Abstract:
Gene editing can be performed by introducing gene-editing components into a cell by mechanical cell disruption. Related apparatus, systems, techniques, and articles are also described. The methods and systems of the invention solve the problem of intracellular delivery of gene editing components and gene editing complexes to target cells. The results described herein indicate that delivery of gene editing components, e.g., protein, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA), by mechanical disruption of cell membranes leads to successful gene editing. Because intracellular delivery of gene editing materials is a current challenge, the methods provide a robust mechanism to engineer target cells without the use of potentially harmful viral vectors or electric fields.

Description:
RELATED APPLICATIONS 
       [0001]    This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62/102,347, filed Jan. 12, 2015, which is incorporated herein by reference in its entirety. 
     
    
     STATEMENT AS TO FEDERALLY-SPONSORED RESEARCH 
       [0002]    This invention was made with Government support under Grant Number R01GM101420-01A1 awarded by the National Institutes of Health. The Government has certain rights in the invention. 
     
    
     TECHNICAL FIELD 
       [0003]    The subject matter described herein relates to gene editing by introducing gene-editing components into a cell by mechanical cell disruption. 
       REFERENCE TO THE SEQUENCE LISTING 
       [0004]    This application incorporates-by-reference nucleotide and/or amino acid sequences which are present in the file named “38172-510001WO_Sequence_Listing_ST25.txt,” which is 517 kilobytes in size, and which was created Jan. 12, 2016 in the IBM-PC machine format, having an operating system compatibility with MS-Windows, which is contained in the text file filed Jan. 12, 2016 as part of this application. 
       BACKGROUND 
       [0005]    Genome editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9) and transcription activator-like effector nucleases (TALENs), have shown much potential in their ability to change the genetic code of cells. These technologies could thus enable novel insights in drug discovery and lead to the development of next generation gene therapies. Gene editing complexes, which include a protein component and a nucleic acid component, e.g., deoxyribonucleic acid (DNA) and/or ribonucleic acid (RNA) cannot readily cross the cellular membrane. Thus, delivery of such complexes has been a challenge. 
       SUMMARY 
       [0006]    The methods and systems of the invention solve the problem of intracellular delivery of gene editing components and gene editing complexes to target cells. The results described herein indicate that delivery of gene editing components, e.g., protein, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA), by mechanical disruption of cell membranes leads to successful gene editing. Because intracellular delivery of gene editing materials is a current challenge, the methods provide a robust mechanism to engineer target cells without the use of potentially harmful viral vectors or electric fields. Moreover, the scalability and relative simplicity of the process make it suitable for broad adoption. The strategy and methods are suitable for genome engineering applications in research and therapeutics. 
         [0007]    Accordingly, a method for delivering a protein-nucleic acid complex into a cell is carried out by providing a cell in a suspension solution; passing the solution through a microfluidic channel that includes a cell-deforming constriction; passing the cell through the constriction such that a pressure is applied to the cell causing perturbations of the cell large enough for said protein-nucleic acid complex to pass through; and incubating the cell in a complex-containing solution for a predetermined time before or after the cell passes through the constriction. An exemplary protein-nucleic acid complex comprises gene editing components. For example, the protein-nucleic acid complex comprises a Cas protein (such as a Cas9 protein) and a guide RNA (gRNA) or donor DNA. In other examples, the protein-nucleic acid complex comprises a TALEN protein, Zinc-finger nuclease (ZFN), mega nuclease, or Cre recombinase. 
         [0008]    The methods and system is generally applicable to cytosolic delivery of complexes, e.g., a protein-protein complex, small molecule+RNA complex, etc. 
         [0009]    A variety of target cells types are processed in this manner. For example, the cell comprises a mammalian cell such as an immune cell (e.g., T cell) or a stem cell such as a hematopoetic stem cell. 
         [0010]    The microfluidic system may include a plurality of microfluidic channels. Each of the microfluidic channels of the plurality defines a lumen and is configured such that a cell suspended in a buffer can pass through the lumen. In some embodiments, microfluidic channels include one or more cell-deforming constrictions. In some embodiments, the diameter of the constriction is a function of the diameter of the cell. Thus, there may be many microfluidic channels within a microfluidic system of the invention. For example, the microfluidic system may include a plurality of the microfluidic channels arranged in parallel, e.g., 2, 5, 10, 20, 40, 45, 50, 75, 100, 500, 1,000 or more. 
         [0011]    Microfluidic systems having a plurality of parallel microfluidic channels allow for the high-throughput delivery of payloads to cells. Many cells can be passed through each parallel channel one after the other. It will be understood that, depending on context, a reference to a “cell” herein may refer to more than one cell. 
         [0012]    The diameter of the constriction is chosen depending on the dimensions of the cell type to be treated. In some embodiments, the cell may be primarily compressed by the fluid flow. In some embodiments, the diameter is less than the diameter of the cell. For example, the diameter of the constriction may be substantially or about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 20-99% of the diameter of the cell. For example, the constriction is substantially 20-99% of the diameter of the cell, e.g., a diameter of the constriction is substantially 60% of the diameter of the cell. Non-limiting examples of the diameter of the constriction include substantially or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 2-10 μm, or 10-20 μm. Different lengths of the constriction are also possible. Non-limiting examples of constriction lengths include substantially or about 10, 15, 20, 24, 30, 40, 50, 60, 70, 80, 90, 100, 10-40, 10-50, 10-60, or 10-100 μm. 
         [0013]    The subject matter described herein provides many technical advantages over methods that deliver components (or nucleic acids encoding the components) of the complex piecemeal. Most gene editing systems require complex formation to occur inside the cell, which may be an inefficient process. Advantages of delivering the RNA and Cas (such as Cas9) in complex form (or other protein/nucleic acid gene editing composite assemblies) include better efficiency and specificity compared to other methods. By obviating the need for mRNA or DNA manipulation to express the Cas protein (such as a Cas9 protein), one can reduce how much time the cell spends exposed to the protein thus reducing the chance of off-target effects. Having the editing components delivered to the cell in complexed form also eliminates/minimizes the risk of the Cas (such as Cas9) complexing with other RNA strands in the cell and cleaving the wrong sites. For example, the RNA alone may be detected by intracellular and extracellular Toll-like receptor (TLR) and pattern recognition receptors, prompting an interferon response or other antiviral pathways. The complexed form does not interact with these pathways and can thus avoid undesirable side effects. 
         [0014]    By complexing in vitro prior to delivery into a cell, one can precisely control the Cas (such as Cas9) and gRNA complexing reaction thus ensuring optimal functionality, while complexes forming in the cytosol may not be as efficient. For example, delivering the complex cytosolically ensures simultaneous interaction of Cas (such as Cas9) and gRNA with the target DNA. The complexes formed in vitro and delivered to the cell as described herein are fully functional and ready-to-go upon gaining access to the cytoplasm of the target cell. 
         [0015]    The approach described here is relevant to any protein+RNA/DNA based system to guide the nuclease as the delivery process is independent of the exact size and composition of the complex and because complex formation of the editing materials occurs and is controlled in vitro under their optimal conditions. 
         [0016]    Implementations of the invention may also provide one or more of the following features. Deforming the cell includes deforming the cell for substantially or about 1 μs to 10 ms, e.g., 10 μs, 50 μs, 100 μs, 500 μs, and 750 μs. Incubating occurs for 0.0001 seconds to 20 minutes or more, e.g., substantially or about 1 second, 30 seconds, 90 seconds, 270 seconds, and 900 seconds. 
         [0017]    The pressure and speeds at which a cell is passed through a microfluidic channel may also vary. In some embodiments, a pressure of substantially or about 10-35 psi is used to pass the solution containing a cell through a microfluidic channel. The speed may be adjusted for a variety of reasons, including to improve viability of the treated cells while maintaining high payload delivery. In some embodiments, the cell passes through the microfluidic channel at a speed of substantially or about 300 mm/s, 400 mm/s, 500 mm/s, 600 mm/s, 700 mm/s, 800 mm/s, 900 mm/s, 100-300 mm/s, 200-700 mm/s, 250-400 mm/s, 1-1000 mm/s, 1 m/s, 2 m/s, 3 m/s, 4 m/s, 5 m/s, 6 m/s, 7 m/s, 8 m/s, 9 m/s, 10 m/s, 0.01-5 m/s, 5-10 m/s, or 0.01-10 m/s. Where the cell is a plurality of cells, substantially or about 5, 10, 20, 30, 40, 50, 60, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 90-95, or 80-99% or more of the cells may be viable after passing through the constriction. In some embodiments, the cells are viable for at least about any of one hour, two hours, three hours, four hours, five hours, six hours, seven hours, eight hours, nine hours, ten hours, twelve hours, eighteen hours, twenty four hours, or forty eight hours after passing through the constriction. 
         [0018]    In some examples, a device of the invention includes 2, 10, 20, 25, 45, 50, 75, 100 or more channels. In some embodiments, cells are moved, e.g., pushed, through the channels or conduits by application of pressure. In some embodiments, a cell driver can apply the pressure. A cell driver can include, for example, a pressure pump, a gas cylinder, a compressor, a vacuum pump, a syringe, a syringe pump, a peristaltic pump, a manual syringe, a pipette, a piston, a capillary actor, and gravity. As an alternative to channels, the cells may be passed through a constriction in the form of a net. In either case, the width of the constriction through which the cells traverse is 20-99% of the width or diameter of the cell to be treated in its unconstricted, i.e., suspended, state. Temperature can affect the uptake of compositions and affect viability. 
         [0019]    In certain embodiments, a temperature of 0 to 45° C. is used during cell treatment, e.g., 0-25° C. In various embodiments, the methods are carried out at room temperature (e.g., 20° C.), physiological temperature (e.g., 39° C.), higher than physiological temperature, or reduced temperature (e.g., 0.1° C.), or temperatures between these exemplary temperatures (e.g., 0.1 to 40° C.). 
         [0020]    In some embodiments relating to immune cells, treatment of unstimulated T cells, B cells and/or monocytes is carried out at temperature of 4-8° C., e.g., on ice. In another example, dendritic cells, activated T cells, and/or activated B cells are treated using the device at temperatures of 20-25° C., e.g., at typical ambient room temperature. 
         [0021]    In some embodiments, following controlled injury (e.g., perturbations) to the cell by constriction, stretching, and/or a pulse of high shear rate, the cells are incubated in a delivery solution that contains the complex that one wishes to introduce into the cell. Controlled injury may be characterized as small, e.g., 200 nm in diameter, perturbation in the cell membrane. The recovery period for the cells is on the order of a few minutes to close the injury caused by passing through the constriction. The delivery period comprises 1-10 minutes or longer, e.g., 15, 20, 30, 60 minutes or more, with 2-5 minutes being optimal when operated at room temperature. 
         [0022]    In some embodiments of the device and methods described herein, passage of stem cells or progenitor cells such as induced pluripotent stem cells (iPSCs) through a constriction channel does not induce differentiation, but does reliably induce uptake of compositions into the cell. For example, gene editing compounds are introduced into such cells without complications associated with the method by which the factor(s) was introduced into the cell. 
         [0023]    The size and duration of temporary perturbations in cell membranes can be modified by adjusting various factors, such as the diameter of cell-deforming constrictions and the speed at which cells pass through the constrictions. Disclosures regarding the size and duration of perturbations provided herein should not be interpreted as limiting. Non-limiting descriptions of perturbations and recovery are provided in Sharei et al., (2014) Integr. Biol., 6, 470-475, the entire content of which is incorporated herein by reference. In some embodiments, the perturbations of the cell membrane may be characterized by a maximum diameter of substantially or about 1-20, 1-600, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 600 nm. In various embodiments, perturbations of the cell membrane having a maximum diameter of substantially or about 1-20, 1-600, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 600 nm persist on the cell membrane for at least substantially or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 1-10 minutes or more (11, 13, 15, 18, 20 minutes or more). 
         [0024]    In various embodiments, the diameter is less than the diameter of the cell. For example, the diameter of the constriction may be substantially or about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 20-99% of the diameter of the cell. Non-limiting examples of the diameter of the constriction include substantially or about 4, 5, 6, 7, 8, 9, 10, 15, 20 4-10 μm, or 10-20 μm. Different lengths of the constriction are also possible. Non-limiting examples of constriction lengths include substantially or about 10, 15, 20, 24, 30, 40, 50, 60, 70, 80, 90, 100 10-40, 10-50, 10-60, or 10-100 μm. 
         [0025]    Many cells are between 5-20 μm in diameter, e.g. unstimulated T cells are 7-8 μm in diameter. For example, the diameter of the constriction portion is 4.5, 5, 5.5, 6, or 6.5 μm for processing of single cells. In another example, the size/diameter of the constricted portion for processing of a human egg is between 60 μm and 80 μm, although larger and smaller constrictions are possible (diameter of a human ovum is approximately 100 μm). In yet another example, embryos (e.g., clusters of 2-3 cells) are processed using a constriction diameter of between 12 μm and 17 μm. In a non-limiting example relating to unstimulated T and B cells, the device comprises a constriction having a length of about 10, 15, 20, 25, 30, or 10-30 μm, a width of about 3, 3.5, 4, or 3-4 μm, a depth of about 15, 20, 25, or 15-25 μm, and/or an about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 5-15 degree angle. Examples of microfluidic devices useful for delivering payloads into immune cells are described in PCT International Patent Application No. PCT/US2015/058489, Delivery of Biomolecules to Immune Cells, filed Oct. 30, 2015, the entire contents of which are incorporated herein by reference. 
         [0026]    In addition to single cells, even very large cells, e.g., eggs (approximately 200 μm in diameter), clusters of cells, e.g., 2-5 cell clusters such as an embryo comprising 2-3 cells, are treated to take up target compositions. The size of the aperture is adjusted accordingly, i.e., such that the width of the constriction is just below the size of the cluster. For example, the width of the channel is 20-99% of the width of the cell cluster. 
         [0027]    Cells or cell clusters are purified/isolated or enriched for the desired cell type. Dendritic cells or other cells, e.g., immune cells such as macrophages, B cells, T cells, or stem cells such as embryonic stem cells or iPS, used in the methods are purified or enriched. For example, cells are isolated or enriched by virtue of their expression of cell surface markers or other identifying characteristics. Dendritic cells are identified and isolated by virtue of their expression of the β-intergrin, CD11c or other identifying cell surface markers. With regard to cells, the term “isolated” means that the cell is substantially free of other cell types or cellular material with which it naturally occurs. For example, a sample of cells of a particular tissue type or phenotype is “substantially pure” when it is at least 60% of the cell population. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99% or 100%, of the cell population. Purity is measured by any appropriate standard method, for example, by fluorescence-activated cell sorting (FACS). 
         [0028]    Payload compositions such as polynucleotides, polypeptides, or other agents (e.g., Cas9 and gRNA) are purified and/or isolated. Specifically, as used herein, an “isolated” or “purified” nucleic acid molecule, polynucleotide, polypeptide, or protein, is substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. Purified compounds are at least 60% by weight (dry weight) the compound of interest. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight the compound of interest. For example, a purified compound is one that is at least 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99%, or 100% (w/w) of the desired compound by weight. Purity is measured by any appropriate standard method, for example, by column chromatography, thin layer chromatography, or high-performance liquid chromatography (HPLC) analysis. A purified or isolated polynucleotide (ribonucleic acid (RNA) or deoxyribonucleic acid (DNA)) is free of the genes or sequences that flank it in its naturally-occurring state. Examples of a an isolated or purified nucleic acid molecule include: (a) a DNA which is part of a naturally occurring genomic DNA molecule, but is not flanked by both of the nucleic acid sequences that flank that part of the molecule in the genome of the organism in which it naturally occurs; (b) a nucleic acid incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner, such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. Isolated nucleic acid molecules according to the present invention further include molecules produced synthetically, as well as any nucleic acids that have been altered chemically and/or that have modified backbones. 
         [0029]    Complexes are prepared from purified modules or components, e.g., purified protein(s) and purified nucleic acids (RNA and/or DNA). Thus, the ratios of the components are controlled and tailored as desired to achieve a desired gene editing result. The present method is particularly suitable for delivery of sensitive payloads, e.g., protein-RNA/DNA complexes, e.g., complexes that are 40 kDa, 50 kDa, 75 kDa, 100 kDa, and up to 120, 130, 150, 200, 250, 300 kDa or more. 
         [0030]    Surfactants (e.g., 0.1-10% w/w) are optionally used (e.g., poloxamer, animal derived serum, albumin protein) in the flow buffer. Delivery of molecules into cells is not affected by the presence of surfactants; however, surfactants are optionally used to reduce clogging of the device during operation. 
         [0031]    In some aspects, the device is made from silicon, metal (e.g., stainless steel), plastic (e.g., polystyrene), ceramics, or any other material suitable for forming one or more appropriately sized channels or conduits. In some aspects, the device is formed of materials suitable for etching micron scaled features and includes one or more channels or conduits through which cells pass. Silicon is particularly well suited, because micro patterning methods are well established with this material, thus it is easier to fabricate new devices, change designs, etc. Additionally, the stiffness of silicon can provide advantages over more flexible substrates like Polydimethylsiloxane (PDMS), e.g., higher delivery rates. For example, the device includes 2, 10, 20, 25, 45, 50 75, 100 or more channels. The device is microfabricated by etching the silicon. Cells are moved, e.g., pushed, through the channels or conduits by application of pressure. A cell driver can apply the pressure. A cell driver can include, for example, a pressure pump, a gas cylinder, a compressor, a vacuum pump, a syringe, a syringe pump, a peristaltic pump, a manual syringe, a pipette, a piston, a capillary actor, and gravity. As an alternative to channels, the cells may be passed through a constriction in the form of a net. In either case, the width of the constriction through which the cells traverse is 20-99% of the width or diameter of the cell to be treated in its unconstricted, i.e., suspended state. 
         [0032]    Various implementations of the invention may also provide one or more of the following clinical and research capabilities. Quantitative delivery of gene-editing complexes or components thereof to cell models for improved screening and dosage studies can be achieved. The method could be deployed as a high throughput method of screening protein activity in the cytosol to help identify protein therapeutics or understand disease mechanisms. The devices and techniques are useful for intracellular delivery of gene-editing complexes to a specific subset of circulating blood cells (e.g. lymphocytes) or even whole blood; high throughput delivery of complexes or components thereof into cells, especially oocytes and zygotes; targeted cell differentiation by introducing gene-editing (optionally together with genetic material such as donor DNA) to induce cell reprogramming to produce iPS cells; delivery of DNA and/or recombination enzymes into embryonic stem cells for the development of transgenic or mutant stem cell lines; delivery of DNA and/or recombination enzymes into zygotes for the development of transgenic or mutant organisms; dendritic cell (DC) cell activation; iPS cell generation; creating mutations in normal or diseased cells (such as cancer cells) to study the contribution of one or more genes to cellular function and/or disease; and stem cell differentiation. Skin cells used in connection with plastic surgery are also modified using the devices and method described herein. Methods of delivering gene-editing proteins disclosed herein may also be used to generate CAR-T cells or to genetically modify hematopoietic stem cells (HSCs) for treating genetic and other diseases. In embodiments relating to HSCs, a subject may receive an autologous, syngeneic, or an allogeneic edited HSC. In various embodiments, cells of a subject may be ablated before the subject receives a gene-edited cell. For example, bone marrow cells of a subject may be ablated with radiation or chemically before the subject receives a gene-edited HSC. In some embodiments, a gene associated with beta thalassemia or sickle cell anemia is edited using a method or composition disclosed herein. Cells processed ex vivo or in vitro, i.e., outside of the body of a subject, in accordance with the invention are useful for subsequent administration to a subject in need of treatment or diagnosis of a pathology. In alternative embodiments, in vivo cell processing is carried out. 
         [0033]    In various embodiments, the SHP2 gene is edited/mutated to reduce the activity thereof or knock out or reduce SHP2 expression. In such embodiments relating to gene editing in T cells, the T cells become less responsive to immunosuppressive signals and have increased activity toward tumors. In such embodiments, the T cells may be more responsive to tumor antigens and more effective at treating cancer. 
         [0034]    Aspects of the present subject matter relate to the rapid and transient delivery of protein-protein as well as protein-nucleic acid complexes, e.g., gene-editing complexes to cells. A nucleic acid component of the complex comprises a deoxynucleic acid (DNA), ribonucleic acid (RNA, e.g., mRNA, gRNA) or other double-stranded or single stranded nucleic acid compounds, respectively. For example, the delivery of a gene-editing complex (e.g., a ribonucleoprotein (RNP)) may achieve gene editing faster than if an expression vector encoding components of the gene editing complex (e.g. a Cas protein and a gRNA) was delivered to the cell. For example, the gene may be edited (e.g., mutated or replaced) in the cell 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, or 0.1-4 hours sooner than in a corresponding cell that has received microfluidic or electroporation-mediated delivery of an expression vector that encodes gene editing complex components. 
         [0035]    Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. 
         [0036]    Related apparatus, systems, techniques, and articles are also described. 
         [0037]    The details of one or more variations of the subject matter described herein are set forth in the accompanying drawings and the description below. Other features and advantages of the subject matter described herein will be apparent from the description and drawings, and from the claims. 
     
    
     
       DESCRIPTION OF DRAWINGS 
         [0038]      FIGS. 1A and 1B  are schematic diagrams of a microfluidic system in which cells are exposed to the delivery material (payload) after passing through the constriction; 
           [0039]      FIGS. 2A and 2B  are schematic diagrams of an embodiment of a microfluidic system in depicting parameters such as channel depth, width, and length. 
           [0040]      FIGS. 3A and 3B  are a series of flow cytometry plots ( FIG. 3A ) and a bar graph ( FIG. 3B ) of the recombination efficiency for K562 reporter cells that had genetic editing material delivered to cell cytoplasm using the microfluidic device illustrated in  FIGS. 1-2 . For the reporter used, there is a frame-shifted GFP gene in the cell line. To perform the editing the Cas9 gRNA complex and a donor oligonucleotide would be delivered. The complex would cut near the GFP site and the oligonucleotide would insert itself into the cut site. Successful insertion of the oligo would correct the gene and result in GFP expression which is what is seen in this figure. Thus, in this assay something turned on upon gene editing as opposed to turned off. A gene would be expected to be turned off in instances where a gene (or depending on the context, a nucleotide or portion thereof) was being deleted in the absence of a donor oligonucleotide. 
           [0041]      FIG. 4  is a series of FACs plots showing β 2  microglobulin component of MHC class 1 (B2M) expression vs. delivered dextran for four different cell populations obtained using FACS. The delivery of the RNP using the 30-4 chip at 90 psi results in a 54.4% reduction in B2M expression as compared to the endocytosis control whereas the 10-4 chip at 90 psi results in a 25.2% reduction in B2M expression. B2M expression on the CAS9 control is not significantly different than the endocytosis control. The longer constriction chip results in more delivery of the RNP complex and a larger reduction in B2M expression. 
           [0042]      FIG. 5  is a series of FACs plots showing reduced B2M expression in a dose dependent manner determined by FACS as a measure of functional editing with the indicated conditions. 
           [0043]      FIG. 6  shows a FoxP3 genomic sequence running from the first sheet of  FIG. 6  to the last sheet of  FIG. 6  (SEQ ID NO: 56). Exons belonging to FoxP3 are shown in underlined and highlighted letters. Other exons within this region that do not belong to FoxP3 are shown in non-underlined highlighted letters. 
           [0044]      FIG. 7  shows a FoxP3 translated amino acid sequence (SEQ ID NO: 57). Alternating exons are underlined and non-underlined. Bold with italics indicate a residue overlap splice site. 
           [0045]      FIG. 8  shows a SHP1 genomic sequence running from the first sheet of  FIG. 8  to the last sheet of  FIG. 8  (SEQ ID NO: 58). Exons belonging to SHP1 are shown in underlined and highlighted letters. Other exons within this region that do not belong to SHP1 are shown in non-underlined highlighted letters. 
           [0046]      FIG. 9  shows a SHP1 translated amino acid sequence (SEQ ID NO: 59). Alternating exons are underlined and non-underlined. Bold with italics indicate a residue overlap splice site. 
           [0047]      FIG. 10  shows a SHP2 genomic sequence running from the first sheet of  FIG. 10  to the last sheet of  FIG. 10  (SEQ ID NO: 60). Exons belonging to SHP2 are shown in underlined and highlighted letters. SEQ ID NO: 60 is also as follows: 
           [0000]    
         
           
                 
                 
               
             
                 
                   AGGCTCAAGCAATCCTCTCACCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCGCGCCA 
                     
                 
                 
                     
                 
                 
                   CCACGCCCGGCTAATTTTTGTATTTTTTGTAGAGATGGGATTTCACTATTTTGCCCGGGC 
                 
                 
                     
                 
                 
                   TGGTTCCCAACTCCTGGACTCAAGCGATTCGCCCGCCTCAGCCTCCCAAAGGGAAGTGCT 
                 
                 
                     
                 
                 
                   GGGATTTCAGGCGTGTGCCACCGCTCCCACCCCAAAGTAGTATTTATTGTAATTATTATT 
                 
                 
                     
                 
                 
                   ATTATTTTGAGACGGAGTCTCGCTCTATTGCCAGGCTGGAGTGCAGTGGCGCGATCTCGG 
                 
                 
                     
                 
                 
                   CTCAATGCAACCTCTGCCTCCCGGGTTCAAGCGATTCTCCTGCTTCAGACTCCCAAGCAG 
                 
                 
                     
                 
                 
                   CTGGGACTACAGGCGCCCCCCACCACGCCAGGCTAATTCTTGAATTTTTAGTGGAGACGG 
                 
                 
                     
                 
                 
                   GGTTTCACCATGTTGGCCAGGATGGTCTCGATCTCTTGACCTCGTGATCCGCCCACCTCG 
                 
                 
                     
                 
                 
                   GCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCAGCCTATTATTATTTTT 
                 
                 
                     
                 
                 
                   TTAGGCAGTGTCTTGCCCTGTCGCTCAGGGTGTAGTGCAGTGGCGTGATCACGACTCACT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TTTTTGCATTTTTTGTAGAGATGAGGTCTTGCTTTTTTGCCCAGGCTGGCCTCGAACTCC 
                 
                 
                     
                 
                 
                   TTGGCTTAAGCGAACCTCTTGCCGCAGCCTCCCAAAGTGTTGGGATTACGGGCGTGAACC 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   GAGCCCCGAGGGGCCCGGCGCGGGCCTCGGCCCGGCCACCGCCGCGTTCGGTTAGCCCCG 
                 
                 
                     
                 
                 
                   TCCGGAAGGGGGCGCCCCGGCCGGGCTTCGGGCTCCCGCCCCGGGTCGGGGTTGGGGGCC 
                 
                 
                     
                 
                 
                   GGTTCCCTCCTCGTCCCCTCGCCCTCCAGGGGCCGGGGGCCGGCCCCACCGCGCCCCCAC 
                 
                 
                     
                 
                 
                   CCCTCGGGTCCCCATTCATTTCCTGCCTCCCCGAGTTCCGGCTGCGGCAGCCCCGGGGAT 
                 
                 
                     
                 
                 
                   GCCCGTCAGGCCCGGGGCAGGTAGAGCCGCCGAGGGAACCACGGGTGCCAGCGGCCAGGC 
                 
                 
                     
                 
                 
                   TCAGCGCCGCATTCCTGACCCATTGCCTCATGAGAATTGCCTCATGGTGATTCCGAAATA 
                 
                 
                     
                 
                 
                   ACCCTGCTCACTTGGGGAGGCTCCTTGGGACACGAGAGGGGAGTTGCGCGGGGCCGGGCC 
                 
                 
                     
                 
                 
                   CCCAGTGGTCTAGTCGTTCTGGCTCACTGTGCCACTTTCGTGCATTTGGGGACTTCACGC 
                 
                 
                     
                 
                 
                   AGGACCCCTGACCCTTTTATATGCCTCTTTGTGTCTTCTTTTCCTCCTACCCCTCACGTG 
                 
                 
                     
                 
                 
                   CCAGAAATGGAAAAACTGACTGTATCTGCAGCCACTAGAAGTATTTCCTTCCTCTGCGAT 
                 
                 
                     
                 
                 
                   CTTCGCTTTGGGAGATGGAAAGGAAGGGAGCCGCATCTCGTTATTTAATCCTTCACTGCA 
                 
                 
                     
                 
                 
                   ACCTTAACAGTCAGGTCACTTTACTGGTACCCGTTTTATGGATGAGGAAACCGAGGCCCA 
                 
                 
                     
                 
                 
                   GAAGCAACATGCTAGTAAATGACAAGATTTGAAACTTAGGAGGATTAGTGAGTTAATGAG 
                 
                 
                     
                 
                 
                   ATCCTTTGAAAGGTCAGGGTAATACTACTACTAATAGCTAACATTTGCTTAGTTCTGACC 
                 
                 
                     
                 
                 
                   ACAGCCCTATCAGATGGCTACTATTATCCCCATTGTAAAGATGAGTAAACCGAGTTTCAG 
                 
                 
                     
                 
                 
                   AGGTTAAGTAAATTGCCTAACCTCACAGCTAGTAGGTGGTGGAGACAGAATCCCTACTTT 
                 
                 
                     
                 
                 
                   TAATCACTATGTTGCTTCTATTATTTTGTAACTATTGCTAACCATTTGTAAGCCTTAATT 
                 
                 
                     
                 
                 
                   TTGTTGTCAAACAGTAGTGTGACCTGTTGTTTTCAGATAGTGATCCTGCTATTTTGTATA 
                 
                 
                     
                 
                 
                   GTCACTCTATATACCACTCACACTTAAGACCCATTGTCTATTCTTTTCCATGATTGTTCA 
                 
                 
                     
                 
                 
                   ATTATGGTCACTGTCTCAGACATTTAAAAAACGATTCAAGCTATTGAGGCTATTTGAATG 
                 
                 
                     
                 
                 
                   AGATTTTCTTTTCTTTTTTTCTTTTTTTTTTTGGAGACGGAGGCTCACTCTGTTGCCCAG 
                 
                 
                     
                 
                 
                   GCTGGAGTGCAGTGGCGCAATCTCGGCTCACCACAATCTCCGCCTCCTAGGTTCAAGCGA 
                 
                 
                     
                 
                 
                   TTCTCCTGCCTCAGCCTCCCAAGTAACTAGGACTACAGGCGCACCACTATGCCCGGCTAA 
                 
                 
                     
                 
                 
                   TTTTTGTATTTTTAGTAGAGACAGGGTTTCACTATGTTGGCCAGGCTGGTCTCAAACTCC 
                 
                 
                     
                 
                 
                   TGACCTCGTGATCCGCCCGCCTTGGCCTCCCAAAGTGCTGGAATTACAGGCGTGAGCCAC 
                 
                 
                     
                 
                 
                   CGTACCCAGCCTGAATGAGATTTTTCAAAATATTAGGAATGTCTCCTCCAAACACACCTG 
                 
                 
                     
                 
                 
                   GCATGTTATTCATACATGGATCTGGAATTTAAAAAGGGGAGAAAAAGAAAACTGAGAACT 
                 
                 
                     
                 
                 
                   CGTAGGAAGTGAGTGACTTGGACAGGTCGGTTGGCAAGTGCTTACAGATCTGGGTAATAT 
                 
                 
                     
                 
                 
                   ATAACTGCATTTCAACAGAACAGTGTATAGCCTCAAATGTTCTAATTCTTTAGGGAGCTT 
                 
                 
                     
                 
                 
                   TTAAATAAACAGTTGTCTATTCTTTAATCTGTCAAATAGTCATTGAGCCTTTTGTTCCTG 
                 
                 
                     
                 
                 
                   GTGTCTGCTCTTCCAGACAAGTAAGGATCTGCTGCTTTAGGAGACATCAGACGGGGCTGG 
                 
                 
                     
                 
                 
                   GGGTTGGGAAAAGGTCTGGGTAGTAATAGACCCTACATTGTCCAGTTTGTTCATTTAGAA 
                 
                 
                     
                 
                 
                   GCATAGAAGTGTGGGCATAGTCAAAGTAGCAAGTGGTAAAGATGACAGTTTGAAATGGAG 
                 
                 
                     
                 
                 
                   TAATTCCTTCTCCCCTCCAGCCCTGGTATTATGCACCACCCAAAAAGCCGGGTTATGAAC 
                 
                 
                     
                 
                 
                   ATAATACACATAATTTTGAATGATTCATTATTTTTTGGATTATAAGCCTGTTTTATTTGT 
                 
                 
                     
                 
                 
                   TAACCAGCCTTAATGAGGTATAAATGACATGCAATTAATTGCATATATTTAAATGTACAA 
                 
                 
                     
                 
                 
                   TTTGATCAGTTTTGACATACATATACACTTGGGAAACCACCACCATAGTCAAGATAATGA 
                 
                 
                     
                 
                 
                   ACACATCTATCACCCCTGGTAATTTTGCCTTATGTTCTTTATAATCCTTCCTTTGTTCTT 
                 
                 
                     
                 
                 
                   AGGCAGCCACTATTCTGCTTTCTGTCACTATGTATTAGTTTGCATTTCCTAGAATTTTAT 
                 
                 
                     
                 
                 
                   TTTTAAAAATTTTAAAATTGTTTGAATAGAGATGGGGTCTCACTGTGTTGCCCAGGGCAG 
                 
                 
                     
                 
                 
                   TCTCAAACTCCTGGGTTCAAGTGATCCTCTCACCTTGGCCTCCTGAAGTGTTGGGATTAT 
                 
                 
                     
                 
                 
                   AGGCATGAGACACCCTGCCCAGCCCTAGAATTTTATTATTATTGTTATTATTGTGTTTTT 
                 
                 
                     
                 
                 
                   TTGAGATAGGGTCTCACTTTGTTGCCCAGGCTGGAGTGCAGTGGTGCAATCACTGCAGCC 
                 
                 
                     
                 
                 
                   TTGTTTTCCTAGGCTCAATCCATCCCCCCTCCTCAGCTTTCCGGTTACTGGGGCTACAGG 
                 
                 
                     
                 
                 
                   TGTGCACCACCACACCCGGCTAATTTTTGTATTTTTTTATAGAGACAGGGTTTTGCCATG 
                 
                 
                     
                 
                 
                   TTGGCCAGGCTGGTCTCAAACTCCCGGGCTCAAGCGATCTTCCTGCCTCGGCCTCCCAAA 
                 
                 
                     
                 
                 
                   GTGCTGGGATTACAGGCATGAGCTATTGCGTCCCGCCTTCAAATTACTTTAACCTAGTAT 
                 
                 
                     
                 
                 
                   TAATTCATTCAACAGGAAGTTAATGAGCCAGGCAGGATAAAGCAGTAAGATAGGAAAATA 
                 
                 
                     
                 
                 
                   TTGCTATTTTCATGGCTGAGAGAGAGCAGACAAACACATGACTAAATAGGGCAATTTCAG 
                 
                 
                     
                 
                 
                   GTAGTAATAAATTCTAGGAGGGAAAAAATCCCACAGAAATGTGAGGATGGGAGAATGCAG 
                 
                 
                     
                 
                 
                   TTAGTTTTGATAGGTGGTTTAGAGAAGGTGATCGTGTGAGCTGACACCTGAATGACAATT 
                 
                 
                     
                 
                 
                   AGTAGTCTGAATTTTGTTTTGCTTAATTATCAAAATAACTCCTCTTGGGTTCGGCTTTTA 
                 
                 
                     
                 
                 
                   TATGCATCCAGTAATTAAAATGTAAGTATATTCAATGTACTGATATCTCTCAGCATCATA 
                 
                 
                     
                 
                 
                   GGTAGGAAAACTAAGGCATTCAGCAATTAAGTGACTCCTCCCTTGATCATGTAGCAGTGA 
                 
                 
                     
                 
                 
                   TAGTACTGGATTTAGATTTTGAGGTTGCTTCTCTGCCCTTTTCTGCCTTTGTGAAACCAA 
                 
                 
                     
                 
                 
                   CAAAGCTGCCTGTATTTTCCAACTCTTCCTTCAGCATGTGGTACCTCCTTTACATCTGTT 
                 
                 
                     
                 
                 
                   TTTGTTGCTCTGAAATCCATACGCGACGATGAGCTGAGAGGGGCAGAAAATTGAGCTTGT 
                 
                 
                     
                 
                 
                   TCTGAGACTGGAGGCTTTTGGTTTATCTCTTGCAGGTCAAGTACATTTTGTCCTGGGCTC 
                 
                 
                     
                 
                 
                   TCCCTGGTGGCCACGTTTGTTTATCTCCTGCGGGAGTAAATAAACTTGCCTTGCTGAAAA 
                 
                 
                     
                 
                 
                   ATAACAGTTCTGTGTCTTTGCAGTGGAAACTGGGATGTCTTTATTAACGTTAGGTCCTGA 
                 
                 
                     
                 
                 
                   TGTAAGGCCAAGTTTTTGGTTAGAGTTGCTCAAGTGCAGAGGCCACTGCTAAGATGACTT 
                 
                 
                     
                 
                 
                   ACCCCTCGTGTCCATGGTCAATGTGGAGACTGTTATGAGTGGCACATGATGCTGGAAAAG 
                 
                 
                     
                 
                 
                   CAGAGCCAACTCATGTTTGTAATTGTCCTAGCAGGCCGTGGTGTACTTTGTTAGGCAGCC 
                 
                 
                     
                 
                 
                   ACAGAACAATAGAGAAACTCAGCTTATTCCCCTTCCCTCTGGGAAACACAGACAGTACTT 
                 
                 
                     
                 
                 
                   GCCATCCAACGCCAATGTTTTTAAGGAAGAAAGAGGCAAAAAGTGATGTTGGCAAGGTCT 
                 
                 
                     
                 
                 
                   CTGGGAGTTGTGGACCCCAACCAAGGATTGGAGACCCTGAAATGGATTCAGATGCCCTAA 
                 
                 
                     
                 
                 
                   AATGCAGCCCAGTTCATTACTATGAATTTTGGAGGACTTTGTGCCTTGAGCAAATGTGTA 
                 
                 
                     
                 
                 
                   TATGTGACGCTCTTTGACAACACTGAAATAGGAAAAATACTATCCATGTTCGCGAGGAGC 
                 
                 
                     
                 
                 
                   ACTGAATTTAGAGAGGGAGACAGACTTTTATGCCAGCATCAAATGAATTTGATAAAGCTA 
                 
                 
                     
                 
                 
                   GTACCAAAATGAAATTTGAAATTTTTTTTTTTTGAAATAGAGTCTTACTCAGTCACCCAG 
                 
                 
                     
                 
                 
                   GCTGGAGTGCAGTGATACAATATTGGCTCACTGCAACCTCCACCTCTTGGGTTCAAACAA 
                 
                 
                     
                 
                 
                   TTCTTGTGCCTCAGTCTCCTGAGTAGCTGGGATTACAGGTGCGTGCCACCATGTCTGGCT 
                 
                 
                     
                 
                 
                   AATTTTTATATTTTTAGTAGGGATGGGGTTTCACCATGTTGGCCAGGCCGGTCTTGAACT 
                 
                 
                     
                 
                 
                   CCTGGCCTCAAGTGATCTGCCCACCTTGGCCTTCCAAAGTGCTGGGATTATAGGCATGAG 
                 
                 
                     
                 
                 
                   CTACCACACAAGCCTGAAATTTGAAATGTATTGGTATAGAATATACTGTTTAGAATGTAT 
                 
                 
                     
                 
                 
                   GTGTATATATGTATATTTGTATACTCATATAAACACAAATACACATTGTATGTGTTTCTG 
                 
                 
                     
                 
                 
                   TAATATGTATATCTGTCTACACATACATGTATATACACACATACAATGTCTTTTTTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTTTTTTTGAGACAGGGTCTTACCCTGTTGCCCAGGCTGGAGACTGCAGTGGCATA 
                 
                 
                     
                 
                 
                   ATCTTGGCTCACTGCAGCCTCGACCTCCTGGGCTCAAGTGATCCTCCCATCTCAGCCTCC 
                 
                 
                     
                 
                 
                   TGAGTAGCTGGGACTGACTACAGGCACGTGGCATCAAACTTGTCCAATTTTTCTATTTTT 
                 
                 
                     
                 
                 
                   TTGTAGAGTTAGGGTCTTGCTCTGTTGCCCAGGCTGGTCTCAAATTCCTGGGCTCAAGCT 
                 
                 
                     
                 
                 
                   GTCTGCCTGCCTCGGCCTTCCAAAGTACTAGGATTACAGATGTGAACCACTGTACCTGGC 
                 
                 
                     
                 
                 
                   CTTTACAATGTCTATTTTAAAGATAATGGTTCAAGTTTTTATCATCCCACTGGCCTACTC 
                 
                 
                     
                 
                 
                   TAATGAAACATCTATCCATTCATTGAAGAATTATTTATGGTGGGATAACTCTGTGCCAGG 
                 
                 
                     
                 
                 
                   TACCGTGCTAGGCATTGAGTATTCCAGGTTTTAGGAAACAGCACATGCAAAAGTGCTGAA 
                 
                 
                     
                 
                 
                   GTGGGAGAAGATCTCGGAGTGATTGAAGGCTAGGAGAGAGCAAGTGTGGGAGCTGTGAGG 
                 
                 
                     
                 
                 
                   CTGGGAAGGTGGGAGGTAGGTGGGAGCAGACCACATAGGGATTCTTAATGTCTTTAGTGT 
                 
                 
                     
                 
                 
                   CATGTGGACCATGGAGAGGAGTGTAGATTGTATTTTTAGAGCAATGCAAAATCATAGAAG 
                 
                 
                     
                 
                 
                   GATGTGATCGGGGGAGTGGCATGAGCTGATCTATTTAAAAATATTTCTCTGGCTGCTGTG 
                 
                 
                     
                 
                 
                   AAGGAAGGATTGTAGGAGGCAGGAGTAGATTCAGGGAGATGAGACAAGTGATGAGAGAGG 
                 
                 
                     
                 
                 
                   CTTTGAACTTGGGTAAAAGTAGTTTGTGGAAAGTCTTTTTTGGAGGTAGTTTTTGTTTAT 
                 
                 
                     
                 
                 
                   TGCCTTGTCATCAAAGCAGAGATGCTGACCAATGAAACTCCATGAGAAAATAGTGATTTA 
                 
                 
                     
                 
                 
                   TAAAGACATATCTATGCACTGCCATTAAAAAGCTGCTTGGAAAAAAAGGATAAAAAGCTG 
                 
                 
                     
                 
                 
                   CTTTAACAACTTTTTTTTTTGAGATGGGGTCTTACTCTGTCACCCAGGCTCACGACCTCA 
                 
                 
                     
                 
                 
                   GCTCACTGCAACCTCTGCCTCCCAGGCTCAAGCATTCTCCCACCTCAGCCTCCCGAGTGG 
                 
                 
                     
                 
                 
                   CTGGGACTGCAGGCACACGCCACCATGTCAGGCTAATTGTGTGTGTGTGTGTGTGTGTGT 
                 
                 
                     
                 
                 
                   ATGTGTGTGTGTGTGTGTGTGTGTGTGTGCTGGGACTGCAGGCACACACCACCATGTCAG 
                 
                 
                     
                 
                 
                   GCTAATTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTA 
                 
                 
                     
                 
                 
                   TGTAGAGATGGGGTTTTGCCATGTTGCCCAGGCTGGTCTCAAAATGTTGCCCAGGCTGGT 
                 
                 
                     
                 
                 
                   CTCAAACTCCTGAGCTCAGGTGATCCACCCGCCTCGGCCTCCAAAGTGCTGGAGATTACA 
                 
                 
                     
                 
                 
                   GACGTGAGCCACTGTGCCCACCTAACAACTTTAAAAAAATTTTGACATTTAGTAGGATAT 
                 
                 
                     
                 
                 
                   TTATTGCATTATTGTTGAGATGGCAAAATATTGGAGACAACTGAAATGTTCATCAGTGGG 
                 
                 
                     
                 
                 
                   GGGGGCTAGTTAAATGAAATACAGTGTAGCATGCATTAGAACACTTTTCAAGAATTTAAC 
                 
                 
                     
                 
                 
                   TTTTTTTGTAGCCTTTTACTTATAATGCTTGTCCCTATTGATGCCTTTTTTTTCAGCATG 
                 
                 
                     
                 
                 
                   ACTTACTCTTTTACTATAGGATATTAAAATTTAATTAGATTAGAAATGAGGAATATTCTT 
                 
                 
                     
                 
                 
                   GTAATCTGTAGAAAGTAACAAACTATAAACTTATTCCCCAAGAACAAATATAATAATTTT 
                 
                 
                     
                 
                 
                   TCTGGAGTAGCAGGTAAGAAAGATATAAATTTATATGTATACAAGAAACTGAAATTAGAC 
                 
                 
                     
                 
                 
                   TTTATACATTTAAAGGTTACAAGTGCAGTTTTATTACATGAATGTATTATCCAGCATTGA 
                 
                 
                     
                 
                 
                   AGTCTGGGCTTTTAGTGTAACCAGCACCTGAATAACATACATTGTACCCATTAAGTAATT 
                 
                 
                     
                 
                 
                   TCTCATCCCTCAAACCCCTCCCACCCTGAAATTAGACTTTGGATCCCTAGTTTAAATTCC 
                 
                 
                     
                 
                 
                   ACCCCTCTCTTTTTTTGAGACAAGGTCTCACTCTGTCACCCAGGCTGGAGGGCAATGTTG 
                 
                 
                     
                 
                 
                   CAATGATAGCTTACTGTAGCCTCAACCTCCTGGGCTCAAGGGATACACCCTCCTCAGCCT 
                 
                 
                     
                 
                 
                   CCTGAGTAGCTGGAACTGCAGGCGTGCACCACCACATTCAGCTAATTTTTTGATTTTTTT 
                 
                 
                     
                 
                 
                   ATAGAGATGAGGTCGGAACTCCTGGGCTCAAGCGATTCTCCCCAAGTGCTGGGGTTACAC 
                 
                 
                     
                 
                 
                   ACATGGGCCACTGCCCCCAGCCTAAACCTCCTTTCTCAGTATAGCAGCCTTGAGATGAAG 
                 
                 
                     
                 
                 
                   TTCCTGAAATTACTGGCCAGCTTGACTGTTTCCCCACATCACTGGAGGAGGGGGATGCAT 
                 
                 
                     
                 
                 
                   AGATAAAACAAAATATTCAGCATCATTGTATTTTCTTTTTGTTTCATCAGCATCTTTTTT 
                 
                 
                     
                 
                 
                   TAAAACTCACTTGACATAAGTCCCTAGCCTCAAAGAGTAAAGCCTTTGCAGAATCTGCAT 
                 
                 
                     
                 
                 
                   TCAGATTTCGGGTGTGATTTCCTGACAGATAGTTCAGGTTTGTAAACTCTTTTTTTTTTC 
                 
                 
                     
                 
                 
                   TTTGAGACAGAGTTTCACTCTTGTAGCGCAGGCTGGAGTGCAGTGGCACCATCTTGCCTC 
                 
                 
                     
                 
                 
                   ACTGCAACTTCTGCCCCCTTGATTCACGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTG 
                 
                 
                     
                 
                 
                   GGATTACAGGCATGCGCCACCACACCTGGGTAATTTTTGTATTTTTAGTAGAGATGGGGT 
                 
                 
                     
                 
                 
                   TTCACCATGTTGGCCAGGCTGGTTTTGAACTCCTGACTTCAGGTGATCTACCTGCCTCAG 
                 
                 
                     
                 
                 
                   CCTCCCAAAGTGATGGGATTACAGGTGTGAGCCACCGCAGCCGGCCAAAACTTTGTTTTT 
                 
                 
                     
                 
                 
                   TTTCCTCTTTTTGTTGCTGAGAAATGTAAACTCTTACAGACACAAATTATGTCTCCCATT 
                 
                 
                     
                 
                 
                   TTTTAAAACCCACTCAACACAGGGGTCATGTGTAATAGGCCCTGGAGCTTATTTTAGACA 
                 
                 
                     
                 
                 
                   TTGATTTGAGGCTCTTTTCCCCAAGTGCTGGTTTGTGTGTGTGTGTATGTGTGTGTAAGT 
                 
                 
                     
                 
                 
                   CTTTCTATGAGATGAGTGGTACCTACCTGGGCTGTGTGATCTTTTTTATTTTATTTATTT 
                 
                 
                     
                 
                 
                   TATTTTTGTAGATACGAGGTCTCACTATGTTGCTCAGGCTGGTCTTGAACTCTGGGGCTC 
                 
                 
                     
                 
                 
                   AACCTATCCTCCCTCCTTGGCCTCCTAGAGTGCTGAGATTACAGGTGTGAGCCACTGCAC 
                 
                 
                     
                 
                 
                   CTGGCCAGCGATCCTTAATAAATATAGATAATGGCCGGGCGTGGTGGCTCACACCTATAA 
                 
                 
                     
                 
                 
                   TACCAGTACTTTGAGGGGCCGAGGCTGGCAGGTCACCTGAGCTGAGGAGTTTGAGACCAG 
                 
                 
                     
                 
                 
                   CCTGGGTAACGTGGGTGAAACCCTGTCTCTACAGAAAATAGAAAAATTAGCCAGGTGTGG 
                 
                 
                     
                 
                 
                   TGGTGCATGCCTGTAGTCACAGCTACTTGGGAGGTTGAGACAGGAGAATTGCTTGAACCT 
                 
                 
                     
                 
                 
                   GGAAGGTGGAGGTTGCAGTGAGCCGAGATCGTGTCTTTGAACTCCAGCCTGGGTGACAGA 
                 
                 
                     
                 
                 
                   GTGAGACCTTGTCTCAAAAAAAAATATAGATATAGGCTGGGCGTGGTGGCTCACACCTGT 
                 
                 
                     
                 
                 
                   AATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCAGGAGGTCAGGAGATCGAGACCAT 
                 
                 
                     
                 
                 
                   CCTAGCTAACATGGTGAAACCCTGTCTCTACTAAAAATACAAACAATTAGCCAGGCCTGG 
                 
                 
                     
                 
                 
                   TGGTGGGTGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCGTGAACCC 
                 
                 
                     
                 
                 
                   GGGAGGTGGAGGTTGCAGTGAGCCGAGACTGTGCCACTGCCCTCCAGCCTGGGCGACAGA 
                 
                 
                     
                 
                 
                   GCGAGACTCTGTCTCAAAAAAAAAAAATCTATATATCTATATATCTATATCTATATAGAT 
                 
                 
                     
                 
                 
                   ATAGATATAGATAATGCCAGATGATGGCTGGTTAGAAGGGATTGTCAGGGGCTGGCAGGT 
                 
                 
                     
                 
                 
                   TTTGCAGGTGTTAGAATGAGCAAGATGAGGAGAAGGATGCTTACTTCCCTCTCCTTGTAA 
                 
                 
                     
                 
                 
                   CTCTCTACCCCCTCCCCTCAGTGTTTTTTTATTTTTATTTTTATTTATTTATTTTTTTTG 
                 
                 
                     
                 
                 
                   AGACAAGGTCTTGCTCTGTCACCCACACTGGATTGCAGTGATGCAATCATAGCTCATTGA 
                 
                 
                     
                 
                 
                   AGCCCAAACTCCTGGGCTCAAGTGATCCTCTTGCCTCAGCCTCCCAAGTAACTGGGACCA 
                 
                 
                     
                 
                 
                   CAGGTGCGTACAACTATGCCCAGTTAAGTTTTTCATTTTTTATACAGACGGGGTCTTGCT 
                 
                 
                     
                 
                 
                   ATGCTGTCCAGGCTGGACTTGCACTTCTGGCTTCAAGTGATTCTCTTGCCTCAGTTTCCC 
                 
                 
                     
                 
                 
                   AAAGTGCTGGCATTATGGGCATAAGCCACTGTGCCTAGCCCATCAGTGTCTTTTTATCCT 
                 
                 
                     
                 
                 
                   TTACTCCTATCAAAATTCATTCACTCAGCAGCCATTGATCAAGTGCCTACTATATACATG 
                 
                 
                     
                 
                 
                   TTGAGGACTGGAAATTTATTTGTCTCTTCTCATCTTATCTGGACCCTCTGTGTTAATTGT 
                 
                 
                     
                 
                 
                   AATTAACTGTAATCATTCTGTATTAATTGTAATAAACTTGTTGATAAACTCAAATGAGGC 
                 
                 
                     
                 
                 
                   CATACCGTTTTGCCACTTCCCCTCCTTCCAGGTTATATGGATGTACTTACATTGCAGGTT 
                 
                 
                     
                 
                 
                   TCATTTGTTGGTTCAGTTTTTAAACTAAGCCCTATTGTGTCAAATTATGCTAGGTGTGAG 
                 
                 
                     
                 
                 
                   ATGGGGAGTTCAAGCTGTGTGTTGTCTTTTTTTTTTTTTTTTTTTTTGCCTCACTTACTA 
                 
                 
                     
                 
                 
                   ATATACAAGCGCTTATAACCTTTGAGGCTGGCCCTATACATTAAGATTTTTATTAATTCC 
                 
                 
                     
                 
                 
                   ACTGTTCTTTATCTTCTCTTACTAAGTTCTCAGGGTCGAATGAACTCTAACTGCTCCTTG 
                 
                 
                     
                 
                 
                   CTAGTGATAAGCAAGTTGCAAATTACAGAATTGTCAGTGATTGAATACACGTATTAAACC 
                 
                 
                     
                 
                 
                   TGTAACTGGGAAGCATTTTTGGTAATTATGAATACTTTTGGAAAAAAAAAAGCTATGGAA 
                 
                 
                     
                 
                 
                   GGAAAGTTTAAAATCTACGAAAGCTCAAGTAGATGGTCATGGAATAGCTATTTCAATTTC 
                 
                 
                     
                 
                 
                   TAACTATATATTACTTATTTATTTATTTATTTTTGAGACGGAGTTTAGCTCTTGTTGCCC 
                 
                 
                     
                 
                 
                   AGGCTGGAGTGTAATGGCGTGATCTCAGCTCACTGCAACCTCCACCTCCCGGGTTCAAGC 
                 
                 
                     
                 
                 
                   TATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTATAGACATGTGCCACCACGCCAGG 
                 
                 
                     
                 
                 
                   CTAATTTTGTATTTTTAGTAGAGACGGGGTTTCTCCACATTGGTCAGGCTGGTCTCGAAC 
                 
                 
                     
                 
                 
                   TCCCAACCTCAGCTGATCCGCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGA 
                 
                 
                     
                 
                 
                   GCCACCGCGTCCGGCCTCTTAACTATTGTTTGAAATAATGTAGAGACAGCTCCAGAGCCA 
                 
                 
                     
                 
                 
                   TGAAGAAGTGTATGAAGAAGCAGTGTTAGCTTAAATGACATACATGTCACAATTGCCTAT 
                 
                 
                     
                 
                 
                   GTGAAACTATCATAATTATGCATGAGAAGTATCTATCCTGCATAACCTCCACCAATAATA 
                 
                 
                     
                 
                 
                   ATAATGTTAATAATAGTGAAAACTAATGTTTATTAAGTCCTTACTGTCTCCAGCCTCTGT 
                 
                 
                     
                 
                 
                   GCTAAATACTGGTTACTAAGTTTCCCTGAAAATACTATTCTCATCTGTTTGTTCTTAATA 
                 
                 
                     
                 
                 
                   ACAGGATAGCATAATTGTAAGTTGTAAATGAAATAATACAGTTTATGTAATAAAAGGGTA 
                 
                 
                     
                 
                 
                   AAAGAGAAGACCACCTACCTTATCTTCTGTTGCTGATCTGGATGGATGTAGGTGGTGTTT 
                 
                 
                     
                 
                 
                   ACCTAGTTTCACCTTTGGCAGTTGAAACTACTTTTTTTTTTTTTTTTTTTTTTTTTAAGA 
                 
                 
                     
                 
                 
                   GACAGGGTGGGCCAGGCGCAGTGGCTCACGCCTGTAATCCCCGCACTTTGGGAGGCTGAG 
                 
                 
                     
                 
                 
                   GCGGACAGATCACTTGAGGTCAGAAGTTCGAGACCAGCCTGGCCAACATGGTGAAACCCT 
                 
                 
                     
                 
                 
                   GTCTCTACTAAAAATACAGAAAAATTAACTGGGTGTGGTGGTACACACCTGTAATTCCAG 
                 
                 
                     
                 
                 
                   CTACGTGGGAGGCTGAAGCAGGAGAATCGCTTGAACCCGGGAGTGGAGGTTGCAGTGAGC 
                 
                 
                     
                 
                 
                   TGAGATTGTGCCACTGCACTCCAGCCTGGGTGACAGAGCAGGACTCCGTCTCAAAAAAAA 
                 
                 
                     
                 
                 
                   AAACAACAACAAAAAAAGAAATTTTTAGAAATATGAGATGACAGCAAGAATGAGGGTATT 
                 
                 
                     
                 
                 
                   AAAAAGAAATTTTTAGAACTAAATAGCAGAATGTAATGGTGAAAAGTTTGATTTCTCAAG 
                 
                 
                     
                 
                 
                   TCTGCTTTGCACACAGGCATGTGGCAAACATTCAGTAAGTATAGCTGTAATTTTAACCAG 
                 
                 
                     
                 
                 
                   CTGTAATGTATAATAGCCAACATATCACATTTTTCTTTTTTCTTTTTTGAGACAGAGTCT 
                 
                 
                     
                 
                 
                   TGCTCTGTTGCCCAGGCTGGAGTGCAGTGGCACCATCTCGGCTCACTGCAACCTCTGCCT 
                 
                 
                     
                 
                 
                   CCTGAGTTCAAGTGATTCTTGTGCCTCAGCCTCTCAAGTAGCTGGGATTACAGGTGTGTG 
                 
                 
                     
                 
                 
                   CCACCACACTCGGCTATTTTTTGCATTTTTAGTAGAGATGGGGCTGGTCTTGAACTCCCA 
                 
                 
                     
                 
                 
                   GCCTCAGGTGATCTGCCTGCCTCAGCCTCCCAAAGTGCTGAGATTACAGGTGTGAGCCAC 
                 
                 
                     
                 
                 
                   AGCGCCTGGCCATATATTGCTTTTTTCTTATTATCAGAGCCAGTTCATAATTGTGGAAAA 
                 
                 
                     
                 
                 
                   ATAGTGTTTGTAACAATGTAAGTATGGATAAATCATCTTTTTAATTTTGTGATTCATATA 
                 
                 
                     
                 
                 
                   GGTTTGTTGTTGTTGTTGTTGTTTTGTTTTTATCTTGAGACAGAGTCTTGGTCTGTCACC 
                 
                 
                     
                 
                 
                   CAGGCTGGAGTGTAATGGCACAACCATGGCTCACTGCAGCCTCAGATGCCTGGGTTCAAG 
                 
                 
                     
                 
                 
                   CAATCCTCCCGTCTCAGCCTCTAGAGTAGATGGGACCACAGGTGTGGGCCACCATGCCTG 
                 
                 
                     
                 
                 
                   GGTAATTACAAAACTTTTTTTTTTTTTTCTAGAGATGAGGTCTCACTATGTTGCCCAGGC 
                 
                 
                     
                 
                 
                   TGGTCTCAAACCTTTGACCTCGCTTCAGCCTTTAGAGTAGCTATGACTATAGGCATGTGC 
                 
                 
                     
                 
                 
                   CATCACCCAGCTAATTAAAATTTTTTTTCTTTTTTTTTTTGGTGGAGATGCGGTCTTACT 
                 
                 
                     
                 
                 
                   TTGTTACCCAGACTGCAAGTTAGTTTCAGATATCAACATTTGGTGTTTCCAAATGCACGG 
                 
                 
                     
                 
                 
                   GGAGGCTTTGGAGCAAGTTTTTGGCTCATATGCATAGGTGTCCTAGACATTCACTTTGCA 
                 
                 
                     
                 
                 
                   AATTCTTATTAAAATGACTACAGTAGCATACAGATAGGGAAAAATATCCTTGTCAGTACC 
                 
                 
                     
                 
                 
                   ACCGATTGGGTGAGAAGAGACTGTATATTAAAAACAATGACCATCTTTTTGCCACATAAA 
                 
                 
                     
                 
                 
                   TTGCTGGTGGGGCCAGTTTGAAGAGGGCTTTGTCAGCTGCCTTCTGCCTCTTCCTCTTGA 
                 
                 
                     
                 
                 
                   GTACGTGGAGTTGGAGTCATCCTTGACAGCCTCCTGTTGACACCACCCGGGTCACAGATG 
                 
                 
                     
                 
                 
                   TGAAACTGTGTGGATGTAGGAGAGAGCAGTGATGGGGCTTACCCCAAGGTTGCTCTTCCT 
                 
                 
                     
                 
                 
                   TCCCTCTGGCCACAAATGTTTAGTAAGGAACTGCTCTGTATTAACCATTTGCTAGGGGCT 
                 
                 
                     
                 
                 
                   GCAGATACGGTGGTGAAGAAATAGACATGTTCCTACTCGGGATGCTGAGGTGGGAGGATT 
                 
                 
                     
                 
                 
                   GCTTGAGCCCAGGAGTTGGAGCTGCAGTGAGCCATGATCACACCACTGCACTCCAGCCTG 
                 
                 
                     
                 
                 
                   GGGGACAGAGCGAGACCCTATCTCTAAAAAACAATAAAAGAAATAGATGTGTCCTTCACC 
                 
                 
                     
                 
                 
                   CTCATGGAACTGCCAGTCTAGCCTTCAACCTGGTGACTGTAGAAATGTGTGATTAGATGC 
                 
                 
                     
                 
                 
                   TATATTGCCATGTTGAGTGTCACCCCTGAGAAGCAGGGTTTTTTTTGAGAAGGTAGGATG 
                 
                 
                     
                 
                 
                   GGGGATCTGACTGTGGGACCACCAGAGGGAAAAGCACATGTAAAAGCTGCGTGTACCAAC 
                 
                 
                     
                 
                 
                   TGGAGGAAATCGGAGACGTGATCAGAGAACCAGAGTCAACCAGGGGCCATGCCGTACAGG 
                 
                 
                     
                 
                 
                   GTCCTGTTAAGATCTGTGACTTTTTTCTAAACGTTTTCTTCTGGATAACATCTAAATTTC 
                 
                 
                     
                 
                 
                   TAGTTCCAAATGTGAAACTCCAAGGGCGTTCTGTGCTAAACATTTTGCATGTATTAATTA 
                 
                 
                     
                 
                 
                   ATTTCCACCACACAACATTGCTGTGAATTAAGACAGTTTCTAAGCATGGCAAGAAACCCA 
                 
                 
                     
                 
                 
                   GAAATCATAATGGAAAAATCTGATAAATTTAACAATGCCAACATGAACCTCTGTAGGAAA 
                 
                 
                     
                 
                 
                   AAAAATACCACAGACTAAAAAGGGGGGAAAAAAACCAGAGACAAATATTTGCAACACATA 
                 
                 
                     
                 
                 
                   CAGTAAAGGGTAATTTTCTGGTTATATCAAGAGCTCCTACAAATCAGTAAGAAAAAAAAT 
                 
                 
                     
                 
                 
                   CTAATAGGAAATGAGCAACGACAAACTGACAACTCATAGAAAAGGAAACACAAGTGGTCT 
                 
                 
                     
                 
                 
                   GAAAACATGAAAAAGTGCTCAGTCTCACAAAGAAATGCAAACTAACATGGTACCATTTTC 
                 
                 
                     
                 
                 
                   CATTAATCAGATAGACAAAGATGAAAGAGTTTGGTAATGTATGTAGTATTGGCACAAGTG 
                 
                 
                     
                 
                 
                   AGGGAAAACAGGGGATTTCACACTCTATGCCCGTCCAAACCAGTACCTTATTTTGAGGGT 
                 
                 
                     
                 
                 
                   GGTTTGACAATATTTGTCAAAATAAAAAAATTATATATAGTCATTTGCCACATAATGATG 
                 
                 
                     
                 
                 
                   GTTCAGTTGATGATGGACGGCATACATAATGGTGGTCCCATAAGAATATAATGGGCTGGG 
                 
                 
                     
                 
                 
                   TGCAGTGGCTCTCACCTGCAATCCCAGCACTTTGGGAGGCCGAGGTGGGTGGATTGCCTG 
                 
                 
                     
                 
                 
                   AGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGGTGAAACCCTGTCTCTGCTAAAAACA 
                 
                 
                     
                 
                 
                   TACAAACAATTAGCCAGGCATGGTGGCGGGTGCCTGTAATCCCAGCTACTCAGGAGGCAG 
                 
                 
                     
                 
                 
                   AGGCAGGAGAATCGCTTGAACCCGGAAGGCGGAGGTTGCAGTGAGGTGAGATTGGGCCAC 
                 
                 
                     
                 
                 
                   TGCACTCCCATCTAGATGACAAGGCAAAACTCCATCTCAAAAAAAAAAAAAAAAAAGAAT 
                 
                 
                     
                 
                 
                   ATTATGGGCCCAGCCACAGTGGCTCACACCTGTAATCCCAGTACTTTGGTAGGCCAAGGC 
                 
                 
                     
                 
                 
                   AGGAGAATCATTTGAACTCAGGAGTTTGAGACTAGTGGGGACAACATAGCAAGACCCCAT 
                 
                 
                     
                 
                 
                   CTCAAAAAAAAAAGATTATGGTGGAGCTGTCCTGTATAGACATACCATTTTTAACTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTTTGAGATGGAGTCTTGCTGTGTCACCCAGGCTGATGTGTAGTGGCGTGATCTGG 
                 
                 
                     
                 
                 
                   GCTTACTGAAACCTCCACCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCTTCCTGAGTA 
                 
                 
                     
                 
                 
                   GCTGGGACTGCAGGCGCAGGACACCATATCTGGCTAATTTTTATATATTTAGTAGAGATG 
                 
                 
                     
                 
                 
                   GGGTTTCACCATGTTGGCCAGGCTGGTCTTGAACTCCTGACCTCAAGTGATCCGCCTGCC 
                 
                 
                     
                 
                 
                   TCAGCCTCCCAAAGTGCTGGGATTACAGGCATTAGCCACCATTTACAGGCACCTGGCCAC 
                 
                 
                     
                 
                 
                   CATTTTTAATCTTTTATATTGTATTTAAACTGTACCTTTTCTATGTATGGATGTGTTTAG 
                 
                 
                     
                 
                 
                   ATACACAAATACCATTGTGTTACAGTTACTTACAGTATTCAGTACAGTAGCATGCTGTAC 
                 
                 
                     
                 
                 
                   AGGTGTGTAGCCTAGGAGCAATAGGTTATACCATATAGCCCAGGTGTGTAGTAGGCTCTG 
                 
                 
                     
                 
                 
                   CCATCTAGGTTTGTGTAAGTACGCTCCATGATGTTACCACAGTGACGAAATCGCCTAATG 
                 
                 
                     
                 
                 
                   ATGCATTTCTCAGAACATATTCCTGTTGTTAAGCAATGCATGACCGTATCTTGACAAAGC 
                 
                 
                     
                 
                 
                   CATTTTATTTCTAAAACTTTAATTTTACAGATTTATTTGTAAAAGTATGTAAAAATGATT 
                 
                 
                     
                 
                 
                   GTAAAGGATATGTTCTGCTGCATTATTTGTAATAACAAAAAACCAGAGGATAACATAAAT 
                 
                 
                     
                 
                 
                   GTCCTATAAGAAGGGTTAGATTATGGATGGCACATTCATACAATGGGGTATTATGTAGCC 
                 
                 
                     
                 
                 
                   ATTGAATAAAAGGGTACTGGCTGGGCGCAGTGGCTCATGCCTATAATCTCAACACTTTGG 
                 
                 
                     
                 
                 
                   GTGGCCAAAGAAGGAGGATTGCTTGAAGCCAGGAGCTTGGGGCCAGCCTGGGCAACATAG 
                 
                 
                     
                 
                 
                   CAAGACCCTATCTCTACAAAGGAAAAATAAAACAATTAGCCAGGTTTGGTATTGGACACC 
                 
                 
                     
                 
                 
                   TTCATGGTCCCAGCTACTGAGGAGGCTGAGATTGGAGGGATCGCTTGTGCCTGGCAGGTT 
                 
                 
                     
                 
                 
                   GAGGCTGTAGTGAGCCATGATTGTGCCACTGCACTCCAGGCTGGGAGATAGAGTGGGACC 
                 
                 
                     
                 
                 
                   CTATCTCAAAAAAACAAAAACAAAAACAAAACCTCCTGTAAAATGTCAAGAAGTCCTAGA 
                 
                 
                     
                 
                 
                   TGTGGGCCAGGTGTGGTGGCTCACACTTGTAATCCCTGCACTTTGGGAGGCTGAGGCCAG 
                 
                 
                     
                 
                 
                   GAGTTTGAGACCAGGCAGAGCAAGATAGCAAGACTCCATTTCTACAAAAAATAAAAAAAA 
                 
                 
                     
                 
                 
                   TTAGTTGGGCATAGTGGTGCATTCCTGTAGTCCCAGCTACTCAGGAGGCTGAGGTGGGAG 
                 
                 
                     
                 
                 
                   GATTGCTTGAGCCTGGGAGGTTGAGGCTGCAGTGAGCCATGATCACACCTCTGCACTCCA 
                 
                 
                     
                 
                 
                   ACCTGCGCAACAGAGTGAGACCCTGTCTCTAAAAACAACAACCAAAAAAACCCAGCAAAG 
                 
                 
                     
                 
                 
                   TACTGATAAAGATCTTTGGCTGGGCGCAGTGGCTCACACCTGTAATCCCAACACTTCAGG 
                 
                 
                     
                 
                 
                   AGGCTGAGGCGGGCAGGTCACAAGATCAAGAGATCAAGACCATCCTGGCCAACATGGTGA 
                 
                 
                     
                 
                 
                   AACCCGGTCTCTACTAAAAATACAAAAATTAGCTGGGCATGGTGGCGTGCACCTGTAGTC 
                 
                 
                     
                 
                 
                   TCTGCTACTCGGGAGGCTGAGGCAGGAGAATCACTTGAACCCAGGTGGCAGAGGTTGCAG 
                 
                 
                     
                 
                 
                   TGAGCCGAGATCACGCCACTGCATTCCAGCCTGGCGACAGAGCAAGACTCCGTCTCAAAA 
                 
                 
                     
                 
                 
                   AAAAAAAAAAGAGAGAAAGATCTTCAAGTTGTAGTATGTGAAAAAATCAGGGTGTAAAAC 
                 
                 
                     
                 
                 
                   AAGAGAATCCCATTTGTGTGTGTGTCGAGTGTGTTTCACACAGGCTCAGAGGGAGTAGTG 
                 
                 
                     
                 
                 
                   TGTATATGCACATGAACATACGTGTCAGTGTATATATGTATATATACAAGGTTGTGGGTT 
                 
                 
                     
                 
                 
                   TGTTTGTTTTTTTTGAGACAGAGTCTTACTCTGTTGCCCAGGCTGGGGTGCAGTGGTGCA 
                 
                 
                     
                 
                 
                   ATCTTGACCCACTGCAACCTTCACCTCCCAGGTTCAAGTGATTCTTGTGCCTCAGCCTCC 
                 
                 
                     
                 
                 
                   CAAGTAGCTGAGACTACAGGCACGCACCACCATGCCCAGTTAATTTTTGTATTTTTAGTA 
                 
                 
                     
                 
                 
                   GAGATGGGGTTTCATCATGTTGCCCAGGCTGGTCTGGAACTCCTGGCCTCAAGTGCTCTG 
                 
                 
                     
                 
                 
                   CCCGCCTTGGCCTCCGAAAGTGCTGTTGCCCAGGCTGGAGCTCAGTGGCACAATCGCAGC 
                 
                 
                     
                 
                 
                   TCACTGCAACCCCGACGTCCCAGGCTCAGGCAATCTTTCCGTCTTAGCTTCCCAAGTAAC 
                 
                 
                     
                 
                 
                   TGGGACTACAGGTGTGTGCCATCAATGCCCCACCAATTTTTTAATTTTTTGTAGAGATGG 
                 
                 
                     
                 
                 
                   GGTTTCCCTACGTTGCCCAGGCTGATCTTGAACTCCTGGTCTCAAGCAATCCTCCCACCT 
                 
                 
                     
                 
                 
                   CAGCCTCCCAAAGTGCTGCGATTACAGGTGTGAGCCACCTTGCCCTGCCCTGTACAAAGA 
                 
                 
                     
                 
                 
                   TCTGCATAAAAGCAGTTAATAATACTATGTTTGAGGCTGCCATCACAGGGGTGAGGTCAA 
                 
                 
                     
                 
                 
                   GGACAAGTGTGAGAAATTCTTTTAGAATCTATTTTAAAAAAAGAAGAGATGACAGTGGTG 
                 
                 
                     
                 
                 
                   ACAGTCAGGGAACAGATAAGCAGGTAGATTGTGGGGGTCTAGGCTGTCTAACTGGTGTTT 
                 
                 
                     
                 
                 
                   AAAATGAAGCAACCGCTGAGCCTGCTGTATTTCATTTAATGGAGACTAGTAAAACAACAG 
                 
                 
                     
                 
                 
                   CCAGAAATTCTTCACTTTCCATCTAAGAGAGGCAAAAGTTATTTTCCCTTCAATAACCTG 
                 
                 
                     
                 
                 
                   GGACTGTAGGATTAAGGTTTTTTTTTTTTTTTTTTTAAATACTACAATATGACTACCAGT 
                 
                 
                     
                 
                 
                   ATAATTTAAAAATGATTAGAATTCTATTTGAGTAAGAAATAGGTGTCTGCCTGAAGTAGA 
                 
                 
                     
                 
                 
                   CAGTCACTGAAGTCACTAAGTGGCAAAAGACAGAAAAAAAATTGAAAGTAGGAAACAATC 
                 
                 
                     
                 
                 
                   AGCAGATATGATACCAAACATGAGCTGTCAGTGATAATGGATTAAGTCCTTCAATAATGG 
                 
                 
                     
                 
                 
                   CTGAGCCAGATGGAATTAAAAGAAAAAATCCAGGCCGGGCATGGTGGCTCACACCTGTAA 
                 
                 
                     
                 
                 
                   TCCCAGCACTTTGGGAGGCTGAGGTGGGAGGATCACTTGAGTCCAGGAGTTTGAGACCAG 
                 
                 
                     
                 
                 
                   CCTGAACAACATAGTGGGACCCCATCTCTATTTTATAAAAATATTTTGAAAAAAGAAAAA 
                 
                 
                     
                 
                 
                   AAAATTCAGTTGTGTTCTGCTTTAAAAAGACAAATTGGCACAGAATGTCAAAGAATAAAT 
                 
                 
                     
                 
                 
                   AAAACAAACATGGGCAAAAGAGATTCAGGTGGTACCAATATCGGGCTAAGTAGCATTCAA 
                 
                 
                     
                 
                 
                   GATAAAGATTATTAAATAATAAGTTAGTTAATACTAGAGTAATTGCATATTAATGAAACA 
                 
                 
                     
                 
                 
                   TAATCTATGGTAGAGATATTATAGTCAATAATTGTTTTATGTATTCATTAAGGTAACAAC 
                 
                 
                     
                 
                 
                   AAGCAAACAAGCTTTAATAGTTTTAAATGCTTTATATGCTTTATAGTTCTTTTATGTGCA 
                 
                 
                     
                 
                 
                   TTAATTCATTAATTCTCATTTCCTATGAGGTAAACACTATTATTATCCACATTTTACAGA 
                 
                 
                     
                 
                 
                   TGTAAAAACCGAAGCAGAGAGATTAATTAGCTTGCCCAGGAGATGTGGCATTCTGGGATT 
                 
                 
                     
                 
                 
                   TGAGACAGTGGTTTGGCTCTGTAGGTTGCTTCAATAACCAAGAGATGCTTCAAATCAGAT 
                 
                 
                     
                 
                 
                   TTTTAAAATATGTTTTTCAGAAGCATTTTCCTGATACTTCTCCCCTTACATGGGTGTTAG 
                 
                 
                     
                 
                 
                   TCTTTTGGGTTGAAAAACATGAGTAAGTGCTAGAAGAGCAAAATATGCATCCAGATTTAA 
                 
                 
                     
                 
                 
                   TAGTATGTCTGTTTTTCTGAGCCTTGGCATTTCATTGCTTTTATAATAGAAATGAAGGCT 
                 
                 
                     
                 
                 
                   TTTTTTTTTTTTTGGCTGAGAATAGCACTGAACTCAGTGGGAGGGACTGTGGGTTGTAAG 
                 
                 
                     
                 
                 
                   TTGTCCGCCTCTGAATGGAGTTGAATTTAAGTTTCTTGGTTTCCAAAGAATGATTGATTT 
                 
                 
                     
                 
                 
                   AAAGACCCTCAAATTGCAAGTTAGAACTGACTTCAGTCCTTGAGGTTTTTTACCATTTAA 
                 
                 
                     
