95 

Ser Arg Asn Phe Ser Pro Asp Asp Arg Pro Pro Val Arg Phe Met Glu 
            100                 105                 110 

Thr Asp Glu Leu Ala Tyr Val Ala Thr Arg Ala Arg Glu Val His Asp 
        115                 120                 125 

Leu Trp His Thr Leu Phe Gly Leu Pro Thr Asn Leu Ile Gly Glu Ser 
    130                 135                 140 

Ser Leu Lys Val Ile Glu Phe Glu Gln Met Tyr Leu Pro Met Cys Met 
145                 150                 155                 160 

Leu Ser Val Ile Gly Gly Thr Val Arg Phe Asn Glu Lys Gln Arg Ser 
                165                 170                 175 

Met Phe Leu Lys His Tyr Leu Pro Trp Ala Val Arg Ala Gly Arg Gln 
            180                 185                 190 

Cys Thr Asp Leu Met Cys Val Tyr Tyr Glu Arg His Phe Ser Glu Asp 
        195                 200                 205 

Leu Glu Gln Val Arg Arg Lys Trp Gly Ile Ile Pro Ala Pro Gln His 
    210                 215                 220 

Pro Lys 
225 

 
           
             42  
             167  
             PRT  
             unknown  
             
               part of Mus musculus COQ-4 protein  
             
           
            42 

Ala Leu Tyr Asn Pro Tyr Arg His Asp Met Val Ala Val Leu Gly Glu 
 1               5                  10                  15 

Thr Thr Gly Cys His Thr Leu Lys Phe Leu Arg Asp Gln Met Lys Lys 
            20                  25                  30 

Asp Pro Glu Gly Ala Gln Ile Leu Gln Glu Arg Pro Arg Ile Ser Leu 
        35                  40                  45 

Ser Thr Leu Asp Leu Ser Lys Leu Gln Ser Leu Pro Glu Gly Ser Leu 
    50                  55                  60 

Gly Arg Glu Tyr Leu Arg Phe Leu Asp Val Asn Lys Val Ser Pro Asp 
65                  70                  75                  80 

Thr Arg Ala Pro Thr Arg Phe Val Asp Asp Glu Glu Leu Ala Tyr Val 
                85                  90                  95 

Ile Gln Arg Tyr Arg Glu Val His Asp Met Leu His Thr Leu Leu Gly 
            100                 105                 110 

Met Pro Thr Asn Met Leu Gly Glu Val Val Val Lys Trp Phe Glu Ala 
        115                 120                 125 

Val Gln Thr Gly Leu Pro Met Cys Ile Leu Gly Ala Leu Phe Gly Pro 
    130                 135                 140 

Ile Arg Leu Arg Thr Gln Ser Leu Gln Val Leu Phe Ser Glu Leu Ile 
145                 150                 155                 160 

Pro Trp Ala Ile Gln Asn Gly 
                165 

 
           
             43  
             123  
             PRT  
             unknown  
             
               part of Mus musculus COQ-4 protein  
             
           
            43 

Tyr Pro Asp His Ile Pro Thr Thr Pro Leu Gln Lys Met Leu Leu Ala 
 1               5                  10                  15 

Ala Gly Ala Ala Gly Met Ala Leu Tyr Asn Pro Tyr Arg His Asp Met 
            20                  25                  30 

Val Ala Val Leu Gly Glu Thr Thr Gly Cys His Thr Leu Lys Phe Leu 
        35                  40                  45 

Arg Asp Gln Met Lys Lys Asp Pro Glu Gly Ala Gln Ile Leu Gln Glu 
    50                  55                  60 

Arg Pro Arg Ile Ser Leu Ser Thr Leu Asp Leu Ser Lys Leu Gln Ser 
65                  70                  75                  80 

Leu Pro Glu Gly Ser Leu Gly Arg Glu Tyr Leu Arg Phe Leu Asp Val 
                85                  90                  95 

Asn Lys Val Ser Pro Asp Thr Arg Ala Pro Thr Arg Phe Val Asp Asp 
            100                 105                 110 