                 
                 
                   TGAATAATTAAATTTATGGTAATAAATGGTAATAAATGGTAAAAATGGTAATAAATTTTA 
                 
                 
                     
                 
                 
                   CCATTTAATGAATTTTTCTTAAAAAGCAATTGAATTGTTGATGAAAGGTGATGTTAAAAT 
                 
                 
                     
                 
                 
                   TATCCCAGATTTATCAATCTTTTTTTTATTGCCCCTGGATTTTGAGTCATAGAAAGCCTT 
                 
                 
                     
                 
                 
                   TCCTTATTCTAAGGTTAACAAGACATTCACCCATGTTTTCCTCTAGTATTGCATTGTTTC 
                 
                 
                     
                 
                 
                   ATCTTTTACGTTTATTATTTATTTTATTTTATTTTTTTGAGACAGGGTCTCACTGTGTCA 
                 
                 
                     
                 
                 
                   CTCAGGCTGGAGTGCAGTGGAATGATCTTGGCTCACTGCAGCCTCTGCCTCCCGCCTCCC 
                 
                 
                     
                 
                 
                   GGGTTCAAGCGATTCTGCTGCCTCGGCCTCCCAAGTAGCTGGGATTACAGGCACCTGCCA 
                 
                 
                     
                 
                 
                   CCGCGCCTGGCTAATTTTTGTATTTTTTTTTTAGTACAGATGGGGTTTTGCTGTTGGCCA 
                 
                 
                     
                 
                 
                   GGCTGGTCTCGAACTCCTGACCTTAAGTGATCCACCCGCCTTGGCCTCCCAAAGTGCTGG 
                 
                 
                     
                 
                 
                   GATTACAGGCATGAGCCACCGTGCCCGGCCTAAAATTTATTCTGATATGTGATATGATGT 
                 
                 
                     
                 
                 
                   ATGGTTCTAACTACTTTGTTACGGTGCATTATTTTCTAAATGTGGTATTGGATTCTTTTA 
                 
                 
                     
                 
                 
                   TATTTTGTTTAGAAGTTCTGCATCAATATTCATGAGTACCATTGGTCTCTGTTGTTTTTC 
                 
                 
                     
                 
                 
                   TTGTGCCATCTTTATTGGTATAGGTATCAGTGTTATATTTAGTTTGTAAAAGGAAGTTGG 
                 
                 
                     
                 
                 
                   AAGTTTTCCTTTCTTTTTAGTACTCAGGAATGATTTTAAGAATTGAGACTATTTGGTCTT 
                 
                 
                     
                 
                 
                   TGAAGGTTTGGTAGAAGTCCATTGGGAATCCATCTGGGCCTGGTGATTTTCTGTGCGGTA 
                 
                 
                     
                 
                 
                   GTTCCTTAATTGTTTTCCCTATTTTTTCTTATTTTTAATCAGGTAGCCTCTGAACCAGAA 
                 
                 
                     
                 
                 
                   TAGGTTCAGAGAGGCTCCCTCTATTTTTTTTAATACAAGTTGGTCTGCCTAAGTTTTCTT 
                 
                 
                     
                 
                 
                   ACTCTAATGGGTTAATTTTTGTAGACTGCATTTCCCTGAAAAATTACACGTTTGTTCTAG 
                 
                 
                     
                 
                 
                   GTTTTCTGACTTATTTCCACAACTTTTTAGTCTTTCCCCCTGGAATCATGCCCCTTTCCA 
                 
                 
                     
                 
                 
                   TAAACAGGACTCTGATGTACCTGAAGTATTTTCACACTTCGGGTGGACTTTCTGTTTCTG 
                 
                 
                     
                 
                 
                   GGGGTGGTTTTAGAGCAATTTTAGGCCTGCCACTAGCTACCCTGTTCTCTACACCATGCT 
                 
                 
                     
                 
                 
                   GTTTTTCTCAGAATGCTCTTCTTTTGCACAAAGGCTTGGAGTAGGAGGTTGAGCAGTCAC 
                 
                 
                     
                 
                 
                   TCACTGACGTTTGGTATATTTTCTTTTTTTTGCTTACAGGTAATCTGGAAGTTTGGGCAT 
                 
                 
                     
                 
                 
                   TCTCTTTAAGTTGAGGGTGTGGTTTTCATGTCATTTTATTTGTTTATTGTTTTCTTGTGT 
                 
                 
                     
                 
                 
                   GTGTTTCTTAGAGACAGGGTCCCACTCTTGCCCTGGCTGGAGTGCAGTGGCGTCTTGATC 
                 
                 
                     
                 
                 
                   ATAGCTTACTGCATCCTCAAGCTGCTGGGCTTAGATGAACCTCCCACCTCAGCCTCCTGA 
                 
                 
                     
                 
                 
                   GTAGCTGGGACTACAGGAGCACACCACCATACCTAATTTTTTTTTTTTTGAGACGAAGTC 
                 
                 
                     
                 
                 
                   TTGCTCTGTCCCCCAGATTGGAGTGTAGTGGTGCAATCTCGGCTCACTGCAACCTCTGCC 
                 
                 
                     
                 
                 
                   TCCCGGGTTCAAGCGATTCTCTCACCTCAGCCTCCCGAGTAGCTGAGACTGCAGGTGCAT 
                 
                 
                     
                 
                 
                   GCCACCATACCCGGCTAATTTTTGTATTTTTTAGTAGAAACAGGGTTTCACCATGTTGGC 
                 
                 
                     
                 
                 
                   TAGGCTGGTCTCAAACTCTTGACCTCAAGTGATCCACCCACCTTGGCCTCCCAAAGTGCT 
                 
                 
                     
                 
                 
                   GGGATTACAGGCTTGAGCCACTGTGCCTGGTCCCTGGCTAATTTTTAATTTTTTTGTAGA 
                 
                 
                     
                 
                 
                   GATGGGATCTTGCTATGTTGCCCAGGCTGGTCTTGAACACCTGGCCTTAAGCAATCCTCC 
                 
                 
                     
                 
                 
                   CACCCTAGCCTGCCAAAACACTGGGATTTACAGGCATGAACCATTGTGCCTGGCTTGTTT 
                 
                 
                     
                 
                 
                   TGTTTTTAATTCTATGTTGTTTTTGAAGGATGTATGGGGAGAGATGGATTTAGGCAATCA 
                 
                 
                     
                 
                 
                   TCGTTGTCCTTGGCTACCTGAAAGTCCAGGCACTCTTCTAGATACTTTATAAATATTAAC 
                 
                 
                     
                 
                 
                   TCATTTTATCCTCTCAACAACACTATGACATGGGTACTGTTACACCTTCCATTTTATAGG 
                 
                 
                     
                 
                 
                   ACTTAACAGAGAGGTTAAATATGTAGCCCAGGGTCACAGAGAGCTGGGCTTCAGACCAAG 
                 
                 
                     
                 
                 
                   ACAATCTGGCACCAGAGTCTATGTGGCTACCCCTAAGGCTTTGCCACCATGTGTTAGTGA 
                 
                 
                     
                 
                 
                   TTCTCAGCCTGTCATTTGGGGAGGGGATTGCCCTTTTTTTTAAACTTTTTAAAAAATTTA 
                 
                 
                     
                 
                 
                   TTCTTATTTTATTATATTTTTGAGACAGAGTCTCCCTCTTTTGCCGAGGCTGGAGTGGAG 
                 
                 
                     
                 
                 
                   TGGTGTGATTTCAGCTCACTGTAACCTCTGCCTCTGGGGTTCAAGTGATTCTCATGCCTC 
                 
                 
                     
                 
                 
                   AGCCTCCCAAGTAGCTGGGATTACAGTTGCCAGCCACCATGCCCAGCTAATTTTTGTATT 
                 
                 
                     
                 
                 
                   ATTATTATTATTATTTGAGACGGAGTCTCGCTCTTTTGTTCAGGCTGGAGTGCAGTGCTG 
                 
                 
                     
                 
                 
                   TGATCTCGGCTCTCTGTAACCTTCGTCTCCTGGGTTCAGGTGATTCTCCTGCCTCAGCCT 
                 
                 
                     
                 
                 
                   CCGGAGTAGCTGGGACTATAGGCGCGCACCACCATACTTGGCTAATTTTTTGTATTTTTA 
                 
                 
                     
                 
                 
                   GTAGAGACGGGGTTTCACTATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGAT 
                 
                 
                     
                 
                 
                   CTACCTGCCTTGGCCTTCCAAAGTGCTGGGATTACAGGTGTGAGCCACCATGCATGGCTG 
                 
                 
                     
                 
                 
                   GATTGTCCTTTTTTAAAAAAAAAAACAAAAACAAAAAAAAAAACCCAAACCATAAACCCA 
                 
                 
                     
                 
                 
                   ATATTCTGAAAGATTTGGTCTCCACACCTGTGTTATATAATAATTAGTTTTTCCATTTTT 
                 
                 
                     
                 
                 
                   TTCCTCTTGGTAGAAGGCACATATGCCACTCAGTTTCCAGTTGCCACACCCAATTAACAT 
                 
                 
                     
                 
                 
                   AATTGTTTTGCAGCCAAAAGCAAAAGAGAGTTGACATTTTAATTAGCTTATGTAGGTAGA 
                 
                 
                     
                 
                 
                   CAAATTGAGGCCTAATGTAAGAGTTTCATTATACCTTTTTGAAAAACTATAAATAGCTAG 
                 
                 
                     
                 
                 
                   AAGCCAGTTGTCATTACTTTTTGATTCCTTAGAATTCTGGGCATCTTTCATCTGGAACCA 
                 
                 
                     
                 
                 
                   CAGATGAAAGAAGCTGCAAGGAAGGATTTTTTTTCTTAACGGAATAGTTTAACCATTCTG 
                 
                 
                     
                 
                 
                   AATGCAAAAGTATTGGATGCTAGAATAATAGGTATCACATAAATTGAGGTTGACGTTTTC 
                 
                 
                     
                 
                 
                   CCGGGTGAAATTCTATTCTGTCTCAATTTTCCTTTTTTTTTGAGACGGAATCTTGCTCTG 
                 
                 
                     
                 
                 
                   TCGCCCAGGCTGGAGTGCAGTGGCATGATCTCGGCTCACTGCAAGCTCCACCTCCTGGGT 
                 
                 
                     
                 
                 
                   TCATGCCATTTTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGGGCCTGCCACAAC 
                 
                 
                     
                 
                 
                   ACCCAGCTAATTTTTTTGTATTTTTAGTAGAGACGGGGTTTCCCAGGATGGTCTCAATCT 
                 
                 
                     
                 
                 
                   CCTGACCTCGTGATCCGCCTGCCTCGGCCTCCCAAAGTGCCGGGATTACAGGCGTGAGCC 
                 
                 
                     
                 
                 
                   ACTGTGCCTGGCCTTTTTTTTTTTTTTTTTTTTTTTTTTTTAAGACAGAGTCTCGCTTTG 
                 
                 
                     
                 
                 
                   TTGCCTAGGCTGGAGCGCAGTGGCATGATCTCAGCTTATTGCAACCTCCGCCTCCCGGGT 
                 
                 
                     
                 
                 
                   TCAAGTGATTCTCCTGCCTCAGCCTCCCGAGTATCTGAGATTACAGATGTGTGCCACCAT 
                 
                 
                     
                 
                 
                   GCCTGGCTAATTTTTGTATTTTTAGTACAGATGAGGTTTTGCCATGTTGCCCAGGCTGGC 
                 
                 
                     
                 
                 
                   CTCAAACTCCTGACCTCAGGTAATCCTCCTGCCTCAGCTCTTCCCAAAGTGCTGGGATTA 
                 
                 
                     
                 
                 
                   TAGGCATGAGTCACCGGGCCCAGACTCAATCTTCTGACAAGCTCTCAGAGAGAGTAAAAA 
                 
                 
                     
                 
                 
                   GCAAATGAATATTTCATTATTTTGATCTGAGCTTTACGATTTTTCTTTTCTTTTCTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTTTTTTGAGATGGAGTTTTGCGTTGTTGCCCAGGCTAGAGTGCAGTGGTGGCGAT 
                 
                 
                     
                 
                 
                   CTTGGCTCACCGCACCCTCCGCTTCCCGGGTTCAAGCGATTCTTCTGCCTCAGCCTCCTG 
                 
                 
                     
                 
                 
                   AGTAACTGGGATTACAGGCATGCGCCACCATGCCCGGCTGATTTTGTATTTTTAGTAGGG 
                 
                 
                     
                 
                 
                   ACAGGGTTTCTCCATGTTGGTCAGGCTGGTCTTAAGCTCCCGACCTCAGGTGATCCACCT 
                 
                 
                     
                 
                 
                   GCCTCGGCCTCCCAAAGTGCTGGGATTACAAGCATGAGCCACCTTGCCCAGCCTTTTTTT 
                 
                 
                     
                 
                 
                   TTTAAATCTGAGAAGAGGTCTTGCTCGATTGCCTAGGCTGGAGTGCAGTGGTGCGATCTC 
                 
                 
                     
                 
                 
                   TGCTCACTGCATTCTCTGCCTCCCAGACTCAAGCAATCCTCCCACCTTAGCCTCCTGAGT 
                 
                 
                     
                 
                 
                   AGCTGGGACTACAGGCATATGCCACCACACCTGGCTAATGTTCGTATTTTTTTGTAGAGA 
                 
                 
                     
                 
                 
                   CAGGGTTTTGCCATTTTGCCCAGGCTGGTCTTGAACTCCTGACCTCAGGTGATCCTCCCA 
                 
                 
                     
                 
                 
                   CCTTGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACTGTGCCTGGTCTCCTTCAC 
                 
                 
                     
                 
                 
                   TGTTGTAAGATACTTGAATTGGGTCAATATTTGTGGAGAAGTCTCTTAAAAGTTCACTTG 
                 
                 
                     
                 
                 
                   ATTGTCAGTACTAGAACTCTACATTTAATATTGACATATTCCTGGGAGCATTTCAGAGCA 
                 
                 
                     
                 
                 
                   TTCTATTAGCTTAGAAAGGTCCAGGATAATTTGACTTTAGAAGTTACTGTTACCATGAAT 
                 
                 
                     
                 
                 
                   CTCAATGACTTTTGAAATCCATGAAGAATATCTTTTTTTTTTTTTTGAGACGGAGTCTCA 
                 
                 
                     
                 
                 
                   CTCTGTCGCCCAGGCTGGAGTGCAGTGGTGATCTGGGCTCACTGCAAGCTCCGCCTACTG 
                 
                 
                     
                 
                 
                   GGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCACATGCCAC 
                 
                 
                     
                 
                 
                   CACGCCTGGCTAATTTTTTTGCATTTTTAGTAGAGAGGGGGTTTCACTGTGTTAGCCAGG 
                 
                 
                     
                 
                 
                   ATGGTCTCGATCTCCTGACCTTGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATT 
                 
                 
                     
                 
                 
                   ACAGGCGTGAGCCACCGCGCCTGCCCAAGAATATCTTTTTGCTGGTAACTAGAGAGGACT 
                 
                 
                     
                 
                 
                   CCTCTGAAGCAGATGCCATTCATGATGGATTTCATCATTTATGGGTTTTAAAAAACATTT 
                 
                 
                     
                 
                 
                   TATTTTGAAATAATTTCAAATTTAAATAAGAGTTGCAAAATAGTACAAATAATTCGTGTT 
                 
                 
                     
                 
                 
                   AACTTTTCATCCAGATTTACAAGTCAACCTTATACAGGTTGAGTATCCCTTATCCAAAAT 
                 
                 
                     
                 
                 
                   GCTTGGGACCAGAAGTGTTTTGGATTTCAGATTTTTTCGAATTTTGGAATATTTTTATTA 
                 
                 
                     
                 
                 
                   TATACTTAAGCATCTCTAATCCCCAAATCTCAAATCTGAAATATCTGAAATGCTATGATG 
                 
                 
                     
                 
                 
                   AGCATTTCCTTTGAGTGTTATGTGGGCACTTTTTAAATTTATTTAATTAATTTATTTTTT 
                 
                 
                     
                 
                 
                   GAGATGGAGTATTGCTCCATCACCCAGGCTGGAGTGCAGTGAGCGATCTTGGCTTATTGC 
                 
                 
                     
                 
                 
                   AAACTTCACCTTCTGGGTTCAAGTGATTCTCCTGCCTCAGCCCCCTGAGTAGTTGGGACT 
                 
                 
                     
                 
                 
                   ATAGGCGCTTGCCACCACGGCCGGCTAATTTTTGTATTTTTAGTAGAGACAGGGTTTCAC 
                 
                 
                     
                 
                 
                   CGTGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGGTCCACCTGCCTCCGCCTCC 
                 
                 
                     
                 
                 
                   CAAAGTGCTGGGATTACAGGAGTGAACCACCGCGCCTGGCCATGGATTTTGCAGCATTTT 
                 
                 
                     
                 
                 
                   AGATTTGGGATACTCAACCTGTACCATGTTTACTCTCTCTCCTCTCTCTCTCTCTCTTTT 
                 
                 
                     
                 
                 
                   TATATATATATATATATATATATATATATATATATATATATATATATAAATTATATATAC 
                 
                 
                     
                 
                 
                   ACTACACATATATGTATGTATATGTATGTATTTTATATATAAAATACATATCTACATATA 
                 
                 
                     
                 
                 
                   AAATACACATGTATATATACATGTGTACATATATGTGTCTCTATATTTAAGTTTTGTTGG 
                 
                 
                     
                 
                 
                   AACCACTTGAGGGTAAGTTGCAGACATGGCGTCTCATTGCTCCAAAATACTTCAGTGTGT 
                 
                 
                     
                 
                 
                   ATTTCTTAAATACAAGGACACTTGGTTACATAACCACAGTATATCACCAAATGTATATTA 
                 
                 
                     
                 
                 
                   TAACAAGACTACCATCAAATCCTTATATCTCTTTCAAATTGTTTTAGTAATATCCTTATA 
                 
                 
                     
                 
                 
                   GCAAAAGACAAAACAACAACAAAAACTGTTCCCTTTTATTTTGTTTGTTTTGGTCCATTA 
                 
                 
                     
                 
                 
                   TATGTCCAGGTTATGCATTAATGCATTGTGTTACTTGCTAAGTCTTGTTACTGGCCTTTA 
                 
                 
                     
                 
                 
                   ATTAGGATATTTCTTTGCATCCCGCCAAACTCCTCTTCATGGTTGTATCTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   TTTTGGAGATGGAATTTTGCTTATGTTGCCCAGGCTGGAGTATAATGATGCGATCTTGGC 
                 
                 
                     
                 
                 
                   TCACTGCAACCTCCGTCTCCCGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCGAGTAAC 
                 
                 
                     
                 
                 
                   TGGGATTGCAGGCCTGCGCCACCTTGCCCAGCTAATTTTGGAATTTTGTGAGACGGGGTT 
                 
                 
                     
                 
                 
                   TTGCCATGTTGGTCAGACTAGTCTCGAACTCCTGACCTCATGATCCGCCCGCCTTGGCCT 
                 
                 
                     
                 
                 
                   CCCAAACTGTTGGGATTACAGGTGTGAGCCACTGTGCCCGGTCTTTTTTTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   GAGACAGGGTCTTATTCTGTTGCCTGGCCTGGAGTGCAGTGGTATGATCTTGGCTCACTG 
                 
                 
                     
                 
                 
                   CAACCTGGACCTCCTGGGCTCAGGCGATCCTCCCACCTCAGCCTCCTTAGTAGCTGGGAC 
                 
                 
                     
                 
                 
                   TATAGGCACACACCACCATGCATGGCTAATTTTTATATTTTTTTGTAGAGACTGGGTTTC 
                 
                 
                     
                 
                 
                   GCCATGTTGCCCAAGCTGGTCTTGAACTCCTGGGCTCAAGTGATCCACCTGCCTTGGCCT 
                 
                 
                     
                 
                 
                   CCCAAAATGCTAGGATTACAGGTGTAAGCCACTGCGCCTGGCCCTAATTTTTGCATTTTT 
                 
                 
                     
                 
                 
                   TGTAGAGATGGGGTTTCACTATATTGCCCAGGCTGGTCTTGAACTCCTGGGCTCAAGTGA 
                 
                 
                     
                 
                 
                   TCTTCCCATCACAGCCCCCTAAAGTGCTGGGATTATAGGCGTGAACCACTGTGCCTGGCT 
                 
                 
                     
                 
                 
                   GAGGATTAAGTTTCAACCTCAGGGGAGCGGCATTCAAACTATAGCATTGTCCTTTAGTGA 
                 
                 
                     
                 
                 
                   CTGGCTTAGTTCACTTAGAATGTTTGTCTATTCATCCATCTATAGACACTGTTTTCTTTC 
                 
                 
                     
                 
                 
                   ACCTTTTGGCTTTGCAAATAATGCTGCTGTGAATATGAGTTATAGAAAAATACCAATTTG 
                 
                 
                     
                 
                 
                   AATCCGTGTTTTCAATTACTTTGAGTATATACCTGGAAGTGGAATTTCTGGATCATATGG 
                 
                 
                     
                 
                 
                   TACTTCCAAGTTTTTTTTTTTTCTTTTTTGAGACAAGGTCTCACTCTGTCACCCAGGCTG 
                 
                 
                     
                 
                 
                   GAGTGTAGTGGCACGATCTTGGCTCACTGCAACCTCCGCCTCCCGGGTTCAAGCGATTCT 
                 
                 
                     
                 
                 
                   CCTGCCTCAGCCTCTCAAGTAGCTGGGATTACAGGCACGCGCCACCACGCCCAACTAATT 
                 
                 
                     
                 
                 
                   TTGTATTTTTAGTAGAGATGGGTTTCTCCATGTTGGTCAGGCTGCTCCCGAACTCCCGAC 
                 
                 
                     
                 
                 
                   CTCAGGTGATCTGCCTGCCTCAGCCTCCCAAAATTCTGGGATTACAGGTGTGAGCCACCG 
                 
                 
                     
                 
                 
                   CACCTGGCCTCCATGTTTCAATTTTTAAACAAACAATTAGTTAAAAAAATAGGAAACTAA 
                 
                 
                     
                 
                 
                   GAGAATGAACTATTTCCTGTTTTATTCAGTGGGTTATAATCTGTTACTATCATTGTTTAT 
                 
                 
                     
                 
                 
                   TTTGAGGTACAAATTGTCCCTACTTTGGCCAGCAGAGGATCCTGCAGTTTGTCTCCTGTG 
                 
                 
                     
                 
                 
                   TCCTTTTCATAGCTCCTTGTTGGAACTCTTACTGGCCCACAATAGGATGTTCCAAGTTCA 
                 
                 
                     
                 
                 
                   TCTTCTTACTTTTACTGCCCCAACGCTGGGATCAGCCATTTCTTCAAGGAGGCCAGTTCC 
                 
                 
                     
                 
                 
                   TTTCATTGGAGAATGGAAAACCCAATATGTAGAAACCAAGATAGAGGTGTTAGGTGTGAT 
                 
                 
                     
                 
                 
                   TGCTACTGGAGTGTCATTGCTTCCAAACCCTTTCAGAAGAGACCTAGGAAATGTGTGTGT 
                 
                 
                     
                 
                 
                   GTGTGTATATATATATGTGTGTGTGTGTGTGTATTCATAAAAGCACATACACATACACAT 
                 
                 
                     
                 
                 
                   ACCCCGAAGCATGTATTTCTGTATTATTATTATTTTTTTGAGATGGAGTCTTGCTCTGTC 
                 
                 
                     
                 
                 
                   GCCCAGGCTGGAGTACAGTGGCACGATCATGGCTCACTGCAACCTCTGCCTCCTGGATTC 
                 
                 
                     
                 
                 
                   AAGCAATTCTCCTGTCTCAGCCTCCTGAGTAGCTGGGATTACAGGTGTCCACCACCACGC 
                 
                 
                     
                 
                 
                   CCACCTAATTTTTGTATTTTTAGTAGAGATGGGGTTTCACCACATTGGCCAGGATGGTCT 
                 
                 
                     
                 
                 
                   TGAACTCCTGACGTCAAGTGATCTGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTATAGG 
                 
                 
                     
                 
                 
                   CGTGAGCCACTGTTCCCATCCAGAAGCATACATATCTATTTCTATATCTACATTTCTGTC 
                 
                 
                     
                 
                 
                   TTTACATGTATATATTAAAAATTACAGTTTGCACTAATACCTCCAATTACAATCTAACAT 
                 
                 
                     
                 
                 
                   CATGGGATTTATTCTGGCTTTCTCCCTTCTCATATTTGTGTCTCCCCAACAGTGAGAAAC 
                 
                 
                     
                 
                 
                   CTGGCTTGCTATCCTCAACATGGTAACTTATTTATTAAGAAACTTATTCTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTCTGAGATTGAGTTTCGCTCTTGTTGCCCAAGCTGGAGTGCAGTGGTGTGATCTT 
                 
                 
                     
                 
                 
                   GGCTCACCGCAACCTCTGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCTTCTCAAGT 
                 
                 
                     
                 
                 
                   AGCTGGGATTACAGGCATGCACCACCATGCCCAGCTAATTTCGTATTTTTAGTAGAGATG 
                 
                 
                     
                 
                 
                   GGTTTCTCCATGTTGGTCAGGCTGCTCTGGAACTCCCGACCCCAGCTGATCTGCCTGCCT 
                 
                 
                     
                 
                 
                   CGGCCTCCCAAAGTCCTGGGATTACAGGCGTGAGCCACCGTGCCCTGCCTCTAGTTTATT 
                 
                 
                     
                 
                 
                   TATTTTTATTCCATGTGCTCAGTCTTGCGAGCACGTGGTCTGTTTTCTTGGGCCTGGCCC 
                 
                 
                     
                 
                 
                   CCTCAGTGCACTGTCTTAATACCCTAGCCCCCAGTCCCTCTGATCATATCCCCAGACACC 
                 
                 
                     
                 
                 
                   CCTACTGAATCCCAGGTCTCTACCAAGGGAAAGGCAGGGAGGAGGCATTGACCAAGGAGA 
                 
                 
                     
                 
                 
                   AGAGGGGGAAGGGACAGGGAAGGTCTTGATTTGTATTTTCTAAAATTTTCTACTCTGCTC 
                 
                 
                     
                 
                 
                   ATAATGCGTCTTAGCTGTGTTGTTGTGGAAAGTAGTGCTGACAGTGTCTTGTTTTTTTAT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   GTGTTTTCTAGGTAGGAAGTGGTAAAACCATGCTTGGATAGCTTGCTGCCTGCATTTCGA 
                 
                 
                     
                 
                 
                   GTTTGAAGGCCTTATCTGAGCCCTGGGCTGCCTTCAGGGTTTGGGGAGTGGCCTCCTGGA 
                 
                 
                     
                 
                 
                   CATTTAGCAGAAGAGGAGTAAGGAGGGCCCTTCTTCTCCCTCTGAGACCTCATGGAAGGT 
                 
                 
                     
                 
                 
                   GAGTTGGAGCAGGTCATAGAAGTTCTTAAGCCCTCCAGTGCTTGAGACTTGTTCCACACA 
                 
                 
                     
                 
                 
                   TCTTGAACCTGGTTTCTGCATTTTTCTTTTCCTTCCTGTTGATTTATTTAAAAATTTTAT 
                 
                 
                     
                 
                 
                   TTCTTTTCAATTTTTTTTTTTTTTTAAATAGAGGTGGGATCTTCCAATGTTGGCCAGGTT 
                 
                 
                     
                 
                 
                   GGCCTTGAACTTCTGGCCTCAAGCAATCCTGCCTCGGCCTCCCAAAGTGTTAGGATTACA 
                 
                 
                     
                 
                 
                   GGCGTGAGCCACTATGCCTGGCCTTCTTTTTTTGAGACAAGCTGTTGCTCTGTTGCCCAG 
                 
                 
                     
                 
                 
                   GCTGGAGTGCAGTGGTACGATCACAGCTTACAGCAGCCTTGAACTCCTGGGCTTAAGTGA 
                 
                 
                     
                 
                 
                   TCCTCCCGCCTCAGCCTCCCGGGTAGCTGGGACTCCAGGCTTGTGCCACCATGCTCAGCA 
                 
                 
                     
                 
                 
                   TTTTTAAAAAATATTTTTTGTAGAGATGAGGTCTCACTGTATTACCAAGGCTGATCTTTA 
                 
                 
                     
                 
                 
                   ACTCTTAGCCTCAAGTGATCCTCCTGCCTCAGCCTCCCAAAGTGTTGGGATTACAGGCAT 
                 
                 
                     
                 
                 
                   GAGCCACCACACTCAGACTTTGTTGACTTCTTAATAAGAAAAATACTTGTTAAGAGTTTC 
                 
                 
                     
                 
                 
                   TTCAGATCACTTTCCTTTATCAACAAGTAAAACATGACTGAGGAAGTTGTGGTCCCCTTT 
                 
                 
                     
                 
                 
                   GCTTCCCTGCCCAGGCCCGTTTCCCTCCCTCTTTCCCCAGAGGAAACCACCAAGAGGTTG 
                 
                 
                     
                 
                 
                   GCATATATTCTTCCTGAACGTGTTTTTATAGTTGTACTGCACTTGTACTGTGTATGAACA 
                 
                 
                     
                 
                 
                   ATATAAAGTTGGTTTGTGTGTTTAAAAAATTCACATACATGGATTTATAATGTATGTATC 
                 
                 
                     
                 
                 
                   ATTTTGCAACTTAAAAATTTTTTTTTGAGCTCCATGCTGATTGATAACGATCTATTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTGAGATGGAGTTTCAGTCTTATTGCCCAGGCTGAAGTGCAATGGCGTGATCTCAG 
                 
                 
                     
                 
                 
                   CTCACTGCAACCTCAGCCTCCTGGGTTCAAGCTATTCTCCTGTCTCAGCCTCCGGAGTGG 
                 
                 
                     
                 
                 
                   CTGGGATTACAGGTGCATGCCACCATGCCCAGCTAATTTTTGTATTTTTAGTAGAGATGG 
                 
                 
                     
                 
                 
                   GGTTTCACCATGTCGACCAGGCTGGTCTCAAACTCCTGACCTCAGGTGATCTGCCTGCCT 
                 
                 
                     
                 
                 
                   TGGCCTCCCAAAGTGCTGGAATTACAGGCATGAGCTACCATGCCTGGCCTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTTTGAGACAAAGTCTTGCTCTTTTTCCCAGGCTGGAGTGCAGTGGCCACAATCTT 
                 
                 
                     
                 
                 
                   GGCTCACTGCAACCTCTGCCTCCTGAGTTCAAGCAGTTCTCCTGCCTCAGCCTCCTGAGT 
                 
                 
                     
                 
                 
                   AGCTGGGATTACAGACATGTACCACCATGCCAAGTTAATTTTTGTATTTTTTGTAGAGAC 
                 
                 
                     
                 
                 
                   TAGGTTTTACCATGTTGGCCAGGCTGGTCCTGAACTCCTGACTTAAAGTGATCCATCTGC 
                 
                 
                     
                 
                 
                   CTTGGCTTCCCAAAGTGCTGGGGTTACAGGCATGAGCTATCGCGCCTGGCCTGAGAAATC 
                 
                 
                     
                 
                 
                   TCATTCTTACTCCTACTCCCTTGCACACTATCTCCATTCTGTAGGTAGCCATTTCTATTA 
                 
                 
                     
                 
                 
                   ATTTCTTGTTTACCCTTCTGTGTTTCTTTCATTCTTTTTCTTTTTTTCTTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   GAGACAATCTTGCTCTGTTGCCCAGACTGGAGTGCAGTGGTGTGATCTTGGCTCACCGCA 
                 
                 
                     
                 
                 
                   ACCTCCACCTCCTGGGTTCAAGTGATTTTCATGACTCAGCCACCTAAGTAGTTGGGATTA 
                 
                 
                     
                 
                 
                   CAGCGCCTGGTGTACACTACCACACCCAGCTAATTTGTGTATTTTTAGTAGAGATGGGGT 
                 
                 
                     
                 
                 
                   TTCACCATGTTGTCCAGGCTAATCTCCAACTCTTGGCCTCAAGGGATCTGCCTGTCTCAG 
                 
                 
                     
                 
                 
                   CCTCCCAAAGTGCTGGGATTATAGGCATGAGCCACCATGCCTGGCCCTATGTTTCTTTTT 
                 
                 
                     
                 
                 
                   ATAAAAATAAGCAAATTAATATTTTTATTACTATTTTCCTTTTATTTTTACACATCAAGT 
                 
                 
                     
                 
                 
                   AGAACATTAAATATATTTCTCTGTAATTTTTTTCAGTTACCTAAATCTTTTAGTGATCTC 
                 
                 
                     
                 
                 
                   TCTCATCTTTTTAATCAGCTGGATCGCATTCTATCATGTGAATATTTTATAACTTCTATA 
                 
                 
                     
                 
                 
                   TACTGTCACCAGCAGGTAGCGATTTAGTTGTGTCTAATATTTTAAAATGATATATAATGC 
                 
                 
                     
                 
                 
                   CTCAATGAATATAGTAACCTTTTGCATATATTGTTTTGTGCTTTGGGATAACACTACCTC 
                 
                 
                     
                 
                 
                   GTATTGGAAACTGTGTCATTACATGTGTCTTTAAAATTACATGTGTCTTTTTATTTTTAT 
                 
                 
                     
                 
                 
                   TTTTATTTTTTTTGAGTGGGAGTTTCACTCTTGTTGCCCAGGCTGGAGTGCAGTGGTGAG 
                 
                 
                     
                 
                 
                   ATCTCGGCCGACTGCAACTTCCGCCTCCCGGGTTCAAGCGATTCTCCTGCCTCAGCCTCC 
                 
                 
                     
                 
                 
                   CCAGTAGGTGAGATTACAGGTGCCTGCCACCACGCCCAGCTAATTTTTGTATTTTTAGTA 
                 
                 
                     
                 
                 
                   GGGACGGGGTTTCACCATGTTGGCCAGGCTGGTATCGGTCTGCTGACCTCAGGTGATCCT 
                 
                 
                     
                 
                 
                   CCCACCTCAGCCTCCCAAAGTGCTGGGATTACAGACGTGAGCCACCATGCCTGGCCATCA 
                 
                 
                     
                 
                 
                   CTTTTTTTTTTTTCTTAATTGCTGCATAGTGGCCGGGCACAGTGGCTCACGCCTGTAATC 
                 
                 
                     
                 
                 
                   CCAGCACTTTGGGAGGCCAAGGCAGGCGGCGGATCATGAGGTCAGGAGACCAATACCATC 
                 
                 
                     
                 
                 
                   CTGGCTAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAAAATTTAGCTGGGCGTC 
                 
                 
                     
                 
                 
                   GTGGCGGGCGCCTGTAGTCCCAGCTACTTGGGAGGTTGAGGCAGGAGAATGGTGTGAACC 
                 
                 
                     
                 
                 
                   CGGGACGTGGAGCTTGCAGTGAGCCAAGATTGCACCACTGCACTCCAGCCTGGGTGATGG 
                 
                 
                     
                 
                 
                   AGTGAGACTCTGTCTCAAAAACAAACAAACAAACAAAAAAATTGCTGCATAGTATTCCAT 
                 
                 
                     
                 
                 
                   TGTATGAGTAGTAACACAACAATTTTTATAATGCATAGTATTCCATTGTATGAATAGTAA 
                 
                 
                     
                 
                 
                   TGTAGCACTATTTGTTTATACATTTTTATGATTAAAAAACAAAATGTTTTTCTATTATGA 
                 
                 
                     
                 
                 
                   ATAAAGTGGCAATGAATATTTTTGTACAAGTGTTTTGGTAGCTATACAGTTATTGTCACT 
                 
                 
                     
                 
                 
                   TAATATATGCAATTCGATAGGCCAGTCATTCAAAATAGAAGATATACAAGGTAGGCCGGG 
                 
                 
                     
                 
                 
                   CGTGGTGGCTCACGCCTGTAATCTCAGCACTTTGGGAGGCCGAGGTGGGTGGATCACCTG 
                 
                 
                     
                 
                 
                   TGGTTAGGAGTTTCAGACCAGCCTGACCAACATGGAGAAACCTCATCTCTACTAAAAATA 
                 
                 
                     
                 
                 
                   CAAAAGTAGCTGAGCGTGGTGGCGCATTCCTGTAATCCCAGCTTCTTGGGAGGCTGAGGT 
                 
                 
                     
                 
                 
                   AGGAGAATCACTTGAACCTGGATTTATAATGTATGTAAATCCACCGCGAAGGTTGCGGTG 
                 
                 
                     
                 
                 
                   AACCGAGATCACGTCATTGCACTCCAGCCTGGGCAATAAGAGCGAAACTCCATCTCAAAA 
                 
                 
                     
                 
                 
                   AAAAAAAAAAAAGATATGCAAGGTAAAGATACTAATAAAGACCTTTGTGTTGAGTTGGTT 
                 
                 
                     
                 
                 
                   GACATGTGGTTATTTCACCCATCGTATTTCTTATAGGGAATAGGTAAATTCGTTCCTTGG 
                 
                 
                     
                 
                 
                   GTTTCTTTCAACACTTAGGTAAAATCCGACGTGGAAGATGAGATCTGATTTTACTGGTGT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   AATGCATGACGGTCTGTGTATGACTCTCTGACTCCAAAGGCTTGTGACTGTTTTTTGAGC 
                 
                 
                     
                 
                 
                   TGTAATCTTTAAAGAATTACTAAAGTGAGACTAATAGCATCAAATTATTTTCAGAGTACC 
                 
                 
                     
                 
                 
                   TTTTTCCTGCAAAAGTTTTAATCAGTGTTACTTACACTCATCCTATAGGGGTTGCATACC 
                 
                 
                     
                 
                 
                   ATTCCTGCATATACTTGGTACGTGTATTAGTTTTAAGACTTATTGAACTTCAGCAGATAA 
                 
                 
                     
                 
                 
                   TCTTTGAGAGTTATTAGAGGAAAACAAATGATAATGGAGACACCAAAATAGCAGCAGTTT 
                 
                 
                     
                 
                 
                   TCTATGGTGGCTCTCGACCAGTTATTCAGCAATGTCACCAACAGATGTCAGTTTAAGCTC 
                 
                 
                     
                 
                 
                   AGAAGTGGAAAAGCAGAGAGCTCAGAGGGTCAGCTTTTTCATCAGTTCTTTTAATGTTAT 
                 
                 
                     
                 
                 
                   CACCACAATTATGTGAGAATGACCTTGCTTAGAGAAAATTATGTTATTTTCGAGATCTTT 
                 
                 
                     
                 
                 
                   CCCCCTGTGTTGGAACTAGGCTGATGAAAGCATGGGCTTGACTTATTTATTGATTGTATT 
                 
                 
                     
                 
                 
                   CGTTTTGTACATTCCCAATCTCCTCTCTGACTTGGTGCAAATTCAGGATCTCTTAGTTAG 
                 
                 
                     
                 
                 
                   TTTGTATATTTTGTGTCTTCAGGTATGATTTTTTCAGCTTATACCTTTATGTCAGTGCTA 
                 
                 
                     
                 
                 
                   TTATGTGCTGATAATTTGTTTCTCTAGCTACCACCGTAGCTTCAGGCAAAAGGCTGTCAG 
                 
                 
                     
                 
                 
                   CCAACTCTGTACAGTTTATTTCTAAATTTTACTGTTTTCAGTTGAGTATGGATGAAGAAT 
                 
                 
                     
                 
                 
                   AACTCAAAGTTTATTCTTTTGATGATGAGCCCTTAACACCACCTGCCATGATAGTACTTG 
                 
                 
                     
                 
                 
                   CTTTCTGACCAAGATCCTGAGGGAAAAAGCCACTTTATTATTAGAACTATGTTAAGATGC 
                 
                 
                     
                 
                 
                   TTCCCAAAAAACATGGAGCAGTATTGTCTCAAAGTCTGTCCTTGGATGGCTTTGGATGCC 
                 
                 
                     
                 
                 
                   TACATCAGGACTGTCTGATGTGCTGGTTAAAATGCAGATTCCTGGGCCTCATTCAGACTT 
                 
                 
                     
                 
                 
                   ACATGTATTGATATTGCTGGTTGTGGAGCCTGGGAATTCATATTTTTAGCAAAATCCCTC 
                 
                 
                     
                 
                 
                   ATTTTTACTCCAAGTCTTATGTGCATTATACAGTTTGAGATGATCACCCAGGATATAGTC 
                 
                 
                     
                 
                 
                   CAAAGACACTGGAGGCTGTTGAAGTATAGGTTGTATATATGGAAAAGGTTGGAATGTTTG 
                 
                 
                     
                 
                 
                   AATTAATTTATAATGAAGATCCTTTTTAATTGAGTGTTCACATGCCAAGGCAAGGACAAA 
                 
                 
                     
                 
                 
                   CATTCAAAATGATTTTCTGTCTCTGTTACAACTTTTTCTTTCTTTTTTTTAATTTATTTA 
                 
                 
                     
                 
                 
                   TTTGAGATGGAGTCTCACTCTGTCACCCAGGCTGGAGTCAAGTGACGCGATCTCGGCTCA 
                 
                 
                     
                 
                 
                   CTACAACCTCCGCCTCCCAGATTCAAGTAATTCTCTTGCCTCAGCCTCCCGAGTAGCTGG 
                 
                 
                     
                 
                 
                   GACTACAGGCATGTGCCACCATGCCCAGTTAATTTTTGTATTTTTAGTAGAGACAGGGTT 
                 
                 
                     
                 
                 
                   TTGTCATGTTTGCCAGGCTGGTCTCAAACTCCTGAACTCAGGTGATCCGCCCACCTTGAC 
                 
                 
                     
                 
                 
                   CTCTCAAAGTGCTGGGATTATAGGCGTGAGCCACCGTGCCTGTCTCTATTACAACTTTTT 
                 
                 
                     
                 
                 
                   ATTACAACTTCTTTATTTTGACTTTATTTTTACAAATTATTTATTTATTTTTTTTGAGAT 
                 
                 
                     
                 
                 
                   GGAGTTTCGCTCGTCACCCAGGCTGGAGTGCAATGGTGCGATCTCAGCTCACTGCAACCT 
                 
                 
                     
                 
                 
                   CCGCCTCCCAGGTTCAAGTGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGATTACAGG 
                 
                 
                     
                 
                 
                   CACTTGCCACCACACCCGGCCAATTTTGTATTTTTAGCAGAGACAGGGTTTCACCATGTT 
                 
                 
                     
                 
                 
                   GGTCAGGCTGGTCTCGAATTCTTGACCTCAGGTGATCCACCTGCCTCGGCCTCCCAAAGT 
                 
                 
                     
                 
                 
                   GTTGGGATTACAGGCATGAGCCACCACGTCCGGCCGACTTTTATTTTTTTTTCTTGAGAC 
                 
                 
                     
                 
                 
                   AGGGTCTTGCTCTGTCACCCAAGCTGGAGTGCGGTGGCATGATCATAGCGCACTGCAGCC 
                 
                 
                     
                 
                 
                   TCGACCTCCTGGACTCAAGTGATCCTCCTGCCTCGGCCTTGTGTATAGCTGGGATTACAG 
                 
                 
                     
                 
                 
                   GCAGTTGCCACCATGCCAGGCTAATTTTTAATTGTTTTGTGAAGATGGGGATTTCACTGT 
                 
                 
                     
                 
                 
                   GTTGCCCAGACTGGTCTTGAACTCCTGGCCTCAAGTGATCTTCCTGCCTTGGCCTTCCAA 
                 
                 
                     
                 
                 
                   AGTGTTGGGATTACAGGCATAAGCCACTATGCATGGCCTGTAACTTCTTTAAATGGCTAT 
                 
                 
                     
                 
                 
                   AATTAAACAGTTGGTCCTTTTAAGATTGGGCAATGGACGAATGGCAAATTGCATTTTTAA 
                 
                 
                     
                 
                 
                   AAGAGGAGGGATTTAAAAAAAAACAGGAAAGATTGGGGCATTTGTCTCTAAAGGACTGTG 
                 
                 
                     
                 
                 
                   GACTCATTTAAGAAGTTTAGTGGTCATTCTTACCATCTTTGTGGTTTTTCCTGCCTGCAT 
                 
                 
                     
                 
                 
                   GGGATGCAGATTTTCTGTCTCAGGTGGGATTGATCAATCCCTTGGAGGAATGTGTCTACT 
                 
                 
                     
                 
                 
                   TTTTAATTGTGTTTAGGAGAGCTGACTGTATACAGTAGTTTTGTGAAAGAACAACATGAA 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   AATCTCCAGTTGAAAAATGGGTCTGGCAAGATGTTACCTTTGGGTGATTTTTCTGCTGAC 
                 
                 
                     
                 
                 
                   AGAAGACAGACACCATTACATTCAAAGTCAGATTGTCTTTTATTTATTTATTTATTTATT 
                 
                 
                     
                 
                 
                   TATTTATTTGAGACAGGGTCTTGCTCTATCACCTACAGATGGGGTTTCACCACGTTGGGT 
                 
                 
                     
                 
                 
                   CTGGTGACCCAAATCTTTGGGTGATTTTTCTGCTGGAAGAGGACAAACACCATTACATTC 
                 
                 
                     
                 
                 
                   AAAGTCAGATTTTCTGTTTTTTTTTTTTTTTTGTTTTTGTTTTTTTAATATTCATTTGTT 
                 
                 
                     
                 
                 
                   TATTCATTTGAGACTGGGTCTTGCTCTGTCACGCAGGCTGGAGTGCAACCTCCCTGGGCT 
                 
                 
                     
                 
                 
                   CAGTTGATCTTCCCTCAGCCTCTTGAGTAGCTGGGACTACAGGTGTGTGCCACCATGCCC 
                 
                 
                     
                 
                 
                   AGCTAGTGTTTGTATTTTTTGTGGAGATGGTGTTTTGCCGCATTGCCCAGTGTGGTCTTG 
                 
                 
                     
                 
                 
                   AACTAGTGCTCAAGAGGCCTGCCTCCTTCAACCTCTCAAAGTGTTAGGATTACAGATGTG 
                 
                 
                     
                 
                 
                   AACTACTGTGCCTGATCCAAAGTCAGATTTTCTTTGCTTACTTAGTCAAGTTCGTCTATG 
                 
                 
                     
                 
                 
                   CTTTTATTATACTTAATATATTAGTATAGTTACTGTATTAGTATATTAGCATATTTAATA 
                 
                 
                     
                 
                 
                   TATTATTATACTTATCATACTTGAGTATATTGAGTATATTTACACTTTTAGTATATTTGT 
                 
                 
                     
                 
                 
                   ATACACACACCACATTTTTATTATTTATCTTTTTTTTGAGACAGAGTCTCCCTCTGTCTC 
                 
                 
                     
                 
                 
                   CCAGGCTGAAGCACAGTTGGCTCACTGCAACCTCTGCCTCTTGGGCTCAAGTGATTCTCG 
                 
                 
                     
                 
                 
                   TGCCTCACCCTCCTGAGTAGCAGGGATTACAGGTGTCCACCACCAAGCCTGGCTAATTTT 
                 
                 
                     
                 
                 
                   TGTATTTTTAGTGGATATGGGGTTTTACCATGTTGGCCAGGCTGGTCTCGAACTCCTGAC 
                 
                 
                     
                 
                 
                   CTCAAATGATCTGCCCGCCTTGGCCTCCCAAAGTGCTGGAATTACTGGCGTGAGCCACTG 
                 
                 
                     
                 
                 
                   CACCCAGCCTATTATCTGTCTTTTGATGGACATTTAAGTTGTCTCTATATACTAGCTATT 
                 
                 
                     
                 
                 
                   GTGAATAATGCTGCAGTGAACATGAGAGTGCTTGAAAACACTAATGTAACATAAAGGTAA 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   CTTAAAAACTTAAAACAAATCCTAATAGAGAATTTTGCAAACATACAGAGGTAGACAGAA 
                 
                 
                     
                 
                 
                   TAGTATCATCAGCCTCCATGTACCCATTGCAGCTTCAACTATCAAATCTTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   TTTTTTTTTGAGACAGTCTTACTCTGTCACCCAGTCTGGAGTACAGTGTTGCAATCTTGG 
                 
                 
                     
                 
                 
                   CTCACTACAACCTCTGCTTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAG 
                 
                 
                     
                 
                 
                   CTGGGACTACAGGTGCCCACCACCATGCCCGGCTAGTTTTTGTGTTTTTAATAGAGATGG 
                 
                 
                     
                 
                 
                   GGTTTCACCATGTTGGCCTGGCTGGTCTTGAATTCCCGACCTCAGGTTTTCTGCCCGCCT 
                 
                 
                     
                 
                 
                   TGGCCTCCCGAAGTTTTGGGATTACAGGCGTGAGCTACCACGCCCGGCCCTAAATCTTTT 
                 
                 
                     
                 
                 
                   CTTATTATGATTCCACTCACTGACTGCCGCTATAGTACTTGGAAACATATTCCAGATTTA 
                 
                 
                     
                 
                 
                   TATTATTCCCATATTTATCTGTAAAAGGCATTACAGAGGTTCTTTTTTTTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   TTTGAGATGGAGTTTTGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGTGTTCTTGGCTCA 
                 
                 
                     
                 
                 
                   CTGCAACCTCTGCGTCCCGGGTTCAAGAGCTTCTCCTGCCTCAGCCTCCTGAGTAGCTGG 
                 
                 
                     
                 
                 
                   GATTATAGGTGGTGCCACTACACCCAGCTAATTTTTGTATTTTTAGTAGAGATGGGGTTT 
                 
                 
                     
                 
                 
                   CACCATGTTAGCCAGGCTGGTCTTGAACTCCTGACCTCAAGTGATCTGCCTGCCTCAGCC 
                 
                 
                     
                 
                 
                   TCTCAAAGTGCTGGGATTATAGGCATGAGCCACTGCATCTGGCCTAAGGCTGTACAGAGT 
                 
                 
                     
                 
                 
                   TTTAAAGCAAGTTTTCATTATAGATCCACTTCTGGTTACCTTTAGGTAACCTCACTTATT 
                 
                 
                     
                 
                 
                   CACTTTGGCATTGTTGCTATTTCAAATTTCACCTTTATGATAGTGGAAAATGATATAATC 
                 
                 
                     
                 
                 
                   TCTCTAAATAATGTGGTCTATTCATAAAGAAAAATAGGCTTGAATTTATATCAGCAGAGT 
                 
                 
                     
                 
                 
                   AAAGTGTATGTGAAGACTGAAGAAAGATACATTTTCTGGCTGAACAGAAAACACGGTGAA 
                 
                 
                     
                 
                 
                   ACGATTTGAAAACTTTTATTGTGAATTACAGGGTCCTATGAACCCTCTGTCCGTGCCTTT 
                 
                 
                     
                 
                 
                   ATGAATATCAACATAGACATGTTTTTTTTTTTTTTTTTGCATTAACACCGTTTTCTGTAA 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TGAGTTGTTATATCCTATTTTTAGTGGAGGAGAAGTTGCTCTTGTGTTTGGAATTGGACC 
                 
                 
                     
                 
                 
                   TGAGAGACTTGAAACTGACGTCCTTTTTTAATTCGGCCATTGATTGACACGGAGCAAGTT 
                 
                 
                     
                 
                 
                   GCTGAGAGGGCTTCTTCGAAACAGAAGAGCATTGTGTTCTGAGGGAAGGGAGTTGGCAGT 
                 
                 
                     
                 
                 
                   GAGTAGTCAATGGATGTGCTAGCCGCTCCATTTGGCTCTTTTGGTTTGGACTGGTGGCAA 
                 
                 
                     
                 
                 
                   AATCTCAGAGAAACAAAAGGATCTAATTTCTTCGAAAGATTTCCAGCATGCACTGGGGTC 
                 
                 
                     
                 
                 
                   TTTAGAAACAATCTATAGCCTTAGTGCAGCAAATGAGTATGAGTAAAAGAGAAACACCTT 
                 
                 
                     
                 
                 
                   GTGGTGGCTTTTTTTTTTTTTTTTTTGAGACAGGGTCTCGCTCTGTCGCCGAAGCTGGAG 
                 
                 
                     
                 
                 
                   TGTAGTGGCGTGATCTCGGTTTACTGCAGCCCCGTCCTCCCTGGGCTCAAGTGATCTTCC 
                 
                 
                     
                 
                 
                   CATCTCAGCCTACTGAGTAGCTGGGACTACAGGCACATGCCCCTATGCCTGGCTAATTTT 
                 
                 
                     
                 
                 
                   TGTATTTTTGGTAGAGATGAGGTTTTGCAGTGTTGCCCAGGCTGGTCTTGAACTCTTGGG 
                 
                 
                     
                 
                 
                   CTCAAGTGATCCTCCTACTTAAGCTTCCCGAGTAGCTGGGACTACAGGCACACGATACCA 
                 
                 
                     
                 
                 
                   TGCCCATCTAATTTTTGTATTTTTTTGTAGAGATGGGGTTTTGCAGTGTTGCCCAGGCTG 
                 
                 
                     
                 
                 
                   GTCTTGAACTCTTGGGCTCAAGTGATCCTCCAGCTTTGACGTGCCAAATGTGGTGGCTTT 
                 
                 
                     
                 
                 
                   AATTTCAGAGTTCAAATTGATAACTCTGGTAAGTTAAGTGAACTGATTTCTTTTTTTTTT 
                 
                 
                     
                 
                 
                   AAATTATTTTTGTTGATTATACTTTAAGTTCTGGGATATATGTGCAGAACGTGCAGGTTT 
                 
                 
                     
                 
                 
                   GTACATAGGTATACATGTGCCATCATGGTTTGCTGCACACATTAACCCATCATTTAGGTT 
                 
                 
                     
                 
                 
                   TTAAGTCCTGCATGCATTAGGTGTTTGTCCTAATGCTCTCCCTCCCCTTTAATGCATCAG 
                 
                 
                     
                 
                 
                   TGAAAAAGTGATGATAGGCTGGGCGTGGTGGCTCACTCCTGTAATCTCAGCACTTTGAGA 
                 
                 
                     
                 
                 
                   GGGTGAGGCAGGTGGACCACTTGAATCCAGGAGTTTGCCCCCATCCCCAGACAGTGTGTG 
                 
                 
                     
                 
                 
                   TGATGTTCCCCTCCCTGTGTCCATGTGTTCTCATTGTTTGGTTTTCTGTTCCTGTGTTAG 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   CCAGTAATGGGATTGCTGGGTCAAATGGTATTTCTGGTTCTAGATCCTTGAGGAGTCACC 
                 
                 
                     
                 
                 
                   ACACTGTCTTCCACAATGGTTCAACTAATTTACACTCCCACCAACAGTGTAAAAGCATTC 
                 
                 
                     
                 
                 
                   CTATTTCTCCACATCTTCTCCAGCATCTGTTGTTTCCTGACTTTAAGTGAACTGATCTCT 
                 
                 
                     
                 
                 
                   TTCCTGAAACTAACTTGGGTTGGAGAATGTCCCTGATGGGAATGTGCTGTGTTCCCATTG 
                 
                 
                     
                 
                 
                   CACTCTTCTATATCACTTACCCATTGACAATGTGATCTCTTTCATTTTCTCCTCATCCAT 
                 
                 
                     
                 
                 
                   TTGACAGAAAACTTCAAAAACAAGGATTCTGGCATATTTACCTTTGCAGTTGTCCCCAGC 
                 
                 
                     
                 
                 
                   ATGTAGCACGGTGCCTAGTACACAGAAGAAACTCCATAAATGTTTGTTGAATGAGATTTA 
                 
                 
                     
                 
                 
                   CATTTAACTCATGTTTACATCATTTTATTTTCCTGTTCTGTTTTATGGGAATGATTATTC 
                 
                 
                     
                 
                 
                   TATGCTTTTTGAGGACTACAATTTATAAATATTTGTGGATTGAATGAATAAGTGAATACT 
                 
                 
                     
                 
                 
                   GGGCAAATAAAGTCCTTTTAGCCAGAGTATGTCTGAACAACTTGCTGAGATAGATATGAT 
                 
                 
                     
                 
                 
                   TTCCCATTTTCCAGCTGAGGGGCCTAAGGGAGGTTAAGTAAATTATTCAATCTTCATACC 
                 
                 
                     
                 
                 
                   ACAGTTTTTGTTTTGTTTTGTTTTGTTTTTTTTCCTCCTGAGACAGAGTCTCACTTTGCT 
                 
                 
                     
                 
                 
                   GCCATACTGGAGTACAGTGGTGCAATCATAGCTCACTGCAGCGTCCAACTTCTGGGCTCA 
                 
                 
                     
                 
                 
                   CGCCATCCTCCCACCTCAGCCTCCTGAGTAGCTGGTACTACAGGTGTGCACCACCATAGC 
                 
                 
                     
                 
                 
                   CGGCTAATTTTTCATTTTTTGTAGATATGGGGTCTCACTGTGTTACTCAGGTTGGTCTTG 
                 
                 
                     
                 
                 
                   AACTTCTGAGCTCAAACAATTCTCCTGTCTTGGCCTCTCAAAGTGTTGGGATTACAGGTG 
                 
                 
                     
                 
                 
                   TGAGCCACTGTGCCCGGCCCATACCACAGATATTGATTGAATTCCAGCAGTGGGGAGGAG 
                 
                 
                     
                 
                 
                   TGTGGAATAGAACATTCTCAGTCCTTGCTCAACATTACTGAACAGAGACTTGAATTTGAG 
                 
                 
                     
                 
                 
                   TTTATTCTCTCATCCCAGGCTTCGCGTTAGGCTCTGAAGACACTAGTGAACAAGACAGAC 
                 
                 
                     
                 
                 
                   AGGGTTACTGCCTTTAAAGGGAGCTTTTAGTTGAGAGAAGGAAAACAGTGATGAAAAGCA 
                 
                 
                     
                 
                 
                   TCAGTGAAAAAGTGATGATAGGCTGGGGCGTAGTGGCTACTCCTGTAATCTCAGCACTTT 
                 
                 
                     
                 
                 
                   TAGAGGGTGAGGCAGGCAGCTCACTTGATTCCAGGAGTTTGAGACCAGGCTGGGCAACAT 
                 
                 
                     
                 
                 
                   GGTAAAACCCCGTCTCTACAAAAAATACAAAAAGTAGCTGGGTGTGGGGGTGCGCACCCA 
                 
                 
                     
                 
                 
                   CAGTCCCAGCTACTCTGGGGGTTGAGGTGGGAGGATTGCTCGAGCCTGGGAGATTGAGGC 
                 
                 
                     
                 
                 
                   TGCAGTGAGCTGAGATCACGTCACTGCTCTCCAGCCTGAGCAACAGAGCCAGAACCTGTC 
                 
                 
                     
                 
                 
                   CCAAAAAAAAAAAAAATTGATGATAAACATAGTGAGACAGAATTTTGAAATCTCAGCCTC 
                 
                 
                     
                 
                 
                   ACTGTTGCCTTCCTTGTCCCCTGCCTGCCTAAATAATAAAAGGCAGCATTTCAGCAGTCA 
                 
                 
                     
                 
                 
                   TTCATTTCATTACTTTCACTTCATTTCACCTTCATAAAGCCTCATGAGGTAAGATGGGAA 
                 
                 
                     
                 
                 
                   GATACAGAAGTTTTAGAAACCGCTCATCAAAATTGAATGGAAAGCCGATTGTTCCAAAAC 
                 
                 
                     
                 
                 
                   TTTTTAGTGTGGAAAATTTCTATTATATGCAAAAGTAGAGAGAATGGGATAGTTATAGCA 
                 
                 
                     
                 
                 
                   GTATACCTGACACCCAGCATTAACAACTGTTGATAATATGGCCAATCTTTTTCGACTCTG 
                 
                 
                     
                 
                 
                   CCCCACTCACTTCCCCAGCCCTGACTTGTCTTGAAGCAAATACTTTTTTTTTTTTTTTGA 
                 
                 
                     
                 
                 
                   GATAGAGTTTTGTTTTGTTTTGTTTTTTGTTTTTGAGATGGAGTCTCACTCTGTCCCCCA 
                 
                 
                     
                 
                 
                   AGCTGGAGTGCTGTGGCTTGATCTTGGCTCACTACAACCTCCGCCTCCTGGGTTCAAGTG 
                 
                 
                     
                 
                 
                   ATTCTTGTGCCTCAGCCTCCTGAGTAACTGGGATTACAGGTGTGTACCACCATGCCCAGC 
                 
                 
                     
                 
                 
                   TAATTTTTGTATTTTTAGTAGGGACAGGGTTTTCACTATGTTGGCCACGCTGGTCTCAAA 
                 
                 
                     
                 
                 
                   CTCCTGACCTCAGGTGATCCGCCTGACTTGGCCTCCGAAAGTGCTGGGATTGTAGGTGTG 
                 
                 
                     
                 
                 
                   AGCCACTGCTCCCGGCCTTGAAGCAAATCTTAACACATCATTTCGTCTGTAACTATTTTA 
                 
                 
                     
                 
                 
                   TTTCAAAAAATTATAACCTGAATAGCATTATCATATCTAAAACTATTAACAGTATTTCCT 
                 
                 
                     
                 
                 
                   TAATATTAACACATATCAGTCACATTTTCCTGATTGCTACACACACACACACACACACAC 
                 
                 
                     
                 
                 
                   ACACACACACACTTGCAATTTGTGTTTTTTTCTTTTTAGATGGATCTCACTCTGTTGCCC 
                 
                 
                     
                 
                 
                   AGGCTGGAGTGCAATGGTGCATTCTCAGCTCACTGCAACCTCCACCTCCTGGGCTCAACT 
                 
                 
                     
                 
                 
                   GATTCTCTTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGGTGCCCACCACCTCACCTGG 
                 
                 
                     
                 
                 
                   CTAGTTTTTGTATTTTTAGTAGAGGTGGGGTTTCACCATGTTGGCCAGGTTGGTCTCAAA 
                 
                 
                     
                 
                 
                   CTTCCGACCTCAGGTGATCCACCCACCTTGGCCTCCCAAAGTGCTGGGATTACAGGCATG 
                 
                 
                     
                 
                 
                   AGCCACTGTGCCCAGCAGCAATTTGTTTGAATTGGGAGTGCTTTCTTCCACCTTGATTAT 
                 
                 
                     
                 
                 
                   GAAAAAATTTCAAATGTGTATAAAACAGATTCATATAAAGGATCCTGATATGCCATTATC 
                 
                 
                     
                 
                 
                   AGCTTTATCAATTATCCCTGTCATCATATTTTTTATTTATAAATATTTCAATATTTGTGG 
                 
                 
                     
                 
                 
                   AATCCTTAAAAATGCATCACATAACCCAACATTGTTCATATTATACCAATTGTCTTATAA 
                 
                 
                     
                 
                 
                   TTTAAAAATATTTTGTTCAATCATTTTTCAGATAAGCTTCACACACTGTGGTTGGCTAAG 
                 
                 
                     
                 
                 
                   TCTCATAATATTTCTGTTGTAAAAATCTTAAGTCTGGGCGTGGTGGCACACGGCTGTCAT 
                 
                 
                     
                 
                 
                   TCCAGCACTTTGGGAGGCTGAGGTGGGCGGATCACGAGGTCAAGAGATCGAGACCATCCT 
                 
                 
                     
                 
                 
                   GGCCAACATGGTGAAACCCGGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGGTAGT 
                 
                 
                     
                 
                 
                   GCGTGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCAGAA 
                 
                 
                     
                 
                 
                   GGTGGCAGTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTAGAGACAGAGTGCG 
                 
                 
                     
                 
                 
                   GCTTCATCTCAAAACGAAACAAAACAAAACAATCTTAAGTCTCTTAGAATACTTTGATGC 
                 
                 
                     
                 
                 
                   CCCTTCCATCTCTCTTTTTCTGTCTTCCTTCCCCCTCTCCCTGTCTTTTCTGCTGTTGAA 
                 
                 
                     
                 
                 
                   GAAAGCAGATCATTTGTCCTGAGAGTTACTTATAGTCTGAATTTTGCTGAGTGCCTCTCT 
                 
                 
                     
                 
                 
                   GTGGTGGACTTAAGCATGTATCCATCCCTTATATTTCTTGTAAGTTGATATATCTAGAGA 
                 
                 
                     
                 
                 
                   CTTCATTGGATACAAGTTTTCTTTGGCAAGATAGCATGTATGGTGGTGTATCAGGAGGTG 
                 
                 
                     
                 
                 
                   TTTATGTCCTGTTGTTTCTTCTCTGATTTTCTTAGCAGCTCCTGATCATTATTACTTAGA 
                 
                 
                     
                 
                 
                   TCCATTAATTCATAAGGGACTATATGGTAGTGATATTGTAATTTTATCATTCTTCTTCAT 
                 
                 
                     
                 
                 
                   TTGTTAGGTTGGCATATTTCTATAAAAAGCTTTTCATCGCCGAGGGTTGATTTTTTCCTT 
                 
                 
                     
                 
                 
                   CTTACTAAGCAGTTTTCTTTTCTTTTTCTTTTTTTTTTTTTTGAGGTAGGTCTCACTGTG 
                 
                 
                     
                 
                 
                   TTGCTCAGGCTGGTGTGCAGTGGCGCAAACACACAGTTGCGAACTCTTGGGCTGAGGTGA 
                 
                 
                     
                 
                 
                   TCCTCCTGCCTCAGTTTCCTGTGTAGTTGGGACCACAGGTGCATGCCACCATGCCTGGCT 
                 
                 
                     
                 
                 
                   AATTTTTTGATTCTTTTGTAGAGATGAGGTCTCACTTTATTTCCCAGGCTGGTCTTGAAT 
                 
                 
                     
                 
                 
                   GTCTGGGCTCAAGCAATCTTTCTACCTCAGCCTCCTGAGTAGCTGGGACTACAGGCACAT 
                 
                 
                     
                 
                 
                   ACCACCATGCCCAGCTAATTTTTTAATTTTTATTTTTAGTAGAGATGTGGTCGTATTATG 
                 
                 
                     
                 
                 
                   TTGCTCAGGATGGTCTCGAACTGCAGAGCTCAAGTGATCCTCCTGCCTCAGCCTCCCAGT 
                 
                 
                     
                 
                 
                   GTGCTGGGATTATAGGTGTACTACAGGCAAGAGCCAATGAGCCTGGTCAGATTTTTTTTT 
                 
                 
                     
                 
                 
                   CCTGATTTGAAATCTGTTATGGGTTCAATTGATACTTCCAAATCAAACTCAGGGTTTCAG 
                 
                 
                     
                 
                 
                   GATTTTTACTAACCTCATTGATCTTACCCATGTATCTCCTTTCTCTAATGCCAAAAATCC 
                 
                 
                     
                 
                 
                   TACTTCTTGAAGCCATAATAAGATTATTCATTTGTTTTATCCCACATTACACACAACAAT 
                 
                 
                     
                 
                 
                   CTTAGAATAATGACTTCCCAATAATATGATTACTGAAAACAGTTTAATTTTTTTTGCGCT 
                 
                 
                     
                 
                 
                   TTTCAAAAAAATCCTTCAGAGATGTGTAGTCAAGTTACTGTATTCTGCTGGGCACAGTGG 
                 
                 
                     
                 
                 
                   CTCACGCCTATAATCCCAGTACTTTGGGAGGACAAGAAGGGAGGATCGCTGGACCTCAGG 
                 
                 
                     
                 
                 
                   AGTTTGAGACCAGCCGGGGCAATATAGTGAGACCCTGTCTCTACAAAAGAAAATTAAAAA 
                 
                 
                     
                 
                 
                   TTAACCAGACATGGTGGCATGTCCCTATAGTCCCAGCTATTGAGAGGCTGTGGCGAGAGT 
                 
                 
                     
                 
                 
                   AGGCTTAAGCCCAGGAGTTTGAAGCTGCAGTGAGATACGATTGTGACACTGTACTCTAGG 
                 
                 
                     
                 
                 
                   GTGACAGAGCAGGGACCCTGTTTTTAAAAAAAAAAAATGAAAAAACTTCCTGTGCCTTAG 
                 
                 
                     
                 
                 
                   ACTCATTTGTAATCGTCCTTCTCTCTGTGTGGCTATATGCTAACTGGGTATATGGTTAGT 
                 
                 
                     
                 
                 
                   TTATTTGTTTCATTTAAAAAATCTCTTTCTGTTAAGTTTTATTTATAATTACACAAATAC 
                 
                 
                     
                 
                 
                   TGGCTTTGATAGTCAAATTGAAAAAACAAAGTGTATTCAAAGAAGTCTACCTTCTATCCT 
                 
                 
                     
                 
                 
                   TGTCCTTTCCTATGTTTTAGCCATAGTATAAAAAGTTATGGTTTATCATTATATTTCAAA 
                 
                 
                     
                 
                 
                   AATATAAGAAGATATTCCCATATCCCACTTTTTCTTAAACAGTAGCATAACTTTACATAC 
                 
                 
                     
                 
                 
                   TTTTTTCTAACCTTGCTTTTTTAAATATCCTGGACATCCTGGATATCCATAATAGTGTCT 
                 
                 
                     
                 
                 
                   AGAGATAGTCTTCATTCTTTTTTTACTGTATAGTAATCCACTGTGTACTTGTACCATAGT 
                 
                 
                     
                 
                 
                   TTATTCAACCTATTGATGGGCATTTGGGTAGTTTCCAAATGTATCACAGAGAGGATTACA 
                 
                 
                     
                 
                 
                   GTGAATAGCCTTGTGTATGCATCCTGCTTTACTTTTGCTGACTACTGGTAATATTAACAT 
                 
                 
                     
                 
                 
                   TTTTTATGTTCTGTATTTAAAAAATGGTGGTTATTATTCATCTATAACTTTTATTATACA 
                 
                 
                     
                 
                 
                   TGACTTTGGTTAGCATGCTTTAACCTTTTAGCATAACATTTGCAAGCTACTTGTTTTAAT 
                 
                 
                     
                 
                 
                   TAAAATTTTGGTTAAATGTAAAAAATAGTGAGCTATTTTGTAATCTAGATTCAATAGAAT 
                 
                 
                     
                 
                 
                   CTTATACTTCCTTTACAAATGATAGCTGAGTTGATCATTTGTGTAAATGACTGTGAACTT 
                 
                 
                     
                 
                 
                   AAAAATTACAGCATTTTTTAAAATAAATTTTTTTAACATTTTAAAATTATTTAAAATAAT 
                 
                 
                     
                 
                 
                   AGACACACAAAGTAAAAAGAGAAGAAAAAAAAAAGAGACAGGGTCTTGCTATGTTGCCCA 
                 
                 
                     
                 
                 
                   GGCTGGTCTCAAACTCCCAGGCTCAAATGATCCTCCTGCCTTGGCCTCCTAAAGTGTAAG 
                 
                 
                     
                 
                 
                   CCACCACACTTGGCAAAAATTAGTTTCTTTAAAACAAAAACATTACAGGTTATCTGGTAC 
                 
                 
                     
                 
                 
                   CATGGTAGCTTCTTTAACACTAGGTTCACTTAGAACAAAGCTTAGGAACAAAGTCAGACT 
                 
                 
                     
                 
                 
                   TTCACAAAGAGCTTGTGTGGCAATGGGGTATTTTTTGCAAATTCCATTGGTGGGGTCAAG 
                 
                 
                     
                 
                 
                   ATGTGAGTTTAGAAGGAACTCTTAGCCTGACTCTTCTGGCCATGGAAAAAGATGGTTGCT 
                 
                 
                     
                 
                 
                   TCTAAATGCTGACCTGGTGATTTTACACTGTCACATCTCAAATTGTGGTCATCTTTTATA 
                 
                 
                     
                 
                 
                   CATTATTAACAACAAAAGGGAAAAATTGAGTTGACTTTAAGAGGAAGTGGAAAATAACGA 
                 
                 
                     
                 
                 
                   GATCACATCTGTACTCTACAGGCTCTCCACAGAGGTCAGACTGAGGTGGTAAAATTGTTG 
                 
                 
                     
                 
                 
                   TGCACTAAATTAGGGCATTAACGTTTCATGGAAACTGAAGCTATATCTAAATAGCTGATG 
                 
                 
                     
                 
                 
                   GCCTGCTTTCTAGATCTCCTATATACCTGCTTCTCAAATTCAGTCTGTTTTAAAAAATTG 
                 
                 
                     
                 
                 
                   CCCTTTGAGGTTGGAACCAGCGAAATAAGGCTGAAAACAGAATAAGCCATTATTGAAAAA 
                 
                 
                     
                 
                 
                   ATTAGGAACTTGGAAGCAGATACTCATAATCTAAATCCTCTGAAGCTAAAGTTTGATCCA 
                 
                 
                     
                 
                 
                   CAATAGCAAAGCATTATCATTTTAGTGATTGTACCTTAGTTGTTTCCTGGCAGGTGATAA 
                 
                 
                     
                 
                 
                   ATTTGGGATCACTTTCTTCTTACAGTGTGCTCTGATAGTCTTTAAAACAAACCAGAGCTC 
                 
                 
                     
                 
                 
                   TAAATTGTAATGCCATTGGTAATTTAACTCTGATTTGTCTCTATGCCTGTCTCCTGGTGT 
                 
                 
                     
                 
                 
                   TCTGTAAAATTCTACACGTCATTTCAGGTATCACTATCCAGAAGACGTTACTTTTGCCTT 
                 
                 
                     
                 
                 
                   TGATGCACTTTAAAATGTGAAGTCTCTTGTGAAGCTCTTTGGTTATTTTCTCCTTTGCTG 
                 
                 
                     
                 
                 
                   CTGAAATAAATTCAGGTTGATGATTTTCTTGTAGGATATGTTGTGTGATCTAGACATTGC 
                 
                 
                     
                 
                 
                   AAACCCAAGTCTTTGATTTTTTTTTCCCTACAGATTGCCTGTTTCTTTTTTATTTTAATT 
                 
                 
                     
                 
                 
                   TTTATTAGTTATTATTATTTTTGAGATGGAGTCTCACTCTGTCACCCAGGCTGGAGTGCA 
                 
                 
                     
                 
                 
                   GAGGTGTGATAGCTCACTGCAACCTCCACCTCCCGGGTTCTTGTGCCTCAGCCACCCAGG 
                 
                 
                     
                 
                 
                   TAGCTGGGATTACAGGCACGTACCACCACTCTCAGCTAATTTTTTTGTATTTTTAGTAGG 
                 
                 
                     
                 
                 
                   GATGGGATTTCTCCATGTTGGCCAGGCTGATCTCAAACTCCTGACCTTAAGTGATCTTCC 
                 
                 
                     
                 
                 
                   TGCCTTGGTCTCTGAAAGTGTTGGGATTACAGGTGTGAGCCACTGTGCCTGGCCAGTTAT 
                 
                 
                     
                 
                 
                   TAATTTTTTTAAAGAGATGGGGTCTCACTATCTTGCCCAGGCTGGAGTGCAGTGGCTCTT 
                 
                 
                     
                 
                 
                   TACAGGCACTGTTGTAGTGCACTGCAGCCTTGAACTCCTGGGCTCAAGTGATCCTCCTGA 
                 
                 
                     
                 
                 
                   GAGGCTGGAATTACAGGCACACACCACTGTGTCCAACAGATTGCCCATTTGTGATCTGTG 
                 
                 
                     
                 
                 
                   TAAATATCTCTCACTTCCTGCAGTATCTCTGCTCAAGAATGTAAAGAGATGGATAATATT 
                 
                 
                     
                 
                 
                   TTTAGATTTGTTGAAACAAAGTAAAGTTCTGCTCAAATGAGAATGACACTAACTAAATGA 
                 
                 
                     
                 
                 
                   AAAGGCCGGTTATAATTCTGTAATTTTGTGCCTGCAATGTGTGTGTTATTGTACACTTGA 
                 
                 
                     
                 
                 
                   ATCGGCCCTGTGCATTGTGGCGAGGTGCATATTGCATGGTTGTATTGAAAAGGTGCTTGG 
                 
                 
                     
                 
                 
                   GCCGGGCGTGGTGGCTCACACCTGTAATCCCAGCAATTTGGGAGGCTGAGGCAGCTGGAT 
                 
                 
                     
                 
                 
                   TACCTGAGGTTAGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAACCCTGTTTCTAGTA 
                 
                 
                     
                 
                 
                   AAAAATACAAAAAATTAGCTGGGTGTGGTGGTGGGTGCCTGTAATACCAGCTACTAGGGA 
                 
                 
                     
                 
                 
                   GGCTAAGGCAGGGAGAATTGCTTAAACCTGGGAGGCAGAGGTTGCAGTGAGCTGAGATTG 
                 
                 
                     
                 
                 
                   TGCCACTGCACTCCAGCCTGAGTGTATCACAAAAAAAAAAAAAAAAGGTTTTTGCCCTCT 
                 
                 
                     
                 
                 
                   CTCTGTGCCTGCTGCTCCCTGTTGAGTCCTATAGGCCTGAGCTGCCAGGGGGTACTGTGG 
                 
                 
                     
                 
                 
                   GCTGAGACTGGACATTGCAACCGACTGCAAGGCACCGTGGGACCCAGGTTGTGGATGGAC 
                 
                 
                     
                 
                 
                   TGTCTCTCGGGCTTTCTTCTTTCCATTCATCTTCCTCCTCTAACTCCCCTCTGTATCCAG 
                 
                 
                     
                 
                 
                   TATCCTTGCTCTCCATACACCTGCTTCATTCTTTTTCCTTCAGTAGATTTTTCTGCTTCT 
                 
                 
                     
                 
                 
                   TGACTTACAAACCCTACTTCTAGCCCCTTTCAGATATTGAAACTAGCAACTTTCAGGCTT 
                 
                 
                     
                 
                 
                   TGTACCAAAGTCTCAGAGATTCTCATTGACTCGGATGCCATCCATCTCTAGTCCAAAGAA 
                 
                 
                     
                 
                 
                   CAATGTCAAGGACATGAACATGTGGAACAAAAGTGTCTGCTGTGGACACCTTTGGGGAGA 
                 
                 
                     
                 
                 
                   AATAGTTTTCAGTGATGAGGGTTGTAGTGAGTTGGGCAGATATCCCAAAAATATCTGCCA 
                 
                 
                     
                 
                 
                   AAAACTATAGACACTTCTGGTTGCAGTGACTTATTCCTTCCTTCATTCAGCAAATACTGA 
                 
                 
                     
                 
                 
                   TTGAACACCGACTGTATGTCTGGATCTATTCTAGGTTTTGGGGGTGGAGCAGTGAACAAA 
                 
                 
                     
                 
                 
                   TCAGTCTTTATCTTTATAGAGTGTACAGTCAAGTGGGAGAGACAGGCAGTAAACAAAGAA 
                 
                 
                     
                 
                 
                   ACAGTTCAATATTCAATCTGTGAGATGGTGATAAGTGCTACAGAGAAAACAAACTAGTGT 
                 
                 
                     
                 
                 
                   AAGATAAAAAGGGTGTTTTGATAGGCCTTTACTATTTAGGTCTCTTTGATAAGGTGGCAT 
                 
                 
                     
                 
                 
                   TTGAACAAAGCTCTGAAGGAAATAATGGAGCCAACCATGCATATAACCTCAGGGAGAACA 
                 
                 
                     
                 
                 
                   TTCTAGGTAGAGGGAACAGCAAGTGCAAAGGCCCTGAAGTGGGGGTTTGTTTACCTTGTT 
                 
                 
                     
                 
                 
                   GCACAATCTGCACACAGGCCAGTACAATTGGAATGGATGGGAAATGTAAAAGAGAGAAGT 
                 
                 
                     
                 
                 
                   TGAAAAGGCCAGGTGCAGTGGCTCATGCCTACAATCCCAGCATTTTGGGAGGCTGAAGTG 
                 
                 
                     
                 
                 
                   GGAGGAATTTGAGATCAGCCTGGGCAACAGAACCAGACCTCGGGCTAATTTTTGTATTTT 
                 
                 
                     
                 
                 
                   TAGTAGAGACAGGGTTTCACCATATTGGCCAGGCTGATCTCAAACTCCTGACCTCAGGTG 
                 
                 
                     
                 
                 
                   ATCCTCCTGCCTCAGCCTCCCAAAGTGCTAGGATTACAGGTGTGAGCCATGGCCCCCAGC 
                 
                 
                     
                 
                 
                   CGTATCTTTGTCTTAAAAAGTAATCTCTGTGCTTGGTAGGCCAAGAATTTAAAATATAAA 
                 
                 
                     
                 
                 
                   AAATTTAAGAAAGAAAAAAAATAAGTAAAGTAACTATACAGGTTGGTCTGGCCGTAATGG 
                 
                 
                     
                 
                 
                   TGAGTGTCATTATTTTTCTTCCCTAGGTATTTTGGCTCTGTTGCTCAGAGCAGTGCAGGC 
                 
                 
                     
                 
                 
                   GAAATGGTCATTAGGGCATCGTCATGGTGCCTGGGGATGCCTGGCTCAGCCAGTTTATTT 
                 
                 
                     
                 
                 
                   TCTGTCTGCCTCTCTCCTTGGTCCTTTTCCTCCACTTTCATTCATGAAATTCTAGTCAAG 
                 
                 
                     
                 
                 
                   AGCTGGGTCCAGTGGTTTTCAATCCAAGGGCTTTGGAAGCCTCTGGGGTCTATTTTGGTC 
                 
                 
                     
                 
                 
                   ATTGCAGTCACTGGGCTGCTGCTCCTGGCATTTAGGTTGGCAGGGGTCTGGGCTGGGAAG 
                 
                 
                     
                 
                 
                   CAGGAATGTTCAGTGGCCATAAATGTAAGGGTTGGTCTTACATTTACATAAGGGAGACAA 
                 
                 
                     
                 
                 
                   TGAAAACTTAACTCCTCCACAGTAGTGGAGTAGTGCCGTTGGGTACTCACAGTCAGTAGT 
                 
                 
                     
                 
                 
                   GCCGTTGGGTACTCACATGTACAACATGGATCAGGACATTGACTTTCTGTGGATACCTTT 
                 
                 
                     
                 
                 
                   TAATAGTTTATTAGATGTGTTAGGCTGTTTTGCACTGCTCTAAAGGAATATCTGAGTCTA 
                 
                 
                     
                 
                 
                   GGTAATTTATAAAGACAAGAGGTTTAATTGGCTCATGGTTCTGAAGGCTGTACAAGCATG 
                 
                 
                     
                 
                 
                   GCTCCAGCATCTGCTTCTGGTGAGGGCCTCAGGAAGCTTCCGGTCATAGTGGAAGGCAAA 
                 
                 
                     
                 
                 
                   AGGAGGGCAGACGATCACATGGCCGGAGTGGTGGCAAGGGTGGGGTGGGAGCCACGCTCT 
                 
                 
                     
                 
                 
                   TTTTTTAATTTTATTTTAATTTGAGACAGTGTCTCACTCTTTTGCCCAGCCTGGAGTGCA 
                 
                 
                     
                 
                 
                   GTGGCGTGATCTCAGCTCACTGCAGCCTCTGCCTCCCAGGTTCAAGCAATTCTCCTGCCT 
                 
                 
                     
                 
                 
                   CAGCCTCCTGAGTAGTTGGGACTACAGGCGCGCATCACAATGCCCAGCTGATTTTTGTAT 
                 
                 
                     
                 
                 
                   TTTTAGCAGAGACAGGGTTTCACCATGTTGGCCAGGCTGGTCTCGGACTCCTGATCTCAA 
                 
                 
                     
                 
                 
                   GTAATCCGCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGCGCAC 
                 
                 
                     
                 
                 
                   GGCCACCACACTGTTTTAAACAACCAGATTGCACGTGAACTTAGAGTGAGAACTCACTGT 
                 
                 
                     
                 
                 
                   GAGGATGGCACCAAAACATTCATGAAGGATCCACCACCTTCCTTTAGGCCCCACCTCCAA 
                 
                 
                     
                 
                 
                   CACTGGAGGTCATATTTCAACTTGAGATTTGGAGGGGACAGACATCCAAACCGTATCATT 
                 
                 
                     
                 
                 
                   AAATTTAATAGTTTTATGCAGTTTTTTTGGCTCTAGATCTGTTTAGACTCCTGCAGTCAG 
                 
                 
                     
                 
                 
                   GTGTCTGTAACTAGCCTCTGGTCCTTTTTGAGAGTTCACAGTTTGGTGCAAACCCTTTGG 
                 
                 
                     
                 
                 
                   ATGTATTATTTGGGAAAATGGGATATCTGGCAGCCTGTGTCCCTGCTTTACATTATCCTT 
                 
                 
                     
                 
                 
                   TTTGCTGCCTGCCCCAAGCCTCCTCATTAGCATCCCTGCCAAGGCCAGTGGAGAAGGATG 
                 
                 
                     
                 
                 
                   GAGATGCGGTGACATTCAGCTTGACAGGTCATTAGCAGCTTTTGTGCCCTAGGGACTGCT 
                 
                 
                     
                 
                 
                   GGTGGGAGGGAGGTTGTGGAAGATAAACCCTGACAGGAATGTATTCTCCTCGAGGGCAGG 
                 
                 
                     
                 
                 
                   GTTTATTTGATATTTTTCTGGAGCTTAGAACCATAAGCCTGGTGCTGGGGAGGAAGCGCC 
                 
                 
                     
                 
                 
                   CTTAGCATTTGGTAGCCTCTGTGGGCAGAGCATGGAAAGTCACAACTTCTGAATTGTTTG 
                 
                 
                     
                 
                 
                   TATTTTCAGTCTCACTCTAGATGGATGGCATCTTCTGCTATGGGAAATGAAATATGTTTA 
                 
                 
                     
                 
                 
                   GGCAACTTGAGTCCCAGGTGCAGATGAGGCTGGGCTAATTGGTGCACTAGGGAAGGAGCC 
                 
                 
                     
                 
                 
                   GGGGGAGAGATGTGCTGTTAGCTATTATCAATCTGTGACAACTGTCAGCTGCTGGCAGTT 
                 
                 
                     
                 
                 
                   AGCACCCACCTGAGCCTGGGATGCAGGGGTGCCTCTCCTGTCCTCTGTGGAAGCCTCTGG 
                 
                 
                     
                 
                 
                   ACCCAGCAGCCATCTTGACTGTGCACTGTTCAAGCCCCAAGTCCGCCTGGAAGAGGTGAT 
                 
                 
                     
                 
                 
                   TGAGAACTTACTGCAGGATAAGGAAAGCGCAGGACAGGTGCAGTGGCTCACGCCTGTAAT 
                 
                 
                     
                 
                 
                   CTCAGTGCTTTGGGAGGCTGAGGCCGGAGGAGGGCTGGAGTCCTTGAGTGCGAGACCAGC 
                 
                 
                     
                 
                 
                   CTGGGCAACATAGTGAGACCCTGTCTTTACAAAAAGGAAAAGAATTAGCCAGATGTGGTG 
                 
                 
                     
                 
                 
                   GTGCGTGCCTGTAGTCCCAGCCACTCAAGAGGCTGAGGTGCGAGGATCACTTGAGCCCAG 
                 
                 
                     
                 
                 
                   GAGTTTGAGGTTACAGTGAGCTATGATCATACCACTGCATTCCAGCCTGGGTGAGAGAGC 
                 
                 
                     
                 
                 
                   ATAGCTCTGTCCCAACAACAAAAAAAAAGATTAAGGGAAGCCTCTGGCAGACCTGATGAT 
                 
                 
                     
                 
                 
                   GGGTGGCCCAGCCAAAATGAGTATTGATGAGGATTTCCCTGGTCTGGAACTCTGAATTTA 
                 
                 
                     
                 
                 
                   GTCTGGCAAAGTATTCCCTTTGTGTTGTGAGATGATTCTTGGTGTTACCCCATCACGGTA 
                 
                 
                     
                 
                 
                   GGTAAGATGAATTAGCAAATGAGAAAGGCTTTCTCTTTTTCATCCTTATCTAGTCCGTAG 
                 
                 
                     
                 
                 
                   ATGAAGCCTGAAGAAGGTCTCCATATGGTAGTAGTAAGTGTTTAACATCTACCTCTAACA 
                 
                 
                     
                 
                 
                   CTTGCCTGTGTCTTTTTTTTTTTGCAAAGCCTCAGGAATGCCCCAGTATCTAGGTAGAAT 
                 
                 
                     
                 
                 
                   TTGATAATATTTCATTTTTGTTATATTCCCTTTTCTGTTTACCTTCTATATACAGCAAAA 
                 
                 
                     
                 
                 
                   TGAAAAAATTTTTAAAATTTGTGCAAGTAAGGGCAATTTCTTTTTTCTTTTTCTTTTTTT 
                 
                 
                     
                 
                 
                   TTGAGACAGGGTCTTGCTCTGGCACCCAGGCTGGAGTGCAGTGACACAATCTCGGCTCAC 
                 
                 
                     
                 
                 
                   TGCAACCTCTGCTTCCTGGGTTTAAGCGATTCTCCTGCCTCAGGCTTCCAAGTAGCTGGG 
                 
                 
                     
                 
                 
                   ATTACAGGTGCCTGCCACCACTCCCAGCTAATTTTCATATTTTTAGTAGAGACCAGGTTT 
                 
                 
                     
                 
                 
                   TGCCATGTTGACTGGGCTGGTCTTGAACTCCTGACCTCAGGTGATCCATCCACCTTGGCC 
                 
                 
                     
                 
                 
                   TCCCAAAGTGCTGGGATTATAGGCTTGAGCCACTGGGCCTGGCTGAGGCAGTTTCTTTTT 
                 
                 
                     
                 
                 
                   GAAATATATTTTGTGAAGGAGAAAAAGAGGAGTTCAGTTTAAAGAAACAAATGACATAAG 
                 
                 
                     
                 
                 
                   AGGTGGTATGCAGAGATGCCAAAGCATCTTGAAGGTGCTTTTTTTTTTGGAAACAGAGTC 
                 
                 
                     
                 
                 
                   TTGCTTCATTGCCCAGTCTGGTCTGCAGTGGTGCAATCATGGTTCCCTGCAGCCTTGACC 
                 
                 
                     
                 
                 
                   TTCTGGGCTCAAGTAATCCTCCCACCTCAGCCTCTCAAGTAGCTGGGACTACAGATGCAT 
                 
                 
                     
                 
                 
                   GCCACTATGTCTGGCTAATCTTTAAATTTTTTGTAGAAGCCAGCTCTCACCATATTGCCC 
                 
                 
                     
                 
                 
                   AGGCTGGTCTTGACCTCCTGTCCTCGAGCAAAAATACCGATTTTGATTAAGTCTGGGGTA 
                 
                 
                     
                 
                 
                   GGACCTGGGGCTGGGATTCTAACCAGCTCCCAGGTGGTGCTAATGCTGCTGGTCTACAGA 
                 
                 
                     
                 
                 
                   CCACACGTGGAGTAGCCAGTGTAGAGTTCATGTAGCAATAGTGATGTCATAGAAATAGCC 
                 
                 
                     
                 
                 
                   AGTATCTGTATACTTGCTTTGTTGTATGTCACGCACTGTATAGTGATGTACATGCATCTC 
                 
                 
                     
                 
                 
                   ATTTGACCCTCACCCCGCCCCTTTGGGGGTAGAAAGGATTGTGCTCATTTCACACTCAAG 
                 
                 
                     
                 
                 
                   GAAACTGAGGCACAGACAGGCAAAGTAGCTTGGCGAAACAGAAAGGAACTTAGAGGCAGG 
                 
                 
                     
                 
                 
                   CCCTGATTAGCTCAGAGACTAGAAGGCCTTGTGCGTCATCCTGAACAGCTTGGACTTGAT 
                 
                 
                     
                 
                 
                   CTTGAAGGTGGAGGGAGAAATTGAAGGGTAATTAAACAGGAACTGTAGGAAATTCACCTT 
                 
                 
                     
                 
                 
                   GCATAGTGATTGCTTTGGCCACGTGTGCCCTGCCACCGCCCCCCCACCTCAGTGAAGTGT 
                 
                 
                     
                 
                 
                   CATGCGAAGTTGGGTTCGTAAATGAAGGCCCGAATGCTTTCCTGACAAGTTTGTTTTAAA 
                 
                 
                     
                 
                 
                   TCAAGCTGCTAATTAGTCCCAGTCCCCCTCCCCCGGTATGTATTTTTTTGTTGATGTCGT 
                 
                 
                     
                 
                 
                   TTCACTTCATTTAGTTGAAGTGATTGATTCAGTTCAGTGTTTGAACTTCTTTTTGAACCT 
                 
                 
                     
                 
                 
                   CACCTTAATAACCTGTCTAAACATCAAGGTTAAACCTTCTTGCTAACACAGCAGTATTGC 
                 
                 
                     
                 
                 
                   TTGGTAAGACTGGCTCACAGTCCAAGGAAATGCTTGCCCAGAGAGGGCAAACTGCCTTAA 
                 
                 
                     
                 
                 
                   CTCCTTAACCTGAGCTCATTAAAAAAAATTCAAATGACTGATTCCTTGTCACAGTTCTAC 
                 
                 
                     
                 
                 
                   CTACATTGTTTTTATTTTTGTCCAGGTTTCAGCTAGTTAAATGCTTTTGTGATGAGCTTA 
                 
                 
                     
                 
                 
                   TGTCCAGGCTGAAGGTTGCATTTTGAAACTGAGCGTCAAATACCAATTTAAAGTCCAGAC 
                 
                 
                     
                 
                 
                   CTTTACACTTGTGAAATTCAGATAAATGAAATGGAAATAAAACAGGGCTGCTGTGTTGTG 
                 
                 
                     
                 
                 
                   AAATATGACTGTGTTTTTCCTTGTAGGACTCTTTGAGGGTAGCCATTTTGGCATTTTATA 
                 
                 
                     
                 
                 
                   TATAAATTTTCTTTTCTTAGCCTACCTTTTACTTTCTTGATTTGCCTATTTGTGATTTCC 
                 
                 
                     
                 
                 
                   CATTAAACACTAGGCTTTTTGTAAACCAATTATCCCTTGAAATTGACTTTTTTTTTTTTT 
                 
                 
                     
                 
                 
                   GAGACAGGATCTTGTTTTGCCACACAGGCTGGAGTGCCGTGGCTCCATCATATGATAAAC 
                 
                 
                     
                 
                 
                   AGAAAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGACCCTGTCTTATTTAAAACA 
                 
                 
                     
                 
                 
                   AAAAAAGAAGAAGAAAAAAAGAATATAGATCACAGCTGTTATTTGTATATGCTACGCCAA 
                 
                 
                     
                 
                 
                   TCCTTGTTGGGTTTCATTCTTTATAATTGTTATTTTTAAAGATTTTTCTTATGAATATTC 
                 
                 
                     
                 
                 
                   TATTGTTTCATTGTAGAAAATTTAAGGGAGAACACAGTGGGAAAAAAAAAACAAGAAAAG 
                 
                 
                     
                 
                 
                   GACTTCATAATCCTGCTACCCTGGGAGAAAAAAAAAATCACCATTACCTATTTGGTTCTT 
                 
                 
                     
                 
                 
                   CTCCCACTTTTTTTTTTTTCGAGATGGAGTCTCCCTTTGTTACCCAGGCTGGAGGGCAGG 
                 
                 
                     
                 
                 
                   GACGTGATCTTGGCTCTCTGCAACCTCTGCCTCCTGGGTTCAAGCGATTCTCGTGCCTCA 
                 
                 
                     
                 
                 
                   GCCTCCCGAGTATCTGGGATTACAGGGGTGTGCCATCACACCTGGCTAATTTTTGTATTT 
                 
                 
                     
                 
                 
                   TTAGTAGAGACGGGGTTTTGTCATGTTGGCCAGGCTGGTTTGTTGGCCATGTCTGGTTTT 
                 
                 
                     
                 
                 
                   TTGTCATATTGGCCAGTCTGTTTGTCATGTCAGGCTGACATGTTTTGTCATGTTGGCCAG 
                 
                 
                     
                 
                 
                   GCTGGTCTTTAACTCCTGACTTCAGGTAATCCTGAAGTGCTAGGATTATAGGCGTGAGCC 
                 
                 
                     
                 
                 
                   ATTGCACCTGGCCTTCTGCCTTTTTTTTAAAGAAAAAAAATTAAAACATTTTTTTCTTTT 
                 
                 
                     
                 
                 
                   TAAGATAGCGTCTCATTTTGTTGCCCAGGCTGGTCTTGAACTCCTGGGCTCAAGTGATCC 
                 
                 
                     
                 
                 
                   TCCAGCCTCAGCCTCTGGAGTAGCTGGGACTACAGATGCACATCATGGTGTCCTTATGCC 
                 
                 
                     
                 
                 
                   ATTTCTTTTGTACGTAGGTGAATGCAAGTGTATGATTACATCATATGCTATTTTGGAGGT 
                 
                 
                     
                 
                 
                   TTGACTTTCTTTTCACTTTCATCATCTTTCCAAGGTGTTATTTTCCTAGTACATCTTTTT 
                 
                 
                     
                 
                 
                   AAATGGACATAGAACATTCTTTTGTATGAACAAACAATAGTTTTATTTAGGCGGTCCTTT 
                 
                 
                     
                 
                 
                   CCTGTTGGACATTTATATTATTTTCAGCATTTCTCCACAGTTGTTGCAGCATTCAGATGA 
                 
                 
                     
                 
                 
                   ACCTTCTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTTTCGCCCAGGCTGGAGTGCAG 
                 
                 
                     
                 
                 
                   TGGCACAATCTCTCCTCAAGTGATTCCTGTGTCACCCTCCCACGTAGCTGGGATTACAGG 
                 
                 
                     
                 
                 
                   TGCCCATGTCTGGCTAATTTTTGTGTTTTTGGTAGAGCTGTGGTTTTACCATGTTGGCCA 
                 
                 
                     
                 
                 
                   GGCTGGTTTCGAACTCCTGCCCTGAAGTGATCTGCCCACCTCAGCCTCCCAAAGTGTGGG 
                 
                 
                     
                 
                 
                   GATTACAGGTGTAAGCCATCACGCCTGACCCAGATGAACATTCTTGTAGCTATCGCACAC 
                 
                 
                     
                 
                 
                   AATTCTGAACATTTCCTAGGATGAATTCCTTAAAGAAGTAATGCTGATCCAGGCTTTTTT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   CACTCTTGGAGATTTTGATTCCTAGCACCTCTGTACCTTTCCTCAGGGTCGTGTGCTCTT 
                 
                 
                     
                 
                 
                   GTTAGCACATCGGAGGCCTTAGCTTCTTTAATTGCAAGCAGTTTCCAAAATAATCAACCA 
                 
                 
                     
                 
                 
                   TGGTGGGTGTTGATGACTTCATTCACTGAGCTCCCGTGATGCTGATTACTGAGTAAAGTT 
                 
                 
                     
                 
                 
                   GCCACTAGGTGGCTTTGTCTGTGGTTGGTTCCTTCTGTTAATTAATTTTCTGTCTGCCCA 
                 
                 
                     
                 
                 
                   AGATAGATCATCTCAAGGCTTGGGATCTCTCAGTGTCAGGGACCTTAGGGTGCCAGATTT 
                 
                 
                     
                 
                 
                   GTGTCTTGACTCCTCCTCACTGGGCCTGTGAGTCCTGGGTAAGGCCTGCCTCCTTTCTGG 
                 
                 
                     
                 
                 
                   GACTCAGTTCCCTTAAGTGGGAAACAGACAAACACCTCCTGAGGGCTCCTAGAACTGTTC 
                 
                 
                     
                 
                 
                   TGCTTGCTGATCCCCTGAGCTCAAGTTACTGGAGAAAGGGTATATACCTAAACTGCTCAG 
                 
                 
                     
                 
                 
                   AAGAAGACTTTGTGGGCCGGGCGCAGTGGCTCACACCTGTAATCCCAGCACTTTCGGAGG 
                 
                 
                     
                 
                 
                   CCGAGGCAAGCGGATCACCTCTGATCAGGAGTTCAAGACCAGCCTGGCCAACATGGTGAA 
                 
                 
                     
                 
                 
                   ACCCCATCTCTACTAAAAATACAAAAATTAGCCATATGTGGTGGTGTGCGCCTGTAATCC 
                 
                 
                     
                 
                 
                   CAGCTACTCGGGAGGCTGAGGCGGGAAATTGGTTGAACCCAGGAGATGGAGGTTGCAGTG 
                 
                 
                     
                 
                 
                   AGCCGAGATGTGCCATTGCACTCCAGCCTGGGTGACAAGAGCAAAACTCCGTCTCAAAAA 
                 
                 
                     
                 
                 
                   AAAAAAAGGAAGACTTTGTGAATATTCGCAAAGCTGTAAAGCTGTACCTTTCAATTTTTT 
                 
                 
                     
                 
                 
                   TTTGAGACATAGTCTCACTCTGTTGCTCAGGGTGCAGTCACAGCTCACTGTAGCCTCAAC 
                 
                 
                     
                 
                 
                   CTCCTGGGCTCAAGCGATTCTCCCACCTCAGCCTCCTGATTAGCTGGGACAATAGGCAGG 
                 
                 
                     
                 
                 
                   CACCAGTACACCTGGTTGATTTTACAGTTTTTCTGTAGGCCGGCGCAGTGGCTTACGCCT 
                 
                 
                     
                 
                 
                   GTAATCCCAGCACCCTGGGAGGCCGAGGTGGGCGGATCACCTGAGGTTAGGAGTTCGAGA 
                 
                 
                     
                 
                 
                   GTAGCCTGGCCAACATGGTGAAACCCCATCTCTATTAAAAATTACAAAAATTAGCTGGGC 
                 
                 
                     
                 
                 
                   GTGGTGGTGGATGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCTGAGGCAGGAGAATC 
                 
                 
                     
                 
                 
                   GCTTGAACCTGGGAGGCGGAGGTTGCAATGAGCCGGAGGTGCTATGTGCACCACTGCACT 
                 
                 
                     
                 
                 
                   CCAGGCTGGGCGACAGAGTGAGACTCTGTCTCAAAACAAAAAACGATTTAAAAAATAATA 
                 
                 
                     
                 
                 
                   AAATTTTTTCTAGGGCGGGGTCTCCCTATGTTGCCCAGGCTGGTCTTGAACTCCTGGGCT 
                 
                 
                     
                 
                 
                   CAAGTAGTCCTCCTGCCTCAGCCTCCCAAACTGTTGGGATTACCAGTGCAAGCCATTGTG 
                 
                 
                     
                 
                 
                   CCTGGCTGTACCTTCTGTAACACCCAAATGCCACCTGGCAAAGCCCAAGTTGAATCATGA 
                 
                 
                     
                 
                 
                   GGAAAAAAGGCCTGGAAGGATGTAGACCTTCCTTTTTTCTACTTATTTATTTATTTATTT 
                 
                 
                     
                 
                 
                   TTGAGATAGGGTCTTACTCTGTTGCCCAGGCTGGAGTGCAGTGGCATGATCATGGGTCAC 
                 
                 
                     
                 
                 
                   TGCAGCCTCAACCTCCCGGGCTCAAGTGGTCCTTCCCACCCCAGCCTGCAATGTAGCTGG 
                 
                 
                     
                 
                 
                   GACTACAGGCATGTGCTACCATGCCCAGCTAATTTTTGTATTTTTTGTAATTATTTTTTT 
                 
                 
                     
                 
                 
                   TGTAGAGACAGGGTTTCGTCATGTTGCCTAGGCTGGTCTCGAATTCCTGGGCTCAAACGA 
                 
                 
                     
                 
                 
                   TCTGCCTGCATCGGCCTCCCAAAGTGTTGGGATTACAGGTGTGAACCACTGTGTCTGGCT 
                 
                 
                     
                 
                 
                   ATATCTTCTGTAACACCCAAATGCCACCAGGCAAAGCCCAAGTTGAACCAGGAGGGAAAA 
                 
                 
                     
                 
                 
                   AGGCCTGGCAGGATGTAGGCCTTGCATGAGGATCTCAGAAACTGCACTAAACCAGTCACA 
                 
                 
                     
                 
                 
                   GTTCCTCTCTCCCGAGGTCTAACTCTATGCTGAACTCTTTGCATTTTTATCTCACTTAAT 
                 
                 
                     
                 
                 
                   CCATATCACATGCACAGGAAGGAAGCATTCGTAGTATCCTGGTTTCCTAGACCATTTTAG 
                 
                 
                     
                 
                 
                   CAAGGTTATAAGTGAAGGGGAGTGGGTGGGAGAACTGGCACTAGAGCCCCCAAAGTCACT 
                 
                 
                     
                 
                 
                   GTTCTTAGCACCACTCTAATGCATGGGGTTCTCCATTGATGTGCTATGCAAGGCAGTGCA 
                 
                 
                     
                 
                 
                   CTGAGGAGAAAGGAAGGAACATTTACAACTTCTCTTTATTTATATCCTGTCCCTAAAAAA 
                 
                 
                     
                 
                 
                   AAAAGAAAAAGAAAAATTTGTCTGAGGCCTAGATTGATTGCAGGGAGTGCATAATGTTTT 
                 
                 
                     
                 
                 
                   ATTGATTGATTGATTGATTGTATATAGAGATGGGGGGTCTCACTATATTGCCCAGGCTGA 
                 
                 
                     
                 
                 
                   TCTCGAACTCCTAGGCTCAAGCAATCCTCCTGCTTTGGCTTCCCAAAGTGCTGGGATTAC 
                 
                 
                     
                 
                 
                   AGGCATGAGCGACTGCACCTGGCTATGCATACTATATTTATCCAACTTACAAATAAGGCT 
                 
                 
                     
                 
                 
                   TGCTTGCCTGTAGTGCATATGTGTATACATTTCAGCATAGAAAAACTGTGTGATTGGGGG 
                 
                 
                     
                 
                 
                   TTGTGATCAAATTTGGAGAGCATTGCTCTCATGTCTTATCAGGTCAGAGTCATTTTGTCA 
                 
                 
                     
                 
                 
                   AATCTTGTAAACCATTCTTTGTGTGTGTCTATGCATGAAACATAGTCTTTCTCTTTCTGC 
                 
                 
                     
                 
                 
                   ATGCATATGTACATATACATGGTATATATGTATATCATATCTACATGGATATTGTAATGT 
                 
                 
                     
                 
                 
                   ATATGTATGAGGATGGGGGAAAGTGGAGACATTTGTAATACTGAGAAAAGGCAGTGAGGA 
                 
                 
                     
                 
                 
                   ATTTGCAGAGAAGCAGTTTGAGCTGTAGCATGGTACTAGTGACCTTGAGGAAGCCTTATC 
                 
                 
                     
                 
                 
                   CTTTTTTTTTGGAATTTATTTTTTCAATTTTTAGAAATAGACAAGAGTTTCTCTATGTTG 
                 
                 
                     
                 
                 
                   CCCAGGCTGGTCTTGACCTCCTGGGCCCAAACTATCCTCCTGCCTTGGCTTCCCAAAGTG 
                 
                 
                     
                 
                 
                   CCAGGATTACAGGTGTGGACCACCATGCCTGGCCACCTTGTCCTTTCTATGTCTAAGTTG 
                 
                 
                     
                 
                 
                   TGACATCTGCTCAGGGGTCAGGTGGTATTAAATGGTATAAAATGTATGGGAAAGTGAAGG 
                 
                 
                     
                 
                 
                   GATCAATGGTATGCAGTATCTAAATAGAATATCGCTTTTTCCTCCCTTAAAGGTCTCATT 
                 
                 
                     
                 
                 
                   CAGATGTTTCCTCTGATGAACATCTCATTTCCTTAAAGATGAGGAGTCTGAAGCAAAAAA 
                 
                 
                     
                 
                 
                   GACATTATTCTTTTAAGACACATGGCTGTCTTACTAATTCCCATTGCAAAATATGTTGTT 
                 
                 
                     
                 
                 
                   TAGGTAGAGCACTCAGATTTTTATACGAATAATAGACTTTTGTACAGAATTTGGACAGTT 
                 
                 
                     
                 
                 
                   GATACTATCAGAGCCTTGTGATATTCCACTGCATTATGCTTCACTAAAAAATACCTGGCT 
                 
                 
                     
                 
                 
                   GGGTGCGGTGGCTCACAACTGTAATCCCAGCACTTTGGGAGGCTGAGGTGGGCAGATCAC 
                 
                 
                     
                 
                 
                   CTGAGGTCAGGAGTTCAAGATCAGCCTGGCTAACATGGCAAAACCCCATCTCTACTAAAA 
                 
                 
                     
                 
                 
                   ATACAAAAATTAGCCAGATGTGGTGGCACGCTCCTGTAATCCCAGTTACTCAGGAGGCTG 
                 
                 
                     
                 
                 
                   AGGTATGAGAATTGCTTGAGCCCAGGAGGCAGAGGTTGCAGAGAGCCGAGATAGTGCTAT 
                 
                 
                     
                 
                 
                   TGCACTCCAACCTGGGTGACAGAGGAAAACCCTGTCTCAAAAAATAAATTTAAAACAACA 
                 
                 
                     
                 
                 
                   ACAACAACAACAACAAAAACCCCTCTTTATTATGGAAATTTTCAAATATATTCAAGAGCA 
                 
                 
                     
                 
                 
                   TAAAGAACCCACATGTACCCATCACCCAGCTTCAACAATTATCAACTCATGCCCAGTCTT 
                 
                 
                     
                 
                 
                   GGTTTCATCTATACTCTGATCCACATCTCCTCTCTCCTTGAATTATTTTGAAGCCCATCT 
                 
                 
                     
                 
                 
                   CAGACATCATGTCATATATGTATACTTCAATCTTCTTTTTTTTTAAAACTCCCCCTCCCC 
                 
                 
                     
                 
                 
                   TTTTCTTTTTTCTTGAGACTGTGTCTCACTCTGTCATCCAGGCTGGAGTGATCTTGGCTC 
                 
                 
                     
                 
                 
                   ACTGCAATGTCCGCCTCTCGGGTTCAAGCGATTTTTGTACCTCAGCCTCCCTAGTAGCTA 
                 
                 
                     
                 
                 
                   GGATTACAGATGTGGACCAACATGCCTGGCTAATTTTTGTATTTTTAATAGAGACAGGGT 
                 
                 
                     
                 
                 
                   TTTGTCATGTTGGCCAGGCTGGTCTTGACCTCCTGACCTCATATGATCCACCTGCCTTGG 
                 
                 
                     
                 
                 
                   CCTCCCAAAGTGCTGAAATTATAGGCCACTGCGCCCAGCCCAAAATTTCTTGGTTTGAAA 
                 
                 
                     
                 
                 
                   TAATTTTGGAACTCATAAGAAGTTACACATATAGTAGAGAGAATTTTCTTGTACCTTCTC 
                 
                 
                     
                 
                 
                   TGAGCTTCCTATATACCCAATGATAACATCCTATATACCCATAGTATATGATCAAAACTA 
                 
                 
                     
                 
                 
                   GGAAATTGTGAAGATGGCATTTTGAGACATCAGGCAGTGTTCACGTTACTGTTTTGCTTA 
                 
                 
                     
                 
                 
                   CCTGGGCTTTAATTTTTATGTGTTTTTTTTTCAATCATTGAATGAACAAAACTTGGACTA 
                 
                 
                     
                 
                 
                   GGCTGGGGAGTAACTGATTTGAACTGTTTTTTCCTGAAGCAGTCCAGGACTTATGTGACC 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TGTTTTCTGACCATACATTTCTAGCCTATTTTTGTATTTTAAATCCTTCCTCATGTCCTG 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TTTAAAGTATCAGACATGTCAGATTGGCCATGTTTAGGAATTGAATAAATGAATTAAGCT 
                 
                 
                     
                 
                 
                   TACTGTAACTGATTCTCTGGAAAAAAGGGACTAGGAGAAATTTGATTATGTTATTCCTTG 
                 
                 
                     
                 
                 
                   GTGTAGTTTTCTTTATGTTTCTTCTGCTTGGGATTTGTTGAGCTTCTTGGCTCCATGGAT 
                 
                 
                     
                 
                 
                   TTGTAGTTTTCCTTAAATTTGGATAATGTTCAGTCTTAGTTTCTTCAGATACATATCCTG 
                 
                 
                     
                 
                 
                   GGCTGGGCATGGTGGCTCATGCCTGTAGTCCCAGCACTGTGGGGTGTTGAGGTGGGCGGA 
                 
                 
                     
                 
                 
                   TCACTTGAGGTCAGGAGTTTGAGACCAGCCTGGGCAATGTAGTAAGACCCCATCTCTTAA 
                 
                 
                     
                 
                 
                   AAAAAAAAAATGTACCCTGCACAACCTTGTCCTAGGACAGCAGTCATACGTGTATTAGAC 
                 
                 
                     
                 
                 
                   TACTTGAAGTTGTCTCATAGCCCACTGATACTTGGTTTATTTTATTCAGTTTTTTCTCCC 
                 
                 
                     
                 
                 
                   CGTGTTTCATTTCGAATAGCTTCTTTTGCTATGTCTCCAAGTTAATCTTCTGCAATATGT 
                 
                 
                     
                 
                 
                   CATCCGCTCTTAATCCTATCCAGAGTATTTTTCATCACAGACATTGTATTTTTCATCTCT 
                 
                 
                     
                 
                 
                   AGAAGTGTTAATGTCATCTATAGCTTTCCTTTTAACATGTGTAGCATTTTCCTTACCTTT 
                 
                 
                     
                 
                 
                   TGAATGTATGGAGTATTTCTGTTGTTGTTTTTTGTTTTGTAGAGACAGGGTCTCGGTCTG 
                 
                 
                     
                 
                 
                   TTGCCCAGGCCGGAGTGCAGTGGCATGATCTCAGCTCACTGCAGCCTCTGCCTCCCGGTT 
                 
                 
                     
                 
                 
                   CAAATGATTCTCATGCCTCAGCCTCCCAAGTAGCTGGGACTACAGGTGCGTGCCACCACG 
                 
                 
                     
                 
                 
                   CCTGGCTAATTTTTGTATTTTTAGTAGAGATGGGGTTTTGCCATGTTGGCCAGGCTGGTT 
                 
                 
                     
                 
                 
                   TTGGAACCCCTGAGCTTAGGTGATCCACCTTCCTTGACCTCCCAAAGTGTTGGGATTATA 
                 
                 
                     
                 
                 
                   GGTGTGAGCCACCATGCCTGGCCATGTTGTCTGTTTTAATTAACTCTGCCTAACTGTCCT 
                 
                 
                     
                 
                 
                   CCCAAATGGTTGCTGCAGTGCTCACTCCCACCAGCAGCACCTGCCTAGGACTCATTACTC 
                 
                 
                     
                 
                 
                   CATACTCTTCAAGACACTTCAGATTAAAAAAATAAATTGTAACACCCCACACCTACAGAA 
                 
                 
                     
                 
                 
                   GAGCGGACAGATCTTATTGAGTGACAGCCCTCTGTGTTATCTCAAAGTGAGCCCACCATG 
                 
                 
                     
                 
                 
                   GTGGTTTTTTTTTTAAATATGGAAAAGTTCTGTGTTTTTGTTTGTGTTCTAGTGAAAGTT 
                 
                 
                     
                 
                 
                   CTTTTTTAGATATCCTTTAATTGGTTTATATAAGATTTTATGTGGAATGTAGCAGTCATA 
                 
                 
                     
                 
                 
                   CCTATAAATTAAACCTAAGGCAGATGGAGAACTTTGGAGTTGAGCCTTCCTACTGTAATT 
                 
                 
                     
                 
                 
                   TTCATATTGGATGTGAAGGGCAGTGTGATTTTCATAAGACTTTCATTGTTGTACTCCTAG 
                 
                 
                     
                 
                 
                   TTGGTATACTTCTGAATACCTTTGAGGCCAGTTCTGGTCATCGTGAAACAAAGGTTTCCT 
                 
                 
                     
                 
                 
                   TCAGCAAATGCCTGTGGTAACATTAGGTGTTCTTGAATTAATGGACCAATGAAAACATCT 
                 
                 
                     
                 
                 
                   TTGTAGTTTCTGCTTCAGGCAAGGGTTTTTTGCCCTAAATGTGGATAGGAAGAATGAAGC 
                 
                 
                     
                 
                 
                   CCTTCATCCTCCTTTTTGCCTGATTATAGCTATAGGAGGTTCACCTGTTCTCAGAAGACA 
                 
                 
                     
                 
                 
                   TGAGGATTGTGAAGAGAGGGGTCTTGTGTTGCTTCAGAGGAATCAGTATCAGTCCCTTTC 
                 
                 
                     
                 
                 
                   AGAAGCTCTCCTGGATAGACAGGCATTAGGGCCAAATCACTCTGCCCCACCCCTCACCAC 
                 
                 
                     
                 
                 
                   CATGTCCTACTCTCTGCTCCCTGTCTCATTCTTCCTCTTTACTTTGGTGGTGCCGAGAGG 
                 
                 
                     
                 
                 
                   ATGACATGATGGGTATTGATTCTCTCCACAGACCTTTCTGACATCCTACTTTCAGTATCC 
                 
                 
                     
                 
                 
                   CCCCAGTGCACAGAAGACAAGCCAGACTGTGGACTGTGTTTGATTCCTGGGCTCTATTTT 
                 
                 
                     
                 
                 
                   AAAAGACAGTGTATTAGTTCTCACATTTTAGAATTTGTTTGCCAAGGTTTCCACGGGAGT 
                 
                 
                     
                 
                 
                   TTAGAAACTAGGGGGAGGGCTGATGTTTAAAGTTAGCTAAAATGTTCTTTTCAGGGTCAT 
                 
                 
                     
                 
                 
                   GATTTAATTTTATATTCTCTGGTGAGTTCCCTATAGTGACTGGGAGCAGTCCTCAGTCTT 
                 
                 
                     
                 
                 
                   GATTGGCCAGTGACAGCATAGAGTACAATTAATATTAGGAGTGCTCATTTGGGGAAACTA 
                 
                 
                     
                 
                 
                   AAATTTGCATCAAATCTGTCAGAGGTGTTTGGATCTACAAAATACCGGAGGGAAAGCTGA 
                 
                 
                     
                 
                 
                   ATTGAGAATCATAATAAATAAAAGACCACATCGTTCTTTTTTTTTTTTTTTTTTGGGACT 
                 
                 
                     
                 
                 
                   GTATCTTGCTCTGTCACTCAGGCTGCAGTGCAGTGGCACTATCTTGGATCACTGCAGGCT 
                 
                 
                     
                 
                 
                   CCGCCTCCCGGATTCAAGCGATTTTCCTGCCTCAGTGCCTGAGTAGCTGGGATTACAGGC 
                 
                 
                     
                 
                 
                   GTGTGCCACTACACCTGGCTAATTTTTGTAATTTTAGTAGAGACAGGTTTCACCATGTTG 
                 
                 
                     
                 
                 
                   GCCAGGCTGGTCTCAAACTCCTGGCCTCAAGTGATCCACCCGGCTTCCCAAAGTGCTGGG 
                 
                 
                     
                 
                 
                   ATTACAGGCGTGAGCCACTGCGCCCAACCAAGACCACATCCTTTTATTGAACGTTCCTCC 
                 
                 
                     
                 
                 
                   TACCATGTTTTCTTTTTTCTTTCAATTAATCATTGACTCATTGACTCTCACTGTTGATGT 
                 
                 
                     
                 
                 
                   CTGTAGCTGCTCTCTTATTTCCAGTTTTATAGCTGTAAATTTCTCTGTCTTCCTAAGATA 
                 
                 
                     
                 
                 
                   CAAGGTAAATTTCTCTTGCTGATATTGGTGGTTTTGGAAAGTGAGTGGTGTGGATGACTG 
                 
                 
                     
                 
                 
                   CCCAGAAAACAACAGAACACAAAAGCATTCTCTGCCCAGAACACATCACCAAATAGATAC 
                 
                 
                     
                 
                 
                   AAACTCATCTCTTACTGAGTGAAATAGCTTCCTTTTTGGCAGCAAGAATGATTTTCTTGG 
                 
                 
                     
                 
                 
                   TGCCATATTTTTCAATCCGCCTGCTCTTGAAGCCAGCAGCTATTGCAGACTTGGCATTCC 
                 
                 
                     
                 
                 
                   CAGGCACCCAGTTAAGGGAAAGTGACGTGTAGAGGAGGTATCAGATGGGTCTGGATATAG 
                 
                 
                     
                 
                 
                   AAAAAGCAGCTGGTTCAAAACCCCATGGGCTGCCTTTCTGTGATAGAGTTATTCACACTT 
                 
                 
                     
                 
                 
                   GGGTTAGATAAGGCACAGAGTCCTCCTACACTGGTGCGGAAATGAAACAGACAGTCTGGC 
                 
                 
                     
                 
                 
                   TCGTTGGGCAGCCTAGCCTCCTCCAGAATCTGTGCTTGCCTTCCCTATGGAGTGACTGGT 
                 
                 
                     
                 
                 
                   AGATCTTAGAATTCAGACCTCAGTGGTTGCTAGCCAGCACTCTCACATTGGTTGGTCCTT 
                 
                 
                     
                 
                 
                   CTCTCTGCATCTTTGATTCTTTAGAGATAGATAAACCAAGCACCGACTCTCCTTTGACAT 
                 
                 
                     
                 
                 
                   GTGCTTGGAACAGACACCTGCACGAGCTGCCTTTCTCCTCCCACTTCTGCCTGGTCTTCC 
                 
                 
                     
                 
                 
                   AAACACCTGCTTTTCTTGTTTGAACTCTTCCTTTTTTTTTGAGACAGAACCTCTCTCTGT 
                 
                 
                     
                 
                 
                   CACCCAGGCTGGAGTGCAGTGGCATGATCTCAGCTCACTGCAACCTCTGCCTCCCAGGTT 
                 
                 
                     
                 
                 
                   CAAATAATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGATTACAGGTGCCTGCTATCACG 
                 
                 
                     
                 
                 
                   CCTGGCTAATTTTTGTATTTTTAGTAGAGACACGGTTTCACCATTTGGCCAGGTTGGTCT 
                 
                 
                     
                 
                 
                   CAAACCTCTGGTCTCAAGTGATCTGCCCGCCTCGGCCACCCGAACTGCTGGGATTACAGG 
                 
                 
                     
                 
                 
                   CATGAGCCACTGCGCCCCAGCTGATTCTTTACAGATAAACAAACATTGACTCTGCTTTGA 
                 
                 
                     
                 
                 
                   CATGTGCTTGGATCAGGTAACTGCACCAGCTGCCTTTCTCCTCCCACTTCTGCCTGGTCC 
                 
                 
                     
                 
                 
                   TCCGAATGCCTGCTTTTCTTATTTGAACTCTTCTGTCCTTTTCTGAAAACCTAACAGATG 
                 
                 
                     
                 
                 
                   CGAAACAGGCCATTTTCCATGTTGGTGGTTATTAAGCAAGACTTGAACATTTGTTTGTTG 
                 
                 
                     
                 
                 
                   CTTGTTTAGGCTTTTATTTCAGAGTTCACAGAATTAACTTTCTTTTTTTCTGATCTCTTC 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TGTGTAGGAATTCAGGGTCTTGCCGTTACTCATGTTTGCATACATGCATGCATTCGCTCA 
                 
                 
                     
                 
                 
                   CTCATTGATTCAGTAGCCATTTATTAGCTTCCTTCTATGTGCCAGGTACAGTTTAAGCAG 
                 
                 
                     
                 
                 
                   TACTGGTACATTGTGAACAAGGCAGGTAGTGTTCCTGCCCTCATCGAGCCTAGGGAGATA 
                 
                 
                     
                 
                 
                   GACAATTTAAAAACAAATAACTGGCCAGGCGCCGTGGCTCAGGCCTGTAATCCCAGCACT 
                 
                 
                     
                 
                 
                   TTGGGAGGCTGAGGTGGGTGGATCGCTTGAGCCGGGGAGTTCGAGACCAGCCCTGGGTGG 
                 
                 
                     
                 
                 
                   GAGACTGGGATAGGGTGACCTGAGTGGCTACAAGGTCTGTTAGGAGGCCTCCGCAGGGGC 
                 
                 
                     
                 
                 
                   CTATGTTGATGGCCTCCTCTCCAAGTATCCACAGACTTCAGCAGTTGTTCTTTTTTGTTC 
                 
                 
                     
                 
                 
                   CTTCCTTTGGAATGGAATATTATATAAAATGGCAGAATAAACTGGAAGAGAAGCAGTAGA 
                 
                 
                     
                 
                 
                   TGTGAGAGGTGCCGGGGGGTGAAGTCTGCAGGATGTGGGGATTGTTTGGCTTTTGGAGGA 
                 
                 
                     
                 
                 
                   GGAAGGAGGGATTCAAGACACATTGTAGAGGTTTGAGTCTGAGCGGACAGTGGTGCTGTG 
                 
                 
                     
                 
                 
                   GCAGACACCACAAAAGCTGGAAGGAGAACTGATGTGGGCAGTGATTTGTTTTCTTCTGGA 
                 
                 
                     
                 
                 
                   TGTGTTCAGCTGGGCATCTGAACAGTCATGTGGACATTCATCTATTCATTCAGAGATATT 
                 
                 
                     
                 
                 
                   TGTTCAATGACCTCTTGGTTCCTGGCACCATGCTGCTTGCTGGAGATAGAGCTGGGGAAC 
                 
                 
                     
                 
                 
                   AAAACAGATGGAATCCCTGCACTCCCAAGTGTACACTATACTGGCCAGTAATCTACCAGC 
                 
                 
                     
                 
                 
                   CCAGTAATTGCACATATAAATATATCATTATAAACTGTAATCAGGGCTAGAAAGAAAAAA 
                 
                 
                     
                 
                 
                   TGCAGGAGTTTAGGGTTCATTTGGAGGGGGAAGGGACTTTTTTTTTTTTTTTTTTGAAAC 
                 
                 
                     
                 
                 
                   AGAATCTTGTTCTGTCACCCAGACTGGAGTGCACTGGTGCATTCACGGCTCACTGCAGCC 
                 
                 
                     
                 
                 
                   ACAACCTCCTAAGCTCAAGTGATCCTCTCACCTCAGCCTCCCATGTAGCTGGGGGCTACA 
                 
                 
                     
                 
                 
                   GGTGTGTGCCACCATGCCCACCCAATTGTTAAATTTTTTATAGAGACGGTTGTCTCATTA 
                 
                 
                     
                 
                 
                   TGTTGCCCAGGCTGGTCTTGAACTCCTGGGCTTAAGCGATCCTGCTGCCACATGCAGCCT 
                 
                 
                     
                 
                 
                   CCCAAGGTGCTGGAATTACAGGCGTGAGCCAGCGCACCCGGCCAAGGGAGGGGAGGTTCT 
                 
                 
                     
                 
                 
                   TAAGGCATAGGGAACAATGTGTTTGAGTCAGCAAAGGAGGTTGTGGGGGTTTGTCCTAAG 
                 
                 
                     
                 
                 
                   TGTGGTAAGCAGCCAGAGTTGGATTTAAGTTTTTAAGAGATTCCCCTCCACCCTGTAGAG 
                 
                 
                     
                 
                 
                   ACTGGAGGGGGCAGGAGTTGTTCTAGGGATTAGGACCAATTTGGAGGTAGTGCAGCCGTC 
                 
                 
                     
                 
                 
                   AGAGTAAAAAATAATAGGGATTGAACTAGGCCAGTGCCCAGGGTGCCTGAAAGAAGAGGA 
                 
                 
                     
                 
                 
                   CCCAGTAGAGCTGACTGGAGGCAGACATGCAGGGATTCAGTGAAGGAGTGTACCAAGGGC 
                 
                 
                     
                 
                 
                   GAGGGTGGTGTGCAGGGTGACTGGCAATTTTCTAGCTTGAGAAAGGTCCGGGGGGATGGC 
                 
                 
                     
                 
                 
                   AGTGGAGTTGAGGAAGCTGGGAGGATCAAGGACCTTTTTGTGAACACACAAAGTTTGAGA 
                 
                 
                     
                 
                 
                   TGCCTTGGACACATTGAAGTGGAGCGGTCAGGGAGGCAAGGGTGGAGGTGGGATGCGGAG 
                 
                 
                     
                 
                 
                   GGGAGGTGGGATGCAGAGCGTCGTGGATGGATCAGTTTTGCTCGATAGAGGGACATGTTT 
                 
                 
                     
                 
                 
                   TTCTGTGGCAACAGGAGGGCAAAAGGAGAAGGTGGCCACAGATGCCGGTAGATGAGCTGA 
                 
                 
                     
                 
                 
                   GAGTGATTGTATTCCCTATCCTCTCGGAAGCTTGAGGCAAGGCCATCAACAGACAATCAG 
                 
                 
                     
                 
                 
                   AGGGAATAAGAAGAGATAGAATATATGAAGAAAGGGAGAAAAGATGAAATCGTAATTGTG 
                 
                 
                     
                 
                 
                   TAGCAGGGCAAGAAGTCCAGAAATTTCTGTGCTGTGCCAAGTTCCCAGTTGAGGCGGTGA 
                 
                 
                     
                 
                 
                   ACATGAAAATATACTGATACCCATTGCCTGGTTTTTCTCCAAGGACACTTGGCTCCTAGG 
                 
                 
                     
                 
                 
                   GCACAAAACAGAAAGTACGTGGTTTGTCCAGGCCGAGGGCTTTGCATAGTTGCAGTGGAT 
                 
                 
                     
                 
                 
                   GGAGAGGAGGTCAAGGAATGGAGGCACATGGTAGAGAGAGACTGTCCCCAGAGCACGGGG 
                 
                 
                     
                 
                 
                   ACTCCTGGCCGGATGAGGGGGACAGGGGCAGGAGGAGGCAGGTGGAAAGTAGAGGGAGGG 
                 
                 
                     
                 
                 
                   CTCAGTGGTCTGGAGGCTACAGGAAGTGACGGGGGGACCAGAAGGAGCTGGAAACCAGTG 
                 
                 
                     
                 
                 
                   TGGTTGTGGCCCAGGGTGGGATGTTTGGATTTCTGATGTCAGAGAGGGTCCAGTCCTTCT 
                 
                 
                     
                 
                 
                   GATGATGGGGAGGGGTGGAGGCTGAATCTATGGTAGAGATAGTGAGAGGAACTGGAACAA 
                 
                 
                     
                 
                 
                   TGTAGCTGTCAAGTGGAAATGGGAGAAAGGGCTGGGCGTGGTGGCTCACGCCTGTAATCC 
                 
                 
                     
                 
                 
                   CAGCATATTGGGAGGCTGAGGCAAGAGGATCGTGTTAGCTCAGGAGTTCTGGGCTGCATT 
                 
                 
                     
                 
                 
                   GAGCTGTGATTGTGCCACTGCACTCCAGCCTTGGCAACAGAGTGCCCAGTTAAAAATAAA 
                 
                 
                     
                 
                 
                   AATAAAATAAAATAAAAAAATTAAAAAAAAAAGAAGAAGAAAAAAGAGAAAAGTGTCCTT 
                 
                 
                     
                 
                 
                   TTACATCCCTTTTAAAAATGTCACTTAAGGCTGGGCAAAGTGGCTCATGCCTGTAATCCC 
                 
                 
                     
                 
                 
                   TGCACTTTGGGAGGCTGAAGTGGGTGGATTACTTGAGGTCAGGAGTACAAGACCAGCCTG 
                 
                 
                     
                 
                 
                   GCCAACATGGCGAAACTCCTTCTCTACTAAAATTAGCTGGATGTGGTACATGCCTGTAGT 
                 
                 
                     
                 
                 
                   CCCAGCTACTCGGGAGTCGAGTCTGAGGCCCAAGAATTGCTTGAATCGGGGAGGCGTAGG 
                 
                 
                     
                 
                 
                   TTGCAGTGAGCTGTGATCAGGTCACTGTGCACCAGCCTGGATGACAGAGTGAGACTCTGT 
                 
                 
                     
                 
                 
                   CTCAAAAAAAAAAGTCACTTAGCTTAGATTGTCTCTACATATATAGGAAGAAGATGTAGG 
                 
                 
                     
                 
                 
                   AATGAATGGTGCTGCTACAATTACGTCATCTGGATAGACCCAGAAACATGATACTTTTTG 
                 
                 
                     
                 
                 
                   GTTTTCTGTAGCCTTGGTGCCATTGTTGATCTTTATTAATTATCATTATCCTCAAAATAG 
                 
                 
                     
                 
                 
                   CCATAATGTGCTGAGTCTCTTCCTATTTGCTGGGCAGAGGCTGAGTATTTCAGCGAGCTC 
                 
                 
                     
                 
                 
                   ACTGAGTCCTTAAAATTGCATTATGATAGAGAGAAAGAGATTATTATTTGCATTTTGCAA 
                 
                 
                     
                 
                 
                   AATGAAGAAATTGAGGTTTAGAGATACCCAAGGGCCACGTGAGTGTGAGTGCCTGGAATT 
                 
                 
                     
                 
                 
                   GGAGCCTAAATCTAGTCATCTGATAGCAAAGCCTGTTTTCTTATCTGCTTTGCATTAAAT 
                 
                 
                     
                 
                 
                   ATAAGTTTAAAATAGAACAATACTGGCCAGGCTGGGTGGCTCACGCCTGTAATCCCAGCA 
                 
                 
                     
                 
                 
                   CTTTGGGAGGTCGAGGCAGGCAGATCACCTGAGGTCAGGAGTTTGCAACCAGCCTGGCCA 
                 
                 
                     
                 
                 
                   ATATGGCGAAAGAAACCCCATCGCTACTAAAAATACAAAAATTAGCCAGGCATGGTGATG 
                 
                 
                     
                 
                 
                   TGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCTTGAACCCGGGAG 
                 
                 
                     
                 
                 
                   GCAGAGGTTGCAGTGAGCCAAGATCACGCCACTGCACTCCAGCCTGGGCAACAGAGTAAG 
                 
                 
                     
                 
                 
                   ACTCTGTCTTGGAAAAAAAAAAAAAAAAGAATGATACTATAGTCTGTGTTTATATGGTGG 
                 
                 
                     
                 
                 
                   GGAAGGTTGAGTATCAAAAAAATAACAAAGAGGAATGAATGTCTTAAGTGAATGCCTGTT 
                 
                 
                     
                 
                 
                   TCCCCATCTGCTTCCTCTTCTGCTGGGAGGAGAGACCTGGATCCCTAGAGGTTTCAGTTG 
                 
                 
                     
                 
                 
                   CCTCCAGAGCTGAGTGCCACAGGGATGCAGGGGAATAGGGATGTTACCTGTCGCTGGTAA 
                 
                 
                     
                 
                 
                   TTCAGAGAGATGATTCAGGGTATAGTTACCTGAAAGAACAAATTGCCATGCCAGACGTCT 
                 
                 
                     
                 
                 
                   TGGTTCTTATGACAGAGGCAAAGAGTTGCCTCCAGGATTGCCCAAAAGGAGACGAGTTCT 
                 
                 
                     
                 
                 
                   GGGAACCTCACGAAGAGGACCTTTCAGTGGAACCTGGGGAGATTCTCTTCCTCTCCATTG 
                 
                 
                     
                 
                 
                   GATTTAGGAAAGCTTAGAACCGGGTGATTCCTCAACCTCTTGATTTATTTAATTCTTTTC 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   GTTTCTCCTTATTCTTCATGATGTTTGCTTTGTAGCTGTTGACTGCTTTGTAGGTATTGA 
                 
                 
                     
                 
                 
                   GGTGGTGGGGGTGTGGTGGAAATAGGCCTGACTCTTGAGGATCCCTTAAGTCATTTTTGC 
                 
                 
                     
                 
                 
                   TTGGTTCTCTTTTTCCTTCTTTTCTTCTACTCTTCTATGATTCATCTCTTTGATTGTGAT 
                 
                 
                     
                 
                 
                   TCTGTTCTCTCTCTCTCTCTCTCTTTTTTTTTTTTCGTTTTTGAGACAGAGTCTTGTTTT 
                 
                 
                     
                 
                 
                   GTTGCCCAGGCTAGAGTGCAGTGGTGCCATCTTGGCTCACTGCAACCTCCGCCTCCCGGG 
                 
                 
                     
                 
                 
                   TTCAGGCCATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGATTACAGGCATCTGACACTA 
                 
                 
                     
                 
                 
                   CGCCCGGCTAATTTTTGTATTTTAATAGAGACAAGGTTTTGTCATGTTGGCCAGGCTGGT 
                 
                 
                     
                 
                 
                   CTCGAACCCTTGACCTCAGGTGATCCACCTGCCTTGTCCTTCCAAAGTGCTGGGATTACA 
                 
                 
                     
                 
                 
                   GGTATGAGCTACCATGCCCGGCCCATTCTGTTCTCTTCTACCATAAATATATTTCTCCCC 
                 
                 
                     
                 
                 
                   TAACACTATATTTGTTTGCTTCACAAGATTCCAGCTGCTTTTCCACCAAGGCCTTTGATG 
                 
                 
                     
                 
                 
                   GAAGCTGTGCTGTGACCTCTGTAATGAGTCTGTGGGCTGCTGATTCTCCAGTTTGGGCTT 
                 
                 
                     
                 
                 
                   CATGATTATACTGGGGAATATTGGGTTTCCTAAATCTCATTCATTTCTTGGGCAAGTAGA 
                 
                 
                     
                 
                 
                   TATATGTGAAAGTGTTTATTTGTCCAGTTGTTAAAGAAGCTACCATTTATTGAGCCAGCC 
                 
                 
                     
                 
                 
                   TCTGAGCACAATGTTTTTTGTTTTGTTTTGTTTTTAATTTTTAAAATTATTTACTTCTTC 
                 
                 
                     
                 
                 
                   TATTTCAATAACTTTATTATTATTATTTTTTGAGACAGAGTCTCACTCTGTCACCCAGGC 
                 
                 
                     
                 
                 
                   TAGAGTGCAATTGAGCGATCTTAGCTCACTGCAACCTCTGCTTTCTGGGTTCAAGCAATT 
                 
                 
                     
                 
                 
                   CTCATGTCTCAGCCTCCCGAGTAGCTGGGATTACTGGTACGTGACAACATGCCTGGCTAA 
                 
                 
                     
                 
                 
                   TTTTTGTGTTTTTAGTAGAGACGAGGTTTTGCTATGTTGGCCAGGCTGGTCTGGAACTCC 
                 
                 
                     
                 
                 
                   TGGCCCCAAGTGATCCTCCTGCCTCGGCCTCCCAAAGTGCTGGTATTATAGGTGAGAGCC 
                 
                 
                     
                 
                 
                   ACTGCGCCCGGCCCTCTTTCAGTAATTTTGATGTATTTTTTTGTATATGATTCCTGTTTC 
                 
                 
                     
                 
                 
                   ATTCTGTCCAACCAGCACTCTGTATGGTATGTGCTGTTGTCCCCATTTCACAGATGCAGA 
                 
                 
                     
                 
                 
                   AATTAAGGGTCAGAGAGGTTAAGGGACTTACCTCAGGCACGTTGTACTGGAGAAGCTGAA 
                 
                 
                     
                 
                 
                   CTCCAAGAGCAGGTTTGGGCTGACTCCAAAGCCCTATGCTTTTTGCCAACATATTTTCAA 
                 
                 
                     
                 
                 
                   ACATAAATAGACAATTTTATAAATAGCTCCAAAGAGTAGACATTGTTTCTGTTGATATTA 
                 
                 
                     
                 
                 
                   ATGGCTTGGTTTTGAGTCTGAAACCCCCATGAATGATTCTGTTGTCCCTGCTTTTTGTCC 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TAGTTTATGGAAGGAAAGTGCTCACGAAAACAGTCTGGGGAAGAGAGGTTGAATGGGAAA 
                 
                 
                     
                 
                 
                   ATTCTTTCACAAAAATCTGGGCTGAAGACTTCAGTGTGTCTGCCTGAGAACAGAAGTGAC 
                 
                 
                     
                 
                 
                   ACTATTTGAGCTTTTGGCATAAAATGAAGTCTAGGAGCTGCAGAACCCACTGCCATGGCC 
                 
                 
                     
                 
                 
                   TTTTGTTGCATACACAGTGGTGGTCTCTATCCAGCCACCTGACCTTGTTTACAGTATGGG 
                 
                 
                     
                 
                 
                   GTGATTTGTTGGCAAGTGAGGGAATCCTGACTTCTGCCACTTCGTTATTTATGTAGTCTT 
                 
                 
                     
                 
                 
                   CTGGGATCATTGGTATTGGTCAGAAGTTCAACACTGTAGCCATTGCAACATGCTCAGTTA 
                 
                 
                     
                 
                 
                   AAACAGCAAAGACTAAATTAGCATTGTCTCTGAGTCCACTAAAAGTTGTGCATTAAACAA 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   CTCTTGCTAGGCCTCTTGGATACGCTCTCCTTTTGAGCAGGAGGACAGGCTCTGATAGAC 
                 
                 
                     
                 
                 
                   AACTGTTTGATTTCGGAATGGGAAACAAACTCCCAACTAAAAGGGCCTCTGGAAACTGTC 
                 
                 
                     
                 
                 
                   AATTATTCTCCACTTCTCAGCTCTGATTTTTCACTGCAGAGGAGCTTAGGGAAGGGCACC 
                 
                 
                     
                 
                 
                   ATCCTATCAGCCTGGCCTGCCAGATTGAAGAACTGCCATGCAGAAAGGTTCTGATGTTCT 
                 
                 
                     
                 
                 
                   CAGGCTCATGTGGCAAGCGTAAAACTCAAAGCCTTGAAGTTTCTAGCCTGTTCCAGCCTT 
                 
                 
                     
                 
                 
                   GATCCAGGCCATGTTTATCCTGATTCCATCCTTTAAAACGAATGCCTCACTCTTAATAGC 
                 
                 
                     
                 
                 
                   GCACGGCAGTTTGAACCACTAATTTGGTCGAGTTGGAAACAGTGAAATTTCAATTTTAAT 
                 
                 
                     
                 
                 
                   AAGCTGTGCATAATGAAGAGGAATGTGGAATTGGAGCCTTTCCATCTGAAGCTATTCATA 
                 
                 
                     
                 
                 
                   ACAGGCACAAAGCTGAGTTAATTAGGAATATGCTGAGATGAAGGAAATGAGGAGAGCTGC 
                 
                 
                     
                 
                 
                   TCTTTTGGGGGCTGTGCTTCTCTCCCCAACCCCTCAACCCCATTGCCATGCTGCAGATGG 
                 
                 
                     
                 
                 
                   GGTGGTGTCTAAACATCAGTGGCGAGTGCCTGCATTACTCTGCTCGTTGCCTTCCAGAGA 
                 
                 
                     
                 
                 
                   ACTCAGCTTCTCCAAATGCTGAGCTCTTTTCAGAATGGGACCTGCCACCAGTATTTGAAA 
                 
                 
                     
                 
                 
                   GATTTCTAGCCTAGCAGAACAGCAGCCACGTTATCAAAGTTTGGTTGGCCAAAGGAAGGT 
                 
                 
                     
                 
                 
                   ACTTGCTAATTAGTTTAGTAGGTTTTCAGTCCGCACAGACATACGGGATTGTTTTATTGT 
                 
                 
                     
                 
                 
                   ACATAGACATCTTCAGAAACAGTGTATGTATAGAAATGTAAGGTCAAAATTTGAACCTCA 
                 
                 
                     
                 
                 
                   GTGCTTTAAATCTGAATTTGTATTAACTGATATGAAATATTTAGACGGTTACTTTATTTT 
                 
                 
                     
                 
                 
                   ATATCTGTCTTCCATTATACTTAATTTGGCTCAAGAATAGTTAGGCAAAAAGTTGCCCAA 
                 
                 
                     
                 
                 
                   AGAGAAGGATCTCCTAGTAAATACAAAGAGAATGTAACATAGTTGCTACAAGTTGGAGCA 
                 
                 
                     
                 
                 
                   TGTTCAGGGATGTCTTTTTTTTTTTTTTTTTTTGAGAGAGAGGTCTCTCTCTGTTGCCCA 
                 
                 
                     
                 
                 
                   GGCTGGAGTGCAGTGGTGTAATCATGGCTCACTGCAGCCTCAATCTCCCAGGCTTAAGCG 
                 
                 
                     
                 
                 
                   ATCCTCCCACCTCAGCCTCCCAAGTAGCTGGGACTATAGGCATGCGCCACCACACCTAGC 
                 
                 
                     
                 
                 
                   TAATTTTCGCATTTTTTGTAGTGTCACAGTTTCGCCATGTTGCCCAGGCTAGTCTCGAAT 
                 
                 
                     
                 
                 
                   TCCTAGGCTCAAGCAGTGCTTCTGCCTCAGCCTCTCTGAGTAGTTAGGACTACAAATTTG 
                 
                 
                     
                 
                 
                   TGGCTCCATGCCCGGCTAATTTTTTTATCTTTATTTTGTAGAGACAAGGTCTCACTGTGT 
                 
                 
                     
                 
                 
                   TGCCCAGGCTAGTCTTGAACTCCTGGGCTCAAACAACCCTCCCACTTTGGGTTTCCAAAG 
                 
                 
                     
                 
                 
                   TGCTGGGATTACAAGTGTGAGCCACTGAGCCCAGTGACCTCTGGGTTTTAAAAATGTGTA 
                 
                 
                     
                 
                 
                   GGCTTCAATTATTTATTTTAAAAAATGAAATCCTGCAATATATAGTTTTCTGCGTTGTGT 
                 
                 
                     
                 
                 
                   GGTTTGAATCAATCTGGGAACTGGCTTGCTGGCTGATTGTGGTAAAGTAAGAAGTACTTA 
                 
                 
                     
                 
                 
                   ATTTAGTAGAAAGTTTAAATGGCAGACATAACATTAAACCCAGCTGATTTATAAATGAAG 
                 
                 
                     
                 
                 
                   CAAAAGAACAAAACTCATTCAGGATAATTGGTTATTCTAAAATACAGTCATTTCTAAAAT 
                 
                 
                     
                 
                 
                   TATGAAGTGTTCAGGACCTTTGGGAGTGAAAGAATTTGCTAAAGAAGGATCAGTGAAAAA 
                 
                 
                     
                 
                 
                   AAGGAATGATGGGTGAAGAGCTGTGGAGAAGGAAGAGAAGAAACAGCACAAGGAAGGAAG 
                 
                 
                     
                 
                 
                   AATATAAAATCAGATGTGGGAATCCAGGGGAAAGTGCAAACGAAGCAAGATTGAGAAAAT 
                 
                 
                     
                 
                 
                   TCTCAAGTTTTTATAAACAGTTCTCACACTCTGCCAGTTCCTTGGAGGTAGACTTTTTTG 
                 
                 
                     
                 
                 
                   TTAACTTCCAACTACAGTAGTGAAAAAAAAAAAAAAACCCTCAAATTTGCAAAAGCAGTC 
                 
                 
                     
                 
                 
                   TGTGGAATTTTCTTTACCCAGCTTTCCTGACTGTTAACTTTTTAGCACACTTAACTTTAT 
                 
                 
                     
                 
                 
                   CATTCGTTTATTCTCTCTGTTTAAAATTAAAAATGTAAATTTTAAAAAGTAAAATGTTTG 
                 
                 
                     
                 
                 
                   TTGGTTACAAACATTTATACCCCTTTGTCTCTAAATATCATTTCATTTTAAAAAATGAAT 
                 
                 
                     
                 
                 
                   AATCTAAGCCTACACATTCTAAAATGTGTATATTTTCTAAAAATAAGGGCATTCTCTTAC 
                 
                 
                     
                 
                 
                   ATAACCAATGTCACAATTATTTGATACAGTGATCAAAATCAGGAAACTAACATTGATATA 
                 
                 
                     
                 
                 
                   ACACTATTATCTAACCTACAGACCATCTTCAAATTTTGTCCTGCTAGTATCTTTTATGGG 
                 
                 
                     
                 
                 
                   TCCAGGGTCACACAGTGCATTTGGCTATAATGTATCTTTTTTCTCTTTTTTTGAGACAGG 
                 
                 
                     
                 
                 
                   GTCTCACTTTGTTGCCCAGGTTGGAGTGCAGTGGTGCAATTATGGCTCACGGCAGCCTTG 
                 
                 
                     
                 
                 
                   ACCTCCTTGGGCTCAGGTGATCCTCCCACCTCAGCCTCTCGAGTAGCTGGAGACCACAGG 
                 
                 
                     
                 
                 
                   TGTGCACCACCATGCCTGGCTAAGTTTTGTATTTTTTGTAGAGATGGAGCTTCGCCGTGT 
                 
                 
                     
                 
                 
                   TGCCCCGGCTGGCCTTGAACTCCTGGGCTCAAGTGACCCTCCCGCCTTGGCCTCCCAAAG 
                 
                 
                     
                 
                 
                   TGCTGGGATTACAGGCGTGAGTCACCACACCTGGCCAGTTATTAGTATGTTTAGTCTCTT 
                 
                 
                     
                 
                 
                   TAATCTGGAACAGTTTCTCAGTCATTCTTTATTTTTCATGACCTGGATGTTTTTGAAGAG 
                 
                 
                     
                 
                 
                   TTTAGGCCAGCTATTTAGCAGAATGCCTTTCAGTTTGGATTTGTCCAGTGTTTTCTCTTG 
                 
                 
                     
                 
                 
                   ACTATATTCTAGTCATGCATTTTTGGCAGGACTGTCACAGAAATGTTGTTGTAGTCTTCT 
                 
                 
                     
                 
                 
                   TAGTACATCACATCAGGTACACACTGTTGATCTGATTCATTACTAGTGGTGTTAACTTTG 
                 
                 
                     
                 
                 
                   ATCACTTGAATAAGGTGGTGTCTGTCAAATTTGTCCACCGTAAAGTTACTTGAGCAAAAC 
                 
                 
                     
                 
                 
                   GTAGCTGGGACTACAGGCGTAGCAAAAAATGTAGCAAAAAGTAGTATTTTTGCTACATTT 
                 
                 
                     
                 
                 
                   TTTTTTTAGGAACAAAGTATTTTTCCCTTTTAAGTTAATCTCTTGTCCATAAAGTTATTA 
                 
                 
                     
                 
                 
                   TTTTTCCCTTTTAAGTTAATATCTTGTGGGTAGATACTGGAGACTGCGTAAATTACCTAT 
                 
                 
                     
                 
                 
                   TTCTCATAATACTTTTTTTTTTTTTGAGATGGAGTCTCGCACCGTCTCCCAGGCTGGAGT 
                 
                 
                     
                 
                 
                   GCAGTGGTGCAATCTCGGGTCACTGCAAGCTCCACCTCCCGGGTTGACGCCATTCTCCTG 
                 
                 
                     
                 
                 
                   CCTCAGCCTCCCAAGTAGTTGGGACTACAGGCGCCCGCCATCACACCTGGCTAATTTTTT 
                 
                 
                     
                 
                 
                   GTATTTTTAGTAGAGACGGGGTCTCACCGTGTTAGCCAGGATGGTCTTGATCTCCTGACC 
                 
                 
                     
                 
                 
                   TTGTGATCTGCCCGCCTTGGCCTCCCAAAGTGCTGGGATTACAGATGTGAGTCACTGCGC 
                 
                 
                     
                 
                 
                   CCGGCTCTCATAATACTTTTTGCCTACTAATTTTATATTCATTGATTAAATTCTTGCCTG 
                 
                 
                     
                 
                 
                   AAAAAATTATTACTGTGGTATTTGCCAAATGGCAATTTTCTGTTTCCATCATTGCCTTTC 
                 
                 
                     
                 
                 
                   CCCCGCTTTTAAAAGTATAAGTGACAAAGAAAAACTGTATATAAAGTGTACACCATGATA 
                 
                 
                     
                 
                 
                   TTTTGATATATGTATACTTTGTGAAATGATTATCAAAATTGAGTTAAATAATGCATCCAA 
                 
                 
                     
                 
                 
                   CATCTCAGTTACTTTTTTTTTTTTTTGAGACAGAGTCTTGGTTTGTCACTAAGGCTGGAG 
                 
                 
                     
                 
                 
                   TGCAGTGCCACAATCTCGGCTCATTACAACCTCCACCTCCCAGGTTCAAGTGATTCTCCT 
                 
                 
                     
                 
                 
                   GCCTTGGCCTCCCCAGTAGCTGGGATTACAGGTGCCCACCATCACACCCGGCTAATTTTT 
                 
                 
                     
                 
                 
                   GTATTTTTAGTAGAGGTGGGGTTTCACTACGTTGGCCAGGCTGGTCTCGAACTCCTGACC 
                 
                 
                     
                 
                 
                   TCAAATGATCCTCCCGTCTCAGCTTTCCAAAGTGGTGGGATTACAGGCGTGAGCCACTGT 
                 
                 
                     
                 
                 
                   GCCCGGCCACTCTTAGTAAATTTTAAGTGTACATTTTTTTTTTTTTTTTTTTGAGATGGA 
                 
                 
                     
                 
                 
                   GTCTCACTTTGTCACCCTGGCTGGAGTGCAGTGGCATGATCTTGCCACACTGGAACCTCT 
                 
                 
                     
                 
                 