Glu Xaa Leu Ala Tyr Val Asn Gln Lys Tyr Arg 
        115                 120 

 
           
             44  
             89  
             PRT  
             unknown  
             
               part of Mus musculus COQ-4 protein  
             
           
            44 

His Leu Pro Thr Ser Tyr Pro Ser Leu Ser Leu Gly Glu Val Val Val 
 1               5                  10                  15 

Lys Trp Phe Glu Ala Val Gln Thr Gly Leu Pro Met Cys Ile Leu Gly 
            20                  25                  30 

Ala Leu Phe Gly Pro Ile Arg Leu Arg Thr Gln Ser Leu Gln Val Leu 
        35                  40                  45 

Phe Ser Glu Leu Ile Pro Trp Ala Ile Gln Asn Gly Arg Arg Ala Thr 
    50                  55                  60 

Cys Val Leu Asn Ile Tyr Tyr Glu Gln Arg Trp Glu Gln Pro Leu Thr 
65                  70                  75                  80 

Ala Leu Arg Glu Glu Leu Gly Ile Ser 
                85 

 
           
             45  
             218  
             PRT  
             Unknown  
             
               Mus musculs consensus COQ-4 proteein  
             
           
            45 

Tyr Pro Asp His Ile Pro Thr Thr Pro Leu Gln Lys Met Leu Leu Ala 
 1               5                  10                  15 

Ala Gly Ala Ala Gly Met Ala Leu Tyr Asn Pro Tyr Arg His Asp Met 
            20                  25                  30 

Val Ala Val Leu Gly Glu Thr Thr Gly Cys His Thr Leu Lys Phe Leu 
        35                  40                  45 

Arg Asp Gln Met Lys Lys Asp Pro Glu Gly Ala Gln Ile Leu Gln Glu 
    50                  55                  60 

Arg Pro Arg Ile Ser Leu Ser Thr Leu Asp Leu Ser Lys Leu Gln Ser 
65                  70                  75                  80 

Leu Pro Glu Gly Ser Leu Gly Arg Glu Tyr Leu Arg Phe Leu Asp Val 
                85                  90                  95 

Asn Lys Val Ser Pro Asp Thr Arg Ala Pro Thr Arg Phe Val Asp Asp 
            100                 105                 110 

Glu Glu Leu Ala Tyr Val Ile Gln Arg Tyr Arg Glu Val His Asp Met 
        115                 120                 125 

Leu His Thr Leu Leu Gly Met Pro Thr Asn Met Leu Gly Glu Val Val 
    130                 135                 140 

Val Lys Trp Phe Glu Ala Val Gln Thr Gly Leu Pro Met Cys Ile Leu 
145                 150                 155                 160 

Gly Ala Leu Phe Gly Pro Ile Arg Leu Arg Thr Gln Ser Leu Gln Val 
                165                 170                 175 

Leu Phe Ser Glu Leu Ile Pro Trp Ala Ile Gln Asn Gly Arg Arg Ala 
            180                 185                 190 

Thr Cys Val Leu Asn Ile Tyr Tyr Glu Gln Arg Trp Glu Gln Pro Leu 
        195                 200                 205 

Thr Ala Leu Arg Glu Glu Leu Gly Ile Ser 
    210                 215 

 
           
             46  
             137  
             PRT  
             Glycine max COQ-4  
           
            46 

Leu Pro Ala Asn Thr Phe Gly Ala Ala Tyr Ala Arg Phe Met Gly Ser 
 1               5                  10                  15 

Arg Asn Phe Ser Pro Asp Asp Arg Pro Pro Val Arg Phe Met Asp Thr 
            20                  25                  30 

Asp Glu Leu Ala Tyr Val Ala Met Arg Ala Arg Glu Val His Asp Phe 
        35                  40                  45 

Trp His Thr Leu Phe Asp Leu Pro Thr Asn Leu Ile Gly Glu Thr Ala 
    50                  55                  60 