                   GCCTCCTGGGTTCATTCAGGTGCTTCTCCCACCTCAGCCTCCCAAGTAGCTGAGACTACA 
                 
                 
                     
                 
                 
                   GGTACCCGCCACCATGCCTGGCTAATTATTGTATTTTTAGTAGAGATGGGGGTTCACCAT 
                 
                 
                     
                 
                 
                   GTTAGCCAGGCTGGCCTCAAACTCCTGACCTCAGGTGATCTACCCACCTCGGCCTCCCAA 
                 
                 
                     
                 
                 
                   AGTACTGAGATTACAGGCATGAGCCACCACACCCAGCCACATTACGTTAGTATTAACTAT 
                 
                 
                     
                 
                 
                   AATCACCATGCTGTACATTAGATCTCCAAAATGTATTCATCTTATGTAACTTCAAGTTTG 
                 
                 
                     
                 
                 
                   TACCCTTTGACCAAAGTCTCCTTGTTTTCCCTACCCCCAACCCCTGGTAATCACTGCTTT 
                 
                 
                     
                 
                 
                   AATCTCAGTTTTTATGAGTTTGACTGGTTTAGATTCCACATACAAATGAGATCAGGCAGT 
                 
                 
                     
                 
                 
                   GATGGTTTATTTCACTTAGCATAATGTCATCCATGTTCTTGCAAATGACAGGATTTTCTT 
                 
                 
                     
                 
                 
                   CTTTTTAAAACTAATATCCATGCTGGACACGGTGGCTCATGCCTGTAATCCCAGCACTTT 
                 
                 
                     
                 
                 
                   GGAAGGCTGAGGAGGGTGGATCACTTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACAT 
                 
                 
                     
                 
                 
                   GGTGAAACCCCATCTCTACCAAAAATATAAAAAATTAGCTGGATGTGGTGGCGCACACCT 
                 
                 
                     
                 
                 
                   GTGATCCCAGCTACTTGGGACACTGAGGCAGGAGGATCGCTTGAACCCGGGAGGCGGAGG 
                 
                 
                     
                 
                 
                   TTGCAGTGAGCCAAGATGGTGCCACTGCACTTTAGCCTGGATGTTGATGTTGTTCCACTT 
                 
                 
                     
                 
                 
                   GTTTATTTTTATTTTGTTCCCTGTGCTTTTGGTATCAAATCCTAAAAACCATTGCCATGA 
                 
                 
                     
                 
                 
                   CCATTGTCATGTTACTTTCCCCATATGCTTTCTTCTAGAACTTTTAAGGTTCATCATTCC 
                 
                 
                     
                 
                 
                   CTTTTCTGTTTTTAGTTGCAAGCCTACTATAAGGAAGGGCTTTTCTTTCTTCCTTATTTA 
                 
                 
                     
                 
                 
                   TTTATTCATGTCTATCAGAATGGGCACCTTACTACTATTTTTGTTGTTATTGCTTGAATT 
                 
                 
                     
                 
                 
                   GACTTGAATTTGGCTAGTGGAAACCTTTTCAGATCGGGTACTCTGTCCTTTTGATCTCTT 
                 
                 
                     
                 
                 
                   TCCATTTTCAAGCACTTCTTTAGACTTAAGATGGTCTAGGCTCATCTTCTCCTTTCCCAG 
                 
                 
                     
                 
                 
                   CCATTTTTCAAAGGAACCTGATTCCTTTTAGTGAAGAGCAGTATTTTGAAACCAAGATCT 
                 
                 
                     
                 
                 
                   GGGCACTGGGTCTACTTGTTTGTACTGGTACAGTGTTCTTTGAATTGCTAATTAGCTGAT 
                 
                 
                     
                 
                 
                   CAATTACTGCTCTATTTGAGTTCCCTCTTTCTAAAACCTCACATATGTGTACAGACGGTC 
                 
                 
                     
                 
                 
                   CCTGACTTATGATGGTTCGACTTATGATTTTTGATTTTATGATGGTTTGAGAGCAATACA 
                 
                 
                     
                 
                 
                   TCCATTCTGTTTTTCACTTTTCATTCAACACTTTATTTTAAAATAGGGATTGTGAGATGA 
                 
                 
                     
                 
                 
                   TATTGCCCACGTGTAGGCTAATGTAAGTGTTCTGAGCACGTTTAAAGTAGGCTAGGCTAA 
                 
                 
                     
                 
                 
                   GCTGTGGTGTTTGGTAGGTTAGATATGTTAAATGCATTTTCGACTAGTGATATTTTCAAC 
                 
                 
                     
                 
                 
                   TTATGATGAGTTTATTGGGATGTATCCCCATAAAGTCGAGGAGCATTATACATATCTCTG 
                 
                 
                     
                 
                 
                   TATAACAGAGTGAGTTCCTTATACCTTTCATCCACTTTCCCCTGAAGTTAACATTTTACC 
                 
                 
                     
                 
                 
                   TAACCATGATACATTTATCAAAACTAAAACATTAACATCAATACATTGCTATTAACTAAA 
                 
                 
                     
                 
                 
                   CTAGAGTTTAATTGGATTTTGCCAGTTTTCCAATGAATATCCTTTTTCTGTTCCTTGATC 
                 
                 
                     
                 
                 
                   CAATTCATGGTCACACACTGAGTTTGGTCACTTGTCACTGTAGTCTTCTCCAATCTGCGA 
                 
                 
                     
                 
                 
                   CAGCTTCTTAGGCTTTCCTTGTTTTTCATGTACTCTTGACGATTTTTAAGAGTACTGGTC 
                 
                 
                     
                 
                 
                   AGATATCTTGTAGGATATCCCACAACTTGTGTTTAATCTTATGTTTTCTCATGATTAGAC 
                 
                 
                     
                 
                 
                   TTGAGTAATGGATTTTTGGGAAGAATACCACAGAGGTATATTGTTAAGTGTTCTCATCAC 
                 
                 
                     
                 
                 
                   TTGGAGGTAAATGTTATCAACATGGCCTGGTGATGTTAAACTTGTCAGTTTGTTTAGTTA 
                 
                 
                     
                 
                 
                   GTATCTGCCAGATTTTTCTCACTGCATAATTACAAATCCTCCTTAACTTATGATGGGGTT 
                 
                 
                     
                 
                 
                   ACAGCCTGATAAGCCCATCATAAATTGAAAATATCATAAGTCAAAAATGCATTTAAGCA 
                 
                 
                     
                 
                 
                   TCTAAACTACTAAACATCACAGCTTAGCCTAGCCTGCCTTGAACGTATTCAGGACACTTA 
                 
                 
                     
                 
                 
                   CATTAGCCTACAGTTGGGCAAAATCATCTCATGGGAAGCCTGTTTTATAATGTGTTGCAT 
                 
                 
                     
                 
                 
                   ATCTTATGTAATGTGTTGAGTACTGTACTCAGAATGAAAAACAGAAGGGTTGTATTGCTT 
                 
                 
                     
                 
                 
                   TTGCACCATCATAAAATCAAAAAAACCATAAGGCAAACCATCATGAAGTTGGGGACTGCC 
                 
                 
                     
                 
                 
                   TGTACTTTTTTCCTCTTTCCCTGTTCAATTCCTTGGAAGAAAGTCATTTAGTTCAGACCA 
                 
                 
                     
                 
                 
                   TACTCAAGAAAAGGGAAATAAAGCTCCATCTCTTGGAGCTTAATTGAAACTGGAATGACT 
                 
                 
                     
                 
                 
                   AGTTTCTATATACATTATTTAGAATCCTTTTGTAAGAAAGATTTGTTCCTTCTCTCCATT 
                 
                 
                     
                 
                 
                   TATTTATTCCATTATTTATATTGATAGAGACGCATGTACATTTATTTTATACTTTGGGTT 
                 
                 
                     
                 
                 
                   ATAATCTATTTTTCTTGCTCAAATTGTTACAGCTTTGGTCACTGGGAGGTTCTTCAGATT 
                 
                 
                     
                 
                 
                   GGCTCCTGTGTCATTTGACATGTCCCCACCCTCTCGTTTCTGAGTACTTCTCTACTTTGG 
                 
                 
                     
                 
                 
                   CATTACAAAAGATGTTCCAGGCTCCTCTTATATTTTTCCCTGCCGCAGCCCTAGAATCAT 
                 
                 
                     
                 
                 
                   CCATTTTTCTATGGTGCCCTGGTTCCTTTTACTTTAGATGGGGGTTTAGAAACCAATCTG 
                 
                 
                     
                 
                 
                   GGTGTTGGGTGTGCTCATTGCTACTGGAATCACTGCTTCTAGGCCCTCTCAGCAGATAGA 
                 
                 
                     
                 
                 
                   GCTAGAAAACATATGGCTGTATATGAATCCATGGATTCATATATATCTATAATTGTTTTC 
                 
                 
                     
                 
                 
                   TGTATCTGGCCATCTATATATATATTAAGCTAAACATGAATTCATACTGATGTCTCAGAC 
                 
                 
                     
                 
                 
                   TCGAATCCATTGCCGCAGGGCTCATTCTTGCCTTCCTCTTGCTTATTTGTGACTTCTTTC 
                 
                 
                     
                 
                 
                   TCTAACAGGGAGAAACCCCAGTCTCATTATCACCAACCTATCTACTCATTTGTTCAACCC 
                 
                 
                     
                 
                 
                   TGGTATAGGTGTAAAGTAGTTTCAGAATTACTAACCTATACCCATGTGAGAATTGTATTT 
                 
                 
                     
                 
                 
                   GCACTTCTTGTTTGAAGGAAATACATACAACACAGGTAGCGTCTCTACACTTCAGTATAC 
                 
                 
                     
                 
                 
                   AGAGATCTGAACAGTGTTCTCTCTGAGTGAATCATATTGCAGGACAGAAATTACTTTTAA 
                 
                 
                     
                 
                 
                   AAATTCTGTAATGGGTCAGGCCTATAATCCTAGCACTTTGGGAGGCTGAGGTGGGCAGAT 
                 
                 
                     
                 
                 
                   CACCTGAGGTCAGGAGTTCGAGACCAGCCTGGCCAAAATGGTAAAACCCCATCTCTACAA 
                 
                 
                     
                 
                 
                   AAAATACAAAAATTAGCCAGGCGTAGTGGTGTGTGCCTGTAATCCCAGCTACTCAGGAGG 
                 
                 
                     
                 
                 
                   CTGAGGCACGAGAATCACTTGAACCTGGGAGGCAGAGCTTGCAGTGAGCTGAGATTGAGC 
                 
                 
                     
                 
                 
                   CACTGCACTCCAGTCTGGGCGACAGAGCGAGACTCTGTCTCAAAAAAAAAAAAAAAAAAA 
                 
                 
                     
                 
                 
                   AATTCCATAATGATAGCAGAGCTGGAATAGAAATGGGATTGCACAGGCTGAATCTGAGTT 
                 
                 
                     
                 
                 
                   GTTGCAACAGTAAACGAGCAAGATTTAAACTGGCCTTGTGTAGCACTTGCTATTTGGCTC 
                 
                 
                     
                 
                 
                   CTCATATTTTATTAGACGCTTATTCTTTTTTGTTTGGTGTCATTCCTTTGAGAAATATTT 
                 
                 
                     
                 
                 
                   GAGTGCCTTTTCTGTTGCAGACATTGATTAGATGCTGAGGTTGTAACAATGAAGAAGATA 
                 
                 
                     
                 
                 
                   GCCATCGCTGTTGCCTCATGGAACTGAAGTTTTACTAGATGTAAAATTTGAGTTAACATG 
                 
                 
                     
                 
                 
                   AGGCCGTGCCCCTATGTGCCCTATTGTTTCTTCACACAGCTCCCTTCATCTCCTTGGTCC 
                 
                 
                     
                 
                 
                   AATGAAAAGGTTTTTTCATACTTGTTCATTCATTCCTGCATTAATTAAAGTAGGTTGTAC 
                 
                 
                     
                 
                 
                   TGTGCCAGGCACTGGGAATATTTAAGTAGTTGTGTTCCTGAATTGGAAATGAATCCAGCA 
                 
                 
                     
                 
                 
                   TGGTTGGAGTAGAAGGAGCTGGGGGGCAATGTGGAGTGTGATGGGGAGATTGGAAAAGTA 
                 
                 
                     
                 
                 
                   AGCTGAGACCAGATTTTTCAGTTTGGAGGGAGAGGTGGGCCTTGTAGGCCATATTACAGA 
                 
                 
                     
                 
                 
                   TTGTAGACTTTATTTGGAGGGACATGGAAGTCATTGAGGAGTCTGAAGCAGGGGAATGAC 
                 
                 
                     
                 
                 
                   ATAAAAAGATCCTCATTTTAGGCCGGATGTGGTGGCTCACGCCTGTAATCCCAGCACTTT 
                 
                 
                     
                 
                 
                   GGGAGGTTGAAGTGGGTGGATTGCTTGAGGCCAAGAGTTTGAGACTAGCCTGGGCAACAT 
                 
                 
                     
                 
                 
                   GGTGAAACCCTGTCTCTATCAAAAATACAAAAATTAGCTGGGCATGGTGGCTCACACCTG 
                 
                 
                     
                 
                 
                   TAGTCCCAGCTACTTGGGAGGCTGAGGCATGAGAATCGCTTGAACCCGGGAGGCAGAGAT 
                 
                 
                     
                 
                 
                   TGCAGTGAGCCGAGATTGTGCCACTGCATTCCAGCCTGGGTGACAGAGTGAGACTTCGTG 
                 
                 
                     
                 
                 
                   TCAAAAAAAAAACAAAAAACCCCTCATTTTGAAAGGGAACCCTGGCTTGAGGGTGAAGAA 
                 
                 
                     
                 
                 
                   TGGGTGGGCACTAGGCTAGAGCAGCTGCAGGGTCAGTGAGGAGCTGCCGCAGTGCTGCAC 
                 
                 
                     
                 
                 
                   GTGAGAACCCGTCATGGTTTGGTCAGGGTGGGCAGGACTGACAGTGAGCACAGAGCGAAG 
                 
                 
                     
                 
                 
                   TAAAACCAGCAAAATTTCATGATTGGATAGTGGAAGGAATCATGGTGTTTGTAGTCTTCA 
                 
                 
                     
                 
                 
                   AATGTGAACCCAGAGTGCACTGGACAAGTAGTCTAGGCTGCTCTGTAACCAAGGCAAGTG 
                 
                 
                     
                 
                 
                   TTTTCATTTTACCCTCTCTTCCTGCTCTTGGCCTTTGGATTTTTTGTAATTTAAGGTTTA 
                 
                 
                     
                 
                 
                   TGAATGTAATCAGTTACTTAACATGGAAAGATACTTAATACCAGATGATTTTGGAGTCTT 
                 
                 
                     
                 
                 
                   GTGATCAATACCTTCTCTCAATCTTGGGTGTGTGTCAGTTGGCAAGGCCATAAAATTTGT 
                 
                 
                     
                 
                 
                   TATAAACATTGCAGAAGGCTTGGTTACTGTGCTGTGACGTTGAATTTGGGTGGAGATAGA 
                 
                 
                     
                 
                 
                   TCAATTTCAGTTGATTTTCTAGGCTTCAGAAACACATTACCCTCTACTCCACAAACACAA 
                 
                 
                     
                 
                 
                   ATCAAAACAAAACAATCCCTATTCCCTGAGCATTTCTCTTGATCTATAACACAGCCTGGG 
                 
                 
                     
                 
                 
                   CTGTCACAGTACTAAGACAAGCCCATCTGATTTGTGAGTCAGTTTTATTTCTTGGTCTTC 
                 
                 
                     
                 
                 
                   TACATAAGCTAAAAAGTTTCAACATTTTAATGCTTTTCCTTGGATTCCTTTGAGTCATTG 
                 
                 
                     
                 
                 
                   AAGTAATTCCTGTTTCATTTGTACTAATTATTCCACACTAGAAAATTCTGTTGTAATCAC 
                 
                 
                     
                 
                 
                   TTTATGTATTAATAGAAATACTGATTTTTATTTTCAAGGAAGTATTGAGTAGGGAGGGGG 
                 
                 
                     
                 
                 
                   AAATAGGGATTTGCTGTTCAATGGGTATAGAGTTTCAGTAATACAAGACAAAAAACTTCA 
                 
                 
                     
                 
                 
                   GAGATCTTCTATACAGCAGTGGGTATATAGTTAACAATACTGCACATCTAACAGTTTGTT 
                 
                 
                     
                 
                 
                   AAGAGGGTAGATCTCATGTCATGTGTTTTTAAAAATTGCTTTTAAAAAAAGTATCGAGTA 
                 
                 
                     
                 
                 
                   AAAAAGCAGTTTTACTCCTCAGTTTCTATTTATATTTAAAATTTTTATTTAAAAAGTGAG 
                 
                 
                     
                 
                 
                   TTGAGATTTTTAAACCTCAGGATAAGTTTTATTTTTTAAAAAATTTATTTTTTATTATTT 
                 
                 
                     
                 
                 
                   TTTGAGATGGAGTCTCACTCCATCTCAAGTCACCCAGGCTGGAGTGCAGTGGTGTCTTGG 
                 
                 
                     
                 
                 
                   CTCACTGCGACCTCTATCTCCCAGGTTCAAGTGTTTCTGCTGCTTCAGCCTCCTGAGTAG 
                 
                 
                     
                 
                 
                   CTGGGATTACAGGTCTGCACCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGATGG 
                 
                 
                     
                 
                 
                   GGTGTCACCATGTTGGCCAGGTTTGTCTTGAACTCCTAACCTCAAGTGACCACCTGCCTT 
                 
                 
                     
                 
                 
                   GGCCTCTCAAAGTGCTGGGATTACAGGTATGAGCCACAGTGCCCGGCGGGATAAGTTTTA 
                 
                 
                     
                 
                 
                   AAATAATATTCTCTGCTGGCTGGGCATGGTGGCTCATGCCTGTAAACCCAGCACTTTGGG 
                 
                 
                     
                 
                 
                   AGGCTGAGGCAGGAGCATCACTCGAGGCCAAGAGTTTGAGACCAGTCTGGGCAACATAAT 
                 
                 
                     
                 
                 
                   GAGACCCCCTCTCTACAAAAAATAAAAAAAATTTGGCTGAGTGTGGCATGTTCCTGTAGC 
                 
                 
                     
                 
                 
                   TATCGGGAGGCTGAGATGGGAGGATTGCTTGAGCCCAGGAGTTTGAGGCTGCAGTGAGCT 
                 
                 
                     
                 
                 
                   ATGATTGCACCACTGCGCTCTAGTCTGGGTGACAGTGTGAGACCCTGTCTCTTAAAAAAA 
                 
                 
                     
                 
                 
                   AAAAAAAAAAAGGCCAGGCACAGTGGCTCAGGCCTGTAACCCCAGCACTTTGGGAGGCCG 
                 
                 
                     
                 
                 
                   AGGCGGGTGGATCACTTGAGGCCAGGAATTTGAGACCAGGCTGGCCAACATGATGAAACC 
                 
                 
                     
                 
                 
                   CCGTCTCTACTAAAAATACAAAAATAAGCTGGGTGTTGTGGTGCACACCTGTAATCCCAG 
                 
                 
                     
                 
                 
                   CTACTTGGGAGGCTGAGGGAGAGAATTGCTTGAACCTGGGAGGCAGAGGCTACAGTGAGC 
                 
                 
                     
                 
                 
                   CGAGATCACACCACTGCACTCCAGCCTGGGTGACAGAGCAAGACTCCATCTCAAAAACAA 
                 
                 
                     
                 
                 
                   CAACAACAAAAAAACCAAATGTTCTTGCCAATTCTTCCATTTAATATTTAATTTTGAATT 
                 
                 
                     
                 
                 
                   ATATTGTATCTTTCTAAGGATTGTTTCTTATATAAGCAAAGATTTTTCAGTGCTAAACAT 
                 
                 
                     
                 
                 
                   TTACGACTGCTATTCAGAAATGGTTATTTACAAGTCTTTTTGTTTTAAGAAAATGGCTGT 
                 
                 
                     
                 
                 
                   TCAAAAAATTAAAATAGTATATAAACCAAACAAAATATTTTTGCTTTGGATGTCTGTTTT 
                 
                 
                     
                 
                 
                   GCAGCTTCTTCCCTACACTATAAGTTCTTACTGACTGCTTTATCACTTAATAAATTGGTT 
                 
                 
                     
                 
                 
                   TGGCTACTTTAACAGAGGCAAATAGTATCAGGCAAAAAATTATTTTTTATTTTTATTTTT 
                 
                 
                     
                 
                 
                   TGAGACAGTCTCACTCCATCACCCAGGCTGCAGTGCAGTGGCCTGATCTTGGCTCACTGC 
                 
                 
                     
                 
                 
                   AACCTCCACCTCCCAGGTTCAAGCGATTCTCATGCCTCAGCCTCCTGAGTAGCTGGAATT 
                 
                 
                     
                 
                 
                   ATAGGCATGCACCACCACACTCAGCTAATTTTTGTATTTTTAGTAGAGACAGGGTTTTGC 
                 
                 
                     
                 
                 
                   CATGTTGACCAGGCTAGTCTTGAACTCCTGACCTCAAGTGATCCATCTGCTTTGGCCTCC 
                 
                 
                     
                 
                 
                   CAAAGTGCTGGGATAACAGGCATGAGCCACCATGCCCAGCCCTATTTTTTATTTTTTAGA 
                 
                 
                     
                 
                 
                   GATGGGTCTCGCTTTTTAGAGATGGGTCTTGTTGCCCAGGCCAGAGTGCAGTGGTGCGAT 
                 
                 
                     
                 
                 
                   CATAGCTTACTGCAGCCTTGAATTCCTGGGCTCAAGCAATTCTCCTGCCTCAGCCTCCCG 
                 
                 
                     
                 
                 
                   AGTAGCTGGGACTACAGGCCTGTGCCACCAGGCCTGGCTTGTACATTAGTATTTGATATG 
                 
                 
                     
                 
                 
                   GCTACCCTAAGGGCAATCCTATAGTGAAGTCAACATTAGATAATGATGCTCATCTGATGG 
                 
                 
                     
                 
                 
                   ATTAGATTTTCAGAGTTGGCTGTTTCCAGGTGCCTATAGGAGTAGAAAAGGGTGACAAAC 
                 
                 
                     
                 
                 
                   CTCCTAACTAGATGTCCTACCAAATATAGTTCACTCCACATCTGAGATGAGACTGCATGA 
                 
                 
                     
                 
                 
                   CTGCTGGTTTTCTTTGCCTTTTCCCCCCCAGGGTATCATCAGAACCAAAAATAAAGTTTT 
                 
                 
                     
                 
                 
                   AAAGGTGGGTCAGGTGTGTGTTGGCTCATGCCTGTAATCCTAGCACTTTGGGAGGCTGAG 
                 
                 
                     
                 
                 
                   GCAGGTGGATCATCTGAGCTCAGGAGTTCAAGACCAGCCTGGCTAATAACATGGTTAAGC 
                 
                 
                     
                 
                 
                   CCCATCTCTACTAAAATACAAAAAGTTAGCTGGGCATGGTGGTGGGCACCTGTAATCCCA 
                 
                 
                     
                 
                 
                   GCTACTCAGGAGGCTGAGGCATGAAAATCGCTTGAACCCCAGAGGCGGGGGTTGCAGTGA 
                 
                 
                     
                 
                 
                   GCCGAGATCATGCCACTGCACACTAGCCTGAACAACAGAGCAAGGCTCTGTCTCCAAACA 
                 
                 
                     
                 
                 
                   AACAAAAATGGTGCCAGAGTCTTTTCCAGGGCTGAGGGGAGATACAATGAAGTGTGTTAT 
                 
                 
                     
                 
                 
                   TTTTTCTGATAAGAGTGCTACCATCTTTCATTCTTGTGTGCCATTTCTAGTTGGGGTGAA 
                 
                 
                     
                 
                 
                   TTTGTTTTCGGAGTTCCTTTCCCAGCTGTTTGCCTGAAAAACCATGAAATGTGTTCCACA 
                 
                 
                     
                 
                 
                   TGAACTATGAAATGATTAGATGCTAATGTGGCAAAGAAAGTGTGAATTCTCTTGTAGAAA 
                 
                 
                     
                 
                 
                   CAGGGACATTTGGTTCGGTACAGTAAGTTGTTAATGCGTGACTCTGTGCTTTCAAATTCT 
                 
                 
                     
                 
                 
                   GTGGTTCAAAAGTACTTTTCACTCCTACTGTGTATTTACCTTGAGAAGGTGAATCCCCTA 
                 
                 
                     
                 
                 
                   ACAATTTGGTCAATGTATCAGTATTCTCAACCCGTCTATCAATTTTTTTTTCTTTCTCCC 
                 
                 
                     
                 
                 
                   TCTTTTTTCTTTTTTTGGGCAAAATACCTTTTTTGCTTTTTATCCCCTTAAAATAACCAT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   TCATGGTGGTTTAAAAAGGTTTAAAAAACAAAAACAAAAACAAAACACAAGTTTGTAGCA 
                 
                 
                     
                 
                 
                   CATGCCTTTCACTGGTGCACGTTCCTGTTGCCCTACTGTTAGTGTATCTGTGACTGGTGA 
                 
                 
                     
                 
                 
                   TATCTATTGATTGTGTTAATGCTATCTCAACCACGTTTTAATTTTCCTAAGCTGGCCAGG 
                 
                 
                     
                 
                 
                   CACGGTGGCTAACGCCTGTAATCCCAGTGCTTTGGGAGGCCGAGGTTCATGGATTACTTT 
                 
                 
                     
                 
                 
                   GAAGTCAGGAGTTCGAGACCAGCCTGGCCAACATGGTGAAACCCTGTCTCTACTAAAAAT 
                 
                 
                     
                 
                 
                   ACAAAAATTAGCCGGGCATGGTGGCGCATGCCTGTAATCCCAGCTACTCAGGAGGCTGAG 
                 
                 
                     
                 
                 
                   GCAGGAGAATCGCTTGAACCCAGGAAACGGATGTTGCAGTGAGCCGAGATCATGCCACTG 
                 
                 
                     
                 
                 
                   CACTCCAGCCTGGGCGATAGAGTGAGCCTCTGTCTAAAAATAAAATAAAATAAAATAAAT 
                 
                 
                     
                 
                 
                   TCCTAAACTGAAGGCTGACTGCTATGCTAGCTAGGATTATATGGGATTTTAAGTATATCA 
                 
                 
                     
                 
                 
                   AGTGGTGGTTCTCCAAGAAGAATCTAATTTTTCTTTTGATGGGCTGGGGATTGTAACAAA 
                 
                 
                     
                 
                 
                   GGAAGGTCATATGTCTTAATGATGTGTTAAGGCTCTTTGCAAAATCAAAGTAAATAAATT 
                 
                 
                     
                 
                 
                   GACCACTAATGTGTCAGCCCAGCCATGTTCTGCTCATTTGCCACCAGTCAACAGAAATCT 
                 
                 
                     
                 
                 
                   ACTTTGGGTGTTTAAACCAGGAGTCAGCAAACTACAGCTCACAAGGCCAGATGTGGGCCA 
                 
                 
                     
                 
                 
                   TGGCCTGTTACTGTATGGCCTGTTAATGGTTTTAAAGGGTTGTAAAACAAAAGAACACAA 
                 
                 
                     
                 
                 
                   AACAAAGACCCAATAACAAAACAAAGCCCGAAGAATAATATGCGACAGAGACCATGTATG 
                 
                 
                     
                 
                 
                   GCATATAGAGCCTAAAATACTGACTCTCAAGCCCTTCCCAGAAATCCTTCCCGACTCCTT 
                 
                 
                     
                 
                 
                   GTTGAAAACACGGTAGGAAAGCATTTGTCAAATTGAGGATATGAATAGCAATTGTAAGTT 
                 
                 
                     
                 
                 
                   ATTATTTTTCTATATATTCGAAAGTCACTTGCTAGTATAACATTTACCTTTTATTTTTCC 
                 
                 
                     
                 
                 
                   CTAAGAATCTTCTCTCTGTTTGCTTTCGACATGGATTTTTAAACCCCTGCAGATTTTAAT 
                 
                 
                     
                 
                 
                   ATTCTATATAAATGTTTTAGGTGGCATATATGAGGTTTGTATTAACATTTGCTTTCTATT 
                 
                 
                     
                 
                 
                   TAACATTGAAATGAAATTATACAGCAGAGGTATTTTCTCGTCCAAGTTGCCACTTCTTTC 
                 
                 
                     
                 
                 
                   TATCTTTTTTCTTTTCTTTCCCAGTGGACTGCCTGGGAAAATTGATATTTTAAATTGCTC 
                 
                 
                     
                 
                 
                   TCTGCAATAATTTGCAATGGAACTGGAATGCCAGGGTTCTGAGTCCTTGCCAGACAGCTC 
                 
                 
                     
                 
                 
                   GTCCCTCCTGTTGGCATGACTGAGTCAGCTGTCATGATTCCCTCAGTACCAGTGGCATGC 
                 
                 
                     
                 
                 
                   CTGTGACAGACAGCCTGTCTGCCTTTCATTCCCGTCGTCTCCCTTGTAGGGTTCAGATCC 
                 
                 
                     
                 
                 
                   AGGATACACTGGTCCTGGAGCCCCTCTCAGCCTGGCACCCACAGCTGCTGGGTTCCTTAC 
                 
                 
                     
                 
                 
                   TCTCCTGGACTGCTCTGATGTCATCTCCCTGCTCAGCAGAAAGAAGTCTGGGATCTTGAT 
                 
                 
                     
                 
                 
                   GCTTTGGCCCTCTGTCCTAGGCCCTAAACCACCCATTGCCCTTCACATAACCTGAGCTGG 
                 
                 
                     
                 
                 
                   GGCTAAATAGATCTCTCATCACTGCCTGCCTGCTCCTGTATTTTCCCTTCTTGGAGCTTT 
                 
                 
                     
                 
                 
                   TGCCTGTTCAGATCCCTCTACTGGAAATTAATAGGATTTCATTCTATGTGTGCATTTCCA 
                 
                 
                     
                 
                 
                   ACCTTTCTTCACAGTGCGATCCAAATGCCTCATCCTACAGGCCTCCTTAAAACAACCTGC 
                 
                 
                     
                 
                 
                   TTTCTGCCAGACCCCAGGGAGCACCAGGACTTGAGGCTTTTATTGCACTTCTGTTGTTTT 
                 
                 
                     
                 
                 
                   TTTGAGATGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCACGATCTCTGCTCA 
                 
                 
                     
                 
                 
                   CTGCAACCTCCATCTCCCGAGTTCAAGAGATTCTTCTGCCTCAGCCTCTCAAGCAGCTGG 
                 
                 
                     
                 
                 
                   GACTACAGGCATGTGCCATGACACCCGGATAATTTTTGTATTTTTAGTAGAGACGGGGTT 
                 
                 
                     
                 
                 
                   CACCATATTGGCCAGGCTGGTCTCAAACTCCTGACCTCGTGATCCACCCACCTGGGCCTC 
                 
                 
                     
                 
                 
                   CCAAAGTTCTGGGATTACAGGCGTGAGCCACCATGCCCAGCGTTATTTCACTTCTGCCTC 
                 
                 
                     
                 
                 
                   TGTAATTATATTGCTGTATGGCTATCTCTTCTCTCCCTGGGAATGTCAGGTCCTAGGCAC 
                 
                 
                     
                 
                 
                   AGGAACTGTGTCTGTACCATATCTGGTGCCCAAAGAATGTAGTATGTGTTTTATAGATAT 
                 
                 
                     
                 
                 
                   CATGTAAGCTTAAACAGCGTGGTCTACATTTTTGTAAATGTCTTTCTTTTTCTTTTCTCT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   GTGCTCTATTGGTTAATTGTTTATATAATTGGCAGTATTTTTAAGCAGGCAAGCAATTTG 
                 
                 
                     
                 
                 
                   GGAATGTTTTAGCAAAGTGTACCATAATTGAGTTTTACAAACCAGGCTCCTTTTTCCTCT 
                 
                 
                     
                 
                 
                   CCCTGTACTTCTTTTTCCAAGATGGTTTTAGTTTAGAGTTCATTAAACATTAAAATCAAA 
                 
                 
                     
                 
                 
                   CACAGAATTAATTCTGCATGAGGCAAGGCTAGCACTTATTCCAGAGAAATGGCTGATACT 
                 
                 
                     
                 
                 
                   GGTGGTAGAGTGCAGGTATCACTGTTCCTGCAATTTTTATTAGAGTTGGTTAGCCCAGGC 
                 
                 
                     
                 
                 
                   TGTGCTGGGGGATGATCTGTAGGGATCTGGGAAGCATCGGGACTCAGCACTGGGTGGTTG 
                 
                 
                     
                 
                 
                   GGAGTCAGGAAGCCTGAGTTCTCATTTCAGTCAGTCTCTGACCAACTGTGTGGCATGGGG 
                 
                 
                     
                 
                 
                   TGCTAGACCACTTGGCTGCCGACTGGGTCACCGACATCCCTTCCAGCTCTGCTGCTGGAA 
                 
                 
                     
                 
                 
                   ATTCATCTCTCCCATATGTTGCCTCCCCATCAATTACGTTTTTTAAGTGTGACCCAAGTA 
                 
                 
                     
                 
                 
                   TATGATGTATGTTTTCATGATAAATTAGAAACTTATCTGGGCATGGTGGCTCATACCTGT 
                 
                 
                     
                 
                 
                   AATCCCAGCACTTTGGGAGGCTGAGGTGGGCGGATCACCTGAGGTCAGGAGTTCGAGACC 
                 
                 
                     
                 
                 
                   AGCCTGACCAACTAAAATAGTAGAGACCAACCCGTCTCTACTAAAAATAGAAAATTAGCT 
                 
                 
                     
                 
                 
                   GAGCATGGTGGTGCATGCCTATAATCCCAGCTACTCAGGAGGCTGAGGCAGGAGAGGCAG 
                 
                 
                     
                 
                 
                   CGGTTGCAGTGTGCCAAGATCGCGCCATTGCACTCCACCTGGGCCACAAGAGTGAAACTC 
                 
                 
                     
                 
                 
                   CATCTCAAAAAAAAAAAAAAAAAAAAAAAAACTCAGTGTCAGTATTTCATGTCGAAATTC 
                 
                 
                     
                 
                 
                   CACTTCAATGGGTAGTGTAGTTAAAAGCTCTAAGTCTACCTTAAAATCACCTAATGCTTT 
                 
                 
                     
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   
                     
                               
                       
                           
                           
                       
                     
                   
                 
                 
                   ACTCCACCTCTCACACTGGCAAAATACTGACATTTAGCAGCTCTTATCTAGAAGTGACTT 
                 
                 
                     
                 
                 
                   GGAACATAGAATAAAGGCATGAGTTCCTGAAGAATTCATTGAGTGTTTCCTGTAGAAATA 
                 
                 
                     
                 
                 
                   GCTTTAGGAGATAGGGAGTTCTATCTGGGAGAACATATGAGTAACTCAAGAGTAAAAAGT 
                 
                 
                     
                 
                 
                   ATAGTCTGTGTAAACTATAGAAGAAATGCTGGGCATGGTGGCGCGCCCCTGTAATCTCAG 
                 
                 
                     
                 
                 
                   CTACTTGGAGGCTGAGACGGGAGGATTCCTTGAACCCAGGAGCCCAGGAGTTTTAGACCA 
                 
                 
                     
                 
                 
                   GTCTGGGTAACATAGTGAGACCCTTTCTCACCTACTCTCACTGCATGCCCCCCAAAAATA 
                 
                 
                     
                 
                 
                   TATATGTGCGCGCACGCGCGCGCACACACACATACACACACACACACACACACACACACA 
                 
                 
                     
                 
                 
                   CAGAGGAAATTGTTAGAAAACACACAGAACTGAATGTAAATAGTATTAGGTGGGAATAAG 
                 
                 
                     
                 
                 
                   AAGTAAAGGGATGGTAAGGAGGCTTGGAGGAGGAGTAAATTATCTGCTATGGGACATCAG 
                 
                 
                     
                 
                 
                   CTC 
                 
               
            
           
         
       
           [0048]      FIG. 11  shows a SHP2 translated amino acid sequence (SEQ ID NO: 61). Alternating exons are underlined and non-underlined. Bold with italics indicate a residue overlap splice site. 
       
    
    
       [0049]    Like reference symbols in the various drawings indicate like elements. 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0050]    Protein/nucleic acid complexes or assemblies are difficult to manipulate due to their fragility and requirement for structural integrity (e.g., 3-dimensional conformation. Genome editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, transcription activator-like effector nucleases (TALENS), and others, have shown much potential in their ability to change the genetic code of cells. However, their activity is highly dependent on structural and conformational integrity. 
         [0051]    Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) are examples of a class of gene editing tools. These chimeric nucleases are composed of programmable, sequence-specific DNA-binding modules linked to a nonspecific DNA cleavage domain. ZFNs and TALENs enable a broad range of genetic modifications by inducing DNA double-strand breaks that stimulate error-prone nonhomologous end joining or homology-directed repair at specific genomic locations (Gaj et al., 2013, Trends Biotechnol. 31(7):397-405; hereby incorporated by reference). 
         [0052]    Numerous publications describe the use of viruses, mRNA and plasmids to code for the Cas9 and/or gRNA and/or donor oligonucleotides (where relevant). Compared to these methods, the methods and systems described herein utilize a different strategy—delivery of the protein itself, complexed with the guide RNA. This process is fundamentally different, because it does not require the cell to translate/transcribe anything for the editing to work. For that reason, and because the protein/guide complex has a short half-life, the approach of the invention results in faster and more efficient editing with fewer off-target effects. 
       Other Approaches Such as Liposome Mediated Protein Delivery, Microinjection, and Cell-Penetrating Peptides (CPP). 
       [0053]    One example of liposome mediated protein delivery uses GFP fused to Cas-9, has also been used (Zuris et al., 2015, Nature Biotechnology 33:73-80). The GFP is capable of complexing with conventional lipofection agents (e.g. lipofectamine) due to charge interactions and appears to mediate a gene editing response. The main advantages of the invention relative to this approach are: 1) does not require a fusion protein 2) does not require lipofection agents which can have toxicity, endosome escape problems, and issues/problems translating to primary cells. 
         [0054]    Microinjection mediated complex delivery is characterized by extremely low throughput and can be difficult to implement for most mammalian cell types. The latter drawback is highlighted by the fact that the work was done with embryos, i.e., cells that are much larger than a fibroblast or a T cell (cells which are desirable target cells for gene editing endeavors). By enabling high throughput and translatability to smaller primary cells, e.g., fibroblasts, T cells, stem cells, the methods described herein have a big advantage. 
         [0055]    A CPP-based strategy does not involve a complex. One example of such as strategy is described in Ramakrishna et al., 2014, Genome Res. 24(6):1020-7. CPP mediated delivery of individual components is also associated with drawbacks. Conjugating a CPP to the guide and Cas9 requires extra modification that may inhibit function, limit scalability. CPP mediated delivery is known to go through endocytosis and is inefficient or ineffective in many primary cells (particularly immune cells). 
       Target Cells and Payload Compositions 
       [0056]    Any gene can be manipulated using the gene editing strategies described. Some target genes/proteins are particularly relevant in clinical disease and thus gene editing of such target genes/proteins is useful for therapy. Examples include C—C chemokine receptor type 5 (CCR5): prevent human immunodeficiency virus (HIV) infection; major histocompatibility complex class I (MHC-I): reduce graft vs. host disease; cluster of differentiation 1 (CD1): reduce graft vs. host disease; programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PDL-1), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), interferon-regulatory factor (IRF) protein family, TLR protein family, pattern recognition receptors (PRRs): modulate immunity to enhance or dampen effector/antiviral responses; forkhead box P3 (FoxP3): eliminate Treg mediated tolerance; cluster of differentiation 80 (CD80), cluster of differentiation 86 (CD86) and other costimulatory molecules: knockout costimulation abilities to promote tolerance; T cell receptor (TCR), B-cell receptor (BCR): eliminate endogenous TCR or BCR to allow for engineering of T cells and B cells with desired specificity; oncogenes (e.g., Kras, Myc, Tp53): cancer therapy. In another example, targeting transcription factors is used to change cell fate, e.g., delete FoxP3 to remove Treg type function. Delete nuclear factor-kappa B (NF-kB), t-bet, Eomesodermin (Eomes), etc. to alter T cell differentiation. 
         [0057]    A protein coding sequence for forkhead box P3 (FoxP3) is as follows: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 62) 
               
             
          
           
               
                 ATGCCCAACCCCAGGCCTGGCAAGCCCTCGGCCCCTTCCTTGGCCCTTGG 
               
               
                   
               
               
                 CCCATCCCCAGGAGCCTCGCCCAGCTGGAGGGCTGCACCCAAAGCCTCAG 
               
               
                   
               
               
                 ACCTGCTGGGGGCCCGGGGCCCAGGGGGAACCTTCCAGGGCCGAGATCTT 
               
               
                   
               
               
                 CGAGGCGGGGCCCATGCCTCCTCTTCTTCCTTGAACCCCATGCCACCATC 
               
               
                   
               
               
                 GCAGCTGCAGCTGCCCACACTGCCCCTAGTCATGGTGGCACCCTCCGGGG 
               
               
                   
               
               
                 CACGGCTGGGCCCCTTGCCCCACTTACAGGCACTCCTCCAGGACAGGCCA 
               
               
                   
               
               
                 CATTTCATGCACCAGCTCTCAACGGTGGATGCCCACGCCCGGACCCCTGT 
               
               
                   
               
               
                 GCTGCAGGTGCACCCCCTGGAGAGCCCAGCCATGATCAGCCTCACACCAC 
               
               
                   
               
               
                 CCACCACCGCCACTGGGGTCTTCTCCCTCAAGGCCCGGCCTGGCCTCCCA 
               
               
                   
               
               
                 CCTGGGATCAACGTGGCCAGCCTGGAATGGGTGTCCAGGGAGCCGGCACT 
               
               
                   
               
               
                 GCTCTGCACCTTCCCAAATCCCAGTGCACCCAGGAAGGACAGCACCCTTT 
               
               
                   
               
               
                 CGGCTGTGCCCCAGAGCTCCTACCCACTGCTGGCAAATGGTGTCTGCAAG 
               
               
                   
               
               
                 TGGCCCGGATGTGAGAAGGTCTTCGAAGAGCCAGAGGACTTCCTCAAGCA 
               
               
                   
               
               
                 CTGCCAGGCGGACCATCTTCTGGATGAGAAGGGCAGGGCACAATGTCTCC 
               
               
                   
               
               
                 TCCAGAGAGAGATGGTACAGTCTCTGGAGCAGCAGCTGGTGCTGGAGAAG 
               
               
                   
               
               
                 GAGAAGCTGAGTGCCATGCAGGCCCACCTGGCTGGGAAAATGGCACTGAC 
               
               
                   
               
               
                 CAAGGCTTCATCTGTGGCATCATCCGACAAGGGCTCCTGCTGCATCGTAG 
               
               
                   
               
               
                 CTGCTGGCAGCCAAGGCCCTGTCGTCCCAGCCTGGTCTGGCCCCCGGGAG 
               
               
                   
               
               
                 GCCCCTGACAGCCTGTTTGCTGTCCGGAGGCACCTGTGGGGTAGCCATGG 
               
               
                   
               
               
                 AAACAGCACATTCCCAGAGTTCCTCCACAACATGGACTACTTCAAGTTCC 
               
               
                   
               
               
                 ACAACATGCGACCCCCTTTCACCTACGCCACGCTCATCCGCTGGGCCATC 
               
               
                   
               
               
                 CTGGAGGCTCCAGAGAAGCAGCGGACACTCAATGAGATCTACCACTGGTT 
               
               
                   
               
               
                 CACACGCATGTTTGCCTTCTTCAGAAACCATCCTGCCACCTGGAAGAACG 
               
               
                   
               
               
                 CCATCCGCCACAACCTGAGTCTGCACAAGTGCTTTGTGCGGGTGGAGAGC 
               
               
                   
               
               
                 GAGAAGGGGGCTGTGTGGACCGTGGATGAGCTGGAGTTCCGCAAGAAACG 
               
               
                   
               
               
                 GAGCCAGAGGCCCAGCAGGTGTTCCAACCCTACACCTGGCCCCTGA 
               
             
          
         
       
     
         [0058]    Src homology region 2 domain-containing phosphatase-1 (SHP1) is also known as tyrosine-protein phosphatase non-receptor type 6 (PTPN6). A protein coding sequence for SHP1 is as follows: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 63) 
               
             
          
           
               
                 ATGGTGAGGTGGTTTCACCGAGACCTCAGTGGGCTGGATGCAGAGACCCT 
               
               
                   
               
               
                 GCTCAAGGGCCGAGGTGTCCACGGTAGCTTCCTGGCTCGGCCCAGTCGCA 
               
               
                   
               
               
                 AGAACCAGGGTGACTTCTCGCTCTCCGTCAGGGTGGGGGATCAGGTGACC 
               
               
                   
               
               
                 CATATTCGGATCCAGAACTCAGGGGATTTCTATGACCTGTATGGAGGGGA 
               
               
                   
               
               
                 GAAGTTTGCGACTCTGACAGAGCTGGTGGAGTACTACACTCAGCAGCAGG 
               
               
                   
               
               
                 GTGTCCTGCAGGACCGCGACGGCACCATCATCCACCTCAAGTACCCGCTG 
               
               
                   
               
               
                 AACTGCTCCGATCCCACTAGTGAGAGGTGGTACCATGGCCACATGTCTGG 
               
               
                   
               
               
                 CGGGCAGGCAGAGACGCTGCTGCAGGCCAAGGGCGAGCCCTGGACGTTTC 
               
               
                   
               
               
                 TTGTGCGTGAGAGCCTCAGCCAGCCTGGAGACTTCGTGCTTTCTGTGCTC 
               
               
                   
               
               
                 AGTGACCAGCCCAAGGCTGGCCCAGGCTCCCCGCTCAGGGTCACCCACAT 
               
               
                   
               
               
                 CAAGGTCATGTGCGAGGGTGGACGCTACACAGTGGGTGGTTTGGAGACCT 
               
               
                   
               
               
                 TCGACAGCCTCACGGACCTGGTGGAGCATTTCAAGAAGACGGGGATTGAG 
               
               
                   
               
               
                 GAGGCCTCAGGCGCCTTTGTCTACCTGCGGCAGCCGTACTATGCCACGAG 
               
               
                   
               
               
                 GGTGAATGCGGCTGACATTGAGAACCGAGTGTTGGAACTGAACAAGAAGC 
               
               
                   
               
               
                 AGGAGTCCGAGGATACAGCCAAGGCTGGCTTCTGGGAGGAGTTTGAGAGT 
               
               
                   
               
               
                 TTGCAGAAGCAGGAGGTGAAGAACTTGCACCAGCGTCTGGAAGGGCAGCG 
               
               
                   
               
               
                 GCCAGAGAACAAGGGCAAGAACCGCTACAAGAACATTCTCCCCTTTGACC 
               
               
                   
               
               
                 ACAGCCGAGTGATCCTGCAGGGACGGGACAGTAACATCCCCGGGTCCGAC 
               
               
                   
               
               
                 TACATCAATGCCAACTACATCAAGAACCAGCTGCTAGGCCCTGATGAGAA 
               
               
                   
               
               
                 CGCTAAGACCTACATCGCCAGCCAGGGTTGTCTGGAGGCCACGGTCAATG 
               
               
                   
               
               
                 ACTTCTGGCAGATGGCGTGGCAGGAGAACAGCCGTGTCATCGTCATGACC 
               
               
                   
               
               
                 ACCCGAGAGGTGGAGAAAGGCCGGAACAAATGCGTCCCATACTGGCCCGA 
               
               
                   
               
               
                 GGTGGGCATGCAGCGTGCTTATGGGCCCTACTCTGTGACCAACTGCGGGG 
               
               
                   
               
               
                 AGCATGACACAACCGAATACAAACTCCGTACCTTACAGGTCTCCCCGCTG 
               
               
                   
               
               
                 GACAATGGAGACCTGATTCGGGAGATCTGGCATTACCAGTACCTGAGCTG 
               
               
                   
               
               
                 GCCCGACCATGGGGTCCCCAGTGAGCCTGGGGGTGTCCTCAGCTTCCTGG 
               
               
                   
               
               
                 ACCAGATCAACCAGCGGCAGGAAAGTCTGCCTCACGCAGGGCCCATCATC 
               
               
                   
               
               
                 GTGCACTGCAGCGCCGGCATCGGCCGCACAGGCACCATCATTGTCATCGA 
               
               
                   
               
               
                 CATGCTCATGGAGAACATCTCCACCAAGGGCCTGGACTGTGACATTGACA 
               
               
                   
               
               
                 TCCAGAAGACCATCCAGATGGTGCGGGCGCAGCGCTCGGGCATGGTGCAG 
               
               
                   
               
               
                 ACGGAGGCGCAGTACAAGTTCATCTACGTGGCCATCGCCCAGTTCATTGA 
               
               
                   
               
               
                 AACCACTAAGAAGAAGCTGGAGGTCCTGCAGTCGCAGAAGGGCCAGGAGT 
               
               
                   
               
               
                 CGGAGTACGGGAACATCACCTATCCCCCAGCCATGAAGAATGCCCATGCC 
               
               
                   
               
               
                 AAGGCCTCCCGCACCTCGTCCAAGAGCTTGGAGTCTAGTGCAGGGACCGT 
               
               
                   
               
               
                 GGCTGCGTCACCTGTGAGACGGGGTGGCCAGAGGGGACTGCCAGTGCCGG 
               
               
                   
               
               
                 GTCCCCCTGTGCTGTCTCCTGACCTGCACCAACTGCCTGTACTTGCCCCC 
               
               
                   
               
               
                 CTGCACCCGGCTGCAGACACAAGGAGGATGTGTATGAGAACCTGCACACT 
               
               
                   
               
               
                 AAGAACAAGAGGGAGGAGAAAGTGA 
               
             
          
         
       
     
         [0059]    Src homology region 2 domain-containing phosphatase-1 (SHP2) is also known as tyrosine-protein phosphatase non-receptor type 11 (PTPN11). A protein coding sequence for SHP2 is as follows: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 64) 
               
             
          
           
               
                 ATGACATCGCGGAGATGGTTTCACCCAAATATCACTGGTGTGGAGGCAGA 
               
               
                   
               
               
                 AAACCTACTGTTGACAAGAGGAGTTGATGGCAGTTTTTTGGCAAGGCCTA 
               
               
                   
               
               
                 GTAAAAGTAACCCTGGAGACTTCACACTTTCCGTTAGAAGAAATGGAGCT 
               
               
                   
               
               
                 GTCACCCACATCAAGATTCAGAACACTGGTGATTACTATGACCTGTATGG 
               
               
                   
               
               
                 AGGGGAGAAATTTGCCACTTTGGCTGAGTTGGTCCAGTATTACATGGAAC 
               
               
                   
               
               
                 ATCACGGGCAATTAAAAGAGAAGAATGGAGATGTCATTGAGCTTAAATAT 
               
               
                   
               
               
                 CCTCTGAACTGTGCAGATCCTACCTCTGAAAGGTGGTTTCATGGACATCT 
               
               
                   
               
               
                 CTCTGGGAAAGAAGCAGAGAAATTATTAACTGAAAAAGGAAAACATGGTA 
               
               
                   
               
               
                 GTTTTCTTGTACGAGAGAGCCAGAGCCACCCTGGAGATTTTGTTCTTTCT 
               
               
                   
               
               
                 GTGCGCACTGGTGATGACAAAGGGGAGAGCAATGACGGCAAGTCTAAAGT 
               
               
                   
               
               
                 GACCCATGTTATGATTCGCTGTCAGGAACTGAAATACGACGTTGGTGGAG 
               
               
                   
               
               
                 GAGAACGGTTTGATTCTTTGACAGATCTTGTGGAACATTATAAGAAGAAT 
               
               
                   
               
               
                 CCTATGGTGGAAACATTGGGTACAGTACTACAACTCAAGCAGCCCCTTAA 
               
               
                   
               
               
                 CACGACTCGTATAAATGCTGCTGAAATAGAAAGCAGAGTTCGAGAACTAA 
               
               
                   
               
               
                 GCAAATTAGCTGAGACCACAGATAAAGTCAAACAAGGCTTTTGGGAAGAA 
               
               
                   
               
               
                 TTTGAGACACTACAACAACAGGAGTGCAAACTTCTCTACAGCCGAAAAGA 
               
               
                   
               
               
                 GGGTCAAAGGCAAGAAAACAAAAACAAAAATAGATATAAAAACATCCTGC 
               
               
                   
               
               
                 CCTTTGATCATACCAGGGTTGTCCTACACGATGGTGATCCCAATGAGCCT 
               
               
                   
               
               
                 GTTTCAGATTACATCAATGCAAATATCATCATGCCTGAATTTGAAACCAA 
               
               
                   
               
               
                 GTGCAACAATTCAAAGCCCAAAAAGAGTTACATTGCCACACAAGGCTGCC 
               
               
                   
               
               
                 TGCAAAACACGGTGAATGACTTTTGGCGGATGGTGTTCCAAGAAAACTCC 
               
               
                   
               
               
                 CGAGTGATTGTCATGACAACGAAAGAAGTGGAGAGAGGAAAGAGTAAATG 
               
               
                   
               
               
                 TGTCAAATACTGGCCTGATGAGTATGCTCTAAAAGAATATGGCGTCATGC 
               
               
                   
               
               
                 GTGTTAGGAACGTCAAAGAAAGCGCCGCTCATGACTATACGCTAAGAGAA 
               
               
                   
               
               
                 CTTAAACTTTCAAAGGTTGGACAAGGGAATACGGAGAGAACGGTCTGGCA 
               
               
                   
               
               
                 ATACCACTTTCGGACCTGGCCGGACCACGGCGTGCCCAGCGACCCTGGGG 
               
               
                   
               
               
                 GCGTGCTGGACTTCCTGGAGGAGGTGCACCATAAGCAGGAGAGCATCATG 
               
               
                   
               
               
                 GATGCAGGGCCGGTCGTGGTGCACTGCAGTGCTGGAATTGGCCGGACAGG 
               
               
                   
               
               
                 GACGTTCATTGTGATTGATATTCTTATTGACATCATCAGAGAGAAAGGTG 
               
               
                   
               
               
                 TTGACTGCGATATTGACGTTCCCAAAACCATCCAGATGGTGCGGTCTCAG 
               
               
                   
               
               
                 AGGTCAGGGATGGTCCAGACAGAAGCACAGTACCGATTTATCTATATGGC 
               
               
                   
               
               
                 GGTCCAGCATTATATTGAAACACTACAGCGCAGGATTGAAGAAGAGCAGA 
               
               
                   
               
               
                 AAAGCAAGAGGAAAGGGCACGAATATACAAATATTAAGTATTCTCTAGCG 
               
               
                   
               
               
                 GACCAGACGAGTGGAGATCAGAGCCCTCTCCCGCCTTGTACTCCAACGCC 
               
               
                   
               
               
                 ACCCTGTGCAGAAATGAGAGAAGACAGTGCTAGAGTCTATGAAAACGTGG 
               
               
                   
               
               
                 GCCTGATGCAACAGCAGAAAAGTTTCAGATGA 
               
             
          
         
       
     
         [0060]    Other targets include areas of the genome that can have a plasmid or donor DNA inserted into them so that the target cell can express a new gene, e.g. a recombinant TCR, a recombinant BCR, Chimerica Antigen Receptor, fluorescent protein, reprogramming factors. 
         [0061]    In some embodiments, a genomic sequence is edited in a coding region. In certain embodiments, a genomic sequence is edited in a non-coding region. 
         [0062]    In various embodiments relating to FoxP3, a genetic region upstream of FoxP3 may be edited. In such embodiments a region where a transcriptional repressor of Foxp3 might bind is edited. For example a site about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 0.5-2.5, or 0.5-5 kb upstream of the FoxP3 transcriptional start site may be edited. 
         [0063]    Treating Subjects 
         [0064]    Aspects of the present invention relate to editing the genomes of a plurality of a subject&#39;s cells. In various embodiments, cells are removed from a subject, receive a gene-editing complex using a method of the present subject matter, and then are reintroduced back into the subject. For example, mutant cells may be produced in a process involving delivery of a gene-editing complex as described herein. The mutant cells may be heterozygous or homozygous for a mutated allele a gene involved in a disease. In certain embodiments, the mutant cells are null for the gene involved in a disease. 
         [0065]    Cells, such as stem cells (e.g. hematopoietic stem cells) from bone marrow, or circulating immune cells in whole blood, may be treated using methods and devices described herein. Cells may be genetically modified to reduce the expression of a receptor for a pathogen (such as a viral or bacterial pathogen) or a toxin (such as a microbial pathogen toxin). Since a gene-editing protein complex or components thereof may be directly introduced into target cells without the need for expression, no transgene delivery is necessary. This approach has important advantages over traditional gene-therapy approaches, which suffer from aberrant expression, insertion, and silencing, as well as variable delivery of transgene copy number. 
         [0066]    In one embodiment, a gene-editing complex that targets the C—C chemokine receptor type 5 (CCR5) gene is introduced into a blood (such as a CD4+ T cell) or bone marrow cell (such as a hematopoietic stem cell) of a subject who is infected with human immunodeficiency virus (HIV). The gene-editing complex may be designed to mutate the CCR5 gene such that cells receiving the gene-editing complex no longer express CCR5 or express CCR5 at a reduced level. In one example, hematopoietic stem cells expressing a version of CCR5 that binds HIV (or that produce progeny that express the CCR5) are removed from the subject, modified to no longer express a version of CCR5 that binds HIV, and then are transplanted into the subject. In another example, CCR5-expressing CD4+ T cells of the subject receive a gene-editing complex using methods and devices described herein such that the CD4+ T cells no longer express a version of CCR5 that binds HIV. The modified CD4+ T cells are then returned into the subject. Such treatment of the CD4+ T cell may be performed in whole blood from the subject. In these and other embodiments, bone marrow cells or blood cells are modified to no longer express a version of C—X—C chemokine receptor type 4 (CXCR4) to which HIV binds. Similarly, cells of a subject may be modified to have reduced CCR5 expression to treat or prevent an infection associates with  Yersinia pestis  (bubonic plague) or  Variola major  (small pox). 
         [0067]    Subjects, other than humans, containing cells modified by methods and devices disclosed herein are also provided. Such subjects include non-human vertebrate, amphibian, mammalian, and primate subjects. Non-limiting examples include  Danio  sp.,  Fugu  sp.,  Xenopus  sp.,  Mus  sp.,  Rattus  sp., and others. 
         [0068]    Introducing Gene-Editing Proteins and Complexes into Cells 
         [0069]    The delivery of pre-formed protein complexes allows for the study of cellular processes without genetic modification of the cells being studied. The present subject matter is useful for delivering protein complexes and gene editing complexes to cells, including CRISPR. 
         [0070]    The advantages of delivering protein complexes using the methods and devices described herein include the controlled and temporary introduction of test agents for the study of cell and protein complex function. Since transgene expression and cellular assembly of complex components is not needed, the timing and ratios (protein:RNA) of complex function can be controlled. Additionally, the transient nature of delivery enables the observation of changes due to temporary function, rather than prolonged expression which may result in off-target or secondary effects. From an in vivo homing perspective and a gene expression format, microfluidic delivery has far fewer side effects (10-fold) on treated cells rather than electroporation. 
         [0071]    For example, microfluidic delivery results in fewer aberrant and non-specific gene expression changes compared to electroporation. Additionally, the structural and functional integrity of microfluidically squeezed cells is preserved compared to electroporation-mediated cargo delivery. As an example, an increased number of T cells exposed to microfluidic delivery ex vivo (and then introduced into a subject in vivo) home to lymph nodes compared to T cells that have undergone electroporation. Cells (e.g., T cells) treated by electroporation and then administered into a subject are more likely to be cleared from the subject compared to cells treated by microfluidic delivery. Such clearance is related to altered/aberrant gene expression following electroporation that marks such cells for destruction or clearance by the body. 
         [0072]    Target Cells and Payload Compositions 
         [0073]    Any eukaryotic, e.g., mammalian such as human, cell can be processed using the microfluidic device to alter the cell membrane for introduction of protein/nucleic acid complexes or assemblies into the cytosol of the target cell. Exemplary target cells include Lymphocytes/Immune cells: DCs, B cells, T cells, Natural killer cells (NK cells), neutrophils, basophils, eosinophils, innate lymphoid cells, monocytes, macrophages, hematopoietic stem cells, common lymphoid progenitor cells; Stem cells: Embryonic, mesenchymal, induced pluripotent; Other primary cells: Fibroblasts, hepatocytes, cardiomyocytes, neurons, epithelial, epidermal, endothelial, pancreatic islet cells; as well as Cell lines, e.g., cell lines for disease studies: T cell clones, Jurkat cells, HeLa cells, Human Embryonic Kidney 293 (HEK293) cells, U2OS cells, Chinese Hamster Ovary (CHO) cells. Prokaryotic cells can also be processed. The dimensions of the constriction of the device are tailored depending on the cell type to be processed. 
         [0074]    In some embodiments, the cell is a prokaryotic cell. In other embodiments, the cell is a eukaryotic cell. Non-limiting examples of eukaryotic cells include protozoan, algal, fungi, yeast, plant, animal, vertebrate, invertebrate, arthropod, mammalian, rodent, primate, and human cells. The cell may be a cell, e.g., of a unicellular organism or a multicellular organism. The cell may be, e.g., a primary eukaryotic cell or an immortalized eukaryotic cell. In some embodiments, the cell is a cancer cell. In certain embodiments, the cell is other than a human cell. For example, a composition for treating cancer and/or a method of treating cancer or preparing a composition for treating cancer, comprises treating immune cells using the gene-editing methods described herein to reduce the expression/production of immune suppressing signals from tumor cells. An example includes reduction or SHP-2 knockout for increasing immune activity towards tumors. 
         [0075]    In various embodiments, a cell may be in a mixture of two or more cell types or a plurality of cells may be a mixture of two or more cell types. A mixture of cell types may be a co-culture of multiple cell types (such as two or more of those disclosed herein) or a mixture of cell types that naturally occur together, such as in whole blood. 
         [0076]    In some embodiments, the cell is a peripheral blood mononuclear cell. In various embodiments, the cell suspension comprises a purified cell population. In certain embodiments, the cell is a primary cell or a cell line cell. 
         [0077]    In some embodiments, the cell is a blood cell. In some embodiments, the blood cell is an immune cell. In some embodiments, the immune cell is a lymphocyte. In some embodiments, the immune cell is a T cell, B cell, natural killer (NK) cell, dendritic cell (DC), Natural killer T (NKT) cell, mast cell, monocyte, macrophage, basophil, eosinophil, or neutrophil. In some embodiments, the immune cell is an adaptive immune cell such as a T cell and B cell. In some embodiments, the immune cell is an innate immune cell. Exemplary innate immune cells include innate lymphoid cells (ILCs; ILC1, ILC2, ILC3), basophils, eosinophils, mast cells, NK cells, neutrophils, and monocytes. In some embodiments, the immune cell is a memory cell. In some embodiments, the immune cell is a primary human T cell. In some embodiments, the cell is a mouse, dog, cat, horse, rat, goat, monkey, or rabbit cell. 
         [0078]    In some embodiments, the cell is a human cell. In some embodiments, the cell suspension comprises a cell other than a human cell or a non-mammalian cell. In some embodiments, the cell is a chicken, frog, insect, or nematode cell. 
         [0079]    Any physiologically-compatible or cell-compatible buffer system can be used as a solution to bathe/incubate the cells and process the cells through the device. For example, phosphate buffered saline (PBS), Opti-MEM®, Roswell Park Memorial Institute (RPMI), Dulbecco&#39;s Modified Eagle&#39;s Medium (DMEM). A reduced serum or serum-free media or buffer composition is preferable. The buffer or medium is chosen based to maintain and preserve the health or viability of the target cell and/or the effect on gene expression. For example, in some cases the presence of calcium in the buffer is desirable to promote or support mRNA expression. 
         [0080]    Payload compositions include a protein-nucleic acid complex or assembly. Exemplary complexes include components or modules of a gene editing system as described above, e.g., nuclease/guide nucleic acid combination or assembly. For example, gRNA:Cas9 molar ratio ranges from 1:100,000 to 100,000:1, e.g., a preferred range, 1:10 to 10:1, e.g., 1:1 or 1:2, 2:1. Complex concentration in the buffer to facilitate delivery (molar concentrations) typically ranges from 100 mM to 1 nM, e.g., 10 uM to 100 nM. Complexes can be mixed with cells before going through constriction or afterwards. 
         [0081]    Microfluidic Delivery of Gene Editing Complexes 
         [0082]    In order to effect gene editing manipulations, Cas protein (such as Cas9 protein), guide RNA and donor DNA can be delivered to a cell through mechanical deformation using, for example, a microfluidic platform (e.g., as described in U.S. Application Publication No. 20140287509, filed Apr. 17, 2014; PCT International Application No. PCT/US2014/051343 filed Aug. 15, 2014; PCT International Application No. PCT/US2015/060689 filed Nov. 13, 2015; and PCT International Application No. PCT/US2015/058489 filed Oct. 30, 2015, each of which is hereby incorporated by reference). 
         [0083]      FIGS. 1-2  illustrate an example microfluidic system that can be used for the delivery of genome editing protein, RNA, and DNA. The microfluidic system  5  includes a channel  10  defining a tubular lumen. The microfluidic channel  10  includes a constriction  15  that is preferably configured such that only a single target cell  20  can pass through the constriction  15  at one time. Preferably, the cells  20  pass through the channel  10  suspended in a solution buffer  25  that also includes delivery materials  30 , although the delivery materials can be added to the solution buffer  25  after the cells  20  pass through the constriction  15 . As the cell  20  approaches and passes through the constriction  15 , the constriction  15  applies pressure (e.g., mechanical compression) to the cell  20 , squeezing the cell  20  (e.g., shown as cell  20   1 ). The pressure applied to the cell by the constriction  15  causes perturbations (e.g., holes) in the cell membrane (e.g., cell  20   2 ). Once the cell passes through the constriction  15 , the cell  20  begins to uptake the material in the solution buffer  25  through the holes, including the delivery material  30  (e.g., cell  20   3 ). The cell membrane recovers over time, and at least a portion of the delivery material  30  preferably remains trapped inside the cell. 
         [0084]    In some embodiments, the device comprises a constriction length of about 5 μm to about 50 μm or any length or range of lengths therebetween. For example, the constriction length ranges from about 5 μm to about 40 μm, about 5 μm to about 30 μm, about 5 μm to about 20 μm, or about 5 μm to about 10 μm. In some embodiments, the constriction length ranges from about 10 μm to about 50 μm, about 20 μm to about 50 μm, about 30 μm to about 50 μm, or about 40 μm to about 50 μm. In some embodiments, the constriction depth ranges from about 2 μm to about 200 μm or any depth or range of depths there between. For example, the constriction depth ranges from about 2 μm to about 150 μm, about 2 μm to about 100 μm, about 2 μm to about 50 μm, about 2 μm to about 25 μm, about 2 μm to about 15 μm, or about 2 μm to about 10 μm. In some embodiments, the constriction depth ranges from about 10 μm to about 200 μm, about 25 μm to about 200 μm, about 50 μm to about 200 μm, about 100 μm to about 200 μm, or about 150 μm to about 200 μm. In some embodiments, the angle of the entrance or exit portion of the constriction ranges from about 0 degrees to about 90 degrees or any angle or range of angles therebetween. For example, the angle is about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, or about 90 degrees or more. In some embodiments, the pressure ranges from about 50 psi to about 200 psi or any pressure or range of pressures there between. For example, the pressure ranges from about 50 psi to about 150 psi, about 50 psi to about 125 psi, about 50 psi to about 100 psi, or about 50 psi to about 75 psi. In some embodiments, the pressure ranges from about 75 psi to about 200 psi, about 100 psi to about 200 psi, about 125 psi to about 200 psi, about 150 psi to about 200 psi, or about 175 psi to about 200 psi. In some embodiments, the device comprises a constriction width of between about 2 μm and about 10 μm or any width or range of widths therebetween. For example, the constriction width can be any one of about 3 μm, about 4 μm, about 5 μm, about 6 μm, or about 7 μm. 
         [0085]    The data described below was generated using the following materials and methods. Complexes were made as follows: Mix 10 μl of 1 mg/ml nuclear localization signal (NLS) tagged Cas9 protein with 5 μl of 1 mg/ml guide RNA. Incubate on ice for 20 min to allow complexes to form. For delivery, target cells are suspended at 10 million cells/ml in serum-free media. Cells and Cas9-gRNA complexes are mixed immediately before device treatment such that complex concentration is ˜0.15 mg/ml. Cells are treated by the device using pressure, temperature, chip design and buffer conditions specific to the target cell type. For example, for primary human T cells, pressure is approximately 100 psi, on ice, through a 30 μm length, 4 μm width constriction. After a 2 min incubation post-treatment, cells are diluted in media and washed to remove undelivered complexes. Cells are then cultured to allow for gene editing to occur (e.g., 1, 2, 5, 12, 24 hours or more (for non-clinical applications, timeframe depends on assay readout, e.g., 24 hours or later). For clinical use, e.g., for patient therapy, the cells could be injected back into patient immediately after device treatment. Optionally, the cells are incubated in vitro for a time (e.g., 1, 2, 5, 12, 24 hours or more) prior to injecting the cells into a patient recipient. Temperatures, concentrations, iterations of the molecules vary depending on the target cell type. 
         [0086]      FIG. 3  is a series of flow cytometry plots and a bar graph of the recombination efficiency for K562 reporter cells (American Type Culture Collection (ATCC)® CCL-243™, bone marrow-derived cells derived from patient with chronic myelogenous leukemia; lymphoblast morphology) that had genetic editing material delivered to cell cytoplasm using the microfluidic device illustrated in  FIGS. 1-2 . At top are flow cytometry plots of K562 reporter cells that had a protein Cas9, site-specific gRNA, and donor oligonucleotide delivered. A CRISPR complex is ˜150 kDa. These reporter cells had an mCherry gene and thus would normally appear in Q1 of the plots. If the site-specific DNA cleavage and insertion of donor oligonucleotide is successful it would lead to expression of green fluorescent protein (GFP), i.e., cells would appear in Q2. At bottom is a quantification of recombination efficiency based on flow cytometry for multiple device conditions as compared to endocytosis (inlet) and untreated (NC) controls. Delivery of Cas9 protein, guide RNA and donor DNA by cell squeezing led to successful changes in the genome of reporter cell lines. These data indicate that delivery of gene editing components (in the form of a complex or assembly) by mechanical cell disruption leads to effective changes in the genome. 
         [0087]    Delivery of TALEN proteins or mRNA, zinc finger nucleases, mega nucleases, Cre recombinase or any other enzyme capable of cleaving DNA can also be delivered to the cytoplasm of a cell by mechanical disruption of the cell membrane. An exemplary TALEN genome-editing system, including exemplary TALEN proteins, is described in Ding et al., (2013) Cell Stem Cell, 12, 238-251, the entire content of which is incorporated herein by reference. Ding et al., (2013) Cell Stem Cell, 12, 238-251 describes non-limiting examples of generic TALEN amino acid sequences to recognize 15 base pair sequences. Non-limiting examples of generic TALEN amino acid sequences are: 
         [0000]    
       
         
               
             
               
             
               
             
               
             
           
               
                 (SEQ ID NO: 65) 
               
             
          
           
               
                 MDYKDHDGDYKDHDIDYKDDDDKMAPKKKRKVGIHGVPSR VDLRTLGYSQ   
               
               
                   
               
               
                 
                   QQQEKIKPKVRSTVAQHHEALVGHGFTHAHIVALSQHPAALGTVAVTYQN 
                 
               
               
                   
               
               
                 
                   IITALPEATHEDIVGVGKQWSGAPALEALLTDAGELRGPPLQLDTGQLVK 
                 
               
               
                   
               
               
                   IAKRGGVTAMEAVHASRNALTGAPLN LTPEQVVAIAS XX GGKQALETVQR 
               
               
                   
               
               
                 LLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQPLLPVLCQAHGLTPEQV 
               
               
                   
               
               
                 VAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETV 
               
               
                   
               
               
                 QPLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTPE 
               
               
                   
               
               
                 QVVAIAS XX GGKQALETVQPLLPVLCQAHGLTPEQVVAIAS XX GGKQALE 
               
               
                   
               
               
                 TVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQPLLPVLCQAHGLT 
               
               
                   
               
               
                 PEQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQA 
               
               
                   
               
               
                 LETVQPLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAHG 
               
               
                   
               
               
                 LTPEQVVAIAS XX GGKQALETVQPLLPVLCQAHGLTPEQVVAIAS XX GGK 
               
               
                   
               
               
                 QALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQPLLPVLCQA 
               
               
                   
               
               
                 HGLTPEQVVAIAS XX GGRPALE SIVAQLSRPDPALAALTNDHLVALACLG   
               
               
                   
               
               
                   GRPAMDAVKKGLPHAPELIRRVNRRIGERTSHRVA GSQLVKSELEEKKSE 
               
               
                   
               
               
                 LRHKLKYVPHEYIELIEIARNPTQDRILEMKVMEFFMKVYGYPGEHLGGS 
               
               
                   
               
               
                 RKPDGAIYTVGSPIDYGVIVDTKAYSGGYNLPIGQADEMQRYVKENQTRN 
               
               
                   
               
               
                 KHINPNEWWKVYPSSVTEFKFLFVSGHFKGNYKAQLTRLNRKTNVNGAVL 
               
               
                   
               
               
                 SVEELLIGGEMTKAGTLTLEEVRRKFNNGEINF 
               
               
                   
               
             
          
           
               
                 (SEQ ID NO: 66) 
               
             
          
           
               
                 MDYKDHDGDYKDHDIDYKDDDKMAPKKKRKVGIHGVPAR VDLRTLGYSQQ   
               
               
                   
               
               
                 
                   QQEKIKPKVRSTVACHHEALVGHGFTHAHIVALSQHPAALGTVAVTYQHI 
                 
               
               
                   
               
               
                 
                   ITALPEATHEDIVGVGKQWSGARALEALLTDAGELRGPPLQLDTGQLVKI 
                 
               
               
                   
               
               
                   AKRGGVTAMEAVHASRNALTGAPLN LTPEQVVAIAS XX GGKQALETVQRL 
               
               
                   
               
               
                 LPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVV 
               
               
                   
               
               
                 AIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQ 
               
               
                   
               
               
                 RLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQ 
               
               
                   
               
               
                 VVAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALET 
               
               
                   
               
               
                 VQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTP 
               
               
                   
               
               
                 EQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQAL 
               
               
                   
               
               
                 ETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAHGL 
               
               
                   
               
               
                 TPEQVVAIAS XX GGKQALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQ 
               
               
                   
               
               
                 ALETVQRLLPVLCQAHGLTPEQVVAIAS XX GGKQALETVQRLLPVLCQAH 
               
               
                   
               
               
                 GLTPEQVVAIAS XX GGRPALE SIVAQLSRPDPALAALTNDHLVALACLGG   
               
               
                   
               
               
                   RPAMDAVKKGLPHAPELIRRVNRRIGERTSHRVA GSQLVKSELEEKKSEL 
               
               
                   
               
               
                 RHKLKYVPHEYIELIEIARNPTQDRILEMKVMEFFMKVYGYPGEHLGGSR 
               
               
                   
               
               
                 KPDGAIYTVGSPIDYGVIVDTKAYSGGYNLPIGQADEMERYVEENQTRDK 
               
               
                   
               
               
                 HLNPNEWWKVYPSSVTEFKFLFVSGHFKGNYKAQLTRLNHITNCNGAVLS 
               
               
                   
               
               
                 VEELLIGGEMIKAGTLTLEEVRRKFNNGEINF 
               
             
          
         
       