Leu Lys Val Ile Glu Phe Glu Gln Met Gly Leu Pro Met Cys Leu Leu 
65                  70                  75                  80 

Ser Val Ile Gly Gly Thr Ala Arg Phe Ser Glu Lys Gln Arg Lys Leu 
                85                  90                  95 

Phe Tyr His His Tyr Phe Pro Trp Ala Ile His Ala Gly Met Pro Ser 
            100                 105                 110 

Thr Asp Leu Met Cys Val Tyr Tyr Glu Arg His Phe Asp Glu Asp Leu 
        115                 120                 125 

Glu Asp Val Arg Arg Lys Leu Gln Ile 
    130                 135 

 
           
             47  
             136  
             PRT  
             Bos taurus COQ-4  
           
            47 

Tyr Pro Glu His Ile Pro Thr Ser Val Leu Gln Lys Val Leu Leu Ala 
 1               5                  10                  15 

Ala Gly Ser Ala Gly Met Ala Leu Tyr Asp Pro Tyr Arg His Asp Met 
            20                  25                  30 

Val Ala Val Leu Gly Glu Thr Thr Gly Arg Arg Thr Leu Lys Val Leu 
        35                  40                  45 

Arg Asp Gln Met Lys Arg Asp Pro Glu Gly Ala Gln Ile Leu Gln Glu 
    50                  55                  60 

Arg Pro Arg Ile Ser Leu Ser Thr Leu Asp Met Gly Lys Leu Arg Ser 
65                  70                  75                  80 

Leu Pro Glu Gly Ser Phe Gly Cys Ala Tyr Leu His Phe Leu Asp Val 
                85                  90                  95 

Asn Arg Val Ser Pro Asp Thr Arg Ala Pro Thr Arg Phe Val Asp Asp 
            100                 105                 110 

Glu Glu Leu Ala Tyr Val Ile Gln Arg Tyr Arg Glu Ile His Asp Met 
        115                 120                 125 

Leu His Ala Leu Leu Gly Met Pro 
    130                 135 

 
           
             48  
             120  
             PRT  
             Medicago trunculata COQ-4  
           
            48 

Asn Phe Ser Pro Asp Asp Arg Pro Pro Val Arg Phe Met Asp Thr Asp 
 1               5                  10                  15 

Glu Leu Ala Tyr Val Ala Met Arg Ala Arg Glu Val His Asp Phe Trp 
            20                  25                  30 

His Thr Leu Phe Asp Leu Pro Thr Asn Leu Ile Gly Glu Ser Ala Leu 
        35                  40                  45 

Lys Val Ile Glu Phe Glu Gln Met His Leu Pro Met Cys Val Met Ser 
    50                  55                  60 

Val Leu Gly Gly Thr Ala Arg Phe Ser Glu Lys Gln Arg Lys Leu Phe 
65                  70                  75                  80 

Tyr Gln His Tyr Phe Pro Trp Ala Val Arg Ala Gly Thr Gln Cys Asn 
                85                  90                  95 

Asp Leu Met Cys Val Tyr Tyr Glu Gln His Phe His Gln Asp Leu Glu 
            100                 105                 110 

Asp Val Arg Arg Lys Leu Gly Ile 
        115                 120 

 
           
             49  
             113  
             PRT  
             Ancylostoma caninum COQ-4  
           
            49 

Lys Phe Val Gln Asn Ser Glu His Leu Tyr Val Met Gln Arg Tyr Arg 
 1               5                  10                  15 

Glu Thr His Asp Phe Asn His Val Leu Leu Gln Met Pro Thr His Met 
            20                  25                  30 

Leu Gly Glu Val Thr Val Lys Tyr Phe Glu Gly Ile Gln Phe Gly Leu 
        35                  40                  45 

Pro Met Cys Val Thr Ala Gly Leu Phe Gly Ala Ala Arg Leu Arg Lys 
    50                  55                  60 