     
         [0088]    In SEQ ID NOS: 65 and 66, to recognize C: XX=HD; to recognize T: XX=NG; to recognize A: XX=NI; and to recognize G: XX=NN except in the last position where XX=NK. Underline indicates N-term and C-term of TAL effector. 
         [0089]    Although a few variations have been described in detail above, other modifications or additions are possible. For example, genetic editing material can include TALEN proteins, TALEN mRNA, zinc finger nucleases, mega nucleases, Cre recombinase or any other enzyme capable of cleaving DNA delivered to the cytosol by mechanical disruption of the cell membrane. 
         [0090]    Delivery of RNA and Cas9 in Complex Form 
         [0091]    The results achieved were surprising in view of numerous factors that could potentially have impeded successful gene editing by microfluidic delivery of the gene complexes. For example, the Cas9-gRNA complex may have caused a Toll-like receptor (TLR) mediated or other PRR (pattern recognition receptor) mediated response that would have inhibited gene editing function and/or survival but this potential problem was not observed. Since the complex is not guaranteed to be stable once it enters the cytoplasm, it could have been degraded and rendered non-functional, but surprisingly, the delivered complexes were still able to edit. 
         [0092]    The integrity of the gene editing complex was preserved using microfluidic based, cell-squeezing delivery to the cell. The complex does not have the same physical/chemical properties as a gRNA alone or protein alone and thus it was uncertain if the delivery process would behave the same in the context of delivering a complex vs. its individual components. Complexes are larger and less stable than their constituents. Complexes may fall apart due to, e.g., shear forces. Additionally, complexes may not survive membrane transit or in the cytosol because some other elements may break the complexes up before they are functional or have an opportunity to act on cellular targets. Complexes also have a different charge distribution which may affect the ability of a complex to be delivered. Shape and thus transport properties can also change compared to complex constituents. The delivery methods successfully preserved the structural and functional integrity of the complexes. 
         [0093]    The shear forces involved with the delivery process could potentially have disrupted the Protein/gRNA complex and rendered it non-functional but surprisingly the delivery system was effective to introduce the complexes into the cell and the gene editing still worked. It was also not obvious that the complex would still have the appropriate nuclear localization behavior as compared to an uncomplexed Cas (such as Cas9) protein alone with NLS; however, the behavior and function was preserved throughout the process as demonstrated by the gene expression results described above. 
         [0094]    The CRISPR-Cas system is known in the art. Non-limiting aspects of this system are described in U.S. Pat. No. 8,697,359, issued Apr. 15, 2014, the entire content of which is incorporated herein by reference. 
         [0095]    Non-limiting examples of Cas proteins include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csn1 and Csx12), Cas10, Csy1, Csy2, Csy3, Cse1, Cse2, Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1, Csf2, Csf3, Csf4, homologs thereof, or modified versions thereof. These enzymes are known; for example, the amino acid sequence of  S. pyogenes  Cas9 protein may be found in the SwissProt database under accession number Q99ZW2. In some embodiments, the unmodified CRISPR enzyme has DNA cleavage activity, such as Cas9. In some embodiments the CRISPR enzyme is Cas9, and may be Cas9 from  S. pyogenes  or  S. pneumoniae . In some embodiments, the CRISPR enzyme directs cleavage of one or both strands at the location of a target sequence, such as within the target sequence and/or within the complement of the target sequence. In some embodiments, the CRISPR enzyme directs cleavage of one or both strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. In some embodiments, a vector encodes a CRISPR enzyme that is mutated to with respect to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence. For example, an aspartate-to-alanine substitution (D10A) in the RuvC I catalytic domain of Cas9 from  S. pyogenes  converts Cas9 from a nuclease that cleaves both strands to a nickase (cleaves a single strand). Other examples of mutations that render Cas9 a nickase include, without limitation, H840A, N854A, and N863A. In aspects of the invention, nickases may be used for genome editing via homologous recombination. 
         [0096]    Non-limiting examples of Cas9 amino acid and cDNA sequences are provided below. 
         [0097]    The amino acid sequence of a  Streptococcus pyogenes  Cas9 protein may be found in the SwissProt database under accession number Q99ZW2. This amino acid sequence is: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 1) 
               
             
          
           
               
                 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGA 
               
               
                   
               
               
                 LLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHR 
               
               
                   
               
               
                 LEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD 
               
               
                   
               
               
                 LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENP 
               
               
                   
               
               
                 INASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTP 
               
               
                   
               
               
                 NFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI 
               
               
                   
               
               
                 LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEI 
               
               
                   
               
               
                 FFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLR 
               
               
                   
               
               
                 KQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPY 
               
               
                   
               
               
                 YVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDK 
               
               
                   
               
               
                 NLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVD 
               
               
                   
               
               
                 LLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI 
               
               
                   
               
               
                 IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQ 
               
               
                   
               
               
                 LKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDD 
               
               
                   
               
               
                 SLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKV 
               
               
                   
               
               
                 MGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHP 
               
               
                   
               
               
                 VENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDD 
               
               
                   
               
               
                 SIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL 
               
               
                   
               
               
                 TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLI 
               
               
                   
               
               
                 REVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKK 
               
               
                   
               
               
                 YPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEI 
               
               
                   
               
               
                 TLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEV 
               
               
                   
               
               
                 QTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVE 
               
               
                   
               
               
                 KGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK 
               
               
                   
               
               
                 YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPE 
               
               
                   
               
               
                 DNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDK 
               
               
                   
               
               
                 PIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQ 
               
               
                   
               
               
                 SITGLYETRIDLSQLGGD 
               
             
          
         
       
     
         [0098]    SEQ ID NO: 1 may be encoded by the following nucleotide sequence found in the European Nucleotide Archive under accession number AAK33936.2: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 2) 
               
             
          
           
               
                 ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACAAATAGCGTCGG 
               
               
                   
               
               
                 ATGGGCGGTGATCACTGATGAATATAAGGTTCCGTCTAAAAAGTTCAAGG 
               
               
                   
               
               
                 TTCTGGGAAATACAGACCGCCACAGTATCAAAAAAAATCTTATAGGGGCT 
               
               
                   
               
               
                 CTTTTATTTGACAGTGGAGAGACAGCGGAAGCGACTCGTCTCAAACGGAC 
               
               
                   
               
               
                 AGCTCGTAGAAGGTATACACGTCGGAAGAATCGTATTTGTTATCTACAGG 
               
               
                   
               
               
                 AGATTTTTTCAAATGAGATGGCGAAAGTAGATGATAGTTTCTTTCATCGA 
               
               
                   
               
               
                 CTTGAAGAGTCTTTTTTGGTGGAAGAAGACAAGAAGCATGAACGTCATCC 
               
               
                   
               
               
                 TATTTTTGGAAATATAGTAGATGAAGTTGCTTATCATGAGAAATATCCAA 
               
               
                   
               
               
                 CTATCTATCATCTGCGAAAAAAATTGGTAGATTCTACTGATAAAGCGGAT 
               
               
                   
               
               
                 TTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTGGTCA 
               
               
                   
               
               
                 TTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGATGTGGACAAAC 
               
               
                   
               
               
                 TATTTATCCAGTTGGTACAAACCTACAATCAATTATTTGAAGAAAACCCT 
               
               
                   
               
               
                 ATTAACGCAAGTGGAGTAGATGCTAAAGCGATTCTTTCTGCACGATTGAG 
               
               
                   
               
               
                 TAAATCAAGACGATTAGAAAATCTCATTGCTCAGCTCCCCGGTGAGAAGA 
               
               
                   
               
               
                 AAAATGGCTTATTTGGGAATCTCATTGCTTTGTCATTGGGTTTGACCCCT 
               
               
                   
               
               
                 AATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTC 
               
               
                   
               
               
                 AAAAGATACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAG 
               
               
                   
               
               
                 ATCAATATGCTGATTTGTTTTTGGCAGCTAAGAATTTATCAGATGCTATT 
               
               
                   
               
               
                 TTACTTTCAGATATCCTAAGAGTAAATACTGAAATAACTAAGGCTCCCCT 
               
               
                   
               
               
                 ATCAGCTTCAATGATTAAACGCTACGATGAACATCATCAAGACTTGACTC 
               
               
                   
               
               
                 TTTTAAAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATC 
               
               
                   
               
               
                 TTTTTTGATCAATCAAAAAACGGATATGCAGGTTATATTGATGGGGGAGC 
               
               
                   
               
               
                 TAGCCAAGAAGAATTTTATAAATTTATCAAACCAATTTTAGAAAAAATGG 
               
               
                   
               
               
                 ATGGTACTGAGGAATTATTGGTGAAACTAAATCGTGAAGATTTGCTGCGC 
               
               
                   
               
               
                 AAGCAACGGACCTTTGACAACGGCTCTATTCCCCATCAAATTCACTTGGG 
               
               
                   
               
               
                 TGAGCTGCATGCTATTTTGAGAAGACAAGAAGACTTTTATCCATTTTTAA 
               
               
                   
               
               
                 AAGACAATCGTGAGAAGATTGAAAAAATCTTGACTTTTCGAATTCCTTAT 
               
               
                   
               
               
                 TATGTTGGTCCATTGGCGCGTGGCAATAGTCGTTTTGCATGGATGACTCG 
               
               
                   
               
               
                 GAAGTCTGAAGAAACAATTACCCCATGGAATTTTGAAGAAGTTGTCGATA 
               
               
                   
               
               
                 AAGGTGCTTCAGCTCAATCATTTATTGAACGCATGACAAACTTTGATAAA 
               
               
                   
               
               
                 AATCTTCCAAATGAAAAAGTACTACCAAAACATAGTTTGCTTTATGAGTA 
               
               
                   
               
               
                 TTTTACGGTTTATAACGAATTGACAAAGGTCAAATATGTTACTGAAGGAA 
               
               
                   
               
               
                 TGCGAAAACCAGCATTTCTTTCAGGTGAACAGAAGAAAGCCATTGTTGAT 
               
               
                   
               
               
                 TTACTCTTCAAAACAAATCGAAAAGTAACCGTTAAGCAATTAAAAGAAGA 
               
               
                   
               
               
                 TTATTTCAAAAAAATAGAATGTTTTGATAGTGTTGAAATTTCAGGAGTTG 
               
               
                   
               
               
                 AAGATAGATTTAATGCTTCATTAGGTACCTACCATGATTTGCTAAAAATT 
               
               
                   
               
               
                 ATTAAAGATAAAGATTTTTTGGATAATGAAGAAAATGAAGATATCTTAGA 
               
               
                   
               
               
                 GGATATTGTTTTAACATTGACCTTATTTGAAGATAGGGAGATGATTGAGG 
               
               
                   
               
               
                 AAAGACTTAAAACATATGCTCACCTCTTTGATGATAAGGTGATGAAACAG 
               
               
                   
               
               
                 CTTAAACGTCGCCGTTATACTGGTTGGGGACGTTTGTCTCGAAAATTGAT 
               
               
                   
               
               
                 TAATGGTATTAGGGATAAGCAATCTGGCAAAACAATATTAGATTTTTTGA 
               
               
                   
               
               
                 AATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGAT 
               
               
                   
               
               
                 AGTTTGACATTTAAAGAAGACATTCAAAAAGCACAAGTGTCTGGACAAGG 
               
               
                   
               
               
                 CGATAGTTTACATGAACATATTGCAAATTTAGCTGGTAGCCCTGCTATTA 
               
               
                   
               
               
                 AAAAAGGTATTTTACAGACTGTAAAAGTTGTTGATGAATTGGTCAAAGTA 
               
               
                   
               
               
                 ATGGGGCGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACGTGAAAA 
               
               
                   
               
               
                 TCAGACAACTCAAAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAA 
               
               
                   
               
               
                 TCGAAGAAGGTATCAAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCT 
               
               
                   
               
               
                 GTTGAAAATACTCAATTGCAAAATGAAAAGCTCTATCTCTATTATCTCCA 
               
               
                   
               
               
                 AAATGGAAGAGACATGTATGTGGACCAAGAATTAGATATTAATCGTTTAA 
               
               
                   
               
               
                 GTGATTATGATGTCGATCACATTGTTCCACAAAGTTTCCTTAAAGACGAT 
               
               
                   
               
               
                 TCAATAGACAATAAGGTCTTAACGCGTTCTGATAAAAATCGTGGTAAATC 
               
               
                   
               
               
                 GGATAACGTTCCAAGTGAAGAAGTAGTCAAAAAGATGAAAAACTATTGGA 
               
               
                   
               
               
                 GACAACTTCTAAACGCCAAGTTAATCACTCAACGTAAGTTTGATAATTTA 
               
               
                   
               
               
                 ACGAAAGCTGAACGTGGAGGTTTGAGTGAACTTGATAAAGCTGGTTTTAT 
               
               
                   
               
               
                 CAAACGCCAATTGGTTGAAACTCGCCAAATCACTAAGCATGTGGCACAAA 
               
               
                   
               
               
                 TTTTGGATAGTCGCATGAATACTAAATACGATGAAAATGATAAACTTATT 
               
               
                   
               
               
                 CGAGAGGTTAAAGTGATTACCTTAAAATCTAAATTAGTTTCTGACTTCCG 
               
               
                   
               
               
                 AAAAGATTTCCAATTCTATAAAGTACGTGAGATTAACAATTACCATCATG 
               
               
                   
               
               
                 CCCATGATGCGTATCTAAATGCCGTCGTTGGAACTGCTTTGATTAAGAAA 
               
               
                   
               
               
                 TATCCAAAACTTGAATCGGAGTTTGTCTATGGTGATTATAAAGTTTATGA 
               
               
                   
               
               
                 TGTTCGTAAAATGATTGCTAAGTCTGAGCAAGAAATAGGCAAAGCAACCG 
               
               
                   
               
               
                 CAAAATATTTCTTTTACTCTAATATCATGAACTTCTTCAAAACAGAAATT 
               
               
                   
               
               
                 ACACTTGCAAATGGAGAGATTCGCAAACGCCCTCTAATCGAAACTAATGG 
               
               
                   
               
               
                 GGAAACTGGAGAAATTGTCTGGGATAAAGGGCGAGATTTTGCCACAGTGC 
               
               
                   
               
               
                 GCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGAAAACAGAAGTA 
               
               
                   
               
               
                 CAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGAAATTCGGA 
               
               
                   
               
               
                 CAAGCTTATTGCTCGTAAAAAAGACTGGGATCCAAAAAAATATGGTGGTT 
               
               
                   
               
               
                 TTGATAGTCCAACGGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAA 
               
               
                   
               
               
                 AAAGGGAAATCGAAGAAGTTAAAATCCGTTAAAGAGTTACTAGGGATCAC 
               
               
                   
               
               
                 AATTATGGAAAGAAGTTCCTTTGAAAAAAATCCGATTGACTTTTTAGAAG 
               
               
                   
               
               
                 CTAAAGGATATAAGGAAGTTAAAAAAGACTTAATCATTAAACTACCTAAA 
               
               
                   
               
               
                 TATAGTCTTTTTGAGTTAGAAAACGGTCGTAAACGGATGCTGGCTAGTGC 
               
               
                   
               
               
                 CGGAGAATTACAAAAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGA 
               
               
                   
               
               
                 ATTTTTTATATTTAGCTAGTCATTATGAAAAGTTGAAGGGTAGTCCAGAA 
               
               
                   
               
               
                 GATAACGAACAAAAACAATTGTTTGTGGAGCAGCATAAGCATTATTTAGA 
               
               
                   
               
               
                 TGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTTTAGCAG 
               
               
                   
               
               
                 ATGCCAATTTAGATAAAGTTCTTAGTGCATATAACAAACATAGAGACAAA 
               
               
                   
               
               
                 CCAATACGTGAACAAGCAGAAAATATTATTCATTTATTTACGTTGACGAA 
               
               
                   
               
               
                 TCTTGGAGCTCCCGCTGCTTTTAAATATTTTGATACAACAATTGATCGTA 
               
               
                   
               
               
                 AACGATATACGTCTACAAAAGAAGTTTTAGATGCCACTCTTATCCATCAA 
               
               
                   
               
               
                 TCCATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAGCTAGGAGG 
               
               
                   
               
               
                 TGACTGA 
               
             
          
         
       
     
         [0099]    The amino acid sequence of a  Streptococcus thermophilus  Cas9 protein may be found in the UniProt database under accession number Q03J16.1. See also, Sapranauskas et al., (2011) Nucleic Acids Res. 39:9275-9282. This amino acid sequence is: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 3) 
               
             
          
           
               
                 MTKPYSIGLDIGTNSVGWAVTTDNYKVPSKKMKVLGNTSKKYIKKNLLGV 
               
               
                   
               
               
                 LLFDSGITAEGRRLKRTARRRYTRRRNRILYLQEIFSTEMATLDDAFFQR 
               
               
                   
               
               
                 LDDSFLVPDDKRDSKYPIFGNLVEEKAYHDEFPTIYHLRKYLADSTKKAD 
               
               
                   
               
               
                 LRLVYLALAHMIKYRGHFLIEGEFNSKNNDIQKNFQDFLDTYNAIFESDL 
               
               
                   
               
               
                 SLENSKQLEEIVKDKISKLEKKDRILKLFPGEKNSGIFSEFLKLIVGNQA 
               
               
                   
               
               
                 DFRKCFNLDEKASLHFSKESYDEDLETLLGYIGDDYSDVFLKAKKLYDAI 
               
               
                   
               
               
                 LLSGFLTVTDNETEAPLSSAMIKRYNEHKEDLALLKEYIRNISLKTYNEV 
               
               
                   
               
               
                 FKDDTKNGYAGYIDGKTNQEDFYVYLKKLLAEFEGADYFLEKIDREDFLR 
               
               
                   
               
               
                 KQRTFDNGSIPYQIHLQEMRAILDKQAKFYPFLAKNKERIEKILTFRIPY 
               
               
                   
               
               
                 YVGPLARGNSDFAWSIRKRNEKITPWNFEDVIDKESSAEAFINRMTSFDL 
               
               
                   
               
               
                 YLPEEKVLPKHSLLYETFNVYNELTKVRFIAESMRDYQFLDSKQKKDIVR 
               
               
                   
               
               
                 LYFKDKRKVTDKDIIEYLHAIYGYDGIELKGIEKQFNSSLSTYHDLLNII 
               
               
                   
               
               
                 NDKEFLDDSSNEAIIEEIIHTLTIFEDREMIKQRLSKFENIFDKSVLKKL 
               
               
                   
               
               
                 SRRHYTGWGKLSAKLINGIRDEKSGNTILDYLIDDGISNRNFMQLIHDDA 
               
               
                   
               
               
                 LSFKKKIQKAQIIGDEDKGNIKEVVKSLPGSPAIKKGILQSIKIVDELVK 
               
               
                   
               
               
                 VMGGRKPESIVVEMARENQYTNQGKSNSQQRLKRLEKSLKELGSKILKEN 
               
               
                   
               
               
                 IPAKLSKIDNNALQNDRLYLYYLQNGKDMYTGDDLDIDRLSNYDIDHIIP 
               
               
                   
               
               
                 QAFLKDNSIDNKVLVSSASNRGKSDDVPSLEVVKKRKTFWYQLLKSKLIS 
               
               
                   
               
               
                 QRKFDNLTKAERGGLSPEDKAGFIQRQLVETRQITKHVARLLDEKFNNKK 
               
               
                   
               
               
                 DENNRAVRTVKIITLKSTLVSQFRKDFELYKVREINDFHHAHDAYLNAVV 
               
               
                   
               
               
                 ASALLKKYPKLEPEFVYGDYPKYNSFRERKSATEKVYFYSNIMNIFKKSI 
               
               
                   
               
               
                 SLADGRVIERPLIEVNEETGESVWNKESDLATVRRVLSYPQVNVVKKVEE 
               
               
                   
               
               
                 QNHGLDRGKPKGLFNANLSSKPKPNSNENLVGAKEYLDPKKYGGYAGISN 
               
               
                   
               
               
                 SFTVLVKGTIEKGAKKKITNVLEFQGISILDRINYRKDKLNFLLEKGYKD 
               
               
                   
               
               
                 IELIIELPKYSLFELSDGSRRMLASILSTNNKRGEIHKGNQIFLSQKFVK 
               
               
                   
               
               
                 LLYHAKRISNTINENHRKYVENHKKEFEELFYYILEFNENYVGAKKNGKL 
               
               
                   
               
               
                 LNSAFQSWQNHSIDELCSSFIGPTGSERKGLFELTSRGSAADFEFLGVKI 
               
               
                   
               
               
                 PRYRDYTPSSLLKDATLIHQSVTGLYETRIDLAKLGEG 
               
             
          
         
       
     
         [0100]    SEQ ID NO: 3 may be encoded by the following nucleotide sequence found in the European Nucleotide Archive under accession number ABJ66636.1: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 4) 
               
             
          
           
               
                 ATGACTAAGCCATACTCAATTGGACTTGATATTGGAACGAATAGTGTTGG 
               
               
                   
               
               
                 ATGGGCTGTAACAACTGATAATTACAAGGTTCCGTCTAAAAAAATGAAAG 
               
               
                   
               
               
                 TCTTAGGAAATACGAGTAAAAAGTATATCAAAAAGAACCTGTTAGGTGTA 
               
               
                   
               
               
                 TTACTCTTTGACTCTGGAATCACAGCAGAAGGAAGAAGATTGAAGCGTAC 
               
               
                   
               
               
                 TGCAAGAAGACGTTATACTAGACGCCGTAATCGTATCCTTTATTTGCAGG 
               
               
                   
               
               
                 AAATTTTTAGCACAGAGATGGCTACATTAGATGATGCTTTCTTTCAAAGA 
               
               
                   
               
               
                 CTTGACGATTCGTTTTTAGTTCCTGATGATAAACGTGATAGTAAGTATCC 
               
               
                   
               
               
                 GATATTTGGAAACTTAGTAGAAGAAAAAGCCTATCATGATGAATTTCCAA 
               
               
                   
               
               
                 CTATCTATCATTTAAGGAAATATTTAGCAGATAGTACTAAAAAAGCAGAT 
               
               
                   
               
               
                 TTGCGTCTAGTTTATCTTGCATTGGCTCATATGATTAAATATAGAGGTCA 
               
               
                   
               
               
                 CTTCTTAATTGAAGGAGAGTTTAATTCAAAAAATAATGATATTCAGAAGA 
               
               
                   
               
               
                 ATTTTCAAGACTTTTTGGACACTTATAATGCTATTTTTGAATCGGATTTA 
               
               
                   
               
               
                 TCACTTGAGAATAGTAAACAACTTGAGGAAATTGTTAAAGATAAGATTAG 
               
               
                   
               
               
                 TAAATTAGAAAAGAAAGATCGTATTTTAAAACTCTTCCCTGGGGAGAAGA 
               
               
                   
               
               
                 ATTCGGGGATTTTTTCAGAGTTTCTAAAGTTGATTGTAGGAAATCAAGCT 
               
               
                   
               
               
                 GATTTTAGGAAATGTTTTAATTTAGACGAAAAAGCCTCCTTACATTTTTC 
               
               
                   
               
               
                 CAAAGAAAGCTATGATGAAGATTTAGAGACTTTGTTAGGTTATATTGGAG 
               
               
                   
               
               
                 ATGATTACAGTGATGTCTTTCTCAAAGCAAAGAAACTTTATGATGCTATT 
               
               
                   
               
               
                 CTTTTATCGGGTTTTCTGACTGTAACTGATAATGAGACAGAAGCACCTCT 
               
               
                   
               
               
                 CTCTTCTGCTATGATAAAGCGATATAATGAACACAAAGAAGATTTAGCGT 
               
               
                   
               
               
                 TACTAAAGGAATATATAAGAAATATTTCACTAAAAACGTATAATGAAGTA 
               
               
                   
               
               
                 TTTAAAGATGACACCAAAAATGGTTATGCTGGTTATATTGATGGAAAAAC 
               
               
                   
               
               
                 AAATCAGGAAGATTTCTACGTATATCTAAAAAAACTATTGGCTGAATTTG 
               
               
                   
               
               
                 AAGGTGCGGATTATTTTCTTGAAAAAATTGATCGAGAAGATTTTTTGAGA 
               
               
                   
               
               
                 AAGCAACGTACATTTGACAATGGTTCGATACCATATCAGATTCATCTTCA 
               
               
                   
               
               
                 AGAAATGAGAGCAATTCTTGATAAGCAAGCTAAATTTTATCCTTTCTTGG 
               
               
                   
               
               
                 CTAAAAATAAAGAAAGAATCGAGAAGATTTTAACCTTCCGAATTCCTTAT 
               
               
                   
               
               
                 TATGTAGGTCCACTTGCGAGAGGGAATAGTGATTTTGCCTGGTCAATAAG 
               
               
                   
               
               
                 AAAACGAAATGAAAAAATTACACCTTGGAATTTTGAGGACGTTATTGACA 
               
               
                   
               
               
                 AAGAATCTTCGGCAGAGGCCTTCATTAATCGAATGACTAGTTTTGATTTG 
               
               
                   
               
               
                 TATTTGCCAGAAGAGAAGGTACTTCCAAAGCATAGTCTCTTATACGAAAC 
               
               
                   
               
               
                 TTTTAATGTATATAATGAATTAACAAAAGTTAGATTTATTGCCGAAAGTA 
               
               
                   
               
               
                 TGAGAGATTATCAATTTTTAGATAGTAAGCAGAAGAAAGATATTGTTAGA 
               
               
                   
               
               
                 CTTTATTTTAAAGATAAAAGGAAAGTTACTGATAAGGATATTATTGAATA 
               
               
                   
               
               
                 TTTACATGCAATTTATGGGTATGATGGAATTGAATTAAAAGGCATAGAGA 
               
               
                   
               
               
                 AACAGTTTAATTCTAGTTTATCTACTTATCACGATCTTTTAAATATTATT 
               
               
                   
               
               
                 AATGATAAAGAGTTTTTGGATGATAGTTCAAATGAAGCGATTATCGAAGA 
               
               
                   
               
               
                 AATTATCCATACTTTGACAATTTTTGAAGATAGAGAGATGATAAAACAAC 
               
               
                   
               
               
                 GTCTTTCAAAATTTGAGAATATATTCGATAAATCCGTTTTGAAAAAGTTA 
               
               
                   
               
               
                 TCTCGTAGACATTACACTGGCTGGGGTAAGTTATCTGCTAAGCTTATTAA 
               
               
                   
               
               
                 TGGTATTCGAGATGAAAAATCTGGTAATACTATTCTTGATTACTTAATTG 
               
               
                   
               
               
                 ATGATGGTATTTCTAACCGTAATTTCATGCAACTTATTCACGATGATGCT 
               
               
                   
               
               
                 CTTTCTTTTAAAAAGAAGATACAGAAAGCACAAATTATTGGTGACGAAGA 
               
               
                   
               
               
                 TAAAGGTAATATTAAAGAGGTCGTTAAGTCTTTGCCAGGTAGTCCTGCGA 
               
               
                   
               
               
                 TTAAAAAAGGTATTTTACAAAGCATAAAAATTGTAGATGAATTGGTCAAA 
               
               
                   
               
               
                 GTAATGGGAGGAAGAAAACCCGAGTCAATTGTTGTTGAGATGGCTCGTGA 
               
               
                   
               
               
                 AAATCAATATACCAATCAAGGTAAGTCTAATTCCCAACAACGCTTGAAAC 
               
               
                   
               
               
                 GTTTAGAAAAATCTCTCAAAGAGTTAGGTAGTAAGATACTTAAGGAAAAT 
               
               
                   
               
               
                 ATTCCTGCAAAACTTTCTAAAATAGACAATAACGCACTTCAAAATGATCG 
               
               
                   
               
               
                 ACTTTACTTATACTATCTTCAAAATGGAAAAGATATGTATACCGGAGATG 
               
               
                   
               
               
                 ATTTAGATATTGATAGATTAAGTAATTATGATATTGATCATATTATTCCT 
               
               
                   
               
               
                 CAAGCTTTTTTGAAAGATAATTCTATTGACAATAAAGTACTTGTTTCATC 
               
               
                   
               
               
                 TGCTAGTAACCGTGGTAAATCAGATGATGTTCCAAGTTTAGAGGTTGTCA 
               
               
                   
               
               
                 AAAAAAGAAAGACATTTTGGTATCAATTATTGAAATCAAAATTAATTTCT 
               
               
                   
               
               
                 CAACGAAAATTTGATAATCTGACAAAAGCTGAACGGGGAGGATTGTCACC 
               
               
                   
               
               
                 TGAGGACAAAGCTGGTTTTATTCAACGCCAGTTGGTTGAAACACGTCAAA 
               
               
                   
               
               
                 TAACAAAACATGTAGCTCGTTTACTTGATGAGAAATTTAATAATAAAAAA 
               
               
                   
               
               
                 GATGAAAATAATAGAGCGGTACGAACAGTAAAAATTATTACCTTGAAATC 
               
               
                   
               
               
                 TACCTTAGTTTCTCAATTTCGTAAGGATTTTGAACTTTATAAAGTTCGTG 
               
               
                   
               
               
                 AAATCAATGATTTTCATCATGCTCATGATGCTTACTTGAATGCCGTTGTA 
               
               
                   
               
               
                 GCAAGTGCTTTACTTAAGAAATACCCTAAACTAGAGCCAGAATTTGTGTA 
               
               
                   
               
               
                 CGGTGATTATCCAAAATACAATAGTTTTAGAGAAAGAAAGTCCGCTACAG 
               
               
                   
               
               
                 AAAAGGTATATTTCTATTCAAATATCATGAATATCTTTAAAAAATCTATT 
               
               
                   
               
               
                 TCTTTAGCTGATGGTAGAGTTATTGAAAGACCACTTATTGAGGTAAATGA 
               
               
                   
               
               
                 GGAGACCGGCGAATCCGTTTGGAATAAAGAATCTGATTTAGCAACTGTAA 
               
               
                   
               
               
                 GGAGAGTACTCTCTTATCCGCAAGTAAATGTTGTGAAAAAAGTTGAGGAA 
               
               
                   
               
               
                 CAGAATCACGGATTGGATAGAGGAAAACCAAAGGGATTGTTTAATGCAAA 
               
               
                   
               
               
                 TCTTTCCTCAAAGCCAAAACCAAATAGTAATGAAAATTTAGTAGGTGCTA 
               
               
                   
               
               
                 AAGAGTATCTTGACCCCAAAAAGTATGGGGGGTATGCTGGAATTTCTAAT 
               
               
                   
               
               
                 TCTTTTACTGTTCTTGTTAAAGGGACAATTGAAAAAGGTGCTAAGAAAAA 
               
               
                   
               
               
                 AATAACAAATGTACTAGAATTTCAAGGTATTTCTATTTTAGATAGGATTA 
               
               
                   
               
               
                 ATTATAGAAAAGATAAACTTAATTTTTTACTTGAAAAAGGTTATAAAGAT 
               
               
                   
               
               
                 ATTGAGTTAATTATTGAACTACCTAAATATAGTTTATTTGAACTTTCAGA 
               
               
                   
               
               
                 TGGTTCACGTCGTATGTTGGCTAGTATTTTGTCAACGAATAATAAGAGGG 
               
               
                   
               
               
                 GAGAGATTCACAAAGGAAATCAGATTTTTCTTTCACAGAAGTTTGTGAAA 
               
               
                   
               
               
                 TTACTTTATCATGCTAAGAGAATAAGTAACACAATTAATGAGAATCATAG 
               
               
                   
               
               
                 AAAATATGTTGAGAACCATAAAAAAGAGTTTGAAGAATTATTTTACTACA 
               
               
                   
               
               
                 TTCTTGAGTTTAATGAGAATTATGTTGGAGCTAAAAAGAATGGTAAACTC 
               
               
                   
               
               
                 TTAAACTCTGCCTTTCAATCTTGGCAAAATCATAGTATAGATGAACTCTG 
               
               
                   
               
               
                 TAGTAGTTTTATAGGACCTACCGGAAGTGAAAGAAAGGGGCTATTTGAAT 
               
               
                   
               
               
                 TAACCTCTCGTGGAAGTGCTGCTGATTTTGAATTTTTAGGTGTTAAAATT 
               
               
                   
               
               
                 CCAAGGTATAGAGACTATACCCCATCATCCCTATTAAAAGATGCCACACT 
               
               
                   
               
               
                 TATTCATCAATCTGTTACAGGCCTCTATGAAACACGAATAGACCTTGCCA 
               
               
                   
               
               
                 AACTAGGAGAGGGTTAA 
               
             
          
         
       
     
         [0101]    An example of a Cas9 protein comprising a nuclear localization signal (GGSGPPKKKRKV; SEQ ID NO: 5) at the C-terminus thereof has the following amino acid sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 6) 
               
             
          
           
               
                 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGA 
               
               
                   
               
               
                 LLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHR 
               
               
                   
               
               
                 LEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKAD 
               
               
                   
               
               
                 LRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENP 
               
               
                   
               
               
                 INASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTP 
               
               
                   
               
               
                 NFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAI 
               
               
                   
               
               
                 LLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEI 
               
               
                   
               
               
                 FFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLR 
               
               
                   
               
               
                 KQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPY 
               
               
                   
               
               
                 YVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDK 
               
               
                   
               
               
                 NLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVD 
               
               
                   
               
               
                 LLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI 
               
               
                   
               
               
                 IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQ 
               
               
                   
               
               
                 LKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDD 
               
               
                   
               
               
                 SLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKV 
               
               
                   
               
               
                 MGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHP 
               
               
                   
               
               
                 VENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDD 
               
               
                   
               
               
                 SIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNL 
               
               
                   
               
               
                 TKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLI 
               
               
                   
               
               
                 REVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKK 
               
               
                   
               
               
                 YPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEI 
               
               
                   
               
               
                 TLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEV 
               
               
                   
               
               
                 QTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVE 
               
               
                   
               
               
                 KGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPK 
               
               
                   
               
               
                 YSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPE 
               
               
                   
               
               
                 DNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDK 
               
               
                   
               
               
                 PIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQ 
               
               
                   
               
               
                 SITGLYETRIDLSQLGGDGGSGPPKKKRKV 
               
             
          
         
       
     
         [0102]    In some embodiments, a Cas9 nickase may be used in combination with guide sequence(s), e.g., two guide sequences, which target respectively sense and antisense strands of the DNA target. This combination allows both strands to be nicked and used to induce non-homologous end joining (NHEJ). 
         [0103]    As a further example, two or more catalytic domains of Cas9 (RuvC I, RuvC II, and RuvC III) may be mutated to produce a mutated Cas9 substantially lacking all DNA cleavage activity. In some embodiments, a D10A mutation is combined with one or more of H840A, N854A, or N863A mutations to produce a Cas9 enzyme substantially lacking all DNA cleavage activity (where the amino acid numbering is as in SEQ ID NO: 1). In some embodiments, a CRISPR enzyme is considered to substantially lack all DNA cleavage activity when the DNA cleavage activity of the mutated enzyme is less than about 25%, 10%, 5%, 1%, 0.1%, 0.01%, or lower with respect to its non-mutated form. Other mutations may be useful; where the Cas9 or other CRISPR enzyme is from a species other than  S. pyogenes , mutations in corresponding amino acids may be made to achieve similar effects. 
         [0104]    In some embodiments, an enzyme coding sequence encoding a CRISPR enzyme is codon optimized for expression in particular cells, such as eukaryotic cells. The eukaryotic cells may be those of or derived from a particular organism, such as a mammal, including but not limited to human, mouse, rat, rabbit, dog, or non-human primate. In general, codon optimization refers to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing at least one codon (e.g. about or more than about 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more codons) of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit particular bias for certain codons of a particular amino acid. Codon bias (differences in codon usage between organisms) often correlates with the efficiency of translation of messenger RNA (mRNA), which is in turn believed to be dependent on, among other things, the properties of the codons being translated and the availability of particular transfer RNA (tRNA) molecules. The predominance of selected tRNAs in a cell is generally a reflection of the codons used most frequently in peptide synthesis. Accordingly, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are readily available, for example, at the “Codon Usage Database”, and these tables can be adapted in a number of ways. See Nakamura, Y., et al. “Codon usage tabulated from the international DNA sequence databases: status for the year 2000” Nucl. Acids Res. 28:292 (2000). Computer algorithms for codon optimizing a particular sequence for expression in a particular host cell are also available, such as Gene Forge (Aptagen; Jacobus, Pa.), are also available. In some embodiments, one or more codons (e.g. 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, or more, or all codons) in a sequence encoding a CRISPR enzyme corresponds to the most frequently used codon for a particular amino acid. 
         [0105]    In general, a guide sequence is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific binding of a CRISPR complex to the target sequence. In some embodiments, the degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences, non-limiting example of which include the Smith-Waterman algorithm, the Needleman-Wunsch algorithm, algorithms based on the Burrows-Wheeler Transform (e.g. the Burrows Wheeler Aligner), ClustalW, Clustal X, BLAT, Novoalign (Novocraft Technologies, ELAND (Illumina, San Diego, Calif.), SOAP (available at soap.genomics.org.cn), and Maq (available at maq.sourceforge.net). In some embodiments, a guide sequence is about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In some embodiments, a guide sequence is less than about 75, 50, 45, 40, 35, 30, 25, 20, 15, 12, or fewer nucleotides in length. The ability of a guide sequence to direct sequence-specific binding of a CRISPR complex to a target sequence may be assessed by any suitable assay. For example, the components of a CRISPR system sufficient to form a CRISPR complex, including the guide sequence to be tested, may be provided to a host cell having the corresponding target sequence, such as by transfection with vectors encoding the components of the CRISPR sequence, followed by an assessment of preferential cleavage within the target sequence, such as by Surveyor assay as described herein. Similarly, cleavage of a target polynucleotide sequence may be evaluated in a test tube by providing the target sequence, components of a CRISPR complex, including the guide sequence to be tested and a control guide sequence different from the test guide sequence, and comparing binding or rate of cleavage at the target sequence between the test and control guide sequence reactions. Other assays are possible, and will occur to those skilled in the art. 
         [0106]    A guide sequence may be selected to target any target sequence. In some embodiments, the target sequence is a sequence within a genome of a cell. Exemplary target sequences include those that are unique in the target genome. For example, for the  S. pyogenes  Cas9, a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXGG MMMMMMMMNNNNNNNNNNNNXXAGAAW where NNNNNNNNNNNNXGG (N is A, G, T, or C; and X can be a deoxynucleotide) has a single occurrence in the genome. A unique target sequence in a genome may include an  S. pyogenes  Cas9 target site of the form MMMMMMMMMNNNNNNNNNNNXGG where NNNNNNNNNNNXGG (N is A, G, T, or C; and X can be a deoxynucleotide) has a single occurrence in the genome. For the  S. thermophilus  CRISPR1 Cas9, a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXXAGAAW (SEQ ID NO: 7) where NNNNNNNNNNNNXXAGAAW (SEQ ID NO: 8) (N is A, G, T, or C; X can be a deoxynucleotide; and W is A or T) has a single occurrence in the genome. A unique target sequence in a genome may include an  S. thermophilus  CRISPR1 Cas9 target site of the form MMMMMMMMMNNNNNNNNNNNXXAGAAW (SEQ ID NO: 9) where NNNNNNNNNNNXXAGAAW (SEQ ID NO: 10) (N is A, G, T, or C; X can be a deoxynucleotide; and W is A or T) has a single occurrence in the genome. For the  S. pyogenes  Cas9, a unique target sequence in a genome may include a Cas9 target site of the form MMMMMMMMNNNNNNNNNNNNXGGXG where NNNNNNNNNNNNXGGXG (N is A, G, T, or C; and X can be a deoxynucleotide) has a single occurrence in the genome. A unique target sequence in a genome may include an  S. pyogenes  Cas9 target site of the form MMMMMMMMMNNNNNNNNNNNXGGXG where NNNNNNNNNNNXGGXG (N is A, G, T, or C; and X can be a deoxynucleotide) has a single occurrence in the genome. In each of these sequences “M” may be A, G, T, or C, and need not be considered in identifying a sequence as unique. 
         [0107]    In some embodiments, a guide sequence is selected to reduce the degree of secondary structure within the guide sequence. Secondary structure may be determined by any suitable polynucleotide folding algorithm. Some programs are based on calculating the minimal Gibbs free energy. An example of one such algorithm is mFold, as described by Zuker and Stiegler (Nucleic Acids Res. 9 (1981), 133-148). Another example folding algorithm is the online webserver RNAfold, developed at Institute for Theoretical Chemistry at the University of Vienna, using the centroid structure prediction algorithm (see e.g. A. R. Gruber et al., 2008, Cell 106(1): 23-24; and PA Carr and GM Church, 2009, Nature Biotechnology 27(12): 1151-62). Further algorithms may be found in U.S. application Ser. No. 61/836,080; incorporated herein by reference. 
         [0108]    Aspects of the present subject matter relate to delivery of CRISPR/CRISPR/CRISPR from  Prevotella  and  Francisella  1 (Cpf1) gene editing complexes or components thereof (e.g., CPf1 proteins). Examples of human codon optimized Cpf1-family proteins are provided below. 
         [0109]    Human Codon Optimized Cpf1-Family Proteins 
         [0110]    Non-limiting examples of Cpf1-family protein sequences, and aspects of CRISPR/Cpf1 gene-editing, are described in Zetsche et al., Cell 163, 759-771, Oct. 22, 2015, the entire content of which is incorporated herein by reference. 
         [0111]      Francisella tularensis  subsp.  Novicida  U112 (FnCpf1; pY004)), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 11) 
               
             
          
           
               
                 MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKA 
               
               
                   
               
               
                 KQIIDKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKS 
               
               
                   
               
               
                 AKDTIKKQISEYIKDSEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGI 
               
               
                   
               
               
                 ELFKANSDITDIDEALEIIKSFKGWTTYFKGFHENRKNVYSSNDIPTSII 
               
               
                   
               
               
                 YRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKDLAEELTFDIDYKT 
               
               
                   
               
               
                 SEVNQRVFSLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRKGI 
               
               
                   
               
               
                 NEYINLYSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDVVT 
               
               
                   
               
               
                 TMQSFYEQIAAFKTVEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLT 
               
               
                   
               
               
                 DLSQQVFDDYSVIGTAVLEYITQQIAPKNLDNPSKKEQELIAKKTEKAKY 
               
               
                   
               
               
                 LSLETIKLALEEFNKHRDIDKQCRFEEILANFAAIPMIFDEIAQNKDNLA 
               
               
                   
               
               
                 QISIKYQNQGKKDLLQASAEDDVKAIKDLLDQTNNLLHKLKIFHISQSED 
               
               
                   
               
               
                 KANILDKDEHFYLVFEECYFELANIVPLYNKIRNYITQKPYSDEKFKLNF 
               
               
                   
               
               
                 ENSTLANGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENK 
               
               
                   
               
               
                 GEGYKKIVYKLLPGANKMLPKVFFSAKSIKFYNPSEDILRIRNHSTHTKN 
               
               
                   
               
               
                 GSPQKGYEKFEFNIEDCRKFIDFYKQSISKHPEWKDFGFRFSDTQRYNSI 
               
               
                   
               
               
                 DEFYREVENQGYKLTFENISESYIDSVVNQGKLYLFQIYNKDFSAYSKGR 
               
               
                   
               
               
                 PNLHTLYWKALFDERNLQDVVYKLNGEAELFYRKQSIPKKITHPAKEAIA 
               
               
                   
               
               
                 NKNKDNPKKESVFEYDLIKDKRFTEDKFFFHCPITINFKSSGANKFNDEI 
               
               
                   
               
               
                 NLLLKEKANDVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMK 
               
               
                   
               
               
                 TNYHDKLAAIEKDRDSARKDWKKINNIKEMKEGYLSQVVHEIAKLVIEYN 
               
               
                   
               
               
                 AIVVFEDLNFGFKRGRFKVEKQVYQKLEKMLIEKLNYLVFKDNEFDKTGG 
               
               
                   
               
               
                 VLRAYQLTAPFETFKKMGKQTGIIYYVPAGFTSKICPVTGFVNQLYPKYE 
               
               
                   
               
               
                 SVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGDKAAKGKWTIASFGSR 
               
               
                   
               
               
                 LINFRNSDKNHNWDTREVYPTKELEKLLKDYSIEYGHGECIKAAICGESD 
               
               
                   
               
               
                 KKFFAKLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPKNM 
               
               
                   
               
               
                 PQDADANGAYHIGLKGLMLLGRIKNNQEGKKLNLVIKNEEYFEFVQNRNN 
               
               
                   
               
               
                 KRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0112]    SEQ ID NO: 11 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a Human influenza hemagglutinin (HA) tag 
         [0000]    
       
         
               
             
               
               
             
           
               
                 (SEQ ID NO: 13) 
               
             
          
           
               
                   
                 (YPYDVPDYAYPYDVPDYAYPYDVPDYA). 
               
             
          
         
       
     
         [0113]    SEQ ID NO: 11 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 14) 
               
             
          
           
               
                 ATGAGCATCTACCAGGAGTTCGTCAACAAGTATTCACTGAGTAAGACACT 
               
               
                   
               
               
                 GCGGTTCGAGCTGATCCCACAGGGCAAGACACTGGAGAACATCAAGGCCC 
               
               
                   
               
               
                 GAGGCCTGATTCTGGACGATGAGAAGCGGGCAAAAGACTATAAGAAAGCC 
               
               
                   
               
               
                 AAGCAGATCATTGATAAATACCACCAGTTCTTTATCGAGGAAATTCTGAG 
               
               
                   
               
               
                 CTCCGTGTGCATCAGTGAGGATCTGCTGCAGAATTACTCAGACGTGTACT 
               
               
                   
               
               
                 TCAAGCTGAAGAAGAGCGACGATGACAACCTGCAGAAGGACTTCAAGTCC 
               
               
                   
               
               
                 GCCAAGGACACCATCAAGAAACAGATTAGCGAGTACATCAAGGACTCCGA 
               
               
                   
               
               
                 AAAGTTTAAAAATCTGTTCAACCAGAATCTGATCGATGCTAAGAAAGGCC 
               
               
                   
               
               
                 AGGAGTCCGACCTGATCCTGTGGCTGAAACAGTCTAAGGACAATGGGATT 
               
               
                   
               
               
                 GAACTGTTCAAGGCTAACTCCGATATCACTGATATTGACGAGGCACTGGA 
               
               
                   
               
               
                 AATCATCAAGAGCTTCAAGGGATGGACCACATACTTTAAAGGCTTCCACG 
               
               
                   
               
               
                 AGAACCGCAAGAACGTGTACTCCAGCAACGACATTCCTACCTCCATCATC 
               
               
                   
               
               
                 TACCGAATCGTCGATGACAATCTGCCAAAGTTCCTGGAGAACAAGGCCAA 
               
               
                   
               
               
                 ATATGAATCTCTGAAGGACAAAGCTCCCGAGGCAATTAATTACGAACAGA 
               
               
                   
               
               
                 TCAAGAAAGATCTGGCTGAGGAACTGACATTCGATATCGACTATAAGACT 
               
               
                   
               
               
                 AGCGAGGTGAACCAGAGGGTCTTTTCCCTGGACGAGGTGTTTGAAATCGC 
               
               
                   
               
               
                 CAATTTCAACAATTACCTGAACCAGTCCGGCATTACTAAATTCAATACCA 
               
               
                   
               
               
                 TCATTGGCGGGAAGTTTGTGAACGGGGAGAATACCAAGCGCAAGGGAATT 
               
               
                   
               
               
                 AACGAATACATCAATCTGTATAGCCAGCAGATCAACGACAAAACTCTGAA 
               
               
                   
               
               
                 GAAATACAAGATGTCTGTGCTGTTCAAACAGATCCTGAGTGATACCGAGT 
               
               
                   
               
               
                 CCAAGTCTTTTGTCATTGATAAACTGGAAGATGACTCAGACGTGGTCACT 
               
               
                   
               
               
                 ACCATGCAGAGCTTTTATGAGCAGATCGCCGCTTTCAAGACAGTGGAGGA 
               
               
                   
               
               
                 AAAATCTATTAAGGAAACTCTGAGTCTGCTGTTCGATGACCTGAAAGCCC 
               
               
                   
               
               
                 AGAAGCTGGACCTGAGTAAGATCTACTTCAAAAACGATAAGAGTCTGACA 
               
               
                   
               
               
                 GACCTGTCACAGCAGGTGTTTGATGACTATTCCGTGATTGGGACCGCCGT 
               
               
                   
               
               
                 CCTGGAGTACATTACACAGCAGATCGCTCCAAAGAACCTGGATAATCCCT 
               
               
                   
               
               
                 CTAAGAAAGAGCAGGAACTGATCGCTAAGAAAACCGAGAAGGCAAAATAT 
               
               
                   
               
               
                 CTGAGTCTGGAAACAATTAAGCTGGCACTGGAGGAGTTCAACAAGCACAG 
               
               
                   
               
               
                 GGATATTGACAAACAGTGCCGCTTTGAGGAAATCCTGGCCAACTTCGCAG 
               
               
                   
               
               
                 CCATCCCCATGATTTTTGATGAGATCGCCCAGAACAAAGACAATCTGGCT 
               
               
                   
               
               
                 CAGATCAGTATTAAGTACCAGAACCAGGGCAAGAAAGACCTGCTGCAGGC 
               
               
                   
               
               
                 TTCAGCAGAAGATGACGTGAAAGCCATCAAGGATCTGCTGGACCAGACCA 
               
               
                   
               
               
                 ACAATCTGCTGCACAAGCTGAAAATCTTCCATATTAGTCAGTCAGAGGAT 
               
               
                   
               
               
                 AAGGCTAATATCCTGGATAAAGACGAACACTTCTACCTGGTGTTCGAGGA 
               
               
                   
               
               
                 ATGTTACTTCGAGCTGGCAAACATTGTCCCCCTGTATAACAAGATTAGGA 
               
               
                   
               
               
                 ACTACATCACACAGAAGCCTTACTCTGACGAGAAGTTTAAACTGAACTTC 
               
               
                   
               
               
                 GAAAATAGTACCCTGGCCAACGGGTGGGATAAGAACAAGGAGCCTGACAA 
               
               
                   
               
               
                 CACAGCTATCCTGTTCATCAAGGATGACAAGTACTATCTGGGAGTGATGA 
               
               
                   
               
               
                 ATAAGAAAAACAATAAGATCTTCGATGACAAAGCCATTAAGGAGAACAAA 
               
               
                   
               
               
                 GGGGAAGGATACAAGAAAATCGTGTATAAGCTGCTGCCCGGCGCAAATAA 
               
               
                   
               
               
                 GATGCTGCCTAAGGTGTTCTTCAGCGCCAAGAGTATCAAATTCTACAACC 
               
               
                   
               
               
                 CATCCGAGGACATCCTGCGGATTAGAAATCACTCAACACATACTAAGAAC 
               
               
                   
               
               
                 GGGAGCCCCCAGAAGGGATATGAGAAATTTGAGTTCAACATCGAGGATTG 
               
               
                   
               
               
                 CAGGAAGTTTATTGACTTCTACAAGCAGAGCATCTCCAAACACCCTGAAT 
               
               
                   
               
               
                 GGAAGGATTTTGGCTTCCGGTTTTCCGACACACAGAGATATAACTCTATC 
               
               
                   
               
               
                 GACGAGTTCTACCGCGAGGTGGAAAATCAGGGGTATAAGCTGACTTTTGA 
               
               
                   
               
               
                 GAACATTTCTGAAAGTTACATCGACAGCGTGGTCAATCAGGGAAAGCTGT 
               
               
                   
               
               
                 ACCTGTTCCAGATCTATAACAAAGATTTTTCAGCATACAGCAAGGGCAGA 
               
               
                   
               
               
                 CCAAACCTGCATACACTGTACTGGAAGGCCCTGTTCGATGAGAGGAATCT 
               
               
                   
               
               
                 GCAGGACGTGGTCTATAAACTGAACGGAGAGGCCGAACTGTTTTACCGGA 
               
               
                   
               
               
                 AGCAGTCTATTCCTAAGAAAATCACTCACCCAGCTAAGGAGGCCATCGCT 
               
               
                   
               
               
                 AACAAGAACAAGGACAATCCTAAGAAAGAGAGCGTGTTCGAATACGATCT 
               
               
                   
               
               
                 GATTAAGGACAAGCGGTTCACCGAAGATAAGTTCTTTTTCCATTGTCCAA 
               
               
                   
               
               
                 TCACCATTAACTTCAAGTCAAGCGGCGCTAACAAGTTCAACGACGAGATC 
               
               
                   
               
               
                 AATCTGCTGCTGAAGGAAAAAGCAAACGATGTGCACATCCTGAGCATTGA 
               
               
                   
               
               
                 CCGAGGAGAGCGGCATCTGGCCTACTATACCCTGGTGGATGGCAAAGGGA 
               
               
                   
               
               
                 ATATCATTAAGCAGGATACATTCAACATCATTGGCAATGACCGGATGAAA 
               
               
                   
               
               
                 ACCAACTACCACGATAAACTGGCTGCAATCGAGAAGGATAGAGACTCAGC 
               
               
                   
               
               
                 TAGGAAGGACTGGAAGAAAATCAACAACATTAAGGAGATGAAGGAAGGCT 
               
               
                   
               
               
                 ATCTGAGCCAGGTGGTCCATGAGATTGCAAAGCTGGTCATCGAATACAAT 
               
               
                   
               
               
                 GCCATTGTGGTGTTCGAGGATCTGAACTTCGGCTTTAAGAGGGGGCGCTT 
               
               
                   
               
               
                 TAAGGTGGAAAAACAGGTCTATCAGAAGCTGGAGAAAATGCTGATCGAAA 
               
               
                   
               
               
                 AGCTGAATTACCTGGTGTTTAAAGATAACGAGTTCGACAAGACCGGAGGC 
               
               
                   
               
               
                 GTCCTGAGAGCCTACCAGCTGACAGCTCCCTTTGAAACTTTCAAGAAAAT 
               
               
                   
               
               
                 GGGAAAACAGACAGGCATCATCTACTATGTGCCAGCCGGATTCACTTCCA 
               
               
                   
               
               
                 AGATCTGCCCCGTGACCGGCTTTGTCAACCAGCTGTACCCTAAATATGAG 
               
               
                   
               
               
                 TCAGTGAGCAAGTCCCAGGAATTTTTCAGCAAGTTCGATAAGATCTGTTA 
               
               
                   
               
               
                 TAATCTGGACAAGGGGTACTTCGAGTTTTCCTTCGATTACAAGAACTTCG 
               
               
                   
               
               
                 GCGACAAGGCCGCTAAGGGGAAATGGACCATTGCCTCCTTCGGATCTCGC 
               
               
                   
               
               
                 CTGATCAACTTTCGAAATTCCGATAAAAACCACAATTGGGACACTAGGGA 
               
               
                   
               
               
                 GGTGTACCCAACCAAGGAGCTGGAAAAGCTGCTGAAAGACTACTCTATCG 
               
               
                   
               
               
                 AGTATGGACATGGCGAATGCATCAAGGCAGCCATCTGTGGCGAGAGTGAT 
               
               
                   
               
               
                 AAGAAATTTTTCGCCAAGCTGACCTCAGTGCTGAATACAATCCTGCAGAT 
               
               
                   
               
               
                 GCGGAACTCAAAGACCGGGACAGAACTGGACTATCTGATTAGCCCCGTGG 
               
               
                   
               
               
                 CTGATGTCAACGGAAACTTCTTCGACAGCAGACAGGCACCCAAAAATATG 
               
               
                   
               
               
                 CCTCAGGATGCAGACGCCAACGGGGCCTACCACATCGGGCTGAAGGGACT 
               
               
                   
               
               
                 GATGCTGCTGGGCCGGATCAAGAACAATCAGGAGGGGAAGAAGCTGAACC 
               
               
                   
               
               
                 TGGTCATTAAGAACGAGGAATACTTCGAGTTTGTCCAGAATAGAAATAAC 
               
               
                   
               
               
                 AAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGG 
               
               
                   
               
               
                 ATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTG 
               
               
                   
               
               
                 ATTATGCATACCCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0114]      Lachnospiraceae bacterium  MC2017 (Lb3Cpf1; pY005), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 15) 
               
             
          
           
               
                 MDYGNGQFERRAPLTKTITLRLKPIGETRETIREQKLLEQDAAFRKLVET 
               
               
                   
               
               
                 VTPIVDDCIRKIADNALCHFGTEYDFSCLGNAISKNDSKAIKKETEKVEK 
               
               
                   
               
               
                 LLAKVLTENLPDGLRKVNDINSAAFIQDTLTSFVQDDADKRVLIQELKGK 
               
               
                   
               
               
                 TVLMQRFLTTRITALTVWLPDRVFENFNIFIENAEKMRILLDSPLNEKIM 
               
               
                   
               
               
                 KFDPDAEQYASLEFYGQCLSQKDIDSYNLIISGIYADDEVKNPGINEIVK 
               
               
                   
               
               
                 EYNQQIRGDKDESPLPKLKKLHKQILMPVEKAFFVRVLSNDSDARSILEK 
               
               
                   
               
               
                 ILKDTEMLPSKIIEAMKEADAGDIAVYGSRLHELSHVIYGDHGKLSQIIY 
               
               
                   
               
               
                 DKESKRISELMETLSPKERKESKKRLEGLEEHIRKSTYTFDELNRYAEKN 
               
               
                   
               
               
                 VMAAYIAAVEESCAEIMRKEKDLRTLLSKEDVKIRGNRHNTLIVKNYFNA 
               
               
                   
               
               
                 WTVFRNLIRILRRKSEAEIDSDFYDVLDDSVEVLSLTYKGENLCRSYITK 
               
               
                   
               
               
                 KIGSDLKPEIATYGSALRPNSRWWSPGEKFNVKFHTIVRRDGRLYYFILP 
               
               
                   
               
               
                 KGAKPVELEDMDGDIECLQMRKIPNPTIFLPKLVFKDPEAFFRDNPEADE 
               
               
                   
               
               
                 FVFLSGMKAPVTITRETYEAYRYKLYTVGKLRDGEVSEEEYKRALLQVLT 
               
               
                   
               
               
                 AYKEFLENRMIYADLNFGFKDLEEYKDSSEFIKQVETHNTFMCWAKVSSS 
               
               
                   
               
               
                 QLDDLVKSGNGLLFEIWSERLESYYKYGNEKVLRGYEGVLLSILKDENLV 
               
               
                   
               
               
                 SMRTLLNSRPMLVYRPKESSKPMVVHRDGSRVVDRFDKDGKYIPPEVHDE 
               
               
                   
               
               
                 LYRFFNNLLIKEKLGEKARKILDNKKVKVKVLESERVKWSKFYDEQFAVT 
               
               
                   
               
               
                 FSVKKNADCLDTTKDLNAEVMEQYSESNRLILIRNTTDILYYLVLDKNGK 
               
               
                   
               
               
                 VLKQRSLNIINDGARDVDWKERFRQVTKDRNEGYNEWDYSRTSNDLKEVY 
               
               
                   
               
               
                 LNYALKEIAEAVIEYNAILIIEKMSNAFKDKYSFLDDVTFKGFETKLLAK 
               
               
                   
               
               
                 LSDLHFRGIKDGEPCSFTNPLQLCQNDSNKILQDGVIFMVPNSMTRSLDP 
               
               
                   
               
               
                 DTGFIFAINDHNIRTKKAKLNFLSKFDQLKVSSEGCLIMKYSGDSLPTHN 
               
               
                   
               
               
                 TDNRVWNCCCNHPITNYDRETKKVEFIEEPVEELSRVLEENGIETDTELN 
               
               
                   
               
               
                 KLNERENVPGKVVDAIYSLVLNYLRGTVSGVAGQRAVYYSPVTGKKYDIS 
               
               
                   
               
               
                 FIQAMNLNRKCDYYRIGSKERGEWTDFVAQLINKRPAATKKAGQAKKKKG 
               
               
                   
               
               
                 SYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0115]    SEQ ID NO: 15 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0116]    SEQ ID NO: 15 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
           
               
                 ATGGATTACGGCAACGGCCAGTTTGAGCGGAGAGCCCCCCTGACCAAGAC 
               
               
                   
               
               
                 AATCACCCTGCGCCTGAAGCCTATCGGCGAGACACGGGAGACAATCCGCG 
               
               
                   
               
               
                 AGCAGAAGCTGCTGGAGCAGGACGCCGCCTTCAGAAAGCTGGTGGAGACA 
               
               
                   
               
               
                 GTGACCCCTATCGTGGACGATTGTATCAGGAAGATCGCCGATAACGCCCT 
               
               
                   
               
               
                 GTGCCACTTTGGCACCGAGTATGACTTCAGCTGTCTGGGCAACGCCATCT 
               
               
                   
               
               
                 CTAAGAATGACAGCAAGGCCATCAAGAAGGAGACAGAGAAGGTGGAGAAG 
               
               
                   
               
               
                 CTGCTGGCCAAGGTGCTGACCGAGAATCTGCCAGATGGCCTGCGCAAGGT 
               
               
                   
               
               
                 GAACGACATCAATTCCGCCGCCTTTATCCAGGATACACTGACCTCTTTCG 
               
               
                   
               
               
                 TGCAGGACGATGCCGACAAGCGGGTGCTGATCCAGGAGCTGAAGGGCAAG 
               
               
                   
               
               
                 ACCGTGCTGATGCAGCGGTTCCTGACCACACGGATCACAGCCCTGACCGT 
               
               
                   
               
               
                 GTGGCTGCCCGACAGAGTGTTCGAGAACTTTAATATCTTCATCGAGAACG 
               
               
                   
               
               
                 CCGAGAAGATGAGAATCCTGCTGGACTCCCCTCTGAATGAGAAGATCATG 
               
               
                   
               
               
                 AAGTTTGACCCAGATGCCGAGCAGTACGCCTCTCTGGAGTTCTATGGCCA 
               
               
                   
               
               
                 GTGCCTGTCTCAGAAGGACATCGATAGCTACAACCTGATCATCTCCGGCA 
               
               
                   
               
               
                 TCTATGCCGACGATGAGGTGAAGAACCCTGGCATCAATGAGATCGTGAAG 
               
               
                   
               
               
                 GAGTACAATCAGCAGATCCGGGGCGACAAGGATGAGTCCCCACTGCCCAA 
               
               
                   
               
               
                 GCTGAAGAAGCTGCACAAGCAGATCCTGATGCCAGTGGAGAAGGCCTTCT 
               
               
                   
               
               
                 TTGTGCGCGTGCTGTCTAACGACAGCGATGCCCGGAGCATCCTGGAGAAG 
               
               
                   
               
               
                 ATCCTGAAGGACACAGAGATGCTGCCCTCCAAGATCATCGAGGCCATGAA 
               
               
                   
               
               
                 GGAGGCAGATGCAGGCGACATCGCCGTGTACGGCAGCCGGCTGCACGAGC 
               
               
                   
               
               
                 TGAGCCACGTGATCTACGGCGATCACGGCAAGCTGTCCCAGATCATCTAT 
               
               
                   
               
               
                 GACAAGGAGTCCAAGAGGATCTCTGAGCTGATGGAGACACTGTCTCCAAA 
               
               
                   
               
               
                 GGAGCGCAAGGAGAGCAAGAAGCGGCTGGAGGGCCTGGAGGAGCACATCA 
               
               
                   
               
               
                 GAAAGTCTACATACACCTTCGACGAGCTGAACAGGTATGCCGAGAAGAAT 
               
               
                   
               
               
                 GTGATGGCAGCATACATCGCAGCAGTGGAGGAGTCTTGTGCCGAGATCAT 
               
               
                   
               
               
                 GAGAAAGGAGAAGGATCTGAGGACCCTGCTGAGCAAGGAGGACGTGAAGA 
               
               
                   
               
               
                 TCCGGGGCAACAGACACAATACACTGATCGTGAAGAACTACTTTAATGCC 
               
               
                   
               
               
                 TGGACCGTGTTCCGGAACCTGATCAGAATCCTGAGGCGCAAGTCCGAGGC 
               
               
                   
               
               
                 CGAGATCGACTCTGACTTCTACGATGTGCTGGACGATTCCGTGGAGGTGC 
               
               
                   
               
               
                 TGTCTCTGACATACAAGGGCGAGAATCTGTGCCGCAGCTATATCACCAAG 
               
               
                   
               
               
                 AAGATCGGCTCCGACCTGAAGCCCGAGATCGCCACATACGGCAGCGCCCT 
               
               
                   
               
               
                 GAGGCCTAACAGCCGCTGGTGGTCCCCAGGAGAGAAGTTTAATGTGAAGT 
               
               
                   
               
               
                 TCCACACCATCGTGCGGAGAGATGGCCGGCTGTACTATTTCATCCTGCCC 
               
               
                   
               
               
                 AAGGGCGCCAAGCCTGTGGAGCTGGAGGACATGGATGGCGACATCGAGTG 
               
               
                   
               
               
                 TCTGCAGATGAGAAAGATCCCTAACCCAACAATCTTTCTGCCCAAGCTGG 
               
               
                   
               
               
                 TGTTCAAGGACCCTGAGGCCTTCTTTAGGGATAATCCAGAGGCCGACGAG 
               
               
                   
               
               
                 TTCGTGTTTCTGAGCGGCATGAAGGCCCCCGTGACAATCACCAGAGAGAC 
               
               
                   
               
               
                 ATACGAGGCCTACAGGTATAAGCTGTATACCGTGGGCAAGCTGCGCGATG 
               
               
                   
               
               
                 GCGAGGTGTCCGAAGAGGAGTACAAGCGGGCCCTGCTGCAGGTGCTGACC 
               
               
                   
               
               
                 GCCTACAAGGAGTTTCTGGAGAACAGAATGATCTATGCCGACCTGAATTT 
               
               
                   
               
               
                 CGGCTTTAAGGATCTGGAGGAGTATAAGGACAGCTCCGAGTTTATCAAGC 
               
               
                   
               
               
                 AGGTGGAGACACACAACACCTTCATGTGCTGGGCCAAGGTGTCTAGCTCC 
               
               
                   
               
               
                 CAGCTGGACGATCTGGTGAAGTCTGGCAACGGCCTGCTGTTCGAGATCTG 
               
               
                   
               
               
                 GAGCGAGCGCCTGGAGTCCTACTATAAGTACGGCAATGAGAAGGTGCTGC 
               
               
                   
               
               
                 GGGGCTATGAGGGCGTGCTGCTGAGCATCCTGAAGGATGAGAACCTGGTG 
               
               
                   
               
               
                 TCCATGCGGACCCTGCTGAACAGCCGGCCCATGCTGGTGTACCGGCCAAA 
               
               
                   
               
               
                 GGAGTCTAGCAAGCCTATGGTGGTGCACCGGGATGGCAGCAGAGTGGTGG 
               
               
                   
               
               
                 ACAGGTTTGATAAGGACGGCAAGTACATCCCCCCTGAGGTGCACGACGAG 
               
               
                   
               
               
                 CTGTATCGCTTCTTTAACAATCTGCTGATCAAGGAGAAGCTGGGCGAGAA 
               
               
                   
               
               
                 GGCCCGGAAGATCCTGGACAACAAGAAGGTGAAGGTGAAGGTGCTGGAGA 
               
               
                   
               
               
                 GCGAGAGAGTGAAGTGGTCCAAGTTCTACGATGAGCAGTTTGCCGTGACC 
               
               
                   
               
               
                 TTCAGCGTGAAGAAGAACGCCGATTGTCTGGACACCACAAAGGACCTGAA 
               
               
                   
               
               
                 TGCCGAAGTGATGGAGCAGTATAGCGAGTCCAACAGACTGATCCTGATCA 
               
               
                   
               
               
                 GGAATACCACAGATATCCTGTACTATCTGGTGCTGGACAAGAATGGCAAG 
               
               
                   
               
               
                 GTGCTGAAGCAGAGATCCCTGAACATCATCAATGACGGCGCCAGGGATGT 
               
               
                   
               
               
                 GGACTGGAAGGAGAGGTTCCGCCAGGTGACAAAGGATAGAAACGAGGGCT 
               
               
                   
               
               
                 ACAATGAGTGGGATTATTCCAGGACCTCTAACGACCTGAAGGAGGTGTAC 
               
               
                   
               
               
                 CTGAATTATGCCCTGAAGGAGATCGCCGAGGCCGTGATCGAGTACAACGC 
               
               
                   
               
               
                 CATCCTGATCATCGAGAAGATGTCTAATGCCTTTAAGGACAAGTATAGCT 
               
               
                   
               
               
                 TCCTGGACGACGTGACCTTCAAGGGCTTCGAGACAAAGCTGCTGGCCAAG 
               
               
                   
               
               
                 CTGAGCGATCTGCACTTTAGGGGCATCAAGGACGGCGAGCCATGTTCCTT 
               
               
                   
               
               
                 CACAAACCCCCTGCAGCTGTGCCAGAACGATTCTAATAAGATCCTGCAGG 
               
               
                   
               
               
                 ACGGCGTGATCTTTATGGTGCCAAATTCTATGACACGGAGCCTGGACCCC 
               
               
                   
               
               
                 GACACCGGCTTCATCTTTGCCATCAACGACCACAATATCAGGACCAAGAA 
               
               
                   
               
               
                 GGCCAAGCTGAACTTTCTGAGCAAGTTCGATCAGCTGAAGGTGTCCTCTG 
               
               
                   
               
               
                 AGGGCTGCCTGATCATGAAGTACAGCGGCGATTCCCTGCCTACACACAAC 
               
               
                   
               
               
                 ACCGACAATCGCGTGTGGAACTGCTGTTGCAATCACCCAATCACAAACTA 
               
               
                   
               
               
                 TGACCGGGAGACAAAGAAGGTGGAGTTCATCGAGGAGCCCGTGGAGGAGC 
               
               
                   
               
               
                 TGTCCCGCGTGCTGGAGGAGAATGGCATCGAGACAGACACCGAGCTGAAC 
               
               
                   
               
               
                 AAGCTGAATGAGCGGGAGAACGTGCCTGGCAAGGTGGTGGATGCCATCTA 
               
               
                   
               
               
                 CTCTCTGGTGCTGAATTATCTGCGCGGCACAGTGAGCGGAGTGGCAGGAC 
               
               
                   
               
               
                 AGAGGGCCGTGTACTATAGCCCTGTGACCGGCAAGAAGTACGATATCTCC 
               
               
                   
               
               
                 TTTATCCAGGCCATGAACCTGAATAGGAAGTGTGACTACTATAGGATCGG 
               
               
                   
               
               
                 CTCCAAGGAGAGGGGAGAGTGGACCGATTTCGTGGCCCAGCTGATCAACA 
               
               
                   
               
               
                 AAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGA 
               
               
                   
               
               
                 TCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGA 
               
               
                   
               
               
                 TTATGCATACCCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0117]      Butyrivibrio proteoclasticus  (BpCpf1; pY006), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 17) 
               
             
          
           
               
                 MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRAKDYKKA 
               
               
                   
               
               
                 KQIIDKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKKSDDDNLQKDFKS 
               
               
                   
               
               
                 AKDTIKKQISEYIKDSEKFKNLFNQNLIDAKKGQESDLILWLKQSKDNGI 
               
               
                   
               
               
                 ELFKANSDITDIDEALEIIKSFKGWTTYFKGFHENRKNVYSSNDIPTSII 
               
               
                   
               
               
                 YRIVDDNLPKFLENKAKYESLKDKAPEAINYEQIKKDLAEELTFDIDYKT 
               
               
                   
               
               
                 SEVNQRVFSLDEVFEIANFNNYLNQSGITKFNTIIGGKFVNGENTKRKGI 
               
               
                   
               
               
                 NEYINLYSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDVVT 
               
               
                   
               
               
                 TMQSFYEQIAAFKTVEEKSIKETLSLLFDDLKAQKLDLSKIYFKNDKSLT 
               
               
                   
               
               
                 DLSQQVFDDYSVIGTAVLEYITQQIAPKNLDNPSKKEQELIAKKTEKAKY 
               
               
                   
               
               
                 LSLETIKLALEEFNKHRDIDKQCRFEEILANFAAIPMIFDEIAQNKDNLA 
               
               
                   
               
               
                 QISIKYQNQGKKDLLQASAEDDVKAIKDLLDQTNNLLHKLKIFHISQSED 
               
               
                   
               
               
                 KANILDKDEHFYLVFEECYFELANIVPLYNKIRNYITQKPYSDEKFKLNF 
               
               
                   
               
               
                 ENSTLANGWDKNKEPDNTAILFIKDDKYYLGVMNKKNNKIFDDKAIKENK 
               
               
                   
               
               
                 GEGYKKIVYKLLPGANKMLPKVFFSAKSIKFYNPSEDILRIRNHSTHTKN 
               
               
                   
               
               
                 GSPQKGYEKFEFNIEDCRKFIDFYKQSISKHPEWKDFGFRFSDTQRYNSI 
               
               
                   
               
               
                 DEFYREVENQGYKLTFENISESYIDSVVNQGKLYLFQIYNKDFSAYSKGR 
               
               
                   
               
               
                 PNLHTLYWKALFDERNLQDVVYKLNGEAELFYRKQSIPKKITHPAKEAIA 
               
               
                   
               
               
                 NKNKDNPKKESVFEYDLIKDKRFTEDKFFFHCPITINFKSSGANKFNDEI 
               
               
                   
               
               
                 NLLLKEKANDVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMK 
               
               
                   
               
               
                 TNYHDKLAAIEKDRDSARKDWKKINNIKEMKEGYLSQVVHEIAKLVIEYN 
               
               
                   
               
               
                 AIVVFEDLNFGFKRGRFKVEKQVYQKLEKMLIEKLNYLVFKDNEFDKTGG 
               
               
                   
               
               
                 VLRAYQLTAPFETFKKMGKQTGIIYYVPAGFTSKICPVTGFVNQLYPKYE 
               
               
                   
               
               
                 SVSKSQEFFSKFDKICYNLDKGYFEFSFDYKNFGDKAAKGKWTIASFGSR 
               
               
                   
               
               
                 LINFRNSDKNHNWDTREVYPTKELEKLLKDYSIEYGHGECIKAAICGESD 
               
               
                   
               
               
                 KKFFAKLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPKNM 
               
               
                   
               
               
                 PQDADANGAYHIGLKGLMLLGRIKNNQEGKKLNLVIKNEEYFEFVQNRNN 
               
               
                   
               
               
                 KRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0118]    SEQ ID NO: 17 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0119]    SEQ ID NO: 17 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 18) 
               
             
          
           
               
                 ATGAGCATCTACCAGGAGTTCGTCAACAAGTATTCACTGAGTAAGACACT 
               
               
                   
               
               
                 GCGGTTCGAGCTGATCCCACAGGGCAAGACACTGGAGAACATCAAGGCCC 
               
               
                   
               
               
                 GAGGCCTGATTCTGGACGATGAGAAGCGGGCAAAAGACTATAAGAAAGCC 
               
               
                   
               
               
                 AAGCAGATCATTGATAAATACCACCAGTTCTTTATCGAGGAAATTCTGAG 
               
               
                   
               
               
                 CTCCGTGTGCATCAGTGAGGATCTGCTGCAGAATTACTCAGACGTGTACT 
               
               
                   
               
               
                 TCAAGCTGAAGAAGAGCGACGATGACAACCTGCAGAAGGACTTCAAGTCC 
               
               
                   
               
               
                 GCCAAGGACACCATCAAGAAACAGATTAGCGAGTACATCAAGGACTCCGA 
               
               
                   
               
               
                 AAAGTTTAAAAATCTGTTCAACCAGAATCTGATCGATGCTAAGAAAGGCC 
               
               
                   
               
               
                 AGGAGTCCGACCTGATCCTGTGGCTGAAACAGTCTAAGGACAATGGGATT 
               
               
                   
               
               
                 GAACTGTTCAAGGCTAACTCCGATATCACTGATATTGACGAGGCACTGGA 
               
               
                   
               
               
                 AATCATCAAGAGCTTCAAGGGATGGACCACATACTTTAAAGGCTTCCACG 
               
               
                   
               
               
                 AGAACCGCAAGAACGTGTACTCCAGCAACGACATTCCTACCTCCATCATC 
               
               
                   
               
               
                 TACCGAATCGTCGATGACAATCTGCCAAAGTTCCTGGAGAACAAGGCCAA 
               
               
                   
               
               
                 ATATGAATCTCTGAAGGACAAAGCTCCCGAGGCAATTAATTACGAACAGA 
               
               
                   
               
               
                 TCAAGAAAGATCTGGCTGAGGAACTGACATTCGATATCGACTATAAGACT 
               
               
                   
               
               
                 AGCGAGGTGAACCAGAGGGTCTTTTCCCTGGACGAGGTGTTTGAAATCGC 
               
               
                   
               
               
                 CAATTTCAACAATTACCTGAACCAGTCCGGCATTACTAAATTCAATACCA 
               
               
                   
               
               
                 TCATTGGCGGGAAGTTTGTGAACGGGGAGAATACCAAGCGCAAGGGAATT 
               
               
                   
               
               
                 AACGAATACATCAATCTGTATAGCCAGCAGATCAACGACAAAACTCTGAA 
               
               
                   
               
               
                 GAAATACAAGATGTCTGTGCTGTTCAAACAGATCCTGAGTGATACCGAGT 
               
               
                   
               
               
                 CCAAGTCTTTTGTCATTGATAAACTGGAAGATGACTCAGACGTGGTCACT 
               
               
                   
               
               
                 ACCATGCAGAGCTTTTATGAGCAGATCGCCGCTTTCAAGACAGTGGAGGA 
               
               
                   
               
               
                 AAAATCTATTAAGGAAACTCTGAGTCTGCTGTTCGATGACCTGAAAGCCC 
               
               
                   
               
               
                 AGAAGCTGGACCTGAGTAAGATCTACTTCAAAAACGATAAGAGTCTGACA 
               
               
                   
               
               
                 GACCTGTCACAGCAGGTGTTTGATGACTATTCCGTGATTGGGACCGCCGT 
               
               
                   
               
               