Asn His Arg His Arg Phe Leu Thr Gln His Leu Pro Trp Ile Val Glu 
65                  70                  75                  80 

Gln Ala Thr Lys Gly Arg Phe Phe Met Ala Ile Asp Trp Glu Asn His 
                85                  90                  95 

Trp Glu Glu Thr Ile Pro Ser Leu Gln Glu Gln Phe Gly Ile Thr Pro 
            100                 105                 110 

Leu 

 
           
             50  
             113  
             PRT  
             Trypanosoma cruzi COQ-4  
             
               VARIANT  
               (1)...(113)  
               Xaa = Any Amino Acid  
             
           
            50 

Phe Val Ala Ala Thr Thr Arg Ser Ile Trp Asp Pro Val Asn Ala Asp 
 1               5                  10                  15 

Asp Val Ala Ala Val Gly Glu Thr Pro Ala Leu Thr Ala Leu Gly His 
            20                  25                  30 

Met Lys Gln Ser Met Met Ser Asp Arg Thr Gly Arg Met Ile Leu Arg 
        35                  40                  45 

Thr Gln Pro Arg Val Thr Asp Glu Thr Leu Glu Phe Ala Ser Arg Gln 
    50                  55                  60 

Pro Pro Gly Thr Phe Gly His Arg Tyr Ala Gln Phe Met Lys Phe Xaa 
65                  70                  75                  80 

Xaa Phe Thr Pro Asn Gly Arg Thr Pro Val Ala His Ile Ala Asp Pro 
                85                  90                  95 

Thr Leu Ala Tyr Val Met Gln Arg Gln Arg Glu Thr His Asp Phe Leu 
            100                 105                 110 

His 

 
           
             51  
             99  
             PRT  
             Rattus rattus COQ-4  
           
            51 

His Pro Tyr Arg His Asp Met Leu Pro Val Leu Gly Glu Thr Thr Gly 
 1               5                  10                  15 

Cys His Thr Leu Lys Phe Leu Arg Asp Gln Met Lys Lys Asp Pro Glu 
            20                  25                  30 

Gly Ala Gln Ile Leu Gln Glu Arg Pro Arg Ile Ser Leu Ser Thr Leu 
        35                  40                  45 

Asp Leu Ser Lys Leu Gln Ser Leu Pro Glu Gly Ser Leu Gly Arg Glu 
    50                  55                  60 

Tyr Leu Arg Phe Leu Asn Ala Asn Lys Val Ser Pro Asp Thr Arg Ala 
65                  70                  75                  80 

Pro Thr Arg Phe Val Asp Asp Glu Glu Leu Ala Tyr Val Ile Gln Arg 
                85                  90                  95 

Tyr Arg Glu 

 
           
             52  
             122  
             PRT  
             Gossypium hirsutum COQ-4  
             
               VARIANT  
               (1)...(122)  
               Xaa = Any Amino Acid  
             
           
            52 

Ile Lys Leu Ser Pro Trp Gln Gln Ala Ala Val Ala Val Gly Ser Ala 
 1               5                  10                  15 

Val Gly Ala Leu Leu Asp Pro Arg Arg Ala Asp Leu Ile Ala Ala Leu 
            20                  25                  30 

Gly Glu Thr Thr Gly Lys Pro Ala Phe Glu Arg Val Leu Glu Arg Met 
        35                  40                  45 

Arg Arg Ser Pro Glu Gly Lys Thr Xaa Leu Leu Glu Arg Pro Arg Val 
    50                  55                  60 

Ile Ser Ala Asn Val Gly His Ala Trp Asp Leu Pro Lys Asn Thr Phe 
65                  70                  75                  80 

Gly Ala Ala Tyr Ala Arg Phe Leu Gly Ser Xaa Asn Phe Ser Pro Asp 
                85                  90                  95 

Asp Arg Pro Pro Val Arg Phe Met Asp Thr Asp Glu Leu Ala Tyr Val 
            100                 105                 110 

Ala Met Arg Ala Arg Glu Val His Asp Phe 
        115                 120

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