                 CCTGGAGTACATTACACAGCAGATCGCTCCAAAGAACCTGGATAATCCCT 
               
               
                   
               
               
                 CTAAGAAAGAGCAGGAACTGATCGCTAAGAAAACCGAGAAGGCAAAATAT 
               
               
                   
               
               
                 CTGAGTCTGGAAACAATTAAGCTGGCACTGGAGGAGTTCAACAAGCACAG 
               
               
                   
               
               
                 GGATATTGACAAACAGTGCCGCTTTGAGGAAATCCTGGCCAACTTCGCAG 
               
               
                   
               
               
                 CCATCCCCATGATTTTTGATGAGATCGCCCAGAACAAAGACAATCTGGCT 
               
               
                   
               
               
                 CAGATCAGTATTAAGTACCAGAACCAGGGCAAGAAAGACCTGCTGCAGGC 
               
               
                   
               
               
                 TTCAGCAGAAGATGACGTGAAAGCCATCAAGGATCTGCTGGACCAGACCA 
               
               
                   
               
               
                 ACAATCTGCTGCACAAGCTGAAAATCTTCCATATTAGTCAGTCAGAGGAT 
               
               
                   
               
               
                 AAGGCTAATATCCTGGATAAAGACGAACACTTCTACCTGGTGTTCGAGGA 
               
               
                   
               
               
                 ATGTTACTTCGAGCTGGCAAACATTGTCCCCCTGTATAACAAGATTAGGA 
               
               
                   
               
               
                 ACTACATCACACAGAAGCCTTACTCTGACGAGAAGTTTAAACTGAACTTC 
               
               
                   
               
               
                 GAAAATAGTACCCTGGCCAACGGGTGGGATAAGAACAAGGAGCCTGACAA 
               
               
                   
               
               
                 CACAGCTATCCTGTTCATCAAGGATGACAAGTACTATCTGGGAGTGATGA 
               
               
                   
               
               
                 ATAAGAAAAACAATAAGATCTTCGATGACAAAGCCATTAAGGAGAACAAA 
               
               
                   
               
               
                 GGGGAAGGATACAAGAAAATCGTGTATAAGCTGCTGCCCGGCGCAAATAA 
               
               
                   
               
               
                 GATGCTGCCTAAGGTGTTCTTCAGCGCCAAGAGTATCAAATTCTACAACC 
               
               
                   
               
               
                 CATCCGAGGACATCCTGCGGATTAGAAATCACTCAACACATACTAAGAAC 
               
               
                   
               
               
                 GGGAGCCCCCAGAAGGGATATGAGAAATTTGAGTTCAACATCGAGGATTG 
               
               
                   
               
               
                 CAGGAAGTTTATTGACTTCTACAAGCAGAGCATCTCCAAACACCCTGAAT 
               
               
                   
               
               
                 GGAAGGATTTTGGCTTCCGGTTTTCCGACACACAGAGATATAACTCTATC 
               
               
                   
               
               
                 GACGAGTTCTACCGCGAGGTGGAAAATCAGGGGTATAAGCTGACTTTTGA 
               
               
                   
               
               
                 GAACATTTCTGAAAGTTACATCGACAGCGTGGTCAATCAGGGAAAGCTGT 
               
               
                   
               
               
                 ACCTGTTCCAGATCTATAACAAAGATTTTTCAGCATACAGCAAGGGCAGA 
               
               
                   
               
               
                 CCAAACCTGCATACACTGTACTGGAAGGCCCTGTTCGATGAGAGGAATCT 
               
               
                   
               
               
                 GCAGGACGTGGTCTATAAACTGAACGGAGAGGCCGAACTGTTTTACCGGA 
               
               
                   
               
               
                 AGCAGTCTATTCCTAAGAAAATCACTCACCCAGCTAAGGAGGCCATCGCT 
               
               
                   
               
               
                 AACAAGAACAAGGACAATCCTAAGAAAGAGAGCGTGTTCGAATACGATCT 
               
               
                   
               
               
                 GATTAAGGACAAGCGGTTCACCGAAGATAAGTTCTTTTTCCATTGTCCAA 
               
               
                   
               
               
                 TCACCATTAACTTCAAGTCAAGCGGCGCTAACAAGTTCAACGACGAGATC 
               
               
                   
               
               
                 AATCTGCTGCTGAAGGAAAAAGCAAACGATGTGCACATCCTGAGCATTGA 
               
               
                   
               
               
                 CCGAGGAGAGCGGCATCTGGCCTACTATACCCTGGTGGATGGCAAAGGGA 
               
               
                   
               
               
                 ATATCATTAAGCAGGATACATTCAACATCATTGGCAATGACCGGATGAAA 
               
               
                   
               
               
                 ACCAACTACCACGATAAACTGGCTGCAATCGAGAAGGATAGAGACTCAGC 
               
               
                   
               
               
                 TAGGAAGGACTGGAAGAAAATCAACAACATTAAGGAGATGAAGGAAGGCT 
               
               
                   
               
               
                 ATCTGAGCCAGGTGGTCCATGAGATTGCAAAGCTGGTCATCGAATACAAT 
               
               
                   
               
               
                 GCCATTGTGGTGTTCGAGGATCTGAACTTCGGCTTTAAGAGGGGGCGCTT 
               
               
                   
               
               
                 TAAGGTGGAAAAACAGGTCTATCAGAAGCTGGAGAAAATGCTGATCGAAA 
               
               
                   
               
               
                 AGCTGAATTACCTGGTGTTTAAAGATAACGAGTTCGACAAGACCGGAGGC 
               
               
                   
               
               
                 GTCCTGAGAGCCTACCAGCTGACAGCTCCCTTTGAAACTTTCAAGAAAAT 
               
               
                   
               
               
                 GGGAAAACAGACAGGCATCATCTACTATGTGCCAGCCGGATTCACTTCCA 
               
               
                   
               
               
                 AGATCTGCCCCGTGACCGGCTTTGTCAACCAGCTGTACCCTAAATATGAG 
               
               
                   
               
               
                 TCAGTGAGCAAGTCCCAGGAATTTTTCAGCAAGTTCGATAAGATCTGTTA 
               
               
                   
               
               
                 TAATCTGGACAAGGGGTACTTCGAGTTTTCCTTCGATTACAAGAACTTCG 
               
               
                   
               
               
                 GCGACAAGGCCGCTAAGGGGAAATGGACCATTGCCTCCTTCGGATCTCGC 
               
               
                   
               
               
                 CTGATCAACTTTCGAAATTCCGATAAAAACCACAATTGGGACACTAGGGA 
               
               
                   
               
               
                 GGTGTACCCAACCAAGGAGCTGGAAAAGCTGCTGAAAGACTACTCTATCG 
               
               
                   
               
               
                 AGTATGGACATGGCGAATGCATCAAGGCAGCCATCTGTGGCGAGAGTGAT 
               
               
                   
               
               
                 AAGAAATTTTTCGCCAAGCTGACCTCAGTGCTGAATACAATCCTGCAGAT 
               
               
                   
               
               
                 GCGGAACTCAAAGACCGGGACAGAACTGGACTATCTGATTAGCCCCGTGG 
               
               
                   
               
               
                 CTGATGTCAACGGAAACTTCTTCGACAGCAGACAGGCACCCAAAAATATG 
               
               
                   
               
               
                 CCTCAGGATGCAGACGCCAACGGGGCCTACCACATCGGGCTGAAGGGACT 
               
               
                   
               
               
                 GATGCTGCTGGGCCGGATCAAGAACAATCAGGAGGGGAAGAAGCTGAACC 
               
               
                   
               
               
                 TGGTCATTAAGAACGAGGAATACTTCGAGTTTGTCCAGAATAGAAATAAC 
               
               
                   
               
               
                 AAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGG 
               
               
                   
               
               
                 ATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTG 
               
               
                   
               
               
                 ATTATGCATACCCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0120]      Peregrinibacteria bacterium  GW2011_GWA_33_10 (PeCpf1; pY007), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 19) 
               
             
          
           
               
                 MSNFFKNFTNLYELSKTLRFELKPVGDTLTNMKDHLEYDEKLQTFLKDQN 
               
               
                   
               
               
                 IDDAYQALKPQFDEIHEEFITDSLESKKAKEIDFSEYLDLFQEKKELNDS 
               
               
                   
               
               
                 EKKLRNKIGETFNKAGEKWKKEKYPQYEWKKGSKIANGADILSCQDMLQF 
               
               
                   
               
               
                 IKYKNPEDEKIKNYIDDTLKGFFTYFGGFNQNRANYYETKKEASTAVATR 
               
               
                   
               
               
                 IVHENLPKFCDNVIQFKHIIKRKKDGTVEKTERKTEYLNAYQYLKNNNKI 
               
               
                   
               
               
                 TQIKDAETEKMIESTPIAEKIFDVYYFSSCLSQKQIEEYNRIIGHYNLLI 
               
               
                   
               
               
                 NLYNQAKRSEGKHLSANEKKYKDLPKFKTLYKQIGCGKKKDLFYTIKCDT 
               
               
                   
               
               
                 EEEANKSRNEGKESHSVEEIINKAQEAINKYFKSNNDCENINTVPDFINY 
               
               
                   
               
               
                 ILTKENYEGVYWSKAAMNTISDKYFANYHDLQDRLKEAKVFQKADKKSED 
               
               
                   
               
               
                 DIKIPEAIELSGLFGVLDSLADWQTTLFKSSILSNEDKLKIITDSQTPSE 
               
               
                   
               
               
                 ALLKMIFNDIEKNMESFLKETNDIITLKKYKGNKEGTEKIKQWFDYTLAI 
               
               
                   
               
               
                 NRMLKYFLVKENKIKGNSLDTNISEALKTLIYSDDAEWFKWYDALRNYLT 
               
               
                   
               
               
                 QKPQDEAKENKLKLNFDNPSLAGGWDVNKECSNFCVILKDKNEKKYLAIM 
               
               
                   
               
               
                 KKGENTLFQKEWTEGRGKNLTKKSNPLFEINNCEILSKMEYDFWADVSKM 
               
               
                   
               
               
                 IPKCSTQLKAVVNHFKQSDNEFIFPIGYKVTSGEKFREECKISKQDFELN 
               
               
                   
               
               
                 NKVFNKNELSVTAMRYDLSSTQEKQYIKAFQKEYWELLFKQEKRDTKLTN 
               
               
                   
               
               
                 NEIFNEWINFCNKKYSELLSWERKYKDALTNWINFCKYFLSKYPKTTLFN 
               
               
                   
               
               
                 YSFKESENYNSLDEFYRDVDICSYKLNINTTINKSILDRLVEEGKLYLFE 
               
               
                   
               
               
                 IKNQDSNDGKSIGHKNNLHTIYWNAIFENFDNRPKLNGEAEIFYRKAISK 
               
               
                   
               
               
                 DKLGIVKGKKTKNGTEIIKNYRFSKEKFILHVPITLNFCSNNEYVNDIVN 
               
               
                   
               
               
                 TKFYNFSNLHFLGIDRGEKHLAYYSLVNKNGEIVDQGTLNLPFTDKDGNQ 
               
               
                   
               
               
                 RSIKKEKYFYNKQEDKWEAKEVDCWNYNDLLDAMASNRDMARKNWQRIGT 
               
               
                   
               
               
                 IKEAKNGYVSLVIRKIADLAVNNERPAFIVLEDLNTGFKRSRQKIDKSVY 
               
               
                   
               
               
                 QKFELALAKKLNFLVDKNAKRDEIGSPTKALQLTPPVNNYGDIENKKQAG 
               
               
                   
               
               
                 IMLYTRANYTSQTDPATGWRKTIYLKAGPEETTYKKDGKIKNKSVKDQII 
               
               
                   
               
               
                 ETFTDIGFDGKDYYFEYDKGEFVDEKTGEIKPKKWRLYSGENGKSLDRFR 
               
               
                   
               
               
                 GEREKDKYEWKIDKIDIVKILDDLFVNFDKNISLLKQLKEGVELTRNNEH 
               
               
                   
               
               
                 GTGESLRFAINLIQQIRNTGNNERDNDFILSPVRDENGKHFDSREYWDKE 
               
               
                   
               
               
                 TKGEKISMPSSGDANGAFNIARKGIIMNAHILANSDSKDLSLFVSDEEWD 
               
               
                   
               
               
                 LHLNNKTEWKKQLNIFSSRKAMAKRKKKRPAATKKAGQAKKKKGSYPYDV 
               
               
                   
               
               
                 PDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0121]    SEQ ID NO: 19 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0122]    SEQ ID NO: 19 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 20) 
               
             
          
           
               
                 ATGTCCAACTTCTTTAAGAATTTCACCAACCTGTATGAGCTGTCCAAGAC 
               
               
                   
               
               
                 ACTGAGGTTTGAGCTGAAGCCCGTGGGCGACACCCTGACAAACATGAAGG 
               
               
                   
               
               
                 ACCACCTGGAGTACGATGAGAAGCTGCAGACCTTCCTGAAGGATCAGAAT 
               
               
                   
               
               
                 ATCGACGATGCCTATCAGGCCCTGAAGCCTCAGTTCGACGAGATCCACGA 
               
               
                   
               
               
                 GGAGTTTATCACAGATTCTCTGGAGAGCAAGAAGGCCAAGGAGATCGACT 
               
               
                   
               
               
                 TCTCCGAGTACCTGGATCTGTTTCAGGAGAAGAAGGAGCTGAACGACTCT 
               
               
                   
               
               
                 GAGAAGAAGCTGCGCAACAAGATCGGCGAGACATTCAACAAGGCCGGCGA 
               
               
                   
               
               
                 GAAGTGGAAGAAGGAGAAGTACCCTCAGTATGAGTGGAAGAAGGGCTCCA 
               
               
                   
               
               
                 AGATCGCCAATGGCGCCGACATCCTGTCTTGCCAGGATATGCTGCAGTTT 
               
               
                   
               
               
                 ATCAAGTATAAGAACCCAGAGGATGAGAAGATCAAGAATTACATCGACGA 
               
               
                   
               
               
                 TACACTGAAGGGCTTCTTTACCTATTTCGGCGGCTTTAATCAGAACAGGG 
               
               
                   
               
               
                 CCAACTACTATGAGACAAAGAAGGAGGCCTCCACCGCAGTGGCAACAAGG 
               
               
                   
               
               
                 ATCGTGCACGAGAACCTGCCAAAGTTCTGTGACAATGTGATCCAGTTTAA 
               
               
                   
               
               
                 GCACATCATCAAGCGGAAGAAGGATGGCACCGTGGAGAAAACCGAGAGAA 
               
               
                   
               
               
                 AGACCGAGTACCTGAACGCCTACCAGTATCTGAAGAACAATAACAAGATC 
               
               
                   
               
               
                 ACACAGATCAAGGACGCCGAGACAGAGAAGATGATCGAGTCTACACCCAT 
               
               
                   
               
               
                 CGCCGAGAAGATCTTCGACGTGTACTACTTCAGCAGCTGCCTGAGCCAGA 
               
               
                   
               
               
                 AGCAGATCGAGGAGTACAACCGGATCATCGGCCACTATAATCTGCTGATC 
               
               
                   
               
               
                 AACCTGTATAACCAGGCCAAGAGATCTGAGGGCAAGCACCTGAGCGCCAA 
               
               
                   
               
               
                 CGAGAAGAAGTATAAGGACCTGCCTAAGTTCAAGACCCTGTATAAGCAGA 
               
               
                   
               
               
                 TCGGCTGCGGCAAGAAGAAGGACCTGTTTTACACAATCAAGTGTGATACC 
               
               
                   
               
               
                 GAGGAGGAGGCCAATAAGTCCCGGAACGAGGGCAAGGAGTCCCACTCTGT 
               
               
                   
               
               
                 GGAGGAGATCATCAACAAGGCCCAGGAGGCCATCAATAAGTACTTCAAGT 
               
               
                   
               
               
                 CTAATAACGACTGTGAGAATATCAACACCGTGCCCGACTTCATCAACTAT 
               
               
                   
               
               
                 ATCCTGACAAAGGAGAATTACGAGGGCGTGTATTGGAGCAAGGCCGCCAT 
               
               
                   
               
               
                 GAACACCATCTCCGACAAGTACTTCGCCAATTATCACGACCTGCAGGATA 
               
               
                   
               
               
                 GACTGAAGGAGGCCAAGGTGTTTCAGAAGGCCGATAAGAAGTCCGAGGAC 
               
               
                   
               
               
                 GATATCAAGATCCCAGAGGCCATCGAGCTGTCTGGCCTGTTCGGCGTGCT 
               
               
                   
               
               
                 GGACAGCCTGGCCGATTGGCAGACCACACTGTTTAAGTCTAGCATCCTGA 
               
               
                   
               
               
                 GCAACGAGGACAAGCTGAAGATCATCACAGATTCCCAGACCCCCTCTGAG 
               
               
                   
               
               
                 GCCCTGCTGAAGATGATCTTCAATGACATCGAGAAGAACATGGAGTCCTT 
               
               
                   
               
               
                 TCTGAAGGAGACAAACGATATCATCACCCTGAAGAAGTATAAGGGCAATA 
               
               
                   
               
               
                 AGGAGGGCACCGAGAAGATCAAGCAGTGGTTCGACTATACACTGGCCATC 
               
               
                   
               
               
                 AACCGGATGCTGAAGTACTTTCTGGTGAAGGAGAATAAGATCAAGGGCAA 
               
               
                   
               
               
                 CTCCCTGGATACCAATATCTCTGAGGCCCTGAAAACCCTGATCTACAGCG 
               
               
                   
               
               
                 ACGATGCCGAGTGGTTCAAGTGGTACGACGCCCTGAGAAACTATCTGACC 
               
               
                   
               
               
                 CAGAAGCCTCAGGATGAGGCCAAGGAGAATAAGCTGAAGCTGAATTTCGA 
               
               
                   
               
               
                 CAACCCATCTCTGGCCGGCGGCTGGGATGTGAACAAGGAGTGCAGCAATT 
               
               
                   
               
               
                 TTTGCGTGATCCTGAAGGACAAGAACGAGAAGAAGTACCTGGCCATCATG 
               
               
                   
               
               
                 AAGAAGGGCGAGAATACCCTGTTCCAGAAGGAGTGGACAGAGGGCCGGGG 
               
               
                   
               
               
                 CAAGAACCTGACAAAGAAGTCTAATCCACTGTTCGAGATCAATAACTGCG 
               
               
                   
               
               
                 AGATCCTGAGCAAGATGGAGTATGACTTTTGGGCCGACGTGAGCAAGATG 
               
               
                   
               
               
                 ATCCCCAAGTGTAGCACCCAGCTGAAGGCCGTGGTGAACCACTTCAAGCA 
               
               
                   
               
               
                 GTCCGACAATGAGTTCATCTTTCCTATCGGCTACAAGGTGACAAGCGGCG 
               
               
                   
               
               
                 AGAAGTTTAGGGAGGAGTGCAAGATCTCCAAGCAGGACTTCGAGCTGAAT 
               
               
                   
               
               
                 AACAAGGTGTTTAATAAGAACGAGCTGAGCGTGACCGCCATGCGCTACGA 
               
               
                   
               
               
                 TCTGTCCTCTACACAGGAGAAGCAGTATATCAAGGCCTTCCAGAAGGAGT 
               
               
                   
               
               
                 ACTGGGAGCTGCTGTTTAAGCAGGAGAAGCGGGACACCAAGCTGACAAAT 
               
               
                   
               
               
                 AACGAGATCTTCAACGAGTGGATCAATTTTTGCAACAAGAAGTATAGCGA 
               
               
                   
               
               
                 GCTGCTGTCCTGGGAGAGAAAGTACAAGGATGCCCTGACCAATTGGATCA 
               
               
                   
               
               
                 ACTTCTGTAAGTACTTTCTGAGCAAGTATCCCAAGACCACACTGTTCAAC 
               
               
                   
               
               
                 TACTCTTTTAAGGAGAGCGAGAATTATAACTCCCTGGACGAGTTCTACCG 
               
               
                   
               
               
                 GGACGTGGATATCTGTTCTTACAAGCTGAATATCAACACCACAATCAATA 
               
               
                   
               
               
                 AGAGCATCCTGGATAGACTGGTGGAGGAGGGCAAGCTGTACCTGTTTGAG 
               
               
                   
               
               
                 ATCAAGAATCAGGACAGCAACGATGGCAAGTCCATCGGCCACAAGAATAA 
               
               
                   
               
               
                 CCTGCACACCATCTACTGGAACGCCATCTTCGAGAATTTTGACAACAGGC 
               
               
                   
               
               
                 CTAAGCTGAATGGCGAGGCCGAGATCTTCTATCGCAAGGCCATCTCCAAG 
               
               
                   
               
               
                 GATAAGCTGGGCATCGTGAAGGGCAAGAAAACCAAGAACGGCACCGAGAT 
               
               
                   
               
               
                 CATCAAGAATTACAGATTCAGCAAGGAGAAGTTTATCCTGCACGTGCCAA 
               
               
                   
               
               
                 TCACCCTGAACTTCTGCTCCAATAACGAGTATGTGAATGACATCGTGAAC 
               
               
                   
               
               
                 ACAAAGTTCTACAATTTTTCCAACCTGCACTTTCTGGGCATCGATAGGGG 
               
               
                   
               
               
                 CGAGAAGCACCTGGCCTACTATTCTCTGGTGAATAAGAACGGCGAGATCG 
               
               
                   
               
               
                 TGGACCAGGGCACACTGAACCTGCCTTTCACCGACAAGGATGGCAATCAG 
               
               
                   
               
               
                 CGCAGCATCAAGAAGGAGAAGTACTTTTATAACAAGCAGGAGGACAAGTG 
               
               
                   
               
               
                 GGAGGCCAAGGAGGTGGATTGTTGGAATTATAACGACCTGCTGGATGCCA 
               
               
                   
               
               
                 TGGCCTCTAACCGGGACATGGCCAGAAAGAATTGGCAGAGGATCGGCACC 
               
               
                   
               
               
                 ATCAAGGAGGCCAAGAACGGCTACGTGAGCCTGGTCATCAGGAAGATCGC 
               
               
                   
               
               
                 CGATCTGGCCGTGAATAACGAGCGCCCCGCCTTCATCGTGCTGGAGGACC 
               
               
                   
               
               
                 TGAATACAGGCTTTAAGCGGTCCAGACAGAAGATCGATAAGAGCGTGTAC 
               
               
                   
               
               
                 CAGAAGTTCGAGCTGGCCCTGGCCAAGAAGCTGAACTTTCTGGTGGACAA 
               
               
                   
               
               
                 GAATGCCAAGCGCGATGAGATCGGCTCCCCTACAAAGGCCCTGCAGCTGA 
               
               
                   
               
               
                 CCCCCCCTGTGAATAACTACGGCGACATTGAGAACAAGAAGCAGGCCGGC 
               
               
                   
               
               
                 ATCATGCTGTATACCCGGGCCAATTATACCTCTCAGACAGATCCAGCCAC 
               
               
                   
               
               
                 AGGCTGGAGAAAGACCATCTATCTGAAGGCCGGCCCCGAGGAGACAACAT 
               
               
                   
               
               
                 ACAAGAAGGACGGCAAGATCAAGAACAAGAGCGTGAAGGACCAGATCATC 
               
               
                   
               
               
                 GAGACATTCACCGATATCGGCTTTGACGGCAAGGATTACTATTTCGAGTA 
               
               
                   
               
               
                 CGACAAGGGCGAGTTTGTGGATGAGAAAACCGGCGAGATCAAGCCCAAGA 
               
               
                   
               
               
                 AGTGGCGGCTGTACTCCGGCGAGAATGGCAAGTCCCTGGACAGGTTCCGC 
               
               
                   
               
               
                 GGAGAGAGGGAGAAGGATAAGTATGAGTGGAAGATCGACAAGATCGATAT 
               
               
                   
               
               
                 CGTGAAGATCCTGGACGATCTGTTCGTGAATTTTGACAAGAACATCAGCC 
               
               
                   
               
               
                 TGCTGAAGCAGCTGAAGGAGGGCGTGGAGCTGACCCGGAATAACGAGCAC 
               
               
                   
               
               
                 GGCACAGGCGAGTCCCTGAGATTCGCCATCAACCTGATCCAGCAGATCCG 
               
               
                   
               
               
                 GAATACCGGCAATAACGAGAGAGACAACGATTTCATCCTGTCCCCAGTGA 
               
               
                   
               
               
                 GGGACGAGAATGGCAAGCACTTTGACTCTCGCGAGTACTGGGATAAGGAG 
               
               
                   
               
               
                 ACAAAGGGCGAGAAGATCAGCATGCCCAGCTCCGGCGATGCCAATGGCGC 
               
               
                   
               
               
                 CTTCAACATCGCCCGGAAGGGCATCATCATGAACGCCCACATCCTGGCCA 
               
               
                   
               
               
                 ATAGCGACTCCAAGGATCTGTCCCTGTTCGTGTCTGACGAGGAGTGGGAT 
               
               
                   
               
               
                 CTGCACCTGAATAACAAGACCGAGTGGAAGAAGCAGCTGAACATCTTTTC 
               
               
                   
               
               
                 TAGCAGGAAGGCCATGGCCAAGCGCAAGAAGAAAAGGCCGGCGGCCACGA 
               
               
                   
               
               
                 AAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCCTACCCATACGATGTT 
               
               
                   
               
               
                 CCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGA 
               
               
                   
               
               
                 TGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0123]      Parcubacteria bacterium  GWC2011_GWC2_44_17 (PbCpf1; pY008), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 21) 
               
             
          
           
               
                 MENIFDQFIGKYSLSKTLRFELKPVGKTEDFLKINKVFEKDQTIDDSYNQ 
               
               
                   
               
               
                 AKFYFDSLHQKFIDAALASDKTSELSFQNFADVLEKQNKIILDKKREMGA 
               
               
                   
               
               
                 LRKRDKNAVGIDRLQKEINDAEDIIQKEKEKIYKDVRTLFDNEAESWKTY 
               
               
                   
               
               
                 YQEREVDGKKITFSKADLKQKGADFLTAAGILKVLKYEFPEEKEKEFQAK 
               
               
                   
               
               
                 NQPSLFVEEKENPGQKRYIFDSFDKFAGYLTKFQQTKKNLYAADGTSTAV 
               
               
                   
               
               
                 ATRIADNFIIFHQNTKVFRDKYKNNHTDLGFDEENIFEIERYKNCLLQRE 
               
               
                   
               
               
                 IEHIKNENSYNKIIGRINKKIKEYRDQKAKDTKLTKSDFPFFKNLDKQIL 
               
               
                   
               
               
                 GEVEKEKQLIEKTREKTEEDVLIERFKEFIENNEERFTAAKKLMNAFCNG 
               
               
                   
               
               
                 EFESEYEGIYLKNKAINTISRRWFVSDRDFELKLPQQKSKNKSEKNEPKV 
               
               
                   
               
               
                 KKFISIAEIKNAVEELDGDIFKAVFYDKKIIAQGGSKLEQFLVIWKYEFE 
               
               
                   
               
               
                 YLFRDIERENGEKLLGYDSCLKIAKQLGIFPQEKEAREKATAVIKNYADA 
               
               
                   
               
               
                 GLGIFQMMKYFSLDDKDRKNTPGQLSTNFYAEYDGYYKDFEFIKYYNEFR 
               
               
                   
               
               
                 NFITKKPFDEDKIKLNFENGALLKGWDENKEYDFMGVILKKEGRLYLGIM 
               
               
                   
               
               
                 HKNHRKLFQSMGNAKGDNANRYQKMIYKQIADASKDVPRLLLTSKKAMEK 
               
               
                   
               
               
                 FKPSQEILRIKKEKTFKRESKNFSLRDLHALIEYYRNCIPQYSNWSFYDF 
               
               
                   
               
               
                 QFQDTGKYQNIKEFTDDVQKYGYKISFRDIDDEYINQALNEGKMYLFEVV 
               
               
                   
               
               
                 NKDIYNTKNGSKNLHTLYFEHILSAENLNDPVFKLSGMAEIFQRQPSVNE 
               
               
                   
               
               
                 REKITTQKNQCILDKGDRAYKYRRYTEKKIMFHMSLVLNTGKGEIKQVQF 
               
               
                   
               
               
                 NKIINQRISSSDNEMRVNVIGIDRGEKNLLYYSVVKQNGEIIEQASLNEI 
               
               
                   
               
               
                 NGVNYRDKLIEREKERLKNRQSWKPVVKIKDLKKGYISHVIHKICQLIEK 
               
               
                   
               
               
                 YSAIVVLEDLNMRFKQIRGGIERSVYQQFEKALIDKLGYLVFKDNRDLRA 
               
               
                   
               
               
                 PGGVLNGYQLSAPFVSFEKMRKQTGILFYTQAEYTSKTDPITGFRKNVYI 
               
               
                   
               
               
                 SNSASLDKIKEAVKKFDAIGWDGKEQSYFFKYNPYNLADEKYKNSTVSKE 
               
               
                   
               
               
                 WAIFASAPRIRRQKGEDGYWKYDRVKVNEEFEKLLKVWNFVNPKATDIKQ 
               
               
                   
               
               
                 EIIKKEKAGDLQGEKELDGRLRNFWHSFIYLFNLVLELRNSFSLQIKIKA 
               
               
                   
               
               
                 GEVIAVDEGVDFIASPVKPFFTTPNPYIPSNLCWLAVENADANGAYNIAR 
               
               
                   
               
               
                 KGVMILKKIREHAKKDPEFKKLPNLFISNAEWDEAARDWGKYAGTTALNL 
               
               
                   
               
               
                 DHKRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0124]    SEQ ID NO: 21 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0125]    SEQ ID NO: 21 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 22) 
               
             
          
           
               
                 ATGGAGAACATCTTCGACCAGTTTATCGGCAAGTACAGCCTGTCCAAGAC 
               
               
                   
               
               
                 CCTGAGATTCGAGCTGAAGCCCGTGGGCAAGACAGAGGACTTCCTGAAGA 
               
               
                   
               
               
                 TCAACAAGGTGTTTGAGAAGGATCAGACCATCGACGATAGCTACAATCAG 
               
               
                   
               
               
                 GCCAAGTTCTATTTTGATTCCCTGCACCAGAAGTTTATCGACGCCGCCCT 
               
               
                   
               
               
                 GGCCTCCGATAAGACATCCGAGCTGTCTTTCCAGAACTTTGCCGACGTGC 
               
               
                   
               
               
                 TGGAGAAGCAGAATAAGATCATCCTGGATAAGAAGAGAGAGATGGGCGCC 
               
               
                   
               
               
                 CTGAGGAAGCGCGACAAGAACGCCGTGGGCATCGATAGGCTGCAGAAGGA 
               
               
                   
               
               
                 GATCAATGACGCCGAGGATATCATCCAGAAGGAGAAGGAGAAGATCTACA 
               
               
                   
               
               
                 AGGACGTGCGCACCCTGTTCGATAACGAGGCCGAGTCTTGGAAAACCTAC 
               
               
                   
               
               
                 TATCAGGAGCGGGAGGTGGACGGCAAGAAGATCACCTTCAGCAAGGCCGA 
               
               
                   
               
               
                 CCTGAAGCAGAAGGGCGCCGATTTTCTGACAGCCGCCGGCATCCTGAAGG 
               
               
                   
               
               
                 TGCTGAAGTATGAGTTCCCCGAGGAGAAGGAGAAGGAGTTTCAGGCCAAG 
               
               
                   
               
               
                 AACCAGCCCTCCCTGTTCGTGGAGGAGAAGGAGAATCCTGGCCAGAAGAG 
               
               
                   
               
               
                 GTACATCTTCGACTCTTTTGATAAGTTCGCCGGCTATCTGACCAAGTTTC 
               
               
                   
               
               
                 AGCAGACAAAGAAGAATCTGTACGCAGCAGACGGCACCAGCACAGCAGTG 
               
               
                   
               
               
                 GCCACCCGCATCGCCGATAACTTTATCATCTTCCACCAGAATACCAAGGT 
               
               
                   
               
               
                 GTTCCGGGACAAGTACAAGAACAATCACACAGACCTGGGCTTCGATGAGG 
               
               
                   
               
               
                 AGAACATCTTTGAGATCGAGAGGTATAAGAATTGCCTGCTGCAGCGCGAG 
               
               
                   
               
               
                 ATCGAGCACATCAAGAATGAGAATAGCTACAACAAGATCATCGGCCGGAT 
               
               
                   
               
               
                 CAATAAGAAGATCAAGGAGTATCGGGACCAGAAGGCCAAGGATACCAAGC 
               
               
                   
               
               
                 TGACAAAGTCCGACTTCCCTTTCTTTAAGAACCTGGATAAGCAGATCCTG 
               
               
                   
               
               
                 GGCGAGGTGGAGAAGGAGAAGCAGCTGATCGAGAAAACCCGGGAGAAAAC 
               
               
                   
               
               
                 CGAGGAGGACGTGCTGATCGAGCGGTTCAAGGAGTTCATCGAGAACAATG 
               
               
                   
               
               
                 AGGAGAGGTTCACCGCCGCCAAGAAGCTGATGAATGCCTTCTGTAACGGC 
               
               
                   
               
               
                 GAGTTTGAGTCCGAGTACGAGGGCATCTATCTGAAGAATAAGGCCATCAA 
               
               
                   
               
               
                 CACAATCTCCCGGAGATGGTTCGTGTCTGACAGAGATTTTGAGCTGAAGC 
               
               
                   
               
               
                 TGCCTCAGCAGAAGTCCAAGAACAAGTCTGAGAAGAATGAGCCAAAGGTG 
               
               
                   
               
               
                 AAGAAGTTCATCTCCATCGCCGAGATCAAGAACGCCGTGGAGGAGCTGGA 
               
               
                   
               
               
                 CGGCGATATCTTTAAGGCCGTGTTCTACGACAAGAAGATCATCGCCCAGG 
               
               
                   
               
               
                 GCGGCTCTAAGCTGGAGCAGTTCCTGGTCATCTGGAAGTACGAGTTTGAG 
               
               
                   
               
               
                 TATCTGTTCCGGGACATCGAGAGAGAGAACGGCGAGAAGCTGCTGGGCTA 
               
               
                   
               
               
                 TGATAGCTGCCTGAAGATCGCCAAGCAGCTGGGCATCTTCCCACAGGAGA 
               
               
                   
               
               
                 AGGAGGCCCGCGAGAAGGCAACCGCCGTGATCAAGAATTACGCCGACGCC 
               
               
                   
               
               
                 GGCCTGGGCATCTTCCAGATGATGAAGTATTTTTCTCTGGACGATAAGGA 
               
               
                   
               
               
                 TCGGAAGAACACCCCCGGCCAGCTGAGCACAAATTTCTACGCCGAGTATG 
               
               
                   
               
               
                 ACGGCTACTACAAGGATTTCGAGTTTATCAAGTACTACAACGAGTTTAGG 
               
               
                   
               
               
                 AACTTCATCACCAAGAAGCCTTTCGACGAGGATAAGATCAAGCTGAACTT 
               
               
                   
               
               
                 TGAGAATGGCGCCCTGCTGAAGGGCTGGGACGAGAACAAGGAGTACGATT 
               
               
                   
               
               
                 TCATGGGCGTGATCCTGAAGAAGGAGGGCCGCCTGTATCTGGGCATCATG 
               
               
                   
               
               
                 CACAAGAACCACCGGAAGCTGTTTCAGTCCATGGGCAATGCCAAGGGCGA 
               
               
                   
               
               
                 CAACGCCAATAGATACCAGAAGATGATCTATAAGCAGATCGCCGACGCCT 
               
               
                   
               
               
                 CTAAGGATGTGCCCAGGCTGCTGCTGACCAGCAAGAAGGCCATGGAGAAG 
               
               
                   
               
               
                 TTCAAGCCTTCCCAGGAGATCCTGAGAATCAAGAAGGAGAAAACCTTCAA 
               
               
                   
               
               
                 GCGGGAGAGCAAGAACTTTTCCCTGAGAGATCTGCACGCCCTGATCGAGT 
               
               
                   
               
               
                 ACTATAGGAACTGCATCCCTCAGTACAGCAATTGGTCCTTTTATGACTTC 
               
               
                   
               
               
                 CAGTTTCAGGATACCGGCAAGTACCAGAATATCAAGGAGTTCACAGACGA 
               
               
                   
               
               
                 TGTGCAGAAGTACGGCTATAAGATCTCCTTTCGCGACATCGACGATGAGT 
               
               
                   
               
               
                 ATATCAATCAGGCCCTGAACGAGGGCAAGATGTACCTGTTCGAGGTGGTG 
               
               
                   
               
               
                 AACAAGGATATCTATAACACCAAGAATGGCTCCAAGAATCTGCACACACT 
               
               
                   
               
               
                 GTACTTTGAGCACATCCTGTCTGCCGAGAACCTGAATGACCCAGTGTTCA 
               
               
                   
               
               
                 AGCTGTCTGGCATGGCCGAGATCTTTCAGCGGCAGCCCAGCGTGAACGAA 
               
               
                   
               
               
                 AGAGAGAAGATCACCACACAGAAGAATCAGTGTATCCTGGACAAGGGCGA 
               
               
                   
               
               
                 TAGAGCCTACAAGTATAGGCGCTACACCGAGAAGAAGATCATGTTCCACA 
               
               
                   
               
               
                 TGAGCCTGGTGCTGAACACAGGCAAGGGCGAGATCAAGCAGGTGCAGTTT 
               
               
                   
               
               
                 AATAAGATCATCAACCAGAGGATCAGCTCCTCTGACAACGAGATGAGGGT 
               
               
                   
               
               
                 GAATGTGATCGGCATCGATCGCGGCGAGAAGAACCTGCTGTACTATAGCG 
               
               
                   
               
               
                 TGGTGAAGCAGAATGGCGAGATCATCGAGCAGGCCTCCCTGAACGAGATC 
               
               
                   
               
               
                 AATGGCGTGAACTACCGGGACAAGCTGATCGAGAGGGAGAAGGAGCGCCT 
               
               
                   
               
               
                 GAAGAACCGGCAGAGCTGGAAGCCTGTGGTGAAGATCAAGGATCTGAAGA 
               
               
                   
               
               
                 AGGGCTACATCTCCCACGTGATCCACAAGATCTGCCAGCTGATCGAGAAG 
               
               
                   
               
               
                 TATTCTGCCATCGTGGTGCTGGAGGACCTGAATATGAGATTCAAGCAGAT 
               
               
                   
               
               
                 CAGGGGAGGAATCGAGCGGAGCGTGTACCAGCAGTTCGAGAAGGCCCTGA 
               
               
                   
               
               
                 TCGATAAGCTGGGCTATCTGGTGTTTAAGGACAACAGGGATCTGAGGGCA 
               
               
                   
               
               
                 CCAGGAGGCGTGCTGAATGGCTACCAGCTGTCTGCCCCCTTTGTGAGCTT 
               
               
                   
               
               
                 CGAGAAGATGCGCAAGCAGACCGGCATCCTGTTCTACACACAGGCCGAGT 
               
               
                   
               
               
                 ATACCAGCAAGACAGACCCAATCACCGGCTTTCGGAAGAACGTGTATATC 
               
               
                   
               
               
                 TCTAATAGCGCCTCCCTGGATAAGATCAAGGAGGCCGTGAAGAAGTTCGA 
               
               
                   
               
               
                 CGCCATCGGCTGGGATGGCAAGGAGCAGTCTTACTTCTTTAAGTACAACC 
               
               
                   
               
               
                 CTTACAACCTGGCCGACGAGAAGTATAAGAACTCTACCGTGAGCAAGGAG 
               
               
                   
               
               
                 TGGGCCATCTTTGCCAGCGCCCCAAGAATCCGGAGACAGAAGGGCGAGGA 
               
               
                   
               
               
                 CGGCTACTGGAAGTATGATAGGGTGAAAGTGAATGAGGAGTTCGAGAAGC 
               
               
                   
               
               
                 TGCTGAAGGTCTGGAATTTTGTGAACCCAAAGGCCACAGATATCAAGCAG 
               
               
                   
               
               
                 GAGATCATCAAGAAGGAGAAGGCAGGCGACCTGCAGGGAGAGAAGGAGCT 
               
               
                   
               
               
                 GGATGGCCGGCTGAGAAACTTTTGGCACTCTTTCATCTACCTGTTTAACC 
               
               
                   
               
               
                 TGGTGCTGGAGCTGCGCAATTCTTTCAGCCTGCAGATCAAGATCAAGGCA 
               
               
                   
               
               
                 GGAGAAGTGATCGCAGTGGACGAGGGCGTGGACTTCATCGCCAGCCCAGT 
               
               
                   
               
               
                 GAAGCCCTTCTTTACCACACCCAACCCTTACATCCCCTCCAACCTGTGCT 
               
               
                   
               
               
                 GGCTGGCCGTGGAGAATGCAGACGCAAACGGAGCCTATAATATCGCCAGG 
               
               
                   
               
               
                 AAGGGCGTGATGATCCTGAAGAAGATCCGCGAGCACGCCAAGAAGGACCC 
               
               
                   
               
               
                 CGAGTTCAAGAAGCTGCCAAACCTGTTTATCAGCAATGCAGAGTGGGACG 
               
               
                   
               
               
                 AGGCAGCCCGGGATTGGGGCAAGTACGCAGGCACCACAGCCCTGAACCTG 
               
               
                   
               
               
                 GACCACAAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAA 
               
               
                   
               
               
                 AAAGGGATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACG 
               
               
                   
               
               
                 TGCCTGATTATGCATACCCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0126]      Smithella  sp. SC_K08D17 (SsCpf1; pY009), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 23) 
               
             
          
           
               
                 MQTLFENFTNQYPVSKTLRFELIPQGKTKDFIEQKGLLKKDEDRAEKYKK 
               
               
                   
               
               
                 VKNIIDEYHKDFIEKSLNGLKLDGLEKYKTLYLKQEKDDKDKKAFDKEKE 
               
               
                   
               
               
                 NLRKQIANAFRNNEKFKTLFAKELIKNDLMSFACEEDKKNVKEFEAFTTY 
               
               
                   
               
               
                 FTGFHQNRANMYVADEKRTAIASRLIHENLPKFIDNIKIFEKMKKEAPEL 
               
               
                   
               
               
                 LSPFNQTLKDMKDVIKGTTLEEIFSLDYFNKTLTQSGIDIYNSVIGGRTP 
               
               
                   
               
               
                 EEGKTKIKGLNEYINTDFNQKQTDKKKRQPKFKQLYKQILSDRQSLSFIA 
               
               
                   
               
               
                 EAFKNDTEILEAIEKFYVNELLHFSNEGKSTNVLDAIKNAVSNLESFNLT 
               
               
                   
               
               
                 KMYFRSGASLTDVSRKVFGEWSIINRALDNYYATTYPIKPREKSEKYEER 
               
               
                   
               
               
                 KEKWLKQDFNVSLIQTAIDEYDNETVKGKNSGKVIADYFAKFCDDKETDL 
               
               
                   
               
               
                 IQKVNEGYIAVKDLLNTPCPENEKLGSNKDQVKQIKAFMDSIMDIMHFVR 
               
               
                   
               
               
                 PLSLKDTDKEKDETFYSLFTPLYDHLTQTIALYNKVRNYLTQKPYSTEKI 
               
               
                   
               
               
                 KLNFENSTLLGGWDLNKETDNTAIILRKDNLYYLGIMDKRHNRIFRNVPK 
               
               
                   
               
               
                 ADKKDFCYEKMVYKLLPGANKMLPKVFFSQSRIQEFTPSAKLLENYANET 
               
               
                   
               
               
                 HKKGDNFNLNHCHKLIDFFKDSINKHEDWKNFDFRFSATSTYADLSGFYH 
               
               
                   
               
               
                 EVEHQGYKISFQSVADSFIDDLVNEGKLYLFQIYNKDFSPFSKGKPNLHT 
               
               
                   
               
               
                 LYWKMLFDENNLKDVVYKLNGEAEVFYRKKSIAEKNTTIHKANESIINKN 
               
               
                   
               
               
                 PDNPKATSTFNYDIVKDKRYTIDKFQFHIPITMNFKAEGIFNMNQRVNQF 
               
               
                   
               
               
                 LKANPDINIIGIDRGERHLLYYALINQKGKILKQDTLNVIANEKQKVDYH 
               
               
                   
               
               
                 NLLDKKEGDRATARQEWGVIETIKELKEGYLSQVIHKLTDLMIENNAIIV 
               
               
                   
               
               
                 MEDLNFGFKRGRQKVEKQVYQKFEKMLIDKLNYLVDKNKKANELGGLLNA 
               
               
                   
               
               
                 FQLANKFESFQKMGKQNGFIFYVPAWNTSKTDPATGFIDFLKPRYENLNQ 
               
               
                   
               
               
                 AKDFFEKFDSIRLNSKADYFEFAFDFKNFTEKADGGRTKWTVCTTNEDRY 
               
               
                   
               
               
                 AWNRALNNNRGSQEKYDITAELKSLFDGKVDYKSGKDLKQQIASQESADF 
               
               
                   
               
               
                 FKALMKNLSITLSLRHNNGEKGDNEQDYILSPVADSKGRFFDSRKADDDM 
               
               
                   
               
               
                 PKNADANGAYHIALKGLWCLEQISKTDDLKKVKLAISNKEWLEFVQTLKG 
               
               
                   
               
               
                 KRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0127]    SEQ ID NO: 23 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0128]    SEQ ID NO: 23 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 24) 
               
             
          
           
               
                 ATGCAGACCCTGTTTGAGAACTTCACAAATCAGTACCCAGTGTCCAAGAC 
               
               
                   
               
               
                 CCTGCGCTTTGAGCTGATCCCCCAGGGCAAGACAAAGGACTTCATCGAGC 
               
               
                   
               
               
                 AGAAGGGCCTGCTGAAGAAGGATGAGGACCGGGCCGAGAAGTATAAGAAG 
               
               
                   
               
               
                 GTGAAGAACATCATCGATGAGTACCACAAGGACTTCATCGAGAAGTCTCT 
               
               
                   
               
               
                 GAATGGCCTGAAGCTGGACGGCCTGGAGAAGTACAAGACCCTGTATCTGA 
               
               
                   
               
               
                 AGCAGGAGAAGGACGATAAGGATAAGAAGGCCTTTGACAAGGAGAAGGAG 
               
               
                   
               
               
                 AACCTGCGCAAGCAGATCGCCAATGCCTTCCGGAACAATGAGAAGTTTAA 
               
               
                   
               
               
                 GACACTGTTCGCCAAGGAGCTGATCAAGAACGATCTGATGTCTTTCGCCT 
               
               
                   
               
               
                 GCGAGGAGGACAAGAAGAATGTGAAGGAGTTTGAGGCCTTCACCACATAC 
               
               
                   
               
               
                 TTCACCGGCTTCCACCAGAACCGCGCCAATATGTACGTGGCCGATGAGAA 
               
               
                   
               
               
                 GAGAACAGCCATCGCCAGCAGGCTGATCCACGAGAACCTGCCAAAGTTTA 
               
               
                   
               
               
                 TCGACAATATCAAGATCTTCGAGAAGATGAAGAAGGAGGCCCCCGAGCTG 
               
               
                   
               
               
                 CTGTCTCCTTTCAACCAGACCCTGAAGGATATGAAGGACGTGATCAAGGG 
               
               
                   
               
               
                 CACCACACTGGAGGAGATCTTTAGCCTGGATTATTTCAACAAGACCCTGA 
               
               
                   
               
               
                 CACAGAGCGGCATCGACATCTACAATTCCGTGATCGGCGGCAGAACCCCT 
               
               
                   
               
               
                 GAGGAGGGCAAGACAAAGATCAAGGGCCTGAACGAGTACATCAATACCGA 
               
               
                   
               
               
                 CTTCAACCAGAAGCAGACAGACAAGAAGAAGCGGCAGCCAAAGTTCAAGC 
               
               
                   
               
               
                 AGCTGTATAAGCAGATCCTGAGCGATAGGCAGAGCCTGTCCTTTATCGCC 
               
               
                   
               
               
                 GAGGCCTTCAAGAACGACACCGAGATCCTGGAGGCCATCGAGAAGTTTTA 
               
               
                   
               
               
                 CGTGAATGAGCTGCTGCACTTCAGCAATGAGGGCAAGTCCACAAACGTGC 
               
               
                   
               
               
                 TGGACGCCATCAAGAATGCCGTGTCTAACCTGGAGAGCTTTAACCTGACC 
               
               
                   
               
               
                 AAGATGTATTTCCGCTCCGGCGCCTCTCTGACAGACGTGAGCCGGAAGGT 
               
               
                   
               
               
                 GTTTGGCGAGTGGAGCATCATCAATAGAGCCCTGGACAACTACTATGCCA 
               
               
                   
               
               
                 CCACATATCCAATCAAGCCCAGAGAGAAGTCTGAGAAGTACGAGGAGAGG 
               
               
                   
               
               
                 AAGGAGAAGTGGCTGAAGCAGGACTTCAACGTGAGCCTGATCCAGACCGC 
               
               
                   
               
               
                 CATCGATGAGTACGACAACGAGACAGTGAAGGGCAAGAACAGCGGCAAAG 
               
               
                   
               
               
                 TGATCGCCGATTATTTTGCCAAGTTCTGCGACGATAAGGAGACAGACCTG 
               
               
                   
               
               
                 ATCCAGAAGGTGAACGAGGGCTACATCGCCGTGAAGGATCTGCTGAATAC 
               
               
                   
               
               
                 ACCCTGTCCTGAGAACGAGAAGCTGGGCAGCAATAAGGACCAGGTGAAGC 
               
               
                   
               
               
                 AGATCAAGGCCTTTATGGATTCTATCATGGACATCATGCACTTCGTGCGC 
               
               
                   
               
               
                 CCCCTGAGCCTGAAGGATACCGACAAGGAGAAGGATGAGACATTCTACTC 
               
               
                   
               
               
                 CCTGTTCACACCTCTGTACGACCACCTGACCCAGACAATCGCCCTGTATA 
               
               
                   
               
               
                 ACAAGGTGCGGAACTATCTGACCCAGAAGCCTTACAGCACAGAGAAGATC 
               
               
                   
               
               
                 AAGCTGAACTTCGAGAACAGCACCCTGCTGGGCGGCTGGGATCTGAATAA 
               
               
                   
               
               
                 GGAGACAGACAACACAGCCATCATCCTGAGGAAGGATAACCTGTACTATC 
               
               
                   
               
               
                 TGGGCATCATGGACAAGAGGCACAATCGCATCTTTCGGAACGTGCCCAAG 
               
               
                   
               
               
                 GCCGATAAGAAGGACTTCTGCTACGAGAAGATGGTGTATAAGCTGCTGCC 
               
               
                   
               
               
                 TGGCGCCAACAAGATGCTGCCAAAGGTGTTCTTTTCTCAGAGCAGAATCC 
               
               
                   
               
               
                 AGGAGTTTACCCCTTCCGCCAAGCTGCTGGAGAACTACGCCAATGAGACA 
               
               
                   
               
               
                 CACAAGAAGGGCGATAATTTCAACCTGAATCACTGTCACAAGCTGATCGA 
               
               
                   
               
               
                 TTTCTTTAAGGACTCTATCAACAAGCACGAGGATTGGAAGAATTTCGACT 
               
               
                   
               
               
                 TTAGGTTCAGCGCCACCTCCACCTACGCCGACCTGAGCGGCTTTTACCAC 
               
               
                   
               
               
                 GAGGTGGAGCACCAGGGCTACAAGATCTCTTTTCAGAGCGTGGCCGATTC 
               
               
                   
               
               
                 CTTCATCGACGATCTGGTGAACGAGGGCAAGCTGTACCTGTTCCAGATCT 
               
               
                   
               
               
                 ATAATAAGGACTTTTCCCCATTCTCTAAGGGCAAGCCCAACCTGCACACC 
               
               
                   
               
               
                 CTGTACTGGAAGATGCTGTTTGATGAGAACAATCTGAAGGACGTGGTGTA 
               
               
                   
               
               
                 TAAGCTGAATGGCGAGGCCGAGGTGTTCTACCGCAAGAAGAGCATTGCCG 
               
               
                   
               
               
                 AGAAGAACACCACAATCCACAAGGCCAATGAGTCCATCATCAACAAGAAT 
               
               
                   
               
               
                 CCTGATAACCCAAAGGCCACCAGCACCTTCAACTATGATATCGTGAAGGA 
               
               
                   
               
               
                 CAAGAGATACACCATCGACAAGTTTCAGTTCCACATCCCAATCACAATGA 
               
               
                   
               
               
                 ACTTTAAGGCCGAGGGCATCTTCAACATGAATCAGAGGGTGAATCAGTTC 
               
               
                   
               
               
                 CTGAAGGCCAATCCCGATATCAACATCATCGGCATCGACAGAGGCGAGAG 
               
               
                   
               
               
                 GCACCTGCTGTACTATGCCCTGATCAACCAGAAGGGCAAGATCCTGAAGC 
               
               
                   
               
               
                 AGGATACCCTGAATGTGATCGCCAACGAGAAGCAGAAGGTGGACTACCAC 
               
               
                   
               
               
                 AATCTGCTGGATAAGAAGGAGGGCGACCGCGCAACCGCAAGGCAGGAGTG 
               
               
                   
               
               
                 GGGCGTGATCGAGACAATCAAGGAGCTGAAGGAGGGCTATCTGTCCCAGG 
               
               
                   
               
               
                 TCATCCACAAGCTGACCGATCTGATGATCGAGAACAATGCCATCATCGTG 
               
               
                   
               
               
                 ATGGAGGACCTGAACTTTGGCTTCAAGCGGGGCAGACAGAAGGTGGAGAA 
               
               
                   
               
               
                 GCAGGTGTATCAGAAGTTTGAGAAGATGCTGATCGATAAGCTGAATTACC 
               
               
                   
               
               
                 TGGTGGACAAGAATAAGAAGGCAAACGAGCTGGGAGGCCTGCTGAACGCA 
               
               
                   
               
               
                 TTCCAGCTGGCCAATAAGTTTGAGTCCTTCCAGAAGATGGGCAAGCAGAA 
               
               
                   
               
               
                 CGGCTTTATCTTCTACGTGCCCGCCTGGAATACCTCTAAGACAGATCCTG 
               
               
                   
               
               
                 CCACCGGCTTTATCGACTTCCTGAAGCCCCGCTATGAGAACCTGAATCAG 
               
               
                   
               
               
                 GCCAAGGATTTCTTTGAGAAGTTTGACTCTATCCGGCTGAACAGCAAGGC 
               
               
                   
               
               
                 CGATTACTTTGAGTTCGCCTTTGACTTCAAGAATTTCACCGAGAAGGCCG 
               
               
                   
               
               
                 ATGGCGGCAGAACCAAGTGGACAGTGTGCACCACAAACGAGGACAGATAT 
               
               
                   
               
               
                 GCCTGGAATAGGGCCCTGAACAATAACAGGGGCAGCCAGGAGAAGTACGA 
               
               
                   
               
               
                 CATCACAGCCGAGCTGAAGTCCCTGTTCGATGGCAAGGTGGACTATAAGT 
               
               
                   
               
               
                 CTGGCAAGGATCTGAAGCAGCAGATCGCCAGCCAGGAGTCCGCCGACTTC 
               
               
                   
               
               
                 TTTAAGGCCCTGATGAAGAACCTGTCCATCACCCTGTCTCTGAGACACAA 
               
               
                   
               
               
                 TAACGGCGAGAAGGGCGATAATGAGCAGGACTACATCCTGTCCCCTGTGG 
               
               
                   
               
               
                 CCGATTCTAAGGGCCGCTTCTTTGACTCCCGGAAGGCCGACGATGACATG 
               
               
                   
               
               
                 CCAAAGAATGCCGACGCCAACGGCGCCTATCACATCGCCCTGAAGGGCCT 
               
               
                   
               
               
                 GTGGTGTCTGGAGCAGATCAGCAAGACCGATGACCTGAAGAAGGTGAAGC 
               
               
                   
               
               
                 TGGCCATCTCCAACAAGGAGTGGCTGGAGTTCGTGCAGACACTGAAGGGC 
               
               
                   
               
               
                 AAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGG 
               
               
                   
               
               
                 ATCCTACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTG 
               
               
                   
               
               
                 ATTATGCATACCCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0129]      Acidaminococcus  sp. BV3L6 (AsCpf1; pY010), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 25) 
               
             
          
           
               
                 MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKEL 
               
               
                   
               
               
                 KPIIDRIYKTYADQCLQLVQLDWENLSAAIDSYRKEKTEETRNALIEEQA 
               
               
                   
               
               
                 TYRNAIHDYFIGRTDNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVT 
               
               
                   
               
               
                 TTEHENALLRSFDKFTTYFSGFYENRKNVFSAEDISTAIPHRIVQDNFPK 
               
               
                   
               
               
                 FKENCHIFTRLITAVPSLREHFENVKKAIGIFVSTSIEEVFSFPFYNQLL 
               
               
                   
               
               
                 TQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPH 
               
               
                   
               
               
                 RFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRNENVLETAE 
               
               
                   
               
               
                 ALFNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISELTGK 
               
               
                   
               
               
                 ITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAAL 
               
               
                   
               
               
                 DQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARL 
               
               
                   
               
               
                 TGIKLEMEPSLSFYNKARNYATKKPYSVEKFKLNFQMPTLASGWDVNKEK 
               
               
                   
               
               
                 NNGAILFVKNGLYYLGIMPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPD 
               
               
                   
               
               
                 AAKMIPKCSTQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEK 
               
               
                   
               
               
                 EPKKFQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLSSLRP 
               
               
                   
               
               
                 SSQYKDLGEYYAELNPLLYHISFQRIAEKEIMDAVETGKLYLFQIYNKDF 
               
               
                   
               
               
                 AKGHHGKPNLHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMKRMAH 
               
               
                   
               
               
                 RLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEARALLPNVI 
               
               
                   
               
               
                 TKEVSHEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHP 
               
               
                   
               
               
                 ETPIIGIDRGERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKE 
               
               
                   
               
               
                 RVAARQAWSVVGTIKDLKQGYLSQVIHEIVDLMIHYQAVVVLENLNFGFK 
               
               
                   
               
               
                 SKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVGGVLNPYQLTDQFT 
               
               
                   
               
               
                 SFAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPFVWKTIKNHESRKHFLEG 
               
               
                   
               
               
                 FDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVFEKNETQFDAK 
               
               
                   
               
               
                 GTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEEKGIVFRDGSNIL 
               
               
                   
               
               
                 PKLLENDDSHAIDTMVALIRSVLQMRNSNAATGEDYINSPVRDLNGVCFD 
               
               
                   
               
               
                 SRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLA 
               
               
                   
               
               
                 YIQELRNKRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPD 
               
               
                   
               
               
                 YA 
               
             
          
         
       
     
         [0130]    SEQ ID NO: 25 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0131]    SEQ ID NO: 25 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 26) 
               
             
          
           
               
                 ATGACACAGTTCGAGGGCTTTACCAACCTGTATCAGGTGAGCAAGACACT 
               
               
                   
               
               
                 GCGGTTTGAGCTGATCCCACAGGGCAAGACCCTGAAGCACATCCAGGAGC 
               
               
                   
               
               
                 AGGGCTTCATCGAGGAGGACAAGGCCCGCAATGATCACTACAAGGAGCTG 
               
               
                   
               
               
                 AAGCCCATCATCGATCGGATCTACAAGACCTATGCCGACCAGTGCCTGCA 
               
               
                   
               
               
                 GCTGGTGCAGCTGGATTGGGAGAACCTGAGCGCCGCCATCGACTCCTATA 
               
               
                   
               
               
                 GAAAGGAGAAAACCGAGGAGACAAGGAACGCCCTGATCGAGGAGCAGGCC 
               
               
                   
               
               
                 ACATATCGCAATGCCATCCACGACTACTTCATCGGCCGGACAGACAACCT 
               
               
                   
               
               
                 GACCGATGCCATCAATAAGAGACACGCCGAGATCTACAAGGGCCTGTTCA 
               
               
                   
               
               
                 AGGCCGAGCTGTTTAATGGCAAGGTGCTGAAGCAGCTGGGCACCGTGACC 
               
               
                   
               
               
                 ACAACCGAGCACGAGAACGCCCTGCTGCGGAGCTTCGACAAGTTTACAAC 
               
               
                   
               
               
                 CTACTTCTCCGGCTTTTATGAGAACAGGAAGAACGTGTTCAGCGCCGAGG 
               
               
                   
               
               
                 ATATCAGCACAGCCATCCCACACCGCATCGTGCAGGACAACTTCCCCAAG 
               
               
                   
               
               
                 TTTAAGGAGAATTGTCACATCTTCACACGCCTGATCACCGCCGTGCCCAG 
               
               
                   
               
               
                 CCTGCGGGAGCACTTTGAGAACGTGAAGAAGGCCATCGGCATCTTCGTGA 
               
               
                   
               
               
                 GCACCTCCATCGAGGAGGTGTTTTCCTTCCCTTTTTATAACCAGCTGCTG 
               
               
                   
               
               
                 ACACAGACCCAGATCGACCTGTATAACCAGCTGCTGGGAGGAATCTCTCG 
               
               
                   
               
               
                 GGAGGCAGGCACCGAGAAGATCAAGGGCCTGAACGAGGTGCTGAATCTGG 
               
               
                   
               
               
                 CCATCCAGAAGAATGATGAGACAGCCCACATCATCGCCTCCCTGCCACAC 
               
               
                   
               
               
                 AGATTCATCCCCCTGTTTAAGCAGATCCTGTCCGATAGGAACACCCTGTC 
               
               
                   
               
               
                 TTTCATCCTGGAGGAGTTTAAGAGCGACGAGGAAGTGATCCAGTCCTTCT 
               
               
                   
               
               
                 GCAAGTACAAGACACTGCTGAGAAACGAGAACGTGCTGGAGACAGCCGAG 
               
               
                   
               
               
                 GCCCTGTTTAACGAGCTGAACAGCATCGACCTGACACACATCTTCATCAG 
               
               
                   
               
               
                 CCACAAGAAGCTGGAGACAATCAGCAGCGCCCTGTGCGACCACTGGGATA 
               
               
                   
               
               
                 CACTGAGGAATGCCCTGTATGAGCGGAGAATCTCCGAGCTGACAGGCAAG 
               
               
                   
               
               
                 ATCACCAAGTCTGCCAAGGAGAAGGTGCAGCGCAGCCTGAAGCACGAGGA 
               
               
                   
               
               
                 TATCAACCTGCAGGAGATCATCTCTGCCGCAGGCAAGGAGCTGAGCGAGG 
               
               
                   
               
               
                 CCTTCAAGCAGAAAACCAGCGAGATCCTGTCCCACGCACACGCCGCCCTG 
               
               
                   
               
               
                 GATCAGCCACTGCCTACAACCCTGAAGAAGCAGGAGGAGAAGGAGATCCT 
               
               
                   
               
               
                 GAAGTCTCAGCTGGACAGCCTGCTGGGCCTGTACCACCTGCTGGACTGGT 
               
               
                   
               
               
                 TTGCCGTGGATGAGTCCAACGAGGTGGACCCCGAGTTCTCTGCCCGGCTG 
               
               
                   
               
               
                 ACCGGCATCAAGCTGGAGATGGAGCCTTCTCTGAGCTTCTACAACAAGGC 
               
               
                   
               
               
                 CAGAAATTATGCCACCAAGAAGCCCTACTCCGTGGAGAAGTTCAAGCTGA 
               
               
                   
               
               
                 ACTTTCAGATGCCTACACTGGCCTCTGGCTGGGACGTGAATAAGGAGAAG 
               
               
                   
               
               
                 AACAATGGCGCCATCCTGTTTGTGAAGAACGGCCTGTACTATCTGGGCAT 
               
               
                   
               
               
                 CATGCCAAAGCAGAAGGGCAGGTATAAGGCCCTGAGCTTCGAGCCCACAG 
               
               
                   
               
               
                 AGAAAACCAGCGAGGGCTTTGATAAGATGTACTATGACTACTTCCCTGAT 
               
               
                   
               
               
                 GCCGCCAAGATGATCCCAAAGTGCAGCACCCAGCTGAAGGCCGTGACAGC 
               
               
                   
               
               
                 CCACTTTCAGACCCACACAACCCCCATCCTGCTGTCCAACAATTTCATCG 
               
               
                   
               
               
                 AGCCTCTGGAGATCACAAAGGAGATCTACGACCTGAACAATCCTGAGAAG 
               
               
                   
               
               
                 GAGCCAAAGAAGTTTCAGACAGCCTACGCCAAGAAAACCGGCGACCAGAA 
               
               
                   
               
               
                 GGGCTACAGAGAGGCCCTGTGCAAGTGGATCGACTTCACAAGGGATTTTC 
               
               
                   
               
               
                 TGTCCAAGTATACCAAGACAACCTCTATCGATCTGTCTAGCCTGCGGCCA 
               
               
                   
               
               
                 TCCTCTCAGTATAAGGACCTGGGCGAGTACTATGCCGAGCTGAATCCCCT 
               
               
                   
               
               
                 GCTGTACCACATCAGCTTCCAGAGAATCGCCGAGAAGGAGATCATGGATG 
               
               
                   
               
               
                 CCGTGGAGACAGGCAAGCTGTACCTGTTCCAGATCTATAACAAGGACTTT 
               
               
                   
               
               
                 GCCAAGGGCCACCACGGCAAGCCTAATCTGCACACACTGTATTGGACCGG 
               
               
                   
               
               
                 CCTGTTTTCTCCAGAGAACCTGGCCAAGACAAGCATCAAGCTGAATGGCC 
               
               
                   
               
               
                 AGGCCGAGCTGTTCTACCGCCCTAAGTCCAGGATGAAGAGGATGGCACAC 
               
               
                   
               
               
                 CGGCTGGGAGAGAAGATGCTGAACAAGAAGCTGAAGGATCAGAAAACCCC 
               
               
                   
               
               
                 AATCCCCGACACCCTGTACCAGGAGCTGTACGACTATGTGAATCACAGAC 
               
               
                   
               
               
                 TGTCCCACGACCTGTCTGATGAGGCCAGGGCCCTGCTGCCCAACGTGATC 
               
               
                   
               
               
                 ACCAAGGAGGTGTCTCACGAGATCATCAAGGATAGGCGCTTTACCAGCGA 
               
               
                   
               
               
                 CAAGTTCTTTTTCCACGTGCCTATCACACTGAACTATCAGGCCGCCAATT 
               
               
                   
               
               
                 CCCCATCTAAGTTCAACCAGAGGGTGAATGCCTACCTGAAGGAGCACCCC 
               
               
                   
               
               
                 GAGACACCTATCATCGGCATCGATCGGGGCGAGAGAAACCTGATCTATAT 
               
               
                   
               
               
                 CACAGTGATCGACTCCACCGGCAAGATCCTGGAGCAGCGGAGCCTGAACA 
               
               
                   
               
               
                 CCATCCAGCAGTTTGATTACCAGAAGAAGCTGGACAACAGGGAGAAGGAG 
               
               
                   
               
               
                 AGGGTGGCAGCAAGGCAGGCCTGGTCTGTGGTGGGCACAATCAAGGATCT 
               
               
                   
               
               
                 GAAGCAGGGCTATCTGAGCCAGGTCATCCACGAGATCGTGGACCTGATGA 
               
               
                   
               
               
                 TCCACTACCAGGCCGTGGTGGTGCTGGAGAACCTGAATTTCGGCTTTAAG 
               
               
                   
               
               
                 AGCAAGAGGACCGGCATCGCCGAGAAGGCCGTGTACCAGCAGTTCGAGAA 
               
               
                   
               
               
                 GATGCTGATCGATAAGCTGAATTGCCTGGTGCTGAAGGACTATCCAGCAG 
               
               
                   
               
               
                 AGAAAGTGGGAGGCGTGCTGAACCCATACCAGCTGACAGACCAGTTCACC 
               
               
                   
               
               
                 TCCTTTGCCAAGATGGGCACCCAGTCTGGCTTCCTGTTTTACGTGCCTGC 
               
               
                   
               
               
                 CCCATATACATCTAAGATCGATCCCCTGACCGGCTTCGTGGACCCCTTCG 
               
               
                   
               
               
                 TGTGGAAAACCATCAAGAATCACGAGAGCCGCAAGCACTTCCTGGAGGGC 
               
               
                   
               
               
                 TTCGACTTTCTGCACTACGACGTGAAAACCGGCGACTTCATCCTGCACTT 
               
               
                   
               
               
                 TAAGATGAACAGAAATCTGTCCTTCCAGAGGGGCCTGCCCGGCTTTATGC 
               
               
                   
               
               
                 CTGCATGGGATATCGTGTTCGAGAAGAACGAGACACAGTTTGACGCCAAG 
               
               
                   
               
               
                 GGCACCCCTTTCATCGCCGGCAAGAGAATCGTGCCAGTGATCGAGAATCA 
               
               
                   
               
               
                 CAGATTCACCGGCAGATACCGGGACCTGTATCCTGCCAACGAGCTGATCG 
               
               
                   
               
               
                 CCCTGCTGGAGGAGAAGGGCATCGTGTTCAGGGATGGCTCCAACATCCTG 
               
               
                   
               
               
                 CCAAAGCTGCTGGAGAATGACGATTCTCACGCCATCGACACCATGGTGGC 
               
               
                   
               
               
                 CCTGATCCGCAGCGTGCTGCAGATGCGGAACTCCAATGCCGCCACAGGCG 
               
               
                   
               
               
                 AGGACTATATCAACAGCCCCGTGCGCGATCTGAATGGCGTGTGCTTCGAC 
               
               
                   
               
               
                 TCCCGGTTTCAGAACCCAGAGTGGCCCATGGACGCCGATGCCAATGGCGC 
               
               
                   
               
               
                 CTACCACATCGCCCTGAAGGGCCAGCTGCTGCTGAATCACCTGAAGGAGA 
               
               
                   
               
               
                 GCAAGGATCTGAAGCTGCAGAACGGCATCTCCAATCAGGACTGGCTGGCC 
               
               
                   
               
               
                 TACATCCAGGAGCTGCGCAACAAAAGGCCGGCGGCCACGAAAAAGGCCGG 
               
               
                   
               
               
                 CCAGGCAAAAAAGAAAAAGGGATCCTACCCATACGATGTTCCAGATTACG 
               
               
                   
               
               
                 CTTATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGAC 
               
               
                   
               
               
                 TATGCCTAA 
               
             
          
         
       
     
         [0132]      Lachnospiraceae bacterium  MA2020 (Lb2Cpf1; pY011), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 27) 
               
             
          
           
               
                 MYYESLTKQYPVSKTIRNELIPIGKTLDNIRQNNILESDVKRKQNYEHVK 
               
               
                   
               
               
                 GILDEYHKQLINEALDNCTLPSLKIAAEIYLKNQKEVSDREDFNKTQDLL 
               
               
                   
               
               
                 RKEVVEKLKAHENFTKIGKKDILDLLEKLPSISEDDYNALESFRNFYTYF 
               
               
                   
               
               
                 TSYNKVRENLYSDKEKSSTVAYRLINENFPKFLDNVKSYRFVKTAGILAD 
               
               
                   
               
               
                 GLGEEEQDSLFIVETFNKTLTQDGIDTYNSQVGKINSSINLYNQKNQKAN 
               
               
                   
               
               
                 GFRKIPKMKMLYKQILSDREESFIDEFQSDEVLIDNVESYGSVLIESLKS 
               
               
                   
               
               
                 SKVSAFFDALRESKGKNVYVKNDLAKTAMSNIVFENWRTFDDLLNQEYDL 
               
               
                   
               
               
                 ANENKKKDDKYFEKRQKELKKNKSYSLEHLCNLSEDSCNLIENYIHQISD 
               
               
                   
               
               
                 DIENIIINNETFLRIVINEHDRSRKLAKNRKAVKAIKDFLDSIKVLEREL 
               
               
                   
               
               
                 KLINSSGQELEKDLIVYSAHEELLVELKQVDSLYNMTRNYLTKKPFSTEK 
               
               
                   
               
               
                 VKLNFNRSTLLNGWDRNKETDNLGVLLLKDGKYYLGIMNTSANKAFVNPP 
               
               
                   
               
               
                 VAKTEKVFKKVDYKLLPVPNQMLPKVFFAKSNIDFYNPSSEIYSNYKKGT 
               
               
                   
               
               
                 HKKGNMFSLEDCHNLIDFFKESISKHEDWSKFGFKFSDTASYNDISEFYR 
               
               
                   
               
               
                 EVEKQGYKLTYTDIDETYINDLIERNELYLFQIYNKDFSMYSKGKLNLHT 
               
               
                   
               
               
                 LYFMMLFDQRNIDDVVYKLNGEAEVFYRPASISEDELIIHKAGEEIKNKN 
               
               
                   
               
               
                 PNRARTKETSTFSYDIVKDKRYSKDKFTLHIPITMNFGVDEVKRFNDAVN 
               
               
                   
               
               
                 SAIRIDENVNVIGIDRGERNLLYVVVIDSKGNILEQISLNSIINKEYDIE 
               
               
                   
               
               
                 TDYHALLDEREGGRDKARKDWNTVENIRDLKAGYLSQVVNVVAKLVLKYN 
               
               
                   
               
               
                 AIICLEDLNFGFKRGRQKVEKQVYQKFEKMLIDKLNYLVIDKSREQTSPK 
               
               
                   
               
               
                 ELGGALNALQLTSKFKSFKELGKQSGVIYYVPAYLTSKIDPTTGFANLFY 
               
               
                   
               
               
                 MKCENVEKSKRFFDGFDFIRFNALENVFEFGFDYRSFTQRACGINSKWTV 
               
               
                   
               
               
                 CTNGERIIKYRNPDKNNMFDEKVVVVTDEMKNLFEQYKIPYEDGRNVKDM 
               
               
                   
               
               
                 IISNEEAEFYRRLYRLLQQTLQMRNSTSDGTRDYIISPVKNKREAYFNSE 
               
               
                   
               
               
                 LSDGSVPKDADANGAYNIARKGLWVLEQIRQKSEGEKINLAMTNAEWLEY 
               
               
                   
               
               
                 AQTHLLKRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDY 
               
               
                   
               
               
                 A 
               
             
          
         
       
     
         [0133]    SEQ ID NO: 27 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0134]    SEQ ID NO: 27 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 28) 
               
             
          
           
               
                 ATGTACTATGAGTCCCTGACCAAGCAGTACCCCGTGTCTAAGACAATCCG 
               
               
                   
               
               
                 GAATGAGCTGATCCCTATCGGCAAGACACTGGATAACATCCGCCAGAACA 
               
               
                   
               
               
                 ATATCCTGGAGAGCGACGTGAAGCGGAAGCAGAACTACGAGCACGTGAAG 
               
               
                   
               
               
                 GGCATCCTGGATGAGTATCACAAGCAGCTGATCAACGAGGCCCTGGACAA 
               
               
                   
               
               
                 TTGCACCCTGCCATCCCTGAAGATCGCCGCCGAGATCTACCTGAAGAATC 
               
               
                   
               
               
                 AGAAGGAGGTGTCTGACAGAGAGGATTTCAACAAGACACAGGACCTGCTG 
               
               
                   
               
               
                 AGGAAGGAGGTGGTGGAGAAGCTGAAGGCCCACGAGAACTTTACCAAGAT 
               
               
                   
               
               
                 CGGCAAGAAGGACATCCTGGATCTGCTGGAGAAGCTGCCTTCCATCTCTG 
               
               
                   
               
               
                 AGGACGATTACAATGCCCTGGAGAGCTTCCGCAACTTTTACACCTATTTC 
               
               
                   
               
               
                 ACATCCTACAACAAGGTGCGGGAGAATCTGTATTCTGATAAGGAGAAGAG 
               
               
                   
               
               
                 CTCCACAGTGGCCTACAGACTGATCAACGAGAATTTCCCAAAGTTTCTGG 
               
               
                   
               
               
                 ACAATGTGAAGAGCTATAGGTTTGTGAAAACCGCAGGCATCCTGGCAGAT 
               
               
                   
               
               
                 GGCCTGGGAGAGGAGGAGCAGGACTCCCTGTTCATCGTGGAGACATTCAA 
               
               
                   
               
               
                 CAAGACCCTGACACAGGACGGCATCGATACCTACAATTCTCAAGTGGGCA 
               
               
                   
               
               
                 AGATCAACTCTAGCATCAATCTGTATAACCAGAAGAATCAGAAGGCCAAT 
               
               
                   
               
               
                 GGCTTCAGAAAGATCCCCAAGATGAAGATGCTGTATAAGCAGATCCTGTC 
               
               
                   
               
               
                 CGATAGGGAGGAGTCTTTCATCGACGAGTTTCAGAGCGATGAGGTGCTGA 
               
               
                   
               
               
                 TCGACAACGTGGAGTCTTATGGCAGCGTGCTGATCGAGTCTCTGAAGTCC 
               
               
                   
               
               
                 TCTAAGGTGAGCGCCTTCTTTGATGCCCTGAGAGAGTCTAAGGGCAAGAA 
               
               
                   
               
               
                 CGTGTACGTGAAGAATGACCTGGCCAAGACAGCCATGAGCAACATCGTGT 
               
               
                   
               
               
                 TCGAGAATTGGAGGACCTTTGACGATCTGCTGAACCAGGAGTACGACCTG 
               
               
                   
               
               
                 GCCAACGAGAACAAGAAGAAGGACGATAAGTATTTCGAGAAGCGCCAGAA 
               
               
                   
               
               
                 GGAGCTGAAGAAGAATAAGAGCTACTCCCTGGAGCACCTGTGCAACCTGT 
               
               
                   
               
               
                 CCGAGGATTCTTGTAACCTGATCGAGAATTATATCCACCAGATCTCCGAC 
               
               
                   
               
               
                 GATATCGAGAATATCATCATCAACAATGAGACATTCCTGCGCATCGTGAT 
               
               
                   
               
               
                 CAATGAGCACGACAGGTCCCGCAAGCTGGCCAAGAACCGGAAGGCCGTGA 
               
               
                   
               
               
                 AGGCCATCAAGGACTTTCTGGATTCTATCAAGGTGCTGGAGCGGGAGCTG 
               
               
                   
               
               
                 AAGCTGATCAACAGCTCCGGCCAGGAGCTGGAGAAGGATCTGATCGTGTA 
               
               
                   
               
               
                 CTCTGCCCACGAGGAGCTGCTGGTGGAGCTGAAGCAGGTGGACAGCCTGT 
               
               
                   
               
               
                 ATAACATGACCAGAAATTATCTGACAAAGAAGCCTTTCTCTACCGAGAAG 
               
               
                   
               
               
                 GTGAAGCTGAACTTTAATCGCAGCACACTGCTGAACGGCTGGGATCGGAA 
               
               
                   
               
               
                 TAAGGAGACAGACAACCTGGGCGTGCTGCTGCTGAAGGACGGCAAGTACT 
               
               
                   
               
               
                 ATCTGGGCATCATGAACACAAGCGCCAATAAGGCCTTCGTGAATCCCCCT 
               
               
                   
               
               
                 GTGGCCAAGACCGAGAAGGTGTTTAAGAAGGTGGATTACAAGCTGCTGCC 
               
               
                   
               
               
                 AGTGCCCAACCAGATGCTGCCAAAGGTGTTCTTTGCCAAGAGCAATATCG 
               
               
                   
               
               
                 ACTTCTATAACCCCTCTAGCGAGATCTACTCCAATTATAAGAAGGGCACC 
               
               
                   
               
               
                 CACAAGAAGGGCAATATGTTTTCCCTGGAGGATTGTCACAACCTGATCGA 
               
               
                   
               
               
                 CTTCTTTAAGGAGTCTATCAGCAAGCACGAGGACTGGAGCAAGTTCGGCT 
               
               
                   
               
               
                 TTAAGTTCAGCGATACAGCCTCCTACAACGACATCTCCGAGTTCTATCGC 
               
               
                   
               
               
                 GAGGTGGAGAAGCAGGGCTACAAGCTGACCTATACAGACATCGATGAGAC 
               
               
                   
               
               
                 ATACATCAATGATCTGATCGAGCGGAACGAGCTGTACCTGTTCCAGATCT 
               
               
                   
               
               
                 ATAATAAGGACTTTAGCATGTACTCCAAGGGCAAGCTGAACCTGCACACA 
               
               
                   
               
               
                 CTGTATTTCATGATGCTGTTTGATCAGCGCAATATCGACGACGTGGTGTA 
               
               
                   
               
               
                 TAAGCTGAACGGAGAGGCAGAGGTGTTCTATAGGCCAGCCTCCATCTCTG 
               
               
                   
               
               
                 AGGACGAGCTGATCATCCACAAGGCCGGCGAGGAGATCAAGAACAAGAAT 
               
               
                   
               
               
                 CCTAACCGGGCCAGAACCAAGGAGACAAGCACCTTCAGCTACGACATCGT 
               
               
                   
               
               
                 GAAGGATAAGCGGTATAGCAAGGATAAGTTTACCCTGCACATCCCCATCA 
               
               
                   
               
               
                 CAATGAACTTCGGCGTGGATGAGGTGAAGCGGTTCAACGACGCCGTGAAC 
               
               
                   
               
               
                 AGCGCCATCCGGATCGATGAGAATGTGAACGTGATCGGCATCGACCGGGG 
               
               
                   
               
               
                 CGAGAGAAATCTGCTGTACGTGGTGGTCATCGACTCTAAGGGCAACATCC 
               
               
                   
               
               
                 TGGAGCAGATCTCCCTGAACTCTATCATCAATAAGGAGTACGACATCGAG 
               
               
                   
               
               
                 ACAGATTATCACGCACTGCTGGATGAGAGGGAGGGCGGCAGAGATAAGGC 
               
               
                   
               
               
                 CCGGAAGGACTGGAACACCGTGGAGAATATCAGGGACCTGAAGGCCGGCT 
               
               
                   
               
               
                 ACCTGAGCCAGGTGGTGAACGTGGTGGCCAAGCTGGTGCTGAAGTATAAT 
               
               
                   
               
               
                 GCCATCATCTGCCTGGAGGACCTGAACTTTGGCTTCAAGAGGGGCCGCCA 
               
               
                   
               
               
                 GAAGGTGGAGAAGCAGGTGTACCAGAAGTTCGAGAAGATGCTGATCGATA 
               
               
                   
               
               
                 AGCTGAATTACCTGGTCATCGACAAGAGCCGCGAGCAGACATCCCCTAAG 
               
               
                   
               
               
                 GAGCTGGGAGGCGCCCTGAACGCACTGCAGCTGACCTCTAAGTTCAAGAG 
               
               
                   
               
               
                 CTTTAAGGAGCTGGGCAAGCAGTCCGGCGTGATCTACTATGTGCCTGCCT 
               
               
                   
               
               
                 ACCTGACCTCTAAGATCGATCCAACCACAGGCTTCGCCAATCTGTTTTAT 
               
               
                   
               
               
                 ATGAAGTGTGAGAACGTGGAGAAGTCCAAGAGATTCTTTGACGGCTTTGA 
               
               
                   
               
               
                 TTTCATCAGGTTCAACGCCCTGGAGAACGTGTTCGAGTTCGGCTTTGACT 
               
               
                   
               
               
                 ACCGGAGCTTCACCCAGAGGGCCTGCGGCATCAATTCCAAGTGGACCGTG 
               
               
                   
               
               
                 TGCACCAACGGCGAGCGCATCATCAAGTATCGGAATCCAGATAAGAACAA 
               
               
                   
               
               
                 TATGTTCGACGAGAAGGTGGTGGTGGTGACCGATGAGATGAAGAACCTGT 
               
               
                   
               
               
                 TTGAGCAGTACAAGATCCCCTATGAGGATGGCAGAAATGTGAAGGACATG 
               
               
                   
               
               
                 ATCATCAGCAACGAGGAGGCCGAGTTCTACCGGAGACTGTATAGGCTGCT 
               
               
                   
               
               
                 GCAGCAGACCCTGCAGATGAGAAACAGCACCTCCGACGGCACAAGGGATT 
               
               
                   
               
               
                 ACATCATCTCCCCTGTGAAGAATAAGAGAGAGGCCTACTTCAACAGCGAG 
               
               
                   
               
               
                 CTGTCCGACGGCTCTGTGCCAAAGGACGCCGATGCCAACGGCGCCTACAA 
               
               
                   
               
               
                 TATCGCCAGAAAGGGCCTGTGGGTGCTGGAGCAGATCAGGCAGAAGAGCG 
               
               
                   
               
               
                 AGGGCGAGAAGATCAATCTGGCCATGACCAACGCCGAGTGGCTGGAGTAT 
               
               
                   
               
               
                 GCCCAGACACACCTGCTGAAAAGGCCGGCGGCCACGAAAAAGGCCGGCCA 
               
               
                   
               
               
                 GGCAAAAAAGAAAAAGGGATCCTACCCATACGATGTTCCAGATTACGCTT 
               
               
                   
               
               
                 ATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTAT 
               
               
                   
               
               
                 GCCTAA 
               
             
          
         
       
     
         [0135]      Candidatus Methanoplasma termitum  (CMtCpf1; pY012), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 29) 
               
             
          
           
               
                 MNNYDEFTKLYPIQKTIRFELKPQGRTMEHLETFNFFEEDRDRAEKYKIL 
               
               
                   
               
               
                 KEAIDEYHKKFIDEHLTNMSLDWNSLKQISEKYYKSREEKDKKVFLSEQK 
               
               
                   
               
               
                 RMRQEIVSEFKKDDRFKDLFSKKLFSELLKEEIYKKGNHQEIDALKSFDK 
               
               
                   
               
               
                 FSGYFIGLHENRKNMYSDGDEITAISNRIVNENFPKFLDNLQKYQEARKK 
               
               
                   
               
               
                 YPEWIIKAESALVAHNIKMDEVFSLEYFNKVLNQEGIQRYNLALGGYVTK 
               
               
                   
               
               
                 SGEKMMGLNDALNLAHQSEKSSKGRIHMTPLFKQILSEKESFSYIPDVFT 
               
               
                   
               
               
                 EDSQLLPSIGGFFAQIENDKDGNIFDRALELISSYAEYDTERIYIRQADI 
               
               
                   
               
               
                 NRVSNVIFGEWGTLGGLMREYKADSINDINLERTCKKVDKWLDSKEFALS 
               
               
                   
               
               
                 DVLEAIKRTGNNDAFNEYISKMRTAREKIDAARKEMKFISEKISGDEESI 
               
               
                   
               
               
                 HIIKTLLDSVQQFLHFFNLFKARQDIPLDGAFYAEFDEVHSKLFAIVPLY 
               
               
                   
               
               
                 NKVRNYLTKNNLNTKKIKLNFKNPTLANGWDQNKVYDYASLIFLRDGNYY 
               
               
                   
               
               
                 LGIINPKRKKNIKFEQGSGNGPFYRKMVYKQIPGPNKNLPRVFLTSTKGK 
               
               
                   
               
               
                 KEYKPSKEIIEGYEADKHIRGDKFDLDFCHKLIDFFKESIEKHKDWSKFN 
               
               
                   
               
               
                 FYFSPTESYGDISEFYLDVEKQGYRMHFENISAETIDEYVEKGDLFLFQI 
               
               
                   
               
               
                 YNKDFVKAATGKKDMHTIYWNAAFSPENLQDVVVKLNGEAELFYRDKSDI 
               
               
                   
               
               
                 KEIVHREGEILVNRTYNGRTPVPDKIHKKLTDYHNGRTKDLGEAKEYLDK 
               
               
                   
               
               
                 VRYFKAHYDITKDRRYLNDKIYFHVPLTLNFKANGKKNLNKMVIEKFLSD 
               
               
                   
               
               
                 EKAHIIGIDRGERNLLYYSIIDRSGKIIDQQSLNVIDGFDYREKLNQREI 
               
               
                   
               
               
                 EMKDARQSWNAIGKIKDLKEGYLSKAVHEITKMAIQYNAIVVMEELNYGF 
               
               
                   
               
               
                 KRGRFKVEKQIYQKFENMLIDKMNYLVFKDAPDESPGGVLNAYQLTNPLE 
               
               
                   
               
               
                 SFAKLGKQTGILFYVPAAYTSKIDPTTGFVNLFNTSSKTNAQERKEFLQK 
               
               
                   
               
               
                 FESISYSAKDGGIFAFAFDYRKFGTSKTDHKNVWTAYTNGERMRYIKEKK 
               
               
                   
               
               
                 RNELFDPSKEIKEALTSSGIKYDGGQNILPDILRSNNNGLIYTMYSSFIA 
               
               
                   
               
               
                 AIQMRVYDGKEDYIISPIKNSKGEFFRTDPKRRELPIDADANGAYNIALR 
               
               
                   
               
               
                 GELTMRAIAEKFDPDSEKMAKLELKHKDWFEFMQTRGDKRPAATKKAGQA 
               
               
                   
               
               
                 KKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0136]    SEQ ID NO: 29 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0137]    SEQ ID NO: 29 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 30) 
               
             
          
           
               
                 ATGAACAATTACGACGAGTTCACCAAGCTGTATCCTATCCAGAAAACCAT 
               
               
                   
               
               
                 CCGGTTTGAGCTGAAGCCACAGGGCAGAACCATGGAGCACCTGGAGACAT 
               
               
                   
               
               
                 TCAACTTCTTTGAGGAGGACCGGGATAGAGCCGAGAAGTATAAGATCCTG 
               
               
                   
               
               
                 AAGGAGGCCATCGACGAGTACCACAAGAAGTTTATCGATGAGCACCTGAC 
               
               
                   
               
               
                 CAATATGTCCCTGGATTGGAACTCTCTGAAGCAGATCAGCGAGAAGTACT 
               
               
                   
               
               
                 ATAAGAGCAGGGAGGAGAAGGACAAGAAGGTGTTCCTGTCCGAGCAGAAG 
               
               
                   
               
               
                 AGGATGCGCCAGGAGATCGTGTCTGAGTTTAAGAAGGACGATCGCTTCAA 
               
               
                   
               
               
                 GGACCTGTTTTCCAAGAAGCTGTTCTCTGAGCTGCTGAAGGAGGAGATCT 
               
               
                   
               
               
                 ACAAGAAGGGCAACCACCAGGAGATCGACGCCCTGAAGAGCTTCGATAAG 
               
               
                   
               
               
                 TTTTCCGGCTATTTCATCGGCCTGCACGAGAATAGGAAGAACATGTACTC 
               
               
                   
               
               
                 CGACGGCGATGAGATCACCGCCATCTCCAATCGCATCGTGAATGAGAACT 
               
               
                   
               
               
                 TCCCCAAGTTTCTGGATAACCTGCAGAAGTACCAGGAGGCCAGGAAGAAG 
               
               
                   
               
               
                 TATCCTGAGTGGATCATCAAGGCCGAGAGCGCCCTGGTGGCCCACAATAT 
               
               
                   
               
               
                 CAAGATGGACGAGGTGTTCTCCCTGGAGTACTTTAATAAGGTGCTGAACC 
               
               
                   
               
               
                 AGGAGGGCATCCAGCGGTACAACCTGGCCCTGGGCGGCTATGTGACCAAG 
               
               
                   
               
               
                 AGCGGCGAGAAGATGATGGGCCTGAATGATGCCCTGAACCTGGCCCACCA 
               
               
                   
               
               
                 GTCCGAGAAGAGCTCCAAGGGCAGAATCCACATGACCCCCCTGTTCAAGC 
               
               
                   
               
               
                 AGATCCTGTCCGAGAAGGAGTCCTTCTCTTACATCCCCGACGTGTTTACA 
               
               
                   
               
               
                 GAGGATTCTCAGCTGCTGCCTAGCATCGGCGGCTTCTTTGCCCAGATCGA 
               
               
                   
               
               
                 GAATGACAAGGATGGCAACATCTTCGACCGGGCCCTGGAGCTGATCTCTA 
               
               
                   
               
               
                 GCTACGCCGAGTATGATACCGAGCGGATCTATATCAGACAGGCCGACATC 
               
               
                   
               
               
                 AATAGAGTGTCCAACGTGATCTTTGGAGAGTGGGGCACCCTGGGAGGCCT 
               
               
                   
               
               
                 GATGAGGGAGTACAAGGCCGACTCTATCAATGATATCAACCTGGAGCGCA 
               
               
                   
               
               
                 CATGCAAGAAGGTGGACAAGTGGCTGGATTCTAAGGAGTTTGCCCTGAGC 
               
               
                   
               
               
                 GATGTGCTGGAGGCCATCAAGAGGACCGGCAACAATGACGCCTTCAACGA 
               
               
                   
               
               
                 GTATATCTCCAAGATGCGGACAGCCAGAGAGAAGATCGATGCCGCCCGCA 
               
               
                   
               
               
                 AGGAGATGAAGTTCATCAGCGAGAAGATCTCCGGCGATGAGGAGTCTATC 
               
               
                   
               
               
                 CACATCATCAAGACCCTGCTGGACAGCGTGCAGCAGTTCCTGCACTTCTT 
               
               
                   
               
               
                 TAATCTGTTTAAGGCAAGGCAGGACATCCCACTGGATGGAGCCTTCTACG 
               
               
                   
               
               
                 CCGAGTTTGACGAGGTGCACAGCAAGCTGTTTGCCATCGTGCCCCTGTAT 
               
               
                   
               
               
                 AACAAGGTGCGGAACTATCTGACCAAGAACAATCTGAACACAAAGAAGAT 
               
               
                   
               
               
                 CAAGCTGAATTTCAAGAACCCTACACTGGCCAATGGCTGGGACCAGAACA 
               
               
                   
               
               
                 AGGTGTACGATTATGCCTCCCTGATCTTTCTGCGGGACGGCAATTACTAT 
               
               
                   
               
               
                 CTGGGCATCATCAATCCTAAGAGAAAGAAGAACATCAAGTTCGAGCAGGG 
               
               
                   
               
               
                 CTCTGGCAACGGCCCCTTCTACCGGAAGATGGTGTATAAGCAGATCCCCG 
               
               
                   
               
               
                 GCCCTAATAAGAACCTGCCAAGAGTGTTCCTGACCTCCACAAAGGGCAAG 
               
               
                   
               
               
                 AAGGAGTATAAGCCCTCTAAGGAGATCATCGAGGGCTACGAGGCCGACAA 
               
               
                   
               
               
                 GCACATCAGGGGCGATAAGTTCGACCTGGATTTTTGTCACAAGCTGATCG 
               
               
                   
               
               
                 ATTTCTTTAAGGAGTCCATCGAGAAGCACAAGGACTGGTCTAAGTTCAAC 
               
               
                   
               
               
                 TTCTACTTCAGCCCAACCGAGAGCTATGGCGACATCTCTGAGTTCTACCT 
               
               
                   
               
               
                 GGATGTGGAGAAGCAGGGCTATCGCATGCACTTTGAGAATATCAGCGCCG 
               
               
                   
               
               
                 AGACAATCGACGAGTATGTGGAGAAGGGCGATCTGTTTCTGTTCCAGATC 
               
               
                   
               
               
                 TACAACAAGGATTTTGTGAAGGCCGCCACCGGCAAGAAGGACATGCACAC 
               
               
                   
               
               
                 AATCTACTGGAATGCCGCCTTCAGCCCCGAGAACCTGCAGGACGTGGTGG 
               
               
                   
               
               
                 TGAAGCTGAACGGCGAGGCCGAGCTGTTTTATAGGGACAAGTCCGATATC 
               
               
                   
               
               
                 AAGGAGATCGTGCACCGCGAGGGCGAGATCCTGGTGAATAGGACCTACAA 
               
               
                   
               
               
                 CGGCCGCACACCAGTGCCCGACAAGATCCACAAGAAGCTGACCGATTATC 
               
               
                   
               
               
                 ACAATGGCCGGACAAAGGACCTGGGCGAGGCCAAGGAGTACCTGGATAAG 
               
               
                   
               
               
                 GTGAGATACTTCAAGGCCCACTATGACATCACCAAGGATCGGAGATACCT 
               
               
                   
               
               
                 GAACGACAAGATCTATTTCCACGTGCCTCTGACCCTGAACTTCAAGGCCA 
               
               
                   
               
               
                 ACGGCAAGAAGAATCTGAACAAGATGGTCATCGAGAAGTTCCTGTCCGAT 
               
               
                   
               
               
                 GAGAAGGCCCACATCATCGGCATCGACAGGGGCGAGCGCAATCTGCTGTA 
               
               
                   
               
               
                 CTATTCCATCATCGACAGGTCTGGCAAGATCATCGATCAGCAGAGCCTGA 
               
               
                   
               
               
                 ATGTGATCGACGGCTTTGATTATCGGGAGAAGCTGAACCAGAGAGAGATC 
               
               
                   
               
               
                 GAGATGAAGGATGCCCGCCAGTCTTGGAACGCCATCGGCAAGATCAAGGA 
               
               
                   
               
               
                 CCTGAAGGAGGGCTACCTGAGCAAGGCCGTGCACGAGATCACCAAGATGG 
               
               
                   
               
               
                 CCATCCAGTATAATGCCATCGTGGTCATGGAGGAGCTGAACTACGGCTTC 
               
               
                   
               
               
                 AAGCGGGGCCGGTTCAAGGTGGAGAAGCAGATCTATCAGAAGTTCGAGAA 
               
               
                   
               
               
                 TATGCTGATCGATAAGATGAACTACCTGGTGTTTAAGGACGCACCTGATG 
               
               
                   
               
               
                 AGTCCCCAGGAGGCGTGCTGAATGCCTACCAGCTGACAAACCCACTGGAG 
               
               
                   
               
               
                 TCTTTCGCCAAGCTGGGCAAGCAGACCGGCATCCTGTTTTACGTGCCAGC 
               
               
                   
               
               
                 CGCCTATACATCCAAGATCGACCCCACCACAGGCTTCGTGAATCTGTTTA 
               
               
                   
               
               
                 ACACCTCCTCTAAGACAAACGCCCAGGAGCGGAAGGAGTTCCTGCAGAAG 
               
               
                   
               
               
                 TTTGAGAGCATCTCCTATTCTGCCAAGGATGGCGGCATCTTTGCCTTCGC 
               
               
                   
               
               
                 CTTTGACTACAGAAAGTTCGGCACCAGCAAGACAGATCACAAGAACGTGT 
               
               
                   
               
               
                 GGACCGCCTATACAAACGGCGAGAGGATGCGCTACATCAAGGAGAAGAAG 
               
               
                   
               
               
                 CGGAATGAGCTGTTTGACCCTTCTAAGGAGATCAAGGAGGCCCTGACCAG 
               
               
                   
               
               
                 CTCCGGCATCAAGTACGATGGCGGCCAGAACATCCTGCCAGACATCCTGA 
               
               
                   
               
               
                 GGAGCAACAATAACGGCCTGATCTACACAATGTATTCTAGCTTCATCGCC 
               
               
                   
               
               
                 GCCATCCAGATGCGCGTGTACGACGGCAAGGAGGATTATATCATCAGCCC 
               
               
                   
               
               
                 CATCAAGAACTCCAAGGGCGAGTTCTTTAGGACCGACCCCAAGAGGCGCG 
               
               
                   
               
               
                 AGCTGCCTATCGACGCCGATGCCAATGGCGCCTACAACATCGCCCTGAGG 
               
               
                   
               
               
                 GGAGAGCTGACAATGAGGGCAATCGCAGAGAAGTTCGACCCTGATAGCGA 
               
               
                   
               
               
                 GAAGATGGCCAAGCTGGAGCTGAAGCACAAGGATTGGTTCGAGTTTATGC 
               
               
                   
               
               
                 AGACCAGAGGCGACAAAAGGCCGGCGGCCACGAAAAAGGCCGGCCAGGCA 
               
               
                   
               
               
                 AAAAAGAAAAAGGGATCCTACCCATACGATGTTCCAGATTACGCTTATCC 
               
               
                   
               
               
                 CTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTATGCCT 
               
               
                   
               
               
                 AA 
               
             
          
         
       
     
         [0138]      Eubacterium eligens  (EeCpf1; pY013), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 31) 
               
             
          
           
               
                 MNGNRSIVYREFVGVIPVAKTLRNELRPVGHTQEHIIQNGLIQEDELRQE 
               
               
                   
               
               
                 KSTELKNIMDDYYREYIDKSLSGVTDLDFTLLFELMNLVQSSPSKDNKKA 
               
               
                   
               
               
                 LEKEQSKMREQICTHLQSDSNYKNIFNAKLLKEILPDFIKNYNQYDVKDK 
               
               
                   
               
               
                 AGKLETLALFNGFSTYFTDFFEKRKNVFTKEAVSTSIAYRIVHENSLIFL 
               
               
                   
               
               
                 ANMTSYKKISEKALDEIEVIEKNNQDKMGDWELNQIFNPDFYNMVLIQSG 
               
               
                   
               
               
                 IDFYNEICGVVNAHMNLYCQQTKNNYNLFKMRKLHKQILAYTSTSFEVPK 
               
               
                   
               
               
                 MFEDDMSVYNAVNAFIDETEKGNIIGKLKDIVNKYDELDEKRIYISKDFY 
               
               
                   
               
               
                 ETLSCFMSGNWNLITGCVENFYDENIHAKGKSKEEKVKKAVKEDKYKSIN 
               
               
                   
               
               
                 DVNDLVEKYIDEKERNEFKNSNAKQYIREISNIITDTETAHLEYDDHISL 
               
               
                   
               
               
                 IESEEKADEMKKRLDMYMNMYHWAKAFIVDEVLDRDEMFYSDIDDIYNIL 
               
               
                   
               
               
                 ENIVPLYNRVRNYVTQKPYNSKKIKLNFQSPTLANGWSQSKEFDNNAIIL 
               
               
                   
               
               
                 IRDNKYYLAIFNAKNKPDKKIIQGNSDKKNDNDYKKMVYNLLPGANKMLP 
               
               
                   
               
               
                 KVFLSKKGIETFKPSDYIISGYNAHKHIKTSENFDISFCRDLIDYFKNSI 
               
               
                   
               
               
                 EKHAEWRKYEFKFSATDSYSDISEFYREVEMQGYRIDWTYISEADINKLD 
               
               
                   
               
               
                 EEGKIYLFQIYNKDFAENSTGKENLHTMYFKNIFSEENLKDIIIKLNGQA 
               
               
                   
               
               
                 ELFYRRASVKNPVKHKKDSVLVNKTYKNQLDNGDVVRIPIPDDIYNEIYK 
               
               
                   
               
               
                 MYNGYIKESDLSEAAKEYLDKVEVRTAQKDIVKDYRYTVDKYFIHTPITI 
               
               
                   
               
               
                 NYKVTARNNVNDMVVKYIAQNDDIHVIGIDRGERNLIYISVIDSHGNIVK 
               
               
                   
               
               
                 QKSYNILNNYDYKKKLVEKEKTREYARKNWKSIGNIKELKEGYISGVVHE 
               
               
                   
               
               
                 IAMLIVEYNAIIAMEDLNYGFKRGRFKVERQVYQKFESMLINKLNYFASK 
               
               
                   
               
               
                 EKSVDEPGGLLKGYQLTYVPDNIKNLGKQCGVIFYVPAAFTSKIDPSTGF 
               
               
                   
               
               
                 ISAFNFKSISTNASRKQFFMQFDEIRYCAEKDMFSFGFDYNNFDTYNITM 
               
               
                   
               
               
                 GKTQWTVYTNGERLQSEFNNARRTGKTKSINLTETIKLLLEDNEINYADG 
               
               
                   
               
               
                 HDIRIDMEKMDEDKKSEFFAQLLSLYKLTVQMRNSYTEAEEQENGISYDK 
               
               
                   
               
               
                 IISPVINDEGEFFDSDNYKESDDKECKMPKDADANGAYCIALKGLYEVLK 
               
               
                   
               
               
                 IKSEWTEDGFDRNCLKLPHAEWLDFIQNKRYEKRPAATKKAGQAKKKKGS 
               
               
                   
               
               
                 YPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0139]    SEQ ID NO: 31 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0140]    SEQ ID NO: 31 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 32) 
               
             
          
           
               
                 ATGAACGGCAATAGGTCCATCGTGTACCGCGAGTTCGTGGGCGTGATCCC 
               
               
                   
               
               
                 CGTGGCCAAGACCCTGAGGAATGAGCTGCGCCCTGTGGGCCACACACAGG 
               
               
                   
               
               
                 AGCACATCATCCAGAACGGCCTGATCCAGGAGGACGAGCTGCGGCAGGAG 
               
               
                   
               
               
                 AAGAGCACCGAGCTGAAGAACATCATGGACGATTACTATAGAGAGTACAT 
               
               
                   
               
               
                 CGATAAGTCTCTGAGCGGCGTGACCGACCTGGACTTCACCCTGCTGTTCG 
               
               
                   
               
               
                 AGCTGATGAACCTGGTGCAGAGCTCCCCCTCCAAGGACAATAAGAAGGCC 
               
               
                   
               
               
                 CTGGAGAAGGAGCAGTCTAAGATGAGGGAGCAGATCTGCACCCACCTGCA 
               
               
                   
               
               
                 GTCCGACTCTAACTACAAGAATATCTTTAACGCCAAGCTGCTGAAGGAGA 
               
               
                   
               
               
                 TCCTGCCTGATTTCATCAAGAACTACAATCAGTATGACGTGAAGGATAAG 
               
               
                   
               
               
                 GCCGGCAAGCTGGAGACACTGGCCCTGTTTAATGGCTTCAGCACATACTT 
               
               
                   
               
               
                 TACCGACTTCTTTGAGAAGAGGAAGAACGTGTTCACCAAGGAGGCCGTGA 
               
               
                   
               
               
                 GCACATCCATCGCCTACCGCATCGTGCACGAGAACTCCCTGATCTTCCTG 
               
               
                   
               
               
                 GCCAATATGACCTCTTATAAGAAGATCAGCGAGAAGGCCCTGGATGAGAT 
               
               
                   
               
               
                 CGAAGTGATCGAGAAGAACAATCAGGACAAGATGGGCGATTGGGAGCTGA 
               
               
                   
               
               
                 ATCAGATCTTTAACCCTGACTTCTACAATATGGTGCTGATCCAGTCCGGC 
               
               
                   
               
               
                 ATCGACTTCTACAACGAGATCTGCGGCGTGGTGAATGCCCACATGAACCT 
               
               
                   
               
               
                 GTACTGTCAGCAGACCAAGAACAATTATAACCTGTTCAAGATGCGGAAGC 
               
               
                   
               
               
                 TGCACAAGCAGATCCTGGCCTACACCAGCACCAGCTTCGAGGTGCCCAAG 
               
               
                   
               
               
                 ATGTTCGAGGACGATATGAGCGTGTATAACGCCGTGAACGCCTTCATCGA 
               
               
                   
               
               
                 CGAGACAGAGAAGGGCAACATCATCGGCAAGCTGAAGGATATCGTGAATA 
               
               
                   
               
               
                 AGTACGACGAGCTGGATGAGAAGAGAATCTATATCAGCAAGGACTTTTAC 
               
               
                   
               
               
                 GAGACACTGAGCTGCTTCATGTCCGGCAACTGGAATCTGATCACAGGCTG 
               
               
                   
               
               
                 CGTGGAGAACTTCTACGATGAGAACATCCACGCCAAGGGCAAGTCCAAGG 
               
               
                   
               
               
                 AGGAGAAGGTGAAGAAGGCCGTGAAGGAGGACAAGTACAAGTCTATCAAT 
               
               
                   
               
               
                 GACGTGAACGATCTGGTGGAGAAGTATATCGATGAGAAGGAGAGGAATGA 
               
               
                   
               
               
                 GTTCAAGAACAGCAATGCCAAGCAGTACATCCGCGAGATCTCCAACATCA 
               
               
                   
               
               
                 TCACCGACACAGAGACAGCCCACCTGGAGTATGACGATCACATCTCTCTG 
               
               
                   
               
               
                 ATCGAGAGCGAGGAGAAGGCCGACGAGATGAAGAAGCGGCTGGATATGTA 
               
               
                   
               
               
                 TATGAACATGTACCACTGGGCCAAGGCCTTTATCGTGGACGAGGTGCTGG 
               
               
                   
               
               
                 ACAGAGATGAGATGTTCTACAGCGATATCGACGATATCTATAATATCCTG 
               
               
                   
               
               
                 GAGAACATCGTGCCACTGTATAATCGGGTGAGAAACTACGTGACCCAGAA 
               
               
                   
               
               
                 GCCCTACAACTCTAAGAAGATCAAGCTGAATTTCCAGAGCCCTACACTGG 
               
               
                   
               
               
                 CCAATGGCTGGTCCCAGTCTAAGGAGTTCGACAACAATGCCATCATCCTG 
               
               
                   
               
               
                 ATCAGAGATAACAAGTACTATCTGGCCATCTTCAATGCCAAGAACAAGCC 
               
               
                   
               
               
                 AGACAAGAAGATCATCCAGGGCAACTCCGATAAGAAGAACGACAACGATT 
               
               
                   
               
               
                 ACAAGAAGATGGTGTATAACCTGCTGCCAGGCGCCAACAAGATGCTGCCC 
               
               
                   
               
               
                 AAGGTGTTTCTGTCTAAGAAGGGCATCGAGACATTCAAGCCCTCCGACTA 
               
               
                   
               
               
                 TATCATCTCTGGCTACAACGCCCACAAGCACATCAAGACAAGCGAGAATT 
               
               
                   
               
               
                 TTGATATCTCCTTCTGTCGGGACCTGATCGATTACTTCAAGAACAGCATC 
               
               
                   
               
               
                 GAGAAGCACGCCGAGTGGAGAAAGTATGAGTTCAAGTTTTCCGCCACCGA 
               
               
                   
               
               
                 CAGCTACTCCGATATCTCTGAGTTCTATCGGGAGGTGGAGATGCAGGGCT 
               
               
                   
               
               
                 ACAGAATCGACTGGACATATATCAGCGAGGCCGACATCAACAAGCTGGAT 
               
               
                   
               
               
                 GAGGAGGGCAAGATCTATCTGTTTCAGATCTACAATAAGGATTTCGCCGA 
               
               
                   
               
               
                 GAACAGCACCGGCAAGGAGAATCTGCACACAATGTACTTTAAGAACATCT 
               
               
                   
               
               
                 TCTCCGAGGAGAATCTGAAGGACATCATCATCAAGCTGAACGGCCAGGCC 
               
               
                   
               
               
                 GAGCTGTTTTATCGGAGAGCCTCTGTGAAGAATCCCGTGAAGCACAAGAA 
               
               
                   
               
               
                 GGATAGCGTGCTGGTGAACAAGACCTACAAGAATCAGCTGGACAACGGCG 
               
               
                   
               
               
                 ACGTGGTGAGAATCCCCATCCCTGACGATATCTATAACGAGATCTACAAG 
               
               
                   
               
               
                 ATGTATAATGGCTACATCAAGGAGTCCGACCTGTCTGAGGCCGCCAAGGA 
               
               
                   
               
               
                 GTACCTGGATAAGGTGGAGGTGAGGACCGCCCAGAAGGACATCGTGAAGG 
               
               
                   
               
               
                 ATTACCGCTATACAGTGGACAAGTACTTCATCCACACACCTATCACCATC 
               
               
                   
               
               
                 AACTATAAGGTGACCGCCCGCAACAATGTGAATGATATGGTGGTGAAGTA 
               
               
                   
               
               
                 CATCGCCCAGAACGACGATATCCACGTGATCGGCATCGACCGGGGCGAGA 
               
               
                   
               
               
                 GAAACCTGATCTACATCTCCGTGATCGATTCTCACGGCAACATCGTGAAG 
               
               
                   
               
               
                 CAGAAATCCTACAACATCCTGAACAACTACGACTACAAGAAGAAGCTGGT 
               
               
                   
               
               
                 GGAGAAGGAGAAAACCCGGGAGTACGCCAGAAAGAACTGGAAGAGCATCG 
               
               
                   
               
               
                 GCAATATCAAGGAGCTGAAGGAGGGCTATATCTCCGGCGTGGTGCACGAG 
               
               
                   
               
               
                 ATCGCCATGCTGATCGTGGAGTACAACGCCATCATCGCCATGGAGGACCT 
               
               
                   
               
               
                 GAATTATGGCTTTAAGAGGGGCCGCTTCAAGGTGGAGCGGCAGGTGTACC 
               
               
                   
               
               
                 AGAAGTTTGAGAGCATGCTGATCAATAAGCTGAACTATTTCGCCAGCAAG 
               
               
                   
               
               
                 GAGAAGTCCGTGGACGAGCCAGGAGGCCTGCTGAAGGGCTATCAGCTGAC 
               
               
                   
               
               
                 CTACGTGCCCGATAATATCAAGAACCTGGGCAAGCAGTGCGGCGTGATCT 
               
               
                   
               
               
                 TTTACGTGCCTGCCGCCTTCACCAGCAAGATCGACCCATCCACAGGCTTT 
               
               
                   
               
               
                 ATCTCTGCCTTCAACTTTAAGTCTATCAGCACAAATGCCTCTCGGAAGCA 
               
               
                   
               
               
                 GTTCTTTATGCAGTTTGACGAGATCAGATACTGTGCCGAGAAGGATATGT 
               
               
                   
               
               
                 TCAGCTTTGGCTTCGACTACAACAACTTCGATACCTACAACATCACAATG 
               
               
                   
               
               
                 GGCAAGACACAGTGGACCGTGTATACAAACGGCGAGAGACTGCAGTCTGA 
               
               
                   
               
               
                 GTTCAACAATGCCAGGCGCACCGGCAAGACAAAGAGCATCAATCTGACAG 
               
               
                   
               
               
                 AGACAATCAAGCTGCTGCTGGAGGACAATGAGATCAACTACGCCGACGGC 
               
               
                   
               
               
                 CACGATATCAGGATCGATATGGAGAAGATGGACGAGGATAAGAAGAGCGA 
               
               
                   
               
               
                 GTTCTTTGCCCAGCTGCTGAGCCTGTATAAGCTGACCGTGCAGATGCGCA 
               
               
                   
               
               
                 ATTCCTATACAGAGGCCGAGGAGCAGGAGAACGGCATCTCTTACGACAAG 
               
               
                   
               
               
                 ATCATCAGCCCTGTGATCAATGATGAGGGCGAGTTCTTTGACTCCGATAA 
               
               
                   
               
               
                 CTATAAGGAGTCTGACGATAAGGAGTGCAAGATGCCAAAGGACGCCGATG 
               
               
                   
               
               
                 CCAACGGCGCCTACTGTATCGCCCTGAAGGGCCTGTATGAGGTGCTGAAG 
               
               
                   
               
               
                 ATCAAGAGCGAGTGGACCGAGGACGGCTTTGATAGGAATTGCCTGAAGCT 
               
               
                   
               
               
                 GCCACACGCAGAGTGGCTGGACTTCATCCAGAACAAGCGGTACGAGAAAA 
               
               
                   
               
               
                 GGCCGGCGGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCC 
               
               
                   
               
               
                 TACCCATACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTA 
               
               
                   
               
               
                 TGCATACCCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0141]      Moraxella bovoculi  237 (MbCpf1; pY014), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 33) 
               
             
          
           
               
                 MLFQDFTHLYPLSKTVRFELKPIDRTLEHIHAKNFLSQDETMADMHQKVK 
               
               
                   
               
               
                 VILDDYHRDFIADMMGEVKLTKLAEFYDVYLKFRKNPKDDELQKQLKDLQ 
               
               
                   
               
               
                 AVLRKEIVKPIGNGGKYKAGYDRLFGAKLFKDGKELGDLAKFVIAQEGES 
               
               
                   
               
               
                 SPKLAHLAHFEKFSTYFTGFHDNRKNMYSDEDKHTAIAYRLIHENLPRFI 
               
               
                   
               
               
                 DNLQILTTIKQKHSALYDQIINELTASGLDVSLASHLDGYHKLLTQEGIT 
               
               
                   
               
               
                 AYNTLLGGISGEAGSPKIQGINELINSHHNQHCHKSERIAKLRPLHKQIL 
               
               
                   
               
               
                 SDGMSVSFLPSKFADDSEMCQAVNEFYRHYADVFAKVQSLFDGFDDHQKD 
               
               
                   
               
               
                 GIYVEHKNLNELSKQAFGDFALLGRVLDGYYVDVVNPEFNERFAKAKTDN 
               
               
                   
               
               
                 AKAKLTKEKDKFIKGVHSLASLEQAIEHYTARHDDESVQAGKLGQYFKHG 
               
               
                   
               
               
                 LAGVDNPIQKIHNNHSTIKGFLERERPAGERALPKIKSGKNPEMTQLRQL 
               
               
                   
               
               
                 KELLDNALNVAHFAKLLTTKTTLDNQDGNFYGEFGVLYDELAKIPTLYNK 
               
               
                   
               
               
                 VRDYLSQKPFSTEKYKLNFGNPTLLNGWDLNKEKDNFGVILQKDGCYYLA 
               
               
                   
               
               
                 LLDKAHKKVFDNAPNTGKSIYQKMIYKYLEVRKQFPKVFFSKEAIAINYH 
               
               
                   
               
               
                 PSKELVEIKDKGRQRSDDERLKLYRFILECLKIHPKYDKKFEGAIGDIQL 
               
               
                   
               
               
                 FKKDKKGREVPISEKDLFDKINGIFSSKPKLEMEDFFIGEFKRYNPSQDL 
               
               
                   
               
               
                 VDQYNIYKKIDSNDNRKKENFYNNHPKFKKDLVRYYYESMCKHEEWEESF 
               
               
                   
               
               
                 EFSKKLQDIGCYVDVNELFTEIETRRLNYKISFCNINADYIDELVEQGQL 
               
               
                   
               
               
                 YLFQIYNKDFSPKAHGKPNLHTLYFKALFSEDNLADPIYKLNGEAQIFYR 
               
               
                   
               
               
                 KASLDMNETTIHRAGEVLENKNPDNPKKRQFVYDIIKDKRYTQDKFMLHV 
               
               
                   
               
               
                 PITMNFGVQGMTIKEFNKKVNQSIQQYDEVNVIGIDRGERHLLYLTVINS 
               
               
                   
               
               
                 KGEILEQCSLNDITTASANGTQMTTPYHKILDKREIERLNARVGWGEIET 
               
               
                   
               
               
                 IKELKSGYLSHVVHQISQLMLKYNAIVVLEDLNFGFKRGRFKVEKQIYQN 
               
               
                   
               
               
                 FENALIKKLNHLVLKDKADDEIGSYKNALQLTNNFTDLKSIGKQTGFLFY 
               
               
                   
               
               
                 VPAWNTSKIDPETGFVDLLKPRYENIAQSQAFFGKFDKICYNADKDYFEF 
               
               
                   
               
               
                 HIDYAKFTDKAKNSRQIWTICSHGDKRYVYDKTANQNKGAAKGINVNDEL 
               
               
                   
               
               
                 KSLFARHHINEKQPNLVMDICQNNDKEFHKSLMYLLKTLLALRYSNASSD 
               
               
                   
               
               
                 EDFILSPVANDEGVFFNSALADDTQPQNADANGAYHIALKGLWLLNELKN 
               
               
                   
               
               
                 SDDLNKVKLAIDNQTWLNFAQNRKRPAATKKAGQAKKKKGSYPYDVPDYA 
               
               
                   
               
               
                 YPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0142]    SEQ ID NO: 33 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0143]    SEQ ID NO: 33 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 34) 
               
             
          
           
               
                 ATGCTGTTCCAGGACTTTACCCACCTGTATCCACTGTCCAAGACAGTGAG 
               
               
                   
               
               
                 ATTTGAGCTGAAGCCCATCGATAGGACCCTGGAGCACATCCACGCCAAGA 
               
               
                   
               
               
                 ACTTCCTGTCTCAGGACGAGACAATGGCCGATATGCACCAGAAGGTGAAA 
               
               
                   
               
               
                 GTGATCCTGGACGATTACCACCGCGACTTCATCGCCGATATGATGGGCGA 
               
               
                   
               
               
                 GGTGAAGCTGACCAAGCTGGCCGAGTTCTATGACGTGTACCTGAAGTTTC 
               
               
                   
               
               
                 GGAAGAACCCAAAGGACGATGAGCTGCAGAAGCAGCTGAAGGATCTGCAG 
               
               
                   
               
               
                 GCCGTGCTGAGAAAGGAGATCGTGAAGCCCATCGGCAATGGCGGCAAGTA 
               
               
                   
               
               
                 TAAGGCCGGCTACGACAGGCTGTTCGGCGCCAAGCTGTTTAAGGACGGCA 
               
               
                   
               
               
                 AGGAGCTGGGCGATCTGGCCAAGTTCGTGATCGCACAGGAGGGAGAGAGC 
               
               
                   
               
               
                 TCCCCAAAGCTGGCCCACCTGGCCCACTTCGAGAAGTTTTCCACCTATTT 
               
               
                   
               
               
                 CACAGGCTTTCACGATAACCGGAAGAATATGTATTCTGACGAGGATAAGC 
               
               
                   
               
               
                 ACACCGCCATCGCCTACCGCCTGATCCACGAGAACCTGCCCCGGTTTATC 
               
               
                   
               
               
                 GACAATCTGCAGATCCTGACCACAATCAAGCAGAAGCACTCTGCCCTGTA 
               
               
                   
               
               
                 CGATCAGATCATCAACGAGCTGACCGCCAGCGGCCTGGACGTGTCTCTGG 
               
               
                   
               
               
                 CCAGCCACCTGGATGGCTATCACAAGCTGCTGACACAGGAGGGCATCACC 
               
               
                   
               
               
                 GCCTACAATACACTGCTGGGAGGAATCTCCGGAGAGGCAGGCTCTCCTAA 
               
               
                   
               
               
                 GATCCAGGGCATCAACGAGCTGATCAATTCTCACCACAACCAGCACTGCC 
               
               
                   
               
               
                 ACAAGAGCGAGAGAATCGCCAAGCTGAGGCCACTGCACAAGCAGATCCTG 
               
               
                   
               
               
                 TCCGACGGCATGAGCGTGTCCTTCCTGCCCTCTAAGTTTGCCGACGATAG 
               
               
                   
               
               
                 CGAGATGTGCCAGGCCGTGAACGAGTTCTATCGCCACTACGCCGACGTGT 
               
               
                   
               
               
                 TCGCCAAGGTGCAGAGCCTGTTCGACGGCTTTGACGATCACCAGAAGGAT 
               
               
                   
               
               
                 GGCATCTACGTGGAGCACAAGAACCTGAATGAGCTGTCCAAGCAGGCCTT 
               
               
                   
               
               
                 CGGCGACTTTGCACTGCTGGGACGCGTGCTGGACGGATACTATGTGGATG 
               
               
                   
               
               
                 TGGTGAATCCAGAGTTCAACGAGCGGTTTGCCAAGGCCAAGACCGACAAT 
               
               
                   
               
               
                 GCCAAGGCCAAGCTGACAAAGGAGAAGGATAAGTTCATCAAGGGCGTGCA 
               
               
                   
               
               
                 CTCCCTGGCCTCTCTGGAGCAGGCCATCGAGCACTATACCGCAAGGCACG 
               
               
                   
               
               
                 ACGATGAGAGCGTGCAGGCAGGCAAGCTGGGACAGTACTTCAAGCACGGC 
               
               
                   
               
               
                 CTGGCCGGAGTGGACAACCCCATCCAGAAGATCCACAACAATCACAGCAC 
               
               
                   
               
               
                 CATCAAGGGCTTTCTGGAGAGGGAGCGCCCTGCAGGAGAGAGAGCCCTGC 
               
               
                   
               
               
                 CAAAGATCAAGTCCGGCAAGAATCCTGAGATGACACAGCTGAGGCAGCTG 
               
               
                   
               
               
                 AAGGAGCTGCTGGATAACGCCCTGAATGTGGCCCACTTCGCCAAGCTGCT 
               
               
                   
               
               
                 GACCACAAAGACCACACTGGACAATCAGGATGGCAACTTCTATGGCGAGT 
               
               
                   
               
               
                 TTGGCGTGCTGTACGACGAGCTGGCCAAGATCCCCACCCTGTATAACAAG 
               
               
                   
               
               
                 GTGAGAGATTACCTGAGCCAGAAGCCTTTCTCCACCGAGAAGTACAAGCT 
               
               
                   
               
               
                 GAACTTTGGCAATCCAACACTGCTGAATGGCTGGGACCTGAACAAGGAGA 
               
               
                   
               
               
                 AGGATAATTTCGGCGTGATCCTGCAGAAGGACGGCTGCTACTATCTGGCC 
               
               
                   
               
               
                 CTGCTGGACAAGGCCCACAAGAAGGTGTTTGATAACGCCCCTAATACAGG 
               
               
                   
               
               
                 CAAGAGCATCTATCAGAAGATGATCTATAAGTACCTGGAGGTGAGGAAGC 
               
               
                   
               
               
                 AGTTCCCCAAGGTGTTCTTTTCCAAGGAGGCCATCGCCATCAACTACCAC 
               
               
                   
               
               
                 CCTTCTAAGGAGCTGGTGGAGATCAAGGACAAGGGCCGGCAGAGATCCGA 
               
               
                   
               
               
                 CGATGAGCGCCTGAAGCTGTATCGGTTTATCCTGGAGTGTCTGAAGATCC 
               
               
                   
               
               
                 ACCCTAAGTACGATAAGAAGTTCGAGGGCGCCATCGGCGACATCCAGCTG 
               
               
                   
               
               
                 TTTAAGAAGGATAAGAAGGGCAGAGAGGTGCCAATCAGCGAGAAGGACCT 
               
               
                   
               
               
                 GTTCGATAAGATCAACGGCATCTTTTCTAGCAAGCCTAAGCTGGAGATGG 
               
               
                   
               
               
                 AGGACTTCTTTATCGGCGAGTTCAAGAGGTATAACCCAAGCCAGGACCTG 
               
               
                   
               
               
                 GTGGATCAGTATAATATCTACAAGAAGATCGACTCCAACGATAATCGCAA 
               
               
                   
               
               
                 GAAGGAGAATTTCTACAACAATCACCCCAAGTTTAAGAAGGATCTGGTGC 
               
               
                   
               
               
                 GGTACTATTACGAGTCTATGTGCAAGCACGAGGAGTGGGAGGAGAGCTTC 
               
               
                   
               
               
                 GAGTTTTCCAAGAAGCTGCAGGACATCGGCTGTTACGTGGATGTGAACGA 
               
               
                   
               
               
                 GCTGTTTACCGAGATCGAGACACGGAGACTGAATTATAAGATCTCCTTCT 
               
               
                   
               
               
                 GCAACATCAATGCCGACTACATCGATGAGCTGGTGGAGCAGGGCCAGCTG 
               
               
                   
               
               
                 TATCTGTTCCAGATCTACAACAAGGACTTTTCCCCAAAGGCCCACGGCAA 
               
               
                   
               
               
                 GCCCAATCTGCACACCCTGTACTTCAAGGCCCTGTTTTCTGAGGACAACC 
               
               
                   
               
               
                 TGGCCGATCCTATCTATAAGCTGAATGGCGAGGCCCAGATCTTCTACAGA 
               
               
                   
               
               
                 AAGGCCTCCCTGGACATGAACGAGACAACAATCCACAGGGCCGGCGAGGT 
               
               
                   
               
               
                 GCTGGAGAACAAGAATCCCGATAATCCTAAGAAGAGACAGTTCGTGTACG 
               
               
                   
               
               
                 ACATCATCAAGGATAAGAGGTACACACAGGACAAGTTCATGCTGCACGTG 
               
               
                   
               
               
                 CCAATCACCATGAACTTTGGCGTGCAGGGCATGACAATCAAGGAGTTCAA 
               
               
                   
               
               
                 TAAGAAGGTGAACCAGTCTATCCAGCAGTATGACGAGGTGAACGTGATCG 
               
               
                   
               
               
                 GCATCGATCGGGGCGAGAGACACCTGCTGTACCTGACCGTGATCAATAGC 
               
               
                   
               
               
                 AAGGGCGAGATCCTGGAGCAGTGTTCCCTGAACGACATCACCACAGCCTC 
               
               
                   
               
               
                 TGCCAATGGCACACAGATGACCACACCTTACCACAAGATCCTGGATAAGA 
               
               
                   
               
               
                 GGGAGATCGAGCGCCTGAACGCCCGGGTGGGATGGGGCGAGATCGAGACA 
               
               
                   
               
               
                 ATCAAGGAGCTGAAGTCTGGCTATCTGAGCCACGTGGTGCACCAGATCAG 
               
               
                   
               
               
                 CCAGCTGATGCTGAAGTACAACGCCATCGTGGTGCTGGAGGACCTGAATT 
               
               
                   
               
               
                 TCGGCTTTAAGAGGGGCCGCTTTAAGGTGGAGAAGCAGATCTATCAGAAC 
               
               
                   
               
               
                 TTCGAGAATGCCCTGATCAAGAAGCTGAACCACCTGGTGCTGAAGGACAA 
               
               
                   
               
               
                 GGCCGACGATGAGATCGGCTCTTACAAGAATGCCCTGCAGCTGACCAACA 
               
               
                   
               
               
                 ATTTCACAGATCTGAAGAGCATCGGCAAGCAGACCGGCTTCCTGTTTTAT 
               
               
                   
               
               
                 GTGCCCGCCTGGAACACCTCTAAGATCGACCCTGAGACAGGCTTTGTGGA 
               
               
                   
               
               
                 TCTGCTGAAGCCAAGATACGAGAACATCGCCCAGAGCCAGGCCTTCTTTG 
               
               
                   
               
               
                 GCAAGTTCGACAAGATCTGCTATAATGCCGACAAGGATTACTTCGAGTTT 
               
               
                   
               
               
                 CACATCGACTACGCCAAGTTTACCGATAAGGCCAAGAATAGCCGCCAGAT 
               
               
                   
               
               
                 CTGGACAATCTGTTCCCACGGCGACAAGCGGTACGTGTACGATAAGACAG 
               
               
                   
               
               
                 CCAACCAGAATAAGGGCGCCGCCAAGGGCATCAACGTGAATGATGAGCTG 
               
               
                   
               
               
                 AAGTCCCTGTTCGCCCGCCACCACATCAACGAGAAGCAGCCCAACCTGGT 
               
               
                   
               
               
                 CATGGACATCTGCCAGAACAATGATAAGGAGTTTCACAAGTCTCTGATGT 
               
               
                   
               
               
                 ACCTGCTGAAAACCCTGCTGGCCCTGCGGTACAGCAACGCCTCCTCTGAC 
               
               
                   
               
               
                 GAGGATTTCATCCTGTCCCCCGTGGCAAACGACGAGGGCGTGTTCTTTAA 
               
               
                   
               
               
                 TAGCGCCCTGGCCGACGATACACAGCCTCAGAATGCCGATGCCAACGGCG 
               
               
                   
               
               
                 CCTACCACATCGCCCTGAAGGGCCTGTGGCTGCTGAATGAGCTGAAGAAC 
               
               
                   
               
               
                 TCCGACGATCTGAACAAGGTGAAGCTGGCCATCGACAATCAGACCTGGCT 
               
               
                   
               
               
                 GAATTTCGCCCAGAACAGGAAAAGGCCGGCGGCCACGAAAAAGGCCGGCC 
               
               
                   
               
               
                 AGGCAAAAAAGAAAAAGGGATCCTACCCATACGATGTTCCAGATTACGCT 
               
               
                   
               
               
                 TATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTA 
               
               
                   
               
               
                 TGCCTAA 
               
             
          
         
       
     
         [0144]      Leptospira inadai  (LiCpf1; pY015), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 35) 
               
             
          
           
               
                 MEDYSGFVNIYSIQKTLRFELKPVGKTLEHIEKKGFLKKDKIRAEDYKAV 
               
               
                   
               
               
                 KKIIDKYHRAYIEEVFDSVLHQKKKKDKTRFSTQFIKEIKEFSELYYKTE 
               
               
                   
               
               
                 KNIPDKERLEALSEKLRKMLVGAFKGEFSEEVAEKYKNLFSKELIRNEIE 
               
               
                   
               
               
                 KFCETDEERKQVSNFKSFTTYFTGFHSNRQNIYSDEKKSTAIGYRIIHQN 
               
               
                   
               
               
                 LPKFLDNLKIIESIQRRFKDFPWSDLKKNLKKIDKNIKLTEYFSIDGFVN 
               
               
                   
               
               
                 VLNQKGIDAYNTILGGKSEESGEKIQGLNEYINLYRQKNNIDRKNLPNVK 
               
               
                   
               
               
                 ILFKQILGDRETKSFIPEAFPDDQSVLNSITEFAKYLKLDKKKKSIIAEL 
               
               
                   
               
               
                 KKFLSSFNRYELDGIYLANDNSLASISTFLFDDWSFIKKSVSFKYDESVG 
               
               
                   
               
               
                 DPKKKIKSPLKYEKEKEKWLKQKYYTISFLNDAIESYSKSQDEKRVKIRL 
               
               
                   
               
               
                 EAYFAEFKSKDDAKKQFDLLERIEEAYAIVEPLLGAEYPRDRNLKADKKE 
               
               
                   
               
               
                 VGKIKDFLDSIKSLQFFLKPLLSAEIFDEKDLGFYNQLEGYYEEIDSIGH 
               
               
                   
               
               
                 LYNKVRNYLTGKIYSKEKFKLNFENSTLLKGWDENREVANLCVIFREDQK 
               
               
                   
               
               
                 YYLGVMDKENNTILSDIPKVKPNELFYEKMVYKLIPTPHMQLPRIIFSSD 
               
               
                   
               
               
                 NLSIYNPSKSILKIREAKSFKEGKNFKLKDCHKFIDFYKESISKNEDWSR 
               
               
                   
               
               
                 FDFKFSKTSSYENISEFYREVERQGYNLDFKKVSKFYIDSLVEDGKLYLF 
               
               
                   
               
               
                 QIYNKDFSIFSKGKPNLHTIYFRSLFSKENLKDVCLKLNGEAEMFFRKKS 
               
               
                   
               
               
                 INYDEKKKREGHHPELFEKLKYPILKDKRYSEDKFQFHLPISLNFKSKER 
               
               
                   
               
               
                 LNFNLKVNEFLKRNKDINIIGIDRGERNLLYLVMINQKGEILKQTLLDSM 
               
               
                   
               
               
                 QSGKGRPEINYKEKLQEKEIERDKARKSWGTVENIKELKEGYLSIVIHQI 
               
               
                   
               
               
                 SKLMVENNAIVVLEDLNIGFKRGRQKVERQVYQKFEKMLIDKLNFLVFKE 
               
               
                   
               
               
                 NKPTEPGGVLKAYQLTDEFQSFEKLSKQTGFLFYVPSWNTSKIDPRTGFI 
               
               
                   
               
               
                 DFLHPAYENIEKAKQWINKFDSIRFNSKMDWFEFTADTRKFSENLMLGKN 
               
               
                   
               
               
                 RVWVICTTNVERYFTSKTANSSIQYNSIQITEKLKELFVDIPFSNGQDLK 
               
               
                   
               
               
                 PEILRKNDAVFFKSLLFYIKTTLSLRQNNGKKGEEEKDFILSPVVDSKGR 
               
               
                   
               
               
                 FFNSLEASDDEPKDADANGAYHIALKGLMNLLVLNETKEENLSRPKWKIK 
               
               
                   
               
               
                 NKDWLEFVWERNRKRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAY 
               
               
                   
               
               
                 PYDVPDYA 
               
             
          
         
       
     
         [0145]    SEQ ID NO: 35 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0146]    SEQ ID NO: 35 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 36) 
               
             
          
           
               
                 ATGGAGGACTATTCCGGCTTTGTGAACATCTACTCTATCCAGAAAACCCT 
               
               
                   
               
               
                 GAGGTTCGAGCTGAAGCCAGTGGGCAAGACACTGGAGCACATCGAGAAGA 
               
               
                   
               
               
                 AGGGCTTCCTGAAGAAGGACAAGATCCGGGCCGAGGATTACAAGGCCGTG 
               
               
                   
               
               
                 AAGAAGATCATCGATAAGTACCACAGAGCCTATATCGAGGAGGTGTTTGA 
               
               
                   
               
               
                 TTCCGTGCTGCACCAGAAGAAGAAGAAGGACAAGACCCGCTTTTCTACAC 
               
               
                   
               
               
                 AGTTCATCAAGGAGATCAAGGAGTTCAGCGAGCTGTACTATAAGACCGAG 
               
               
                   
               
               
                 AAGAACATCCCCGACAAGGAGAGGCTGGAGGCCCTGAGCGAGAAGCTGCG 
               
               
                   
               
               
                 CAAGATGCTGGTGGGCGCCTTTAAGGGCGAGTTCTCCGAGGAGGTGGCCG 
               
               
                   
               
               
                 AGAAGTATAAGAACCTGTTTTCTAAGGAGCTGATCAGGAATGAGATCGAG 
               
               
                   
               
               
                 AAGTTCTGCGAGACAGACGAGGAGCGCAAGCAGGTGTCTAACTTCAAGAG 
               
               
                   
               
               
                 CTTCACCACATACTTTACCGGCTTCCACTCCAACAGGCAGAATATCTATT 
               
               
                   
               
               
                 CCGACGAGAAGAAGTCTACAGCCATCGGCTACCGCATCATCCACCAGAAC 
               
               
                   
               
               
                 CTGCCTAAGTTCCTGGATAATCTGAAGATCATCGAGTCCATCCAGCGGCG 
               
               
                   
               
               
                 GTTCAAGGACTTCCCATGGTCTGATCTGAAGAAGAACCTGAAGAAGATCG 
               
               
                   
               
               
                 ATAAGAATATCAAGCTGACCGAGTACTTCAGCATCGACGGCTTCGTGAAC 
               
               
                   
               
               
                 GTGCTGAATCAGAAGGGCATCGATGCCTACAACACAATCCTGGGCGGCAA 
               
               
                   
               
               
                 GTCCGAGGAGTCTGGCGAGAAGATCCAGGGCCTGAACGAGTACATCAATC 
               
               
                   
               
               
                 TGTATCGGCAGAAGAACAATATCGACAGAAAGAACCTGCCCAATGTGAAG 
               
               
                   
               
               
                 ATCCTGTTTAAGCAGATCCTGGGCGATAGGGAGACAAAGAGCTTTATCCC 
               
               
                   
               
               
                 TGAGGCCTTCCCAGACGATCAGTCCGTGCTGAACTCTATCACAGAGTTCG 
               
               
                   
               
               
                 CCAAGTACCTGAAGCTGGATAAGAAGAAGAAGAGCATCATCGCCGAGCTG 
               
               
                   
               
               
                 AAGAAGTTTCTGAGCTCCTTCAATCGCTACGAGCTGGACGGCATCTATCT 
               
               
                   
               
               
                 GGCCAACGATAATAGCCTGGCCTCTATCAGCACCTTCCTGTTTGACGATT 
               
               
                   
               
               
                 GGTCCTTTATCAAGAAGTCCGTGTCTTTCAAGTATGACGAGTCCGTGGGC 
               
               
                   
               
               
                 GACCCCAAGAAGAAGATCAAGTCTCCCCTGAAGTACGAGAAGGAGAAGGA 
               
               
                   
               
               
                 GAAGTGGCTGAAGCAGAAGTACTATACAATCTCTTTCCTGAACGATGCCA 
               
               
                   
               
               
                 TCGAGAGCTATTCCAAGTCTCAGGACGAGAAGAGGGTGAAGATCCGCCTG 
               
               
                   
               
               
                 GAGGCCTACTTTGCCGAGTTCAAGAGCAAGGACGATGCCAAGAAGCAGTT 
               
               
                   
               
               
                 CGACCTGCTGGAGAGGATCGAGGAGGCCTATGCCATCGTGGAGCCTCTGC 
               
               
                   
               
               
                 TGGGAGCAGAGTACCCAAGGGACCGCAACCTGAAGGCCGATAAGAAGGAA 
               
               
                   
               
               
                 GTGGGCAAGATCAAGGACTTCCTGGATAGCATCAAGTCCCTGCAGTTCTT 
               
               
                   
               
               
                 TCTGAAGCCTCTGCTGTCCGCCGAGATCTTTGACGAGAAGGATCTGGGCT 
               
               
                   
               
               
                 TCTACAATCAGCTGGAGGGCTACTATGAGGAGATCGATTCTATCGGCCAC 
               
               
                   
               
               
                 CTGTATAACAAGGTGCGGAATTATCTGACCGGCAAGATCTACAGCAAGGA 
               
               
                   
               
               
                 GAAGTTTAAGCTGAACTTCGAGAACAGCACCCTGCTGAAGGGCTGGGACG 
               
               
                   
               
               
                 AGAACCGGGAGGTGGCCAATCTGTGCGTGATCTTCAGAGAGGACCAGAAG 
               
               
                   
               
               
                 TACTATCTGGGCGTGATGGATAAGGAGAACAATACCATCCTGTCCGACAT 
               
               
                   
               
               
                 CCCCAAGGTGAAGCCTAACGAGCTGTTTTACGAGAAGATGGTGTATAAGC 
               
               
                   
               
               
                 TGATCCCCACACCTCACATGCAGCTGCCCCGGATCATCTTCTCTAGCGAC 
               
               
                   
               
               
                 AACCTGTCTATCTATAATCCTAGCAAGTCCATCCTGAAGATCAGAGAGGC 
               
               
                   
               
               
                 CAAGAGCTTTAAGGAGGGCAAGAACTTCAAGCTGAAGGACTGTCACAAGT 
               
               
                   
               
               
                 TTATCGATTTCTACAAGGAGTCTATCAGCAAGAATGAGGACTGGAGCAGA 
               
               
                   
               
               
                 TTCGACTTCAAGTTCAGCAAGACCAGCAGCTACGAGAACATCAGCGAGTT 
               
               
                   
               
               
                 TTACCGGGAGGTGGAGAGACAGGGCTATAACCTGGACTTCAAGAAGGTGT 
               
               
                   
               
               
                 CTAAGTTCTACATCGACAGCCTGGTGGAGGATGGCAAGCTGTACCTGTTC 
               
               
                   
               
               
                 CAGATCTATAACAAGGACTTTTCTATCTTCAGCAAGGGCAAGCCCAATCT 
               
               
                   
               
               
                 GCACACCATCTATTTTCGGTCCCTGTTCTCTAAGGAGAACCTGAAGGACG 
               
               
                   
               
               
                 TGTGCCTGAAGCTGAATGGCGAGGCCGAGATGTTCTTTCGGAAGAAGTCC 
               
               
                   
               
               
                 ATCAACTACGATGAGAAGAAGAAGCGGGAGGGCCACCACCCCGAGCTGTT 
               
               
                   
               
               
                 TGAGAAGCTGAAGTATCCTATCCTGAAGGACAAGAGATACAGCGAGGATA 
               
               
                   
               
               
                 AGTTTCAGTTCCACCTGCCCATCAGCCTGAACTTCAAGTCCAAGGAGCGG 
               
               
                   
               
               
                 CTGAACTTTAATCTGAAAGTGAATGAGTTCCTGAAGAGAAACAAGGACAT 
               
               
                   
               
               
                 CAATATCATCGGCATCGATCGGGGCGAGAGAAACCTGCTGTACCTGGTCA 
               
               
                   
               
               
                 TGATCAATCAGAAGGGCGAGATCCTGAAGCAGACCCTGCTGGACAGCATG 
               
               
                   
               
               
                 CAGTCCGGCAAGGGCCGGCCTGAGATCAACTACAAGGAGAAGCTGCAGGA 
               
               
                   
               
               
                 GAAGGAGATCGAGAGGGATAAGGCCCGCAAGAGCTGGGGCACAGTGGAGA 
               
               
                   
               
               
                 ATATCAAGGAGCTGAAGGAGGGCTATCTGTCTATCGTGATCCACCAGATC 
               
               
                   
               
               
                 AGCAAGCTGATGGTGGAGAACAATGCCATCGTGGTGCTGGAGGACCTGAA 
               
               
                   
               
               
                 CATCGGCTTTAAGCGGGGCAGACAGAAGGTGGAGCGGCAGGTGTACCAGA 
               
               
                   
               
               
                 AGTTCGAGAAGATGCTGATCGATAAGCTGAACTTTCTGGTGTTCAAGGAG 
               
               
                   
               
               
                 AATAAGCCAACCGAGCCAGGAGGCGTGCTGAAGGCCTATCAGCTGACAGA 
               
               
                   
               
               
                 CGAGTTTCAGTCTTTCGAGAAGCTGAGCAAGCAGACCGGCTTTCTGTTCT 
               
               
                   
               
               
                 ACGTGCCAAGCTGGAACACCTCCAAGATCGACCCCAGAACAGGCTTTATC 
               
               
                   
               
               
                 GATTTCCTGCACCCTGCCTACGAGAATATCGAGAAGGCCAAGCAGTGGAT 
               
               
                   
               
               
                 CAACAAGTTTGATTCCATCAGGTTCAATTCTAAGATGGACTGGTTTGAGT 
               
               
                   
               
               
                 TCACCGCCGATACACGCAAGTTTTCCGAGAACCTGATGCTGGGCAAGAAT 
               
               
                   
               
               
                 CGGGTGTGGGTCATCTGCACCACAAATGTGGAGCGGTACTTCACCAGCAA 
               
               
                   
               
               
                 GACCGCCAACAGCTCCATCCAGTACAATAGCATCCAGATCACCGAGAAGC 
               
               
                   
               
               
                 TGAAGGAGCTGTTTGTGGACATCCCTTTCAGCAACGGCCAGGATCTGAAG 
               
               
                   
               
               
                 CCAGAGATCCTGAGGAAGAATGACGCCGTGTTCTTTAAGAGCCTGCTGTT 
               
               
                   
               
               
                 TTACATCAAGACCACACTGTCCCTGCGCCAGAACAATGGCAAGAAGGGCG 
               
               
                   
               
               
                 AGGAGGAGAAGGACTTCATCCTGAGCCCAGTGGTGGATTCCAAGGGCCGG 
               
               
                   
               
               
                 TTCTTTAACTCTCTGGAGGCCAGCGACGATGAGCCCAAGGACGCCGATGC 
               
               
                   
               
               
                 CAATGGCGCCTACCACATCGCCCTGAAGGGCCTGATGAACCTGCTGGTGC 
               
               
                   
               
               
                 TGAATGAGACAAAGGAGGAGAACCTGAGCAGACCAAAGTGGAAGATCAAG 
               
               
                   
               
               
                 AATAAGGACTGGCTGGAGTTCGTGTGGGAGAGGAACCGCAAAAGGCCGGC 
               
               
                   
               
               
                 GGCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCCTACCCAT 
               
               
                   
               
               
                 ACGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATAC 
               
               
                   
               
               
                 CCATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0147]      Lachnospiraceae bacterium  ND2006 (LbCpf1; pY016), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 37) 
               
             
          
           
               
                 MSKLEKFTNCYSLSKTLRFKAIPVGKTQENIDNKRLLVEDEKRAEDYKGV 
               
               
                   
               
               
                 KKLLDRYYLSFINDVLHSIKLKNLNNYISLFRKKTRTEKENKELENLEIN 
               
               
                   
               
               
                 LRKEIAKAFKGNEGYKSLFKKDIIETILPEFLDDKDEIALVNSFNGFTTA 
               
               
                   
               
               
                 FTGFFDNRENMFSEEAKSTSIAFRCINENLTRYISNMDIFEKVDAIFDKH 
               
               
                   
               
               
                 EVQEIKEKILNSDYDVEDFFEGEFFNFVLTQEGIDVYNAIIGGFVTESGE 
               
               
                   
               
               
                 KIKGLNEYINLYNQKTKQKLPKFKPLYKQVLSDRESLSFYGEGYTSDEEV 
               
               
                   
               
               
                 LEVFRNTLNKNSEIFSSIKKLEKLFKNFDEYSSAGIFVKNGPAISTISKD 
               
               
                   
               
               
                 IFGEWNVIRDKWNAEYDDIHLKKKAVVTEKYEDDRRKSFKKIGSFSLEQL 
               
               
                   
               
               
                 QEYADADLSVVEKLKEIIIQKVDEIYKVYGSSEKLFDADFVLEKSLKKND 
               
               
                   
               
               
                 AVVAIMKDLLDSVKSFENYIKAFFGEGKETNRDESFYGDFVLAYDILLKV 
               
               
                   
               
               
                 DHIYDAIRNYVTQKPYSKDKFKLYFQNPQFMGGWDKDKETDYRATILRYG 
               
               
                   
               
               
                 SKYYLAIMDKKYAKCLQKIDKDDVNGNYEKINYKLLPGPNKMLPKVFFSK 
               
               
                   
               
               
                 KWMAYYNPSEDIQKIYKNGTFKKGDMFNLNDCHKLIDFFKDSISRYPKWS 
               
               
                   
               
               
                 NAYDFNFSETEKYKDIAGFYREVEEQGYKVSFESASKKEVDKLVEEGKLY 
               
               
                   
               
               
                 MFQIYNKDFSDKSHGTPNLHTMYFKLLFDENNHGQIRLSGGAELFMRRAS 
               
               
                   
               
               
                 LKKEELVVHPANSPIANKNPDNPKKTTTLSYDVYKDKRFSEDQYELHIPI 
               
               
                   
               
               
                 AINKCPKNIFKINTEVRVLLKHDDNPYVIGIDRGERNLLYIVVVDGKGNI 
               
               
                   
               
               
                 VEQYSLNEIINNFNGIRIKTDYHSLLDKKEKERFEARQNWTSIENIKELK 
               
               
                   
               
               
                 AGYISQVVHKICELVEKYDAVIALEDLNSGFKNSRVKVEKQVYQKFEKML 
               
               
                   
               
               
                 IDKLNYMVDKKSNPCATGGALKGYQITNKFESFKSMSTQNGFIFYIPAWL 
               
               
                   
               
               
                 TSKIDPSTGFVNLLKTKYTSIADSKKFISSFDRIMYVPEEDLFEFALDYK 
               
               
                   
               
               
                 NFSRTDADYIKKWKLYSYGNRIRIFRNPKKNNVFDWEEVCLTSAYKELFN 
               
               
                   
               
               
                 KYGINYQQGDIRALLCEQSDKAFYSSFMALMSLMLQMRNSITGRTDVDFL 
               
               
                   
               
               
                 ISPVKNSDGIFYDSRNYEAQENAILPKNADANGAYNIARKVLWAIGQFKK 
               
               
                   
               
               
                 AEDEKLDKVKIAISNKEWLEYAQTSVKHKRPAATKKAGQAKKKKGSYPYD 
               
               
                   
               
               
                 VPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0148]    SEQ ID NO: 37 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0149]    SEQ ID NO: 37 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 38) 
               
             
          
           
               
                 ATGAGCAAGCTGGAGAAGTTTACAAACTGCTACTCCCTGTCTAAGACCCT 
               
               
                   
               
               
                 GAGGTTCAAGGCCATCCCTGTGGGCAAGACCCAGGAGAACATCGACAATA 
               
               
                   
               
               
                 AGCGGCTGCTGGTGGAGGACGAGAAGAGAGCCGAGGATTATAAGGGCGTG 
               
               
                   
               
               
                 AAGAAGCTGCTGGATCGCTACTATCTGTCTTTTATCAACGACGTGCTGCA 
               
               
                   
               
               
                 CAGCATCAAGCTGAAGAATCTGAACAATTACATCAGCCTGTTCCGGAAGA 
               
               
                   
               
               
                 AAACCAGAACCGAGAAGGAGAATAAGGAGCTGGAGAACCTGGAGATCAAT 
               
               
                   
               
               
                 CTGCGGAAGGAGATCGCCAAGGCCTTCAAGGGCAACGAGGGCTACAAGTC 
               
               
                   
               
               
                 CCTGTTTAAGAAGGATATCATCGAGACAATCCTGCCAGAGTTCCTGGACG 
               
               
                   
               
               
                 ATAAGGACGAGATCGCCCTGGTGAACAGCTTCAATGGCTTTACCACAGCC 
               
               
                   
               
               
                 TTCACCGGCTTCTTTGATAACAGAGAGAATATGTTTTCCGAGGAGGCCAA 
               
               
                   
               
               
                 GAGCACATCCATCGCCTTCAGGTGTATCAACGAGAATCTGACCCGCTACA 
               
               
                   
               
               
                 TCTCTAATATGGACATCTTCGAGAAGGTGGACGCCATCTTTGATAAGCAC 
               
               
                   
               
               
                 GAGGTGCAGGAGATCAAGGAGAAGATCCTGAACAGCGACTATGATGTGGA 
               
               
                   
               
               
                 GGATTTCTTTGAGGGCGAGTTCTTTAACTTTGTGCTGACACAGGAGGGCA 
               
               
                   
               
               
                 TCGACGTGTATAACGCCATCATCGGCGGCTTCGTGACCGAGAGCGGCGAG 
               
               
                   
               
               
                 AAGATCAAGGGCCTGAACGAGTACATCAACCTGTATAATCAGAAAACCAA 
               
               
                   
               
               
                 GCAGAAGCTGCCTAAGTTTAAGCCACTGTATAAGCAGGTGCTGAGCGATC 
               
               
                   
               
               
                 GGGAGTCTCTGAGCTTCTACGGCGAGGGCTATACATCCGATGAGGAGGTG 
               
               
                   
               
               
                 CTGGAGGTGTTTAGAAACACCCTGAACAAGAACAGCGAGATCTTCAGCTC 
               
               
                   
               
               
                 CATCAAGAAGCTGGAGAAGCTGTTCAAGAATTTTGACGAGTACTCTAGCG 
               
               
                   
               
               
                 CCGGCATCTTTGTGAAGAACGGCCCCGCCATCAGCACAATCTCCAAGGAT 
               
               
                   
               
               
                 ATCTTCGGCGAGTGGAACGTGATCCGGGACAAGTGGAATGCCGAGTATGA 
               
               
                   
               
               
                 CGATATCCACCTGAAGAAGAAGGCCGTGGTGACCGAGAAGTACGAGGACG 
               
               
                   
               
               
                 ATCGGAGAAAGTCCTTCAAGAAGATCGGCTCCTTTTCTCTGGAGCAGCTG 
               
               
                   
               
               
                 CAGGAGTACGCCGACGCCGATCTGTCTGTGGTGGAGAAGCTGAAGGAGAT 
               
               
                   
               
               
                 CATCATCCAGAAGGTGGATGAGATCTACAAGGTGTATGGCTCCTCTGAGA 
               
               
                   
               
               
                 AGCTGTTCGACGCCGATTTTGTGCTGGAGAAGAGCCTGAAGAAGAACGAC 
               
               
                   
               
               
                 GCCGTGGTGGCCATCATGAAGGACCTGCTGGATTCTGTGAAGAGCTTCGA 
               
               
                   
               
               
                 GAATTACATCAAGGCCTTCTTTGGCGAGGGCAAGGAGACAAACAGGGACG 
               
               
                   
               
               
                 AGTCCTTCTATGGCGATTTTGTGCTGGCCTACGACATCCTGCTGAAGGTG 
               
               
                   
               
               
                 GACCACATCTACGATGCCATCCGCAATTATGTGACCCAGAAGCCCTACTC 
               
               
                   
               
               
                 TAAGGATAAGTTCAAGCTGTATTTTCAGAACCCTCAGTTCATGGGCGGCT 
               
               
                   
               
               
                 GGGACAAGGATAAGGAGACAGACTATCGGGCCACCATCCTGAGATACGGC 
               
               
                   
               
               
                 TCCAAGTACTATCTGGCCATCATGGATAAGAAGTACGCCAAGTGCCTGCA 
               
               
                   
               
               
                 GAAGATCGACAAGGACGATGTGAACGGCAATTACGAGAAGATCAACTATA 
               
               
                   
               
               
                 AGCTGCTGCCCGGCCCTAATAAGATGCTGCCAAAGGTGTTCTTTTCTAAG 
               
               
                   
               
               
                 AAGTGGATGGCCTACTATAACCCCAGCGAGGACATCCAGAAGATCTACAA 
               
               
                   
               
               
                 GAATGGCACATTCAAGAAGGGCGATATGTTTAACCTGAATGACTGTCACA 
               
               
                   
               
               
                 AGCTGATCGACTTCTTTAAGGATAGCATCTCCCGGTATCCAAAGTGGTCC 
               
               
                   
               
               
                 AATGCCTACGATTTCAACTTTTCTGAGACAGAGAAGTATAAGGACATCGC 
               
               
                   
               
               
                 CGGCTTTTACAGAGAGGTGGAGGAGCAGGGCTATAAGGTGAGCTTCGAGT 
               
               
                   
               
               
                 CTGCCAGCAAGAAGGAGGTGGATAAGCTGGTGGAGGAGGGCAAGCTGTAT 
               
               
                   
               
               
                 ATGTTCCAGATCTATAACAAGGACTTTTCCGATAAGTCTCACGGCACACC 
               
               
                   
               
               
                 CAATCTGCACACCATGTACTTCAAGCTGCTGTTTGACGAGAACAATCACG 
               
               
                   
               
               
                 GACAGATCAGGCTGAGCGGAGGAGCAGAGCTGTTCATGAGGCGCGCCTCC 
               
               
                   
               
               
                 CTGAAGAAGGAGGAGCTGGTGGTGCACCCAGCCAACTCCCCTATCGCCAA 
               
               
                   
               
               
                 CAAGAATCCAGATAATCCCAAGAAAACCACAACCCTGTCCTACGACGTGT 
               
               
                   
               
               
                 ATAAGGATAAGAGGTTTTCTGAGGACCAGTACGAGCTGCACATCCCAATC 
               
               
                   
               
               
                 GCCATCAATAAGTGCCCCAAGAACATCTTCAAGATCAATACAGAGGTGCG 
               
               
                   
               
               
                 CGTGCTGCTGAAGCACGACGATAACCCCTATGTGATCGGCATCGATAGGG 
               
               
                   
               
               
                 GCGAGCGCAATCTGCTGTATATCGTGGTGGTGGACGGCAAGGGCAACATC 
               
               
                   
               
               
                 GTGGAGCAGTATTCCCTGAACGAGATCATCAACAACTTCAACGGCATCAG 
               
               
                   
               
               
                 GATCAAGACAGATTACCACTCTCTGCTGGACAAGAAGGAGAAGGAGAGGT 
               
               
                   
               
               
                 TCGAGGCCCGCCAGAACTGGACCTCCATCGAGAATATCAAGGAGCTGAAG 
               
               
                   
               
               
                 GCCGGCTATATCTCTCAGGTGGTGCACAAGATCTGCGAGCTGGTGGAGAA 
               
               
                   
               
               
                 GTACGATGCCGTGATCGCCCTGGAGGACCTGAACTCTGGCTTTAAGAATA 
               
               
                   
               
               
                 GCCGCGTGAAGGTGGAGAAGCAGGTGTATCAGAAGTTCGAGAAGATGCTG 
               
               
                   
               
               
                 ATCGATAAGCTGAACTACATGGTGGACAAGAAGTCTAATCCTTGTGCAAC 
               
               
                   
               
               
                 AGGCGGCGCCCTGAAGGGCTATCAGATCACCAATAAGTTCGAGAGCTTTA 
               
               
                   
               
               
                 AGTCCATGTCTACCCAGAACGGCTTCATCTTTTACATCCCTGCCTGGCTG 
               
               
                   
               
               
                 ACATCCAAGATCGATCCATCTACCGGCTTTGTGAACCTGCTGAAAACCAA 
               
               
                   
               
               
                 GTATACCAGCATCGCCGATTCCAAGAAGTTCATCAGCTCCTTTGACAGGA 
               
               
                   
               
               
                 TCATGTACGTGCCCGAGGAGGATCTGTTCGAGTTTGCCCTGGACTATAAG 
               
               
                   
               
               
                 AACTTCTCTCGCACAGACGCCGATTACATCAAGAAGTGGAAGCTGTACTC 
               
               
                   
               
               
                 CTACGGCAACCGGATCAGAATCTTCCGGAATCCTAAGAAGAACAACGTGT 
               
               
                   
               
               
                 TCGACTGGGAGGAGGTGTGCCTGACCAGCGCCTATAAGGAGCTGTTCAAC 
               
               
                   
               
               
                 AAGTACGGCATCAATTATCAGCAGGGCGATATCAGAGCCCTGCTGTGCGA 
               
               
                   
               
               
                 GCAGTCCGACAAGGCCTTCTACTCTAGCTTTATGGCCCTGATGAGCCTGA 
               
               
                   
               
               
                 TGCTGCAGATGCGGAACAGCATCACAGGCCGCACCGACGTGGATTTTCTG 
               
               
                   
               
               
                 ATCAGCCCTGTGAAGAACTCCGACGGCATCTTCTACGATAGCCGGAACTA 
               
               
                   
               
               
                 TGAGGCCCAGGAGAATGCCATCCTGCCAAAGAACGCCGACGCCAATGGCG 
               
               
                   
               
               
                 CCTATAACATCGCCAGAAAGGTGCTGTGGGCCATCGGCCAGTTCAAGAAG 
               
               
                   
               
               
                 GCCGAGGACGAGAAGCTGGATAAGGTGAAGATCGCCATCTCTAACAAGGA 
               
               
                   
               
               
                 GTGGCTGGAGTACGCCCAGACCAGCGTGAAGCACAAAAGGCCGGCGGCCA 
               
               
                   
               
               
                 CGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCCTACCCATACGAT 
               
               
                   
               
               
                 GTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATA 
               
               
                   
               
               
                 TGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0150]      Porphyromonas crevioricanis  (PcCpf1; pY017), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 39) 
               
             
          
           
               
                 MDSLKDFTNLYPVSKTLRFELKPVGKTLENIEKAGILKEDEHRAESYRRV 
               
               
                   
               
               
                 KKIIDTYHKVFIDSSLENMAKMGIENEIKAMLQSFCELYKKDHRTEGEDK 
               
               
                   
               
               
                 ALDKIRAVLRGLIVGAFTGVCGRRENTVQNEKYESLFKEKLIKEILPDFV 
               
               
                   
               
               
                 LSTEAESLPFSVEEATRSLKEFDSFTSYFAGFYENRKNIYSTKPQSTAIA 
               
               
                   
               
               
                 YRLIHENLPKFIDNILVFQKIKEPIAKELEHIRADFSAGGYIKKDERLED 
               
               
                   
               
               
                 IFSLNYYIHVLSQAGIEKYNALIGKIVTEGDGEMKGLNEHINLYNQQRGR 
               
               
                   
               
               
                 EDRLPLFRPLYKQILSDREQLSYLPESFEKDEELLRALKEFYDHIAEDIL 
               
               
                   
               
               
                 GRTQQLMTSISEYDLSRIYVRNDSQLTDISKKMLGDWNAIYMARERAYDH 
               
               
                   
               
               
                 EQAPKRITAKYERDRIKALKGEESISLANLNSCIAFLDNVRDCRVDTYLS 
               
               
                   
               
               
                 TLGQKEGPHGLSNLVENVFASYHEAEQLLSFPYPEENNLIQDKDNVVLIK 
               
               
                   
               
               
                 NLLDNISDLQRFLKPLWGMGDEPDKDERFYGEYNYIRGALDQVIPLYNKV 
               
               
                   
               
               
                 RNYLTRKPYSTRKVKLNFGNSQLLSGWDRNKEKDNSCVILRKGQNFYLAI 
               
               
                   
               
               
                 MNNRHKRSFENKMLPEYKEGEPYFEKMDYKFLPDPNKMLPKVFLSKKGIE 
               
               
                   
               
               
                 IYKPSPKLLEQYGHGTHKKGDTFSMDDLHELIDFFKHSIEAHEDWKQFGF 
               
               
                   
               
               
                 KFSDTATYENVSSFYREVEDQGYKLSFRKVSESYVYSLIDQGKLYLFQIY 
               
               
                   
               
               
                 NKDFSPCSKGTPNLHTLYWRMLFDERNLADVIYKLDGKAEIFFREKSLKN 
               
               
                   
               
               
                 DHPTHPAGKPIKKKSRQKKGEESLFEYDLVKDRRYTMDKFQFHVPITMNF 
               
               
                   
               
               
                 KCSAGSKVNDMVNAHIREAKDMHVIGIDRGERNLLYICVIDSRGTILDQI 
               
               
                   
               
               
                 SLNTINDIDYHDLLESRDKDRQQEHRNWQTIEGIKELKQGYLSQAVHRIA 
               
               
                   
               
               
                 ELMVAYKAVVALEDLNMGFKRGRQKVESSVYQQFEKQLIDKLNYLVDKKK 
               
               
                   
               
               
                 RPEDIGGLLRAYQFTAPFKSFKEMGKQNGFLFYIPAWNTSNIDPTTGFVN 
               
               
                   
               
               
                 LFHVQYENVDKAKSFFQKFDSISYNPKKDWFEFAFDYKNFTKKAEGSRSM 
               
               
                   
               
               
                 WILCTHGSRIKNFRNSQKNGQWDSEEFALTEAFKSLFVRYEIDYTADLKT 
               
               
                   
               
               
                 AIVDEKQKDFFVDLLKLFKLTVQMRNSWKEKDLDYLISPVAGADGRFFDT 
               
               
                   
               
               
                 REGNKSLPKDADANGAYNIALKGLWALRQIRQTSEGGKLKLAISNKEWLQ 
               
               
                   
               
               
                 FVQERSYEKDKRPAATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYD 
               
               
                   
               
               
                 VPDYA 
               
             
          
         
       
     
         [0151]    SEQ ID NO: 39 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0152]    SEQ ID NO: 39 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 40) 
               
             
          
           
               
                 ATGGACAGCCTGAAGGATTTCACCAACCTGTACCCCGTGTCCAAGACACT 
               
               
                   
               
               
                 GCGGTTTGAGCTGAAGCCTGTGGGCAAGACCCTGGAGAATATCGAGAAGG 
               
               
                   
               
               
                 CCGGCATCCTGAAGGAGGATGAGCACAGAGCCGAGAGCTACCGGAGAGTG 
               
               
                   
               
               
                 AAGAAGATCATCGATACATATCACAAGGTGTTCATCGACAGCTCCCTGGA 
               
               
                   
               
               
                 GAACATGGCCAAGATGGGCATCGAGAATGAGATCAAGGCCATGCTGCAGT 
               
               
                   
               
               
                 CCTTTTGCGAGCTGTATAAGAAGGACCACAGGACCGAGGGAGAGGACAAG 
               
               
                   
               
               
                 GCCCTGGATAAGATCAGGGCCGTGCTGAGGGGCCTGATCGTGGGAGCCTT 
               
               
                   
               
               
                 CACCGGCGTGTGCGGCCGGCGGGAGAACACAGTGCAGAATGAGAAGTATG 
               
               
                   
               
               
                 AGAGCCTGTTTAAGGAGAAGCTGATCAAGGAGATCCTGCCAGATTTCGTG 
               
               
                   
               
               
                 CTGTCTACAGAGGCCGAGTCCCTGCCCTTTTCTGTGGAGGAGGCCACCAG 
               
               
                   
               
               
                 AAGCCTGAAGGAGTTCGACTCCTTTACATCTTACTTCGCCGGCTTTTATG 
               
               
                   
               
               
                 AGAACCGGAAGAATATCTACTCTACCAAGCCCCAGAGCACAGCCATCGCC 
               
               
                   
               
               
                 TATAGACTGATCCACGAGAACCTGCCTAAGTTCATCGATAATATCCTGGT 
               
               
                   
               
               
                 GTTTCAGAAGATCAAGGAGCCAATCGCCAAGGAGCTGGAGCACATCAGGG 
               
               
                   
               
               
                 CAGACTTCAGCGCCGGCGGCTACATCAAGAAGGATGAGCGCCTGGAGGAC 
               
               
                   
               
               
                 ATCTTTTCCCTGAACTACTATATCCACGTGCTGTCTCAGGCCGGCATCGA 
               
               
                   
               
               
                 GAAGTACAATGCCCTGATCGGCAAGATCGTGACCGAGGGCGATGGCGAGA 
               
               
                   
               
               
                 TGAAGGGCCTGAACGAGCACATCAACCTGTATAATCAGCAGAGGGGCCGC 
               
               
                   
               
               
                 GAGGACCGGCTGCCACTGTTCAGACCCCTGTATAAGCAGATCCTGTCTGA 
               
               
                   
               
               
                 TAGGGAGCAGCTGTCCTATCTGCCAGAGTCTTTCGAGAAGGACGAGGAGC 
               
               
                   
               
               
                 TGCTGAGGGCCCTGAAGGAGTTTTACGATCACATCGCAGAGGACATCCTG 
               
               
                   
               
               
                 GGAAGGACCCAGCAGCTGATGACAAGCATCTCCGAGTACGATCTGTCCCG 
               
               
                   
               
               
                 GATCTATGTGAGAAACGATAGCCAGCTGACCGACATCTCCAAGAAGATGC 
               
               
                   
               
               
                 TGGGCGATTGGAATGCCATCTACATGGCCCGGGAGAGAGCCTATGACCAC 
               
               
                   
               
               
                 GAGCAGGCCCCCAAGCGCATCACAGCCAAGTACGAGAGGGACCGCATCAA 
               
               
                   
               
               
                 GGCCCTGAAGGGCGAGGAGTCTATCAGCCTGGCCAACCTGAACAGCTGCA 
               
               
                   
               
               
                 TCGCCTTCCTGGACAACGTGAGGGATTGTCGCGTGGACACCTATCTGTCT 
               
               
                   
               
               
                 ACACTGGGACAGAAGGAGGGACCTCACGGCCTGAGCAACCTGGTGGAGAA 
               
               
                   
               
               
                 CGTGTTCGCCTCCTACCACGAGGCCGAGCAGCTGCTGTCTTTTCCCTATC 
               
               
                   
               
               
                 CTGAGGAGAACAATCTGATCCAGGACAAGGATAACGTGGTGCTGATCAAG 
               
               
                   
               
               
                 AACCTGCTGGATAATATCAGCGACCTGCAGAGGTTCCTGAAGCCACTGTG 
               
               
                   
               
               
                 GGGCATGGGCGATGAGCCCGACAAGGATGAGAGGTTTTACGGCGAGTACA 
               
               
                   
               
               
                 ATTATATCAGGGGCGCCCTGGACCAGGTCATCCCTCTGTATAACAAGGTG 
               
               
                   
               
               
                 CGGAATTATCTGACCCGCAAGCCATACTCCACACGCAAGGTGAAGCTGAA 
               
               
                   
               
               
                 CTTCGGCAATAGCCAGCTGCTGTCCGGCTGGGATAGGAACAAGGAGAAGG 
               
               
                   
               
               
                 ACAATTCTTGCGTGATCCTGCGCAAGGGCCAGAACTTCTACCTGGCCATC 
               
               
                   
               
               
                 ATGAACAATCGGCACAAGCGGAGCTTCGAGAATAAGATGCTGCCCGAGTA 
               
               
                   
               
               
                 TAAGGAGGGCGAGCCTTACTTCGAGAAGATGGATTATAAGTTTCTGCCAG 
               
               
                   
               
               
                 ACCCCAACAAGATGCTGCCCAAGGTGTTCCTGTCTAAGAAGGGCATCGAG 
               
               
                   
               
               
                 ATCTACAAGCCTAGCCCAAAGCTGCTGGAGCAGTATGGCCACGGCACCCA 
               
               
                   
               
               
                 CAAGAAGGGCGATACCTTCAGCATGGACGATCTGCACGAGCTGATCGACT 
               
               
                   
               
               
                 TCTTTAAGCACTCCATCGAGGCCCACGAGGATTGGAAGCAGTTCGGCTTT 
               
               
                   
               
               
                 AAGTTCAGCGACACCGCCACATACGAGAACGTGAGCAGCTTCTACCGGGA 
               
               
                   
               
               
                 GGTGGAGGACCAGGGCTACAAGCTGTCTTTTAGAAAGGTGTCCGAGTCTT 
               
               
                   
               
               
                 ACGTGTATAGCCTGATCGATCAGGGCAAGCTGTACCTGTTCCAGATCTAT 
               
               
                   
               
               
                 AACAAGGACTTTAGCCCTTGTTCCAAGGGCACCCCAAATCTGCACACACT 
               
               
                   
               
               
                 GTACTGGCGGATGCTGTTCGATGAGAGAAACCTGGCCGACGTGATCTATA 
               
               
                   
               
               
                 AGCTGGATGGCAAGGCCGAGATCTTCTTTCGGGAGAAGTCCCTGAAGAAT 
               
               
                   
               
               
                 GACCACCCAACCCACCCTGCAGGCAAGCCCATCAAGAAGAAGAGCCGGCA 
               
               
                   
               
               
                 GAAGAAGGGCGAGGAGAGCCTGTTCGAGTACGATCTGGTGAAGGACCGGA 
               
               
                   
               
               
                 GATATACCATGGATAAGTTTCAGTTCCACGTGCCAATCACAATGAACTTT 
               
               
                   
               
               
                 AAGTGCTCTGCCGGCAGCAAGGTGAACGACATGGTGAATGCCCACATCAG 
               
               
                   
               
               
                 GGAGGCCAAGGACATGCACGTGATCGGCATCGATAGGGGCGAGCGCAATC 
               
               
                   
               
               
                 TGCTGTATATCTGCGTGATCGACAGCCGCGGCACCATCCTGGATCAGATC 
               
               
                   
               
               
                 TCCCTGAACACAATCAATGACATCGATTATCACGATCTGCTGGAGTCCAG 
               
               
                   
               
               
                 GGACAAGGATCGCCAGCAGGAGCACAGGAACTGGCAGACCATCGAGGGCA 
               
               
                   
               
               
                 TCAAGGAGCTGAAGCAGGGCTACCTGTCTCAGGCCGTGCACCGCATCGCC 
               
               
                   
               
               
                 GAGCTGATGGTGGCCTATAAGGCCGTGGTGGCCCTGGAGGACCTGAACAT 
               
               
                   
               
               
                 GGGCTTCAAGCGGGGCAGACAGAAGGTGGAGAGCAGCGTGTACCAGCAGT 
               
               
                   
               
               
                 TTGAGAAGCAGCTGATCGACAAGCTGAATTATCTGGTGGATAAGAAGAAG 
               
               
                   
               
               
                 CGGCCCGAGGACATCGGAGGCCTGCTGAGAGCCTACCAGTTCACCGCCCC 
               
               
                   
               
               
                 TTTCAAGAGCTTTAAGGAGATGGGCAAGCAGAACGGCTTTCTGTTCTATA 
               
               
                   
               
               
                 TCCCTGCCTGGAACACATCCAATATCGACCCAACCACAGGCTTCGTGAAC 
               
               
                   
               
               
                 CTGTTTCACGTGCAGTACGAGAATGTGGATAAGGCCAAGAGCTTCTTTCA 
               
               
                   
               
               
                 GAAGTTCGACAGCATCTCCTACAACCCTAAGAAGGATTGGTTTGAGTTCG 
               
               
                   
               
               
                 CCTTTGACTATAAGAACTTCACCAAGAAGGCCGAGGGCTCTAGGAGCATG 
               
               
                   
               
               
                 TGGATTCTGTGCACCCACGGCTCCCGGATCAAGAACTTCAGAAATTCTCA 
               
               
                   
               
               
                 GAAGAATGGCCAGTGGGATAGCGAGGAGTTTGCCCTGACCGAGGCCTTCA 
               
               
                   
               
               
                 AGTCCCTGTTTGTGCGGTACGAGATCGATTATACCGCCGACCTGAAAACC 
               
               
                   
               
               
                 GCCATCGTGGACGAGAAGCAGAAGGATTTCTTTGTGGACCTGCTGAAGCT 
               
               
                   
               
               
                 GTTCAAGCTGACCGTGCAGATGAGAAACTCCTGGAAGGAGAAGGACCTGG 
               
               
                   
               
               
                 ATTACCTGATCTCTCCAGTGGCCGGCGCCGATGGCAGGTTCTTTGACACA 
               
               
                   
               
               
                 CGCGAGGGCAATAAGAGCCTGCCCAAGGACGCAGATGCAAACGGAGCCTA 
               
               
                   
               
               
                 TAATATCGCCCTGAAGGGCCTGTGGGCACTGAGGCAGATCAGACAGACCT 
               
               
                   
               
               
                 CCGAGGGCGGCAAGCTGAAGCTGGCCATCTCTAACAAGGAGTGGCTGCAG 
               
               
                   
               
               
                 TTTGTGCAGGAGAGATCCTACGAGAAGGACAAAAGGCCGGCGGCCACGAA 
               
               
                   
               
               
                 AAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCCTACCCATACGATGTTC 
               
               
                   
               
               
                 CAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACCCATATGAT 
               
               
                   
               
               
                 GTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0153]      Prevotella disiens  (PdCpf1; pY018), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 41) 
               
             
          
           
               
                 MENYQEFTNLFQLNKTLRFELKPIGKTCELLEEGKIFASGSFLEKDKVRA 
               
               
                   
               
               
                 DNVSYVKKEIDKKHKIFIEETLSSFSISNDLLKQYFDCYNELKAFKKDCK 
               
               
                   
               
               
                 SDEEEVKKTALRNKCTSIQRAMREAISQAFLKSPQKKLLAIKNLIENVFK 
               
               
                   
               
               
                 ADENVQHFSEFTSYFSGFETNRENFYSDEEKSTSIAYRLVHDNLPIFIKN 
               
               
                   
               
               
                 IYIFEKLKEQFDAKTLSEIFENYKLYVAGSSLDEVFSLEYFNNTLTQKGI 
               
               
                   
               
               
                 DNYNAVIGKIVKEDKQEIQGLNEHINLYNQKHKDRRLPFFISLKKQILSD 
               
               
                   
               
               
                 REALSWLPDMFKNDSEVIKALKGFYIEDGFENNVLTPLATLLSSLDKYNL 
               
               
                   
               
               
                 NGIFIRNNEALSSLSQNVYRNFSIDEAIDANAELQTFNNYELIANALRAK 
               
               
                   
               
               
                 IKKETKQGRKSFEKYEEYIDKKVKAIDSLSIQEINELVENYVSEFNSNSG 
               
               
                   
               
               
                 NMPRKVEDYFSLMRKGDFGSNDLIENIKTKLSAAEKLLGTKYQETAKDIF 
               
               
                   
               
               
                 KKDENSKLIKELLDATKQFQHFIKPLLGTGEEADRDLVFYGDFLPLYEKF 
               
               
                   
               
               
                 EELTLLYNKVRNRLTQKPYSKDKIRLCFNKPKLMTGWVDSKTEKSDNGTQ 
               
               
                   
               
               
                 YGGYLFRKKNEIGEYDYFLGISSKAQLFRKNEAVIGDYERLDYYQPKANT 
               
               
                   
               
               
                 IYGSAYEGENSYKEDKKRLNKVIIAYIEQIKQTNIKKSIIESISKYPNIS 
               
               
                   
               
               
                 DDDKVTPSSLLEKIKKVSIDSYNGILSFKSFQSVNKEVIDNLLKTISPLK 
               
               
                   
               
               
                 NKAEFLDLINKDYQIFTEVQAVIDEICKQKTFIYFPISNVELEKEMGDKD 
               
               
                   
               
               
                 KPLCLFQISNKDLSFAKTFSANLRKKRGAENLHTMLFKALMEGNQDNLDL 
               
               
                   
               
               
                 GSGAIFYRAKSLDGNKPTHPANEAIKCRNVANKDKVSLFTYDIYKNRRYM 
               
               
                   
               
               
                 ENKFLFHLSIVQNYKAANDSAQLNSSATEYIRKADDLHIIGIDRGERNLL 
               
               
                   
               
               
                 YYSVIDMKGNIVEQDSLNIIRNNDLETDYHDLLDKREKERKANRQNWEAV 
               
               
                   
               
               
                 EGIKDLKKGYLSQAVHQIAQLMLKYNAIIALEDLGQMFVTRGQKIEKAVY 
               
               
                   
               
               
                 QQFEKSLVDKLSYLVDKKRPYNELGGILKAYQLASSITKNNSDKQNGFLF 
               
               
                   
               
               
                 YVPAWNTSKIDPVTGFTDLLRPKAMTIKEAQDFFGAFDNISYNDKGYFEF 
               
               
                   
               
               
                 ETNYDKFKIRMKSAQTRWTICTFGNRIKRKKDKNYWNYEEVELTEEFKKL 
               
               
                   
               
               
                 FKDSNIDYENCNLKEEIQNKDNRKFFDDLIKLLQLTLQMRNSDDKGNDYI 
               
               
                   
               
               
                 ISPVANAEGQFFDSRNGDKKLPLDADANGAYNIARKGLWNIRQIKQTKND 
               
               
                   
               
               
                 KKLNLSISSTEWLDFVREKPYLKKRPAATKKAGQAKKKKGSYPYDVPDYA 
               
               
                   
               
               
                 YPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0154]    SEQ ID NO: 41 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0155]    SEQ ID NO: 41 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 42) 
               
             
          
           
               
                 ATGGAGAACTATCAGGAGTTCACCAACCTGTTTCAGCTGAATAAGACACT 
               
               
                   
               
               
                 GAGATTCGAGCTGAAGCCCATCGGCAAGACCTGCGAGCTGCTGGAGGAGG 
               
               
                   
               
               
                 GCAAGATCTTCGCCAGCGGCTCCTTTCTGGAGAAGGACAAGGTGAGGGCC 
               
               
                   
               
               
                 GATAACGTGAGCTACGTGAAGAAGGAGATCGACAAGAAGCACAAGATCTT 
               
               
                   
               
               
                 TATCGAGGAGACACTGAGCTCCTTCTCTATCAGCAACGATCTGCTGAAGC 
               
               
                   
               
               
                 AGTACTTTGACTGCTATAATGAGCTGAAGGCCTTCAAGAAGGACTGTAAG 
               
               
                   
               
               
                 AGCGATGAGGAGGAGGTGAAGAAAACCGCCCTGCGCAACAAGTGTACCTC 
               
               
                   
               
               
                 CATCCAGAGGGCCATGCGCGAGGCCATCTCTCAGGCCTTTCTGAAGAGCC 
               
               
                   
               
               
                 CCCAGAAGAAGCTGCTGGCCATCAAGAACCTGATCGAGAACGTGTTCAAG 
               
               
                   
               
               
                 GCCGACGAGAATGTGCAGCACTTCTCCGAGTTTACCAGCTATTTCTCCGG 
               
               
                   
               
               
                 CTTTGAGACAAACAGAGAGAATTTCTACTCTGACGAGGAGAAGTCCACAT 
               
               
                   
               
               
                 CTATCGCCTATAGGCTGGTGCACGATAACCTGCCTATCTTCATCAAGAAC 
               
               
                   
               
               
                 ATCTACATCTTCGAGAAGCTGAAGGAGCAGTTCGACGCCAAGACCCTGAG 
               
               
                   
               
               
                 CGAGATCTTCGAGAACTACAAGCTGTATGTGGCCGGCTCTAGCCTGGATG 
               
               
                   
               
               
                 AGGTGTTCTCCCTGGAGTACTTTAACAATACCCTGACACAGAAGGGCATC 
               
               
                   
               
               
                 GACAACTATAATGCCGTGATCGGCAAGATCGTGAAGGAGGATAAGCAGGA 
               
               
                   
               
               
                 GATCCAGGGCCTGAACGAGCACATCAACCTGTATAATCAGAAGCACAAGG 
               
               
                   
               
               
                 ACCGGAGACTGCCCTTCTTTATCTCCCTGAAGAAGCAGATCCTGTCCGAT 
               
               
                   
               
               
                 CGGGAGGCCCTGTCTTGGCTGCCTGACATGTTCAAGAATGATTCTGAAGT 
               
               
                   
               
               
                 GATCAAGGCCCTGAAGGGCTTCTACATCGAGGACGGCTTTGAGAACAATG 
               
               
                   
               
               
                 TGCTGACACCTCTGGCCACCCTGCTGTCCTCTCTGGATAAGTACAACCTG 
               
               
                   
               
               
                 AATGGCATCTTTATCCGCAACAATGAGGCCCTGAGCTCCCTGTCCCAGAA 
               
               
                   
               
               
                 CGTGTATCGGAATTTTTCTATCGACGAGGCCATCGATGCCAACGCCGAGC 
               
               
                   
               
               
                 TGCAGACCTTCAACAATTACGAGCTGATCGCCAATGCCCTGCGCGCCAAG 
               
               
                   
               
               
                 ATCAAGAAGGAGACAAAGCAGGGCCGGAAGTCTTTCGAGAAGTACGAGGA 
               
               
                   
               
               
                 GTATATCGATAAGAAGGTGAAGGCCATCGACAGCCTGTCCATCCAGGAGA 
               
               
                   
               
               
                 TCAACGAGCTGGTGGAGAATTACGTGAGCGAGTTTAACTCTAATAGCGGC 
               
               
                   
               
               
                 AACATGCCAAGAAAGGTGGAGGACTACTTCAGCCTGATGAGGAAGGGCGA 
               
               
                   
               
               
                 CTTCGGCTCCAACGATCTGATCGAAAATATCAAGACCAAGCTGAGCGCCG 
               
               
                   
               
               
                 CAGAGAAGCTGCTGGGCACAAAGTACCAGGAGACAGCCAAGGACATCTTC 
               
               
                   
               
               
                 AAGAAGGATGAGAACTCCAAGCTGATCAAGGAGCTGCTGGACGCCACCAA 
               
               
                   
               
               
                 GCAGTTCCAGCACTTTATCAAGCCACTGCTGGGCACAGGCGAGGAGGCAG 
               
               
                   
               
               
                 ATCGGGACCTGGTGTTCTACGGCGATTTTCTGCCCCTGTATGAGAAGTTT 
               
               
                   
               
               
                 GAGGAGCTGACCCTGCTGTATAACAAGGTGCGGAATAGACTGACACAGAA 
               
               
                   
               
               
                 GCCCTATTCCAAGGACAAGATCCGCCTGTGCTTCAACAAGCCTAAGCTGA 
               
               
                   
               
               
                 TGACAGGCTGGGTGGATTCCAAGACCGAGAAGTCTGACAACGGCACACAG 
               
               
                   
               
               
                 TACGGCGGCTATCTGTTTCGGAAGAAGAATGAGATCGGCGAGTACGATTA 
               
               
                   
               
               
                 TTTTCTGGGCATCTCTAGCAAGGCCCAGCTGTTCAGAAAGAACGAGGCCG 
               
               
                   
               
               
                 TGATCGGCGACTACGAGAGGCTGGATTACTATCAGCCAAAGGCCAATACC 
               
               
                   
               
               
                 ATCTACGGCTCTGCCTATGAGGGCGAGAACAGCTACAAGGAGGACAAGAA 
               
               
                   
               
               
                 GCGGCTGAACAAAGTGATCATCGCCTATATCGAGCAGATCAAGCAGACAA 
               
               
                   
               
               
                 ACATCAAGAAGTCTATCATCGAGTCCATCTCTAAGTATCCTAATATCAGC 
               
               
                   
               
               
                 GACGATGACAAGGTGACCCCATCCTCTCTGCTGGAGAAGATCAAGAAGGT 
               
               
                   
               
               
                 GTCTATCGACAGCTACAACGGCATCCTGTCCTTCAAGTCTTTTCAGAGCG 
               
               
                   
               
               
                 TGAACAAGGAAGTGATCGATAACCTGCTGAAAACCATCAGCCCCCTGAAG 
               
               
                   
               
               
                 AACAAGGCCGAGTTTCTGGACCTGATCAATAAGGATTATCAGATCTTCAC 
               
               
                   
               
               
                 CGAGGTGCAGGCCGTGATCGACGAGATCTGCAAGCAGAAAACCTTCATCT 
               
               
                   
               
               
                 ACTTTCCAATCTCCAACGTGGAGCTGGAGAAGGAGATGGGCGATAAGGAC 
               
               
                   
               
               
                 AAGCCCCTGTGCCTGTTCCAGATCAGCAATAAGGATCTGTCCTTCGCCAA 
               
               
                   
               
               
                 GACCTTTAGCGCCAACCTGCGGAAGAAGAGAGGCGCCGAGAATCTGCACA 
               
               
                   
               
               
                 CAATGCTGTTTAAGGCCCTGATGGAGGGCAACCAGGATAATCTGGACCTG 
               
               
                   
               
               
                 GGCTCTGGCGCCATCTTCTACAGAGCCAAGAGCCTGGACGGCAACAAGCC 
               
               
                   
               
               
                 CACACACCCTGCCAATGAGGCCATCAAGTGTAGGAACGTGGCCAATAAGG 
               
               
                   
               
               
                 ATAAGGTGTCCCTGTTCACCTACGACATCTATAAGAACAGGCGCTACATG 
               
               
                   
               
               
                 GAGAATAAGTTCCTGTTTCACCTGAGCATCGTGCAGAACTATAAGGCCGC 
               
               
                   
               
               
                 CAATGACTCCGCCCAGCTGAACAGCTCCGCCACCGAGTATATCAGAAAGG 
               
               
                   
               
               
                 CCGATGACCTGCACATCATCGGCATCGATAGGGGCGAGCGCAATCTGCTG 
               
               
                   
               
               
                 TACTATTCCGTGATCGATATGAAGGGCAACATCGTGGAGCAGGACTCTCT 
               
               
                   
               
               
                 GAATATCATCAGGAACAATGACCTGGAGACAGATTACCACGACCTGCTGG 
               
               
                   
               
               
                 ATAAGAGGGAGAAGGAGCGCAAGGCCAACCGGCAGAATTGGGAGGCCGTG 
               
               
                   
               
               
                 GAGGGCATCAAGGACCTGAAGAAGGGCTACCTGAGCCAGGCCGTGCACCA 
               
               
                   
               
               
                 GATCGCCCAGCTGATGCTGAAGTATAACGCCATCATCGCCCTGGAGGATC 
               
               
                   
               
               
                 TGGGCCAGATGTTTGTGACCCGCGGCCAGAAGATCGAGAAGGCCGTGTAC 
               
               
                   
               
               
                 CAGCAGTTCGAGAAGAGCCTGGTGGATAAGCTGTCCTACCTGGTGGACAA 
               
               
                   
               
               
                 GAAGCGGCCTTATAATGAGCTGGGCGGCATCCTGAAGGCCTACCAGCTGG 
               
               
                   
               
               
                 CCTCTAGCATCACCAAGAACAATTCTGACAAGCAGAACGGCTTCCTGTTT 
               
               
                   
               
               
                 TATGTGCCAGCCTGGAATACAAGCAAGATCGATCCCGTGACCGGCTTTAC 
               
               
                   
               
               
                 AGACCTGCTGCGGCCCAAGGCCATGACCATCAAGGAGGCCCAGGACTTCT 
               
               
                   
               
               
                 TTGGCGCCTTCGATAACATCTCTTACAATGACAAGGGCTATTTCGAGTTT 
               
               
                   
               
               
                 GAGACAAACTACGACAAGTTTAAGATCAGAATGAAGAGCGCCCAGACCAG 
               
               
                   
               
               
                 GTGGACAATCTGCACCTTCGGCAATCGGATCAAGAGAAAGAAGGATAAGA 
               
               
                   
               
               
                 ACTACTGGAATTATGAGGAGGTGGAGCTGACCGAGGAGTTCAAGAAGCTG 
               
               
                   
               
               
                 TTTAAGGACAGCAACATCGATTACGAGAACTGTAATCTGAAGGAGGAGAT 
               
               
                   
               
               
                 CCAGAACAAGGACAATCGCAAGTTCTTTGATGACCTGATCAAGCTGCTGC 
               
               
                   
               
               
                 AGCTGACACTGCAGATGCGGAACTCCGATGACAAGGGCAATGATTATATC 
               
               
                   
               
               
                 ATCTCTCCTGTGGCCAACGCCGAGGGCCAGTTCTTTGACTCCCGCAATGG 
               
               
                   
               
               
                 CGATAAGAAGCTGCCACTGGATGCAGACGCAAACGGAGCCTACAATATCG 
               
               
                   
               
               
                 CCCGCAAGGGCCTGTGGAACATCCGGCAGATCAAGCAGACCAAGAACGAC 
               
               
                   
               
               
                 AAGAAGCTGAATCTGAGCATCTCCTCTACAGAGTGGCTGGATTTCGTGCG 
               
               
                   
               
               
                 GGAGAAGCCTTACCTGAAGAAAAGGCCGGCGGCCACGAAAAAGGCCGGCC 
               
               
                   
               
               
                 AGGCAAAAAAGAAAAAGGGATCCTACCCATACGATGTTCCAGATTACGCT 
               
               
                   
               
               
                 TATCCCTACGACGTGCCTGATTATGCATACCCATATGATGTCCCCGACTA 
               
               
                   
               
               
                 TGCCTAA 
               
             
          
         
       
     
         [0156]      Porphyromonas macacae  (PmCpf1; pY09), including NLS and HA tag: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 43) 
               
             
          
           
               
                 MKTQHFFEDFTSLYSLSKTIRFELKPIGKTLENIKKNGLIRRDEQRLDDY 
               
               
                   
               
               
                 EKLKKVIDEYHEDFIANILSSFSFSEEILQSYIQNLSESEARAKIEKTMR 
               
               
                   
               
               
                 DTLAKAFSEDERYKSIFKKELVKKDIPVWCPAYKSLCKKFDNFTTSLVPF 
               
               
                   
               
               
                 HENRKNLYTSNEITASIPYRIVHVNLPKFIQNIEALCELQKKMGADLYLE 
               
               
                   
               
               
                 MMENLRNVWPSFVKTPDDLCNLKTYNHLMVQSSISEYNRFVGGYSTEDGT 
               
               
                   
               
               
                 KHQGINEWINIYRQRNKEMRLPGLVFLHKQILAKVDSSSFISDTLENDDQ 
               
               
                   
               
               
                 VFCVLRQFRKLFWNTVSSKEDDAASLKDLFCGLSGYDPEAIYVSDAHLAT 
               
               
                   
               
               
                 ISKNIFDRWNYISDAIRRKTEVLMPRKKESVERYAEKISKQIKKRQSYSL 
               
               
                   
               
               
                 AELDDLLAHYSEESLPAGFSLLSYFTSLGGQKYLVSDGEVILYEEGSNIW 
               
               
                   
               
               
                 DEVLIAFRDLQVILDKDFTEKKLGKDEEAVSVIKKALDSALRLRKFFDLL 
               
               
                   
               
               
                 SGTGAEIRRDSSFYALYTDRMDKLKGLLKMYDKVRNYLTKKPYSIEKFKL 
               
               
                   
               
               
                 HFDNPSLLSGWDKNKELNNLSVIFRQNGYYYLGIMTPKGKNLFKTLPKLG 
               
               
                   
               
               
                 AEEMFYEKMEYKQIAEPMLMLPKVFFPKKTKPAFAPDQSVVDIYNKKTFK 
               
               
                   
               
               
                 TGQKGFNKKDLYRLIDFYKEALTVHEWKLFNFSFSPTEQYRNIGEFFDEV 
               
               
                   
               
               
                 REQAYKVSMVNVPASYIDEAVENGKLYLFQIYNKDFSPYSKGIPNLHTLY 
               
               
                   
               
               
                 WKALFSEQNQSRVYKLCGGGELFYRKASLHMQDTTVHPKGISIHKKNLNK 
               
               
                   
               
               
                 KGETSLFNYDLVKDKRFTEDKFFFHVPISINYKNKKITNVNQMVRDYIAQ 
               
               
                   
               
               
                 NDDLQIIGIDRGERNLLYISRIDTRGNLLEQFSLNVIESDKGDLRTDYQK 
               
               
                   
               
               
                 ILGDREQERLRRRQEWKSIESIKDLKDGYMSQVVHKICNMVVEHKAIVVL 
               
               
                   
               
               
                 ENLNLSFMKGRKKVEKSVYEKFERMLVDKLNYLVVDKKNLSNEPGGLYAA 
               
               
                   
               
               
                 YQLTNPLFSFEELHRYPQSGILFFVDPWNTSLTDPSTGFVNLLGRINYTN 
               
               
                   
               
               
                 VGDARKFFDRFNAIRYDGKGNILFDLDLSRFDVRVETQRKLWTLTTFGSR 
               
               
                   
               
               
                 IAKSKKSGKWMVERIENLSLCFLELFEQFNIGYRVEKDLKKAILSQDRKE 
               
               
                   
               
               
                 FYVRLIYLFNLMMQIRNSDGEEDYILSPALNEKNLQFDSRLIEAKDLPVD 
               
               
                   
               
               
                 ADANGAYNVARKGLMVVQRIKRGDHESIHRIGRAQWLRYVQEGIVEKRPA 
               
               
                   
               
               
                 ATKKAGQAKKKKGSYPYDVPDYAYPYDVPDYAYPYDVPDYA 
               
             
          
         
       
     
         [0157]    SEQ ID NO: 43 includes a nuclear localization signal (KRPAATKKAGQAKKKK) (SEQ ID NO: 12), followed by a glycine-serine linker (GS), followed by a HA tag (YPYDVPDYAYPYDVPDYAYPYDVPDYA) (SEQ ID NO: 13). 
         [0158]    SEQ ID NO: 43 may be encoded by the following nucleotide sequence: 
         [0000]    
       
         
               
             
               
             
           
               
                 (SEQ ID NO: 44) 
               
             
          
           
               
                 ATGAAAACCCAGCACTTCTTTGAGGACTTCACAAGCCTGTACTCTCTGAG 
               
               
                   
               
               
                 CAAGACCATCCGGTTTGAGCTGAAGCCAATCGGCAAGACCCTGGAGAACA 
               
               
                   
               
               
                 TCAAGAAGAATGGCCTGATCCGGAGAGATGAGCAGAGACTGGACGATTAC 
               
               
                   
               
               
                 GAGAAGCTGAAGAAAGTGATCGACGAGTATCACGAGGATTTCATCGCCAA 
               
               
                   
               
               
                 CATCCTGAGCTCCTTTTCCTTCTCTGAGGAGATCCTGCAGTCCTACATCC 
               
               
                   
               
               
                 AGAATCTGAGCGAGTCCGAGGCCAGGGCCAAGATCGAGAAAACCATGCGC 
               
               
                   
               
               
                 GACACACTGGCCAAGGCCTTCTCTGAGGATGAGAGGTACAAGAGCATCTT 
               
               
                   
               
               
                 TAAGAAGGAGCTGGTGAAGAAGGACATCCCCGTGTGGTGCCCTGCCTATA 
               
               
                   
               
               
                 AGAGCCTGTGCAAGAAGTTCGATAACTTTACCACATCTCTGGTGCCCTTC 
               
               
                   
               
               
                 CACGAGAACAGGAAGAACCTGTATACCAGCAATGAGATCACAGCCTCTAT 
               
               
                   
               
               
                 CCCTTATCGCATCGTGCACGTGAACCTGCCAAAGTTTATCCAGAATATCG 
               
               
                   
               
               
                 AGGCCCTGTGCGAGCTGCAGAAGAAGATGGGCGCCGACCTGTACCTGGAG 
               
               
                   
               
               
                 ATGATGGAGAACCTGCGCAACGTGTGGCCCAGCTTCGTGAAAACCCCAGA 
               
               
                   
               
               
                 CGACCTGTGCAACCTGAAAACCTATAATCACCTGATGGTGCAGTCTAGCA 
               
               
                   
               
               
                 TCAGCGAGTACAACAGGTTTGTGGGCGGCTATTCCACCGAGGACGGCACA 
               
               
                   
               
               
                 AAGCACCAGGGCATCAACGAGTGGATCAATATCTACAGACAGAGGAATAA 
               
               
                   
               
               
                 GGAGATGCGCCTGCCTGGCCTGGTGTTCCTGCACAAGCAGATCCTGGCCA 
               
               
                   
               
               
                 AGGTGGACTCCTCTAGCTTCATCAGCGATACACTGGAGAACGACGATCAG 
               
               
                   
               
               
                 GTGTTTTGCGTGCTGAGACAGTTCAGGAAGCTGTTTTGGAATACCGTGTC 
               
               
                   
               
               
                 CTCTAAGGAGGACGATGCCGCCTCCCTGAAGGACCTGTTCTGTGGCCTGT 
               
               
                   
               
               
                 CTGGCTATGACCCTGAGGCCATCTACGTGAGCGATGCCCACCTGGCCACA 
               
               
                   
               
               
                 ATCTCCAAGAACATCTTTGACAGATGGAATTACATCTCCGATGCCATCAG 
               
               
                   
               
               
                 GCGCAAGACCGAGGTGCTGATGCCACGGAAGAAGGAGAGCGTGGAGAGAT 
               
               
                   
               
               
                 ATGCCGAGAAGATCTCCAAGCAGATCAAGAAGAGACAGTCTTACAGCCTG 
               
               
                   
               
               
                 GCCGAGCTGGACGATCTGCTGGCCCACTATAGCGAGGAGTCCCTGCCCGC 
               
               
                   
               
               
                 AGGCTTCTCTCTGCTGAGCTACTTTACATCTCTGGGCGGCCAGAAGTATC 
               
               
                   
               
               
                 TGGTGAGCGACGGCGAAGTGATCCTGTACGAGGAGGGCAGCAACATCTGG 
               
               
                   
               
               
                 GACGAGGTGCTGATCGCCTTCAGGGATCTGCAGGTCATCCTGGACAAGGA 
               
               
                   
               
               
                 CTTCACCGAGAAGAAGCTGGGCAAGGATGAGGAGGCCGTGTCTGTGATCA 
               
               
                   
               
               
                 AGAAGGCCCTGGACAGCGCCCTGCGCCTGCGGAAGTTCTTTGATCTGCTG 
               
               
                   
               
               
                 TCCGGCACAGGCGCAGAGATCAGGAGAGACAGCTCCTTCTATGCCCTGTA 
               
               
                   
               
               
                 TACCGACCGGATGGATAAGCTGAAGGGCCTGCTGAAGATGTATGATAAGG 
               
               
                   
               
               
                 TGAGAAACTACCTGACCAAGAAGCCTTATTCCATCGAGAAGTTCAAGCTG 
               
               
                   
               
               
                 CACTTTGACAACCCATCCCTGCTGTCTGGCTGGGATAAGAATAAGGAGCT 
               
               
                   
               
               
                 GAACAATCTGTCTGTGATCTTCCGGCAGAACGGCTACTATTACCTGGGCA 
               
               
                   
               
               
                 TCATGACACCCAAGGGCAAGAATCTGTTCAAGACCCTGCCTAAGCTGGGC 
               
               
                   
               
               
                 GCCGAGGAGATGTTTTATGAGAAGATGGAGTACAAGCAGATCGCCGAGCC 
               
               
                   
               
               
                 TATGCTGATGCTGCCAAAGGTGTTCTTTCCCAAGAAAACCAAGCCAGCCT 
               
               
                   
               
               
                 TCGCCCCAGACCAGAGCGTGGTGGATATCTACAACAAGAAAACCTTCAAG 
               
               
                   
               
               
                 ACAGGCCAGAAGGGCTTTAATAAGAAGGACCTGTACCGGCTGATCGACTT 
               
               
                   
               
               
                 CTACAAGGAGGCCCTGACAGTGCACGAGTGGAAGCTGTTTAACTTCTCCT 
               
               
                   
               
               
                 TTTCTCCAACCGAGCAGTATCGGAATATCGGCGAGTTCTTTGACGAGGTG 
               
               
                   
               
               
                 AGAGAGCAGGCCTACAAGGTGTCCATGGTGAACGTGCCCGCCTCTTATAT 
               
               
                   
               
               
                 CGACGAGGCCGTGGAGAACGGCAAGCTGTATCTGTTCCAGATCTACAATA 
               
               
                   
               
               
                 AGGACTTCAGCCCCTACTCCAAGGGCATCCCTAACCTGCACACACTGTAT 
               
               
                   
               
               
                 TGGAAGGCCCTGTTCAGCGAGCAGAATCAGAGCCGGGTGTATAAGCTGTG 
               
               
                   
               
               
                 CGGAGGAGGAGAGCTGTTTTATAGAAAGGCCAGCCTGCACATGCAGGACA 
               
               
                   
               
               
                 CCACAGTGCACCCCAAGGGCATCTCTATCCACAAGAAGAACCTGAATAAG 
               
               
                   
               
               
                 AAGGGCGAGACAAGCCTGTTCAACTACGACCTGGTGAAGGATAAGAGGTT 
               
               
                   
               
               
                 TACCGAGGACAAGTTCTTTTTCCACGTGCCTATCTCTATCAACTACAAGA 
               
               
                   
               
               
                 ATAAGAAGATCACCAACGTGAATCAGATGGTGCGCGATTATATCGCCCAG 
               
               
                   
               
               
                 AACGACGATCTGCAGATCATCGGCATCGACCGCGGCGAGCGGAATCTGCT 
               
               
                   
               
               
                 GTATATCAGCCGGATCGATACAAGGGGCAACCTGCTGGAGCAGTTCAGCC 
               
               
                   
               
               
                 TGAATGTGATCGAGTCCGACAAGGGCGATCTGAGAACCGACTATCAGAAG 
               
               
                   
               
               
                 ATCCTGGGCGATCGCGAGCAGGAGCGGCTGAGGCGCCGGCAGGAGTGGAA 
               
               
                   
               
               
                 GTCTATCGAGAGCATCAAGGACCTGAAGGATGGCTACATGAGCCAGGTGG 
               
               
                   
               
               
                 TGCACAAGATCTGTAACATGGTGGTGGAGCACAAGGCCATCGTGGTGCTG 
               
               
                   
               
               
                 GAGAACCTGAATCTGAGCTTCATGAAGGGCAGGAAGAAGGTGGAGAAGTC 
               
               
                   
               
               
                 CGTGTACGAGAAGTTTGAGCGCATGCTGGTGGACAAGCTGAACTATCTGG 
               
               
                   
               
               
                 TGGTGGATAAGAAGAACCTGTCCAATGAGCCAGGAGGCCTGTATGCAGCA 
               
               
                   
               
               
                 TACCAGCTGACCAATCCACTGTTCTCTTTTGAGGAGCTGCACAGATACCC 
               
               
                   
               
               
                 CCAGAGCGGCATCCTGTTTTTCGTGGACCCATGGAACACCTCTCTGACAG 
               
               
                   
               
               
                 ATCCCAGCACAGGCTTCGTGAATCTGCTGGGCAGAATCAACTACACCAAT 
               
               
                   
               
               
                 GTGGGCGACGCCCGCAAGTTTTTCGATCGGTTTAACGCCATCAGATATGA 
               
               
                   
               
               
                 CGGCAAGGGCAATATCCTGTTCGACCTGGATCTGTCCAGATTTGATGTGA 
               
               
                   
               
               
                 GGGTGGAGACACAGAGGAAGCTGTGGACACTGACCACATTCGGCTCTCGC 
               
               
                   
               
               
                 ATCGCCAAATCCAAGAAGTCTGGCAAGTGGATGGTGGAGCGGATCGAGAA 
               
               
                   
               
               
                 CCTGAGCCTGTGCTTTCTGGAGCTGTTCGAGCAGTTTAATATCGGCTACA 
               
               
                   
               
               
                 GAGTGGAGAAGGACCTGAAGAAGGCCATCCTGAGCCAGGATAGGAAGGAG 
               
               
                   
               
               
                 TTCTATGTGCGCCTGATCTACCTGTTTAACCTGATGATGCAGATCCGGAA 
               
               
                   
               
               
                 CAGCGACGGCGAGGAGGATTATATCCTGTCTCCCGCCCTGAACGAGAAGA 
               
               
                   
               
               
                 ATCTGCAGTTCGACAGCAGGCTGATCGAGGCCAAGGATCTGCCTGTGGAC 
               
               
                   
               
               
                 GCAGATGCAAACGGAGCATACAATGTGGCCCGCAAGGGCCTGATGGTGGT 
               
               
                   
               
               
                 GCAGAGAATCAAGAGGGGCGACCACGAGTCCATCCACAGGATCGGAAGGG 
               
               
                   
               
               
                 CACAGTGGCTGAGATATGTGCAGGAGGGCATCGTGGAGAAAAGGCCGGCG 
               
               
                   
               
               
                 GCCACGAAAAAGGCCGGCCAGGCAAAAAAGAAAAAGGGATCCTACCCATA 
               
               
                   
               
               
                 CGATGTTCCAGATTACGCTTATCCCTACGACGTGCCTGATTATGCATACC 
               
               
                   
               
               
                 CATATGATGTCCCCGACTATGCCTAA 
               
             
          
         
       
     
         [0159]    Some of the non-limiting sequences shown above include a sequence such as a nuclear localization signal and/or a tag sequence (such as a HA tags). In various embodiments, a different nuclear localization signal may be present. In some embodiments, no nuclear localization signal is used. In certain embodiments no tag (e.g., no HA tag) is used. 
         [0160]    In various embodiments relating to a protein (such as a protein within a gene-editing complex) the protein may include a nuclear localization signal. For example, the protein (e.g., a Cas protein) may comprise a nuclear localization signal (NLS). Such signals are known in the art, and non-limiting examples are described in Kalderon et al., (1984) Cell 39 (3 Pt 2): 499-509; Makkerh et al., (1996)  Curr Biol.  6 (8): 1025-7; and Dingwall et al., (1991)  Trends in Biochemical Sciences  16 (12): 478-81, the contents of each of which are hereby incorporated herein by reference. Specific non-limiting examples of nuclear localization signals include GGSGPPKKKRKV (SEQ ID NO: 5), KRPAATKKAGQAKKKK (SEQ ID NO: 12), PKKKRKV (SEQ ID NO: 45), KR[PAATKKAGQA]KKKK (SEQ ID NO: 46), KR[XXXXXXXXXX]KKKK (SEQ ID NO: 47), KKXK (SEQ ID NO: 48), KRXK (SEQ ID NO: 49), KKXR (SEQ ID NO: 50), KRXR (SEQ ID NO: 51), AVKRPAATKKAGQAKKKKLD (SEQ ID NO: 52), MSRRRKANPTKLSENAKKLAKEVEN (SEQ ID NO: 53), PAAKRVKLD (SEQ ID NO: 54), and KLKIKRPVK (SEQ ID NO: 55). 
       General Definitions and General Techniques 
       [0161]    Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in cell culture, molecular genetics, and biochemistry). 
         [0162]    As used herein, the term “about” in the context of a numerical value or range means±10% of the numerical value or range recited or claimed, unless the context requires a more limited range. 
         [0163]    In the descriptions above and in the claims, phrases such as “at least one of” or “one or more of” may occur followed by a conjunctive list of elements or features. The term “and/or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features. For example, the phrases “at least one of A and B;” “one or more of A and B;” and “A and/or B” are each intended to mean “A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more items. For example, the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.” In addition, use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that an unrecited feature or element is also permissible. 
         [0164]    The terms “plasma membrane” and “cell membrane” are used interchangeably herein, and refer to the semipermeable membrane that separates the interior of a cell from the environment outside the cell. 
         [0165]    As used herein, an “expression vector” is a DNA or RNA vector that is capable of effecting expression of one or more polynucleotides. Preferably, the expression vector is also capable of replicating within the host cell. Expression vectors can be either prokaryotic or eukaryotic, and are typically plasmids. Expression vectors of the present invention include any vectors that function (i.e., direct gene expression) in host cells of the present invention, including in one of the prokaryotic or eukaryotic cells described herein, e.g., protozoan, algal, fungi, yeast, plant, animal, vertebrate, invertebrate, arthropod, mammalian, rodent, primate, or human cells. Expression vectors of the present invention contain regulatory sequences such as transcription control sequences, translation control sequences, origins of replication, and other regulatory sequences that are compatible with the host cell and that control the expression of a polynucleotide. In particular, expression vectors of the present invention include transcription control sequences. Transcription control sequences are sequences which control the initiation, elongation, and termination of transcription. Particularly important transcription control sequences are those which control transcription initiation such as promoter, enhancer, operator and repressor sequences. Suitable transcription control sequences include any transcription control sequence that can function in at least one of the cells of the present invention. A variety of such transcription control sequences are known to those skilled in the art. In preferred embodiments, the methods do not comprise the use of viral vectors such as adenoviruses to deliver nucleic acid molecules or constructs. 
         [0166]    It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “0.2-5 mg” is a disclosure of 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg etc. up to 5.0 mg. 
         [0167]    Unless otherwise implicitly or explicitly contradicted by the context in which it is used, references to cell “squeeze” “squeezing” “deformation” and the like refer to a process used to deliver macromolecules directly into the cytosol of cells with minimal cytotoxicity. The principle underlying this approach is temporary membrane disruption by rapid mechanical deformation, or squeezing, of the target cell, which permits the uptake by diffusion of macromolecules in the fluid medium and is followed by cell membrane repair (see, e.g., U.S. Patent Application Publication No. 2014/0287509, published Sep. 25, 2014; PCT International Patent Application No. PCT/US2015/058489, filed Oct. 30, 2015; and PCT International Patent Application No. PCT/2015/060689, filed Nov. 13, 2015, the entire contents of each of which are incorporated herein by reference). 
         [0168]    As used herein, “gRNA” refers to a CRISPR-Cas system guide RNA. 
         [0169]    As used herein the term “protein complex” refers to a composite unit arising from the specific binding of a protein with a binding partner, wherein said binding partner can be one or more proteins, one or more nucleic acids, or a combination of one or more proteins and one or more nucleic acids, and the like, to form said protein complex. Protein complexes may be protein-protein complexes, protein-nucleic acid complexes, and the like. In certain embodiments, a protein complex may comprise protein-protein interactions, e.g. interactions between different proteins, or dimers, trimers, tetramers or higher oligomers of the same protein. Interactions between subunits of protein complexes (e.g., in protein-protein complexes or protein-nucleic acid complexes that comprise more than one protein) or between proteins and nucleic acids (e.g., in protein-nucleic acid complexes) are usually non-binding interactions, such as those interactions caused by hydrogen bridges, pi electron systems such as (optionally conjugated) C—C double bonds or aromatic rings, e.g. phenyl, and heteroaromatic rings, e.g. pyrrole, imidazole, indole, pyrimidine or purine rings, and interactions between metal atoms and oxygen, nitrogen or sulfur atoms, but may also be weak, and in particular reversible, covalent binding interactions, e.g. sulfur-sulfur bridges. 
         [0170]    A “protein-protein complex” means a composite unit that is a combination of two or more proteins formed by interaction between the proteins. Typically but not necessarily, a “protein complex” is formed by the binding of two or more proteins together through specific non-covalent binding affinities. However, covalent bonds may also be present between the interacting partners. For instance, the two interacting partners can be covalently crosslinked so that the protein complex becomes more stable. 
         [0171]    Similarly, a “protein-nucleic acid complex” means a composite unit that is a combination of at least one protein and at least one nucleic acid formed by interactions that include an interaction between a protein and a nucleic acid. Typically but not necessarily, a “protein-nucleic acid complex” is formed by the binding of a protein and a nucleic acid through non-covalent binding affinities. 
         [0172]    In various embodiments, a gene-editing complex is a protein-nucleic acid complex, such as a RNP. A non-limiting example of an RNP is a CRISPR-Cas RNP comprising a Cas protein and a gRNA. 
         [0173]    Methods and devices described herein deliver an intact and functional gene-editing complex into cells. The components of the gene-editing complex do not disassociate during delivery and remain functional after delivery into the cell. 
         [0174]    Various assays are available to determine whether an intact and functional gene-editing complex has been delivered to a cell. For example, the detection of gene editing by the gene-editing complex may be used to indicate that an intact and functional gene-editing complex was delivered into a cell. Alternatively or in addition, cells to which the gene-editing complex has been delivered may be lysed using non-denaturing conditions (such as a non-denaturing buffer or a French press), and the lysate may be analyzed using a non-denaturing gel to determine whether the gene-editing complex was intact within the cells. Alternatively or in addition, the cells may be lysed using non-denaturing conditions and then immunoprecipitation may be used to isolate the gene-editing complex from the lysate (i.e., to verify that one component of the complex can be co-isolated with another using immunoprecipitation). The isolated gene-editing complex can be assayed before or after delivery to a cell using a non-denaturing gel or a denaturing assay (such as sodium dodecyl sulfate polyacrylamide gel electrophoresis) to determine whether the gene-editing complex was present in a pre-delivery/pre-cell squeeze buffer as well as whether the complex is present after microfluidic/squeeze processing and found intact and/or functional in the treated cells. In some embodiments relating to CRISPR-Cas9 RNPs, a band on a non-denaturing gel of about 145, 150, 155, or 145-160 kDa may indicate that the RNP was delivered as a complete and functional gene-editing complex into the cell. 
         [0175]    As used herein, device dimensions are denoted by a series of numbers indicating length, width, and optionally number of constrictions (e.g., 30 μm-6 m×5 denotes a device with a 30 μm length, 6 μm width, and 5 constrictions). 
       Exemplary Embodiments 
       [0176]    Aspects of the present subject matter provide a method for delivering a protein and a nucleic acid into a cell, the method comprising: providing a cell in a solution; passing the solution through a microfluidic channel that includes a cell-deforming constriction; passing the cell through the constriction such that a pressure is applied to the cell causing perturbations of the cell large enough for the protein and the nucleic acid to pass through; and contacting the cell with the protein and the nucleic acid before, during, and/or after the cell passes through the constriction. 
         [0177]    In some embodiments, said solution comprises the protein and the nucleic acid before, during, and/or after the cell passes through the constriction. 
         [0178]    In some embodiments, the protein and the nucleic acid form a protein-nucleic acid complex. 
         [0179]    In some embodiments, the protein and the nucleic acid are the components of the protein-nucleic acid complex but are not complexed when delivered to the cell. 
         [0180]    In some embodiments, the protein and the nucleic acid form a protein-nucleic acid complex after delivery into the cell. 
         [0181]    In some embodiments, the protein and the nucleic acid form a protein-nucleic acid complex before delivery into the cell. 
         [0182]    In some embodiments, the protein and the nucleic acid comprise gene editing components. 
         [0183]    In some embodiments, said protein-nucleic acid complex comprises a ribonucleoprotein (RNP). 
         [0184]    In some embodiments, (a) the protein is a Cas protein or a Cpf1 protein; and (b) the nucleic acid is a single guide RNA (sgRNA) or a CRISPR RNA (crRNA) and a trans-activating crRNA (tracrRNA). 
         [0185]    In some embodiments, the complex is a RNP comprising a Cas protein or a Cpf1 protein and a sgRNA, wherein the Cas protein or the Cpf1 protein and the sgRNA were complexed using about a 0.5, 2.0, 2.5, or 3.0 molar excess of the Cas protein or Cpf1 protein. 
         [0186]    In some embodiments, the Cas protein comprises a Cas9 protein. 
         [0187]    In some embodiments, said protein-nucleic acid complex comprises a first RNP and a second RNP. 
         [0188]    In some embodiments, the first RNP and the second RNP are both nickases. 
         [0189]    In some embodiments, the first RNP nicks a target sequence different from the target sequence of the second RNP. 
         [0190]    In some embodiments, said protein-nucleic acid complex comprises a TALEN protein, Zinc finger nuclease, mega nuclease, or Cre recombinase. 
         [0191]    In some embodiments, the nucleic acid comprises an mRNA encoding a TALEN protein, a Zinc finger nuclease, a mega nuclease, or a Cre recombinase 
         [0192]    In some embodiments, said protein-nucleic acid complex comprises (a) a nucleic acid molecule that is complexed with a protein via electrostatic attraction; (b) a nucleic acid molecule wrapped around a protein; (c) DNA and a histone; (d) a ribonucleoprotein (RNP); (e) a ribosome, an enzyme telomerase, a vault ribonucleoprotein, RNase P, hnRNP, or a small nuclear RNP (snRNP); or (f) a chromosome comprising a protein. 
         [0193]    In some embodiments, the solution further comprises donor DNA. 
         [0194]    In some embodiments, the solution further comprises donor DNA before, during, and/or after the cell passes through the constriction. 
         [0195]    In some embodiments, said cell comprises a mammalian cell. 
         [0196]    In some embodiments, said cell comprises a human cell. 
         [0197]    In some embodiments, the diameter of the constriction is selected to induce temporary perturbations of the cell membrane large enough for the protein and the nucleic acid to pass through. 
         [0198]    In some embodiments, a diameter of the constriction is about 20-99% of the diameter of the cell. 
         [0199]    In some embodiments, a diameter of the constriction is about 60% of the diameter of the cell. 
         [0200]    In some embodiments, the microfluidic channel is one of a plurality of parallel microfluidic channels in the microfluidic system. 
         [0201]    In some embodiments, the plurality of parallel microfluidic channels comprises at least about 2, 5, 10, 20, 25, 30, 40, 45, 50, 75, 100, 500, 1,000, or 2-1,000 microfluidic channels. 
         [0202]    In some embodiments, the cell is a plurality of cells, and each cell is passed through one of a plurality of parallel microfluidic channels, and wherein each microfluidic channel of the plurality of parallel microfluidic channels includes a cell-deforming constriction. 
         [0203]    In some embodiments, (a) the diameter of the constriction is about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 2-10 μm, or 10-20 μm; (b) the length of the constriction is about 10, 15, 20, 24, 30, 40, 50, 60, 70, 80, 90, 100, 10-40, 10-50, 10-60, or 10-100 μm; (c) a pressure of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 10-100 psi is used to pass the solution through the microfluidic channel; (d) the cell passes through the microfluidic channel at a speed of about 300, 400, 500, 600, 700, 800, 900, 100-300, 200-700, 250-400, 100-1000 mm/s, 1-1000 mm/s, 1 m/s, 2 m/s, 3 m/s, 4 m/s, 5 m/s, 6 m/s, 7 m/s, 8 m/s, 9 m/s, 10 m/s, 0.01-5 m/s, 5-10 m/s, or 0.01-10 m/s; (e) said microfluidic channel comprises multiple cell-deforming constrictions in series; (f) said microfluidic channel comprises a single cell-deforming constriction; (g) the perturbations of the cell membrane include a maximum diameter of about 1-20, 1-600, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 600 nm; and/or (h) perturbations of the cell membrane having a maximum diameter of about 1-20, 1-600, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 600 nm persist on the cell membrane for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 1-10 minutes. 
         [0204]    In some embodiments, (a) the expression of a target gene in the cell is reduced by at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 80, 85, 90, 95, or 99% or more; or (b) the cell is a plurality of cells and the expression of a target gene in the plurality of cells is reduced by at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 80, 85, 90, 95, or 99% or more, after the protein and the nucleic acid are delivered to the cell. 
         [0205]    In some embodiments, (a) the expression of a target gene in the cell is reduced by at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 80, 85, 90, 95, or 99% or more; or (b) the cell is a plurality of cells and the expression of a target gene in the plurality of cells is reduced by at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 80, 85, 90, 95, or 99% or more, about 1, 2, 5, 12, 24, 1-12, 6-12, 6-18, 12-24, or 1-24 hours after the protein and the nucleic acid are delivered to the cell. 
         [0206]    In some embodiments, (a) the expression of a target gene in the cell is increased by at least about 5, 10, 25, 50, 75, 100, 250, 500% or more; or (b) the cell is a plurality of cells and the expression of a target gene in the plurality of cells is increased by at least about 5, 10, 25, 50, 75, 100, 250, 500% or more, after the protein and the nucleic acid are delivered to the cell. 
         [0207]    In some embodiments, (a) the expression of a target gene in the cell is increased by at least about 5, 10, 25, 50, 75, 100, 250, 500% or more; or (b) the cell is a plurality of cells and the expression of a target gene in the plurality of cells is increased by at least about 5, 10, 25, 50, 75, 100, 250, 500% or more, about 1, 2, 5, 12, 24, 1-12, 6-12, 6-18, 12-24, or 1-24 hours after the protein and the nucleic acid are delivered to the cell. 
         [0208]    Aspects of the present subject matter provide a device for delivering a protein-nucleic acid complex to a cell, comprising at least one microfluidic channel, wherein said channel comprises a constriction length of about 30 μm and a constriction width of about 4 μm. 
         [0209]    Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. 
       Example 1: Editing of the B2M Locus in Primary Human T Cells Using CellSqueeze (SQZ) to Deliver CRISPR/Cas9 Gene Editing Complex 
       [0210]    A series of experiments have been undertaken in unstimulated human T cells to demonstrate the ability of the SQZ platform to deliver Cas9 ribonucleoproteins (RNPs; recombinant Cas9 protein complexed with a single-guide RNA) and accomplish efficient genome editing of a model locus, the β 2  microglobulin component of MHC class 1 (B2M). 
         [0211]    Delivery of Cas9 RNP to Unstimulated Human T Cells 
         [0212]    Fresh PBMCs were isolated from human blood using a standard Ficoll gradient. Next, T cells were negatively selected (Human T cell enrichment kit (StemCell Technologies)) counted, washed and resuspended at 10-20×10 6  cells/mL in OptiMEM for delivery. Ten μg of recombinant CAS9 (PNA Bio) was pre-complexed with a 2.5 molar excess of unmodified gRNA (PNA Bio) designed to specifically target the B2M locus. Recombinant CAS9 is reconstituted to a solution with a final concentration of 20 mM Hepes, 150 mM KCl, 1% sucrose. gRNA is added directly to the CAS9 solution and incubated on ice for 20 minutes to form the complex. The complex is added directly to resuspended cells. RNP complexes were incubated on ice 20 minutes prior to SQZ-mediated delivery. The RNP (2.2 uM) was co-delivered with a 3 kD-Cascade Blue Dextran (0.15 mg/mL) used as a proxy for delivery efficiency. Two different chips, 10-4 and 30-4 were used to deliver the complex at a pressures of 60 and 90 psi. The chips have constrictions of the same width (4 microns) but have two different constriction lengths (30 vs. 10 microns). 
         [0213]    At 48 hours post-delivery, a FACS based readout was used to determine B2M protein levels. Reduced B2M expression was used as a measure of functional editing. Two controls were used; 1) T cells incubated with the RNP complex at room temperature for the same time as the delivery process using the Cell Squeeze process (endocytosis control; “endo control”), and 2) T cells squeezed with Cas9 protein but no gRNA. Plots of B2M expression vs. delivered dextran are shown ( FIG. 4 ) for the four different cell populations. B2M expression on the Cas9 control was not significantly different than the endocytosis control. The delivery of the RNP using the 30-4 chip at 90 psi resulted in a 54.4% reduction in B2M expression as compared to the endo control whereas the 10-4 chip at 90 psi resulted in a 25.2% reduction in B2M expression. The longer constriction chip resulted in more delivery of the RNP complex and a larger reduction in B2M expression. 
         [0214]    Dextran delivery was used to define low, mid and high delivered populations. The differences in efficiency of B2M knockdown for these specific populations was then determined using the mean fluorescence intensity (MFI) of B2M staining. For the 10-4 chip, the MFI of the highly delivered population was 18,637 versus 71,173 for the mid delivered populations and 83,676 for the low or non-delivered populations. This nearly 5-fold intensity drop in B2M staining for the high delivered populations demonstrates the degree to which delivery influences RNP activity. Similarly, for the 30-4 chip, the MFI of the highly delivered population was 16,460 versus 44,207 for the mid delivered populations and 54,159 for the low delivered population. These data demonstrated the importance that the cell squeezing delivery system of gene editing complexes to the cytosol of a cell has on editing efficiency, even within a single population. 
         [0215]    To confirm the FACS readout, a second, sequence based analysis, was also employed in which DNA was extracted and amplified using primers flanking the target region thereby generating an amplicon of the edited region for Next Generation Sequencing (NGS). Sequencing results were analyzed using a simple algorithm designed to detect CRISPR variants from NGS reads. As expected, the sequence-based readout showed higher editing efficiencies. Indeed, some of the indels identified in sequencing still resulted in a functional, full length protein (i.e. single base substitutions that did not change the resultant amino acid). 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 
               
             
             
               
                   
               
               
                 Comparison of FACS- and Sequence-based readouts from 10-4 editing 
               
               
                 experiment. 
               
             
          
           
               
                   
                 Endo 
                 Cas9 
                 RNP 
               
               
                   
                   
               
             
          
           
               
                   
                 FACS 
                 0.3 
                 8.15 
                 20.4 
               
               
                   
                 Sequencing 
                 3.87 
                 3.04 
                 27.18 
               
               
                   
                   
               
             
          
         
       
     
         [0216]    These data demonstrated successful editing ability of the RNP complex when delivered by the Cell Squeeze platform. 
         [0217]    Effect of RNP Complex Amount on Editing Efficiency 
         [0218]    RNP complex was delivered to unstimulated human T cells using the 30-4 chip and at two different RNP amounts: 1) the standard 1×RNP complex (10 ug Cas9, 2.5 molar excess of gRNA) and, 2) 0.1× the standard RNP complex amount. At 48 hours post-delivery, a FACS based readout was used to determine B2M protein levels. Reduced B2M expression was used as a measure of functional editing. Plots of B2M expression vs. delivered dextran are shown below for the four different cell populations. Two controls were used; 1) T cells incubated in 1×RNP complex at room temperature for the same time as the delivery process using the Cell Squeeze process (endocytosis control), and 2) T cells squeezed with Cas9 protein but no gRNA ( FIG. 5 ). 
         [0219]    B2M expression on the Cas9 control (Cas9 protein with no gRNA) is not significantly different than the endocytosis control. The lower amount of the RNP complex (0.1×RNP) resulted in a 20.7% reduction of B2M positive cells as compared to the 55.4% reduction in B2M positive cells at the higher amount of RNP complex (1×RNP complex (10 ug CAS9, 2.5 molar excess of gRNA)). This experiment demonstrates a dose-dependent response directly related to the delivery of the RNP. 
       Other Embodiments 
       [0220]    Cited references are incorporated herein by reference. To the extent that any of the incorporated material is inconsistent with the present disclosure, the present disclosure shall control. Furthermore, to the extent necessary, material incorporated by reference herein should be disregarded if necessary to preserve the validity of the claims. 
         [0221]    Further, while the description above refers to the invention, the description may include more than one invention. 
         [0222]    The subject matter described herein can be embodied in systems, apparatus, methods, and/or articles depending on the desired configuration. The implementations set forth in the foregoing description do not represent all implementations consistent with the subject matter described herein. Instead, they are merely some examples consistent with aspects related to the described subject matter. Although a few variations have been described in detail above, other modifications or additions are possible. In particular, further features and/or variations can be provided in addition to those set forth herein. For example, the implementations described above can be directed to various combinations and subcombinations of the disclosed features and/or combinations and subcombinations of several further features disclosed above. In addition, the logic flows depicted in the accompanying figures and/or described herein do not necessarily require the particular order shown, or sequential order, to achieve desirable results. Other implementations may be within the scope of the following claims.