Patent Publication Number: US-2004044405-A1

Title: Vascular stent or graft coated or impregnated with protein tyrosine kinase inhibitors and method of using same

Description:
RELATED APPLICATION  
     [0001] Priority is hereby claimed to provisional application Serial No. 60/343,732, filed Oct. 25, 2001, which provisional application is incorporated herein by reference. 
    
    
     
       FIELD OF THE INVENTION  
       [0002] The invention is directed to methods of selectively inhibiting the proliferation of vascular smooth muscle cells (VSMCs) following vascular injury or surgical interventions such as percutaneous revascularization, without inhibiting the prolifration of endothelial cells. Specifically, the invention is directed to the use of protein tyrosine kinase inhibitors, preferably those that inhibit the Bcr-Abl tyrosine kinase, and most preferably 4-{(4-methyl-1-piperazinyl)methyl}-N-{4-methyl-3-{{4-(3-pyrimidinyl}amino}-phenyl}benzamide methane sulfonate, coated onto vascular stents, native grafts, or prosthetic vascular grafts, to prevent the proliferation of VSMCs selectively, while not adversely affecting the proliferation of endothelial cells.  
       BACKGROUND  
       [0003] Arteriosclerosis is a class of diseases characterized by the thickening and hardening of the arterial walls of blood vessels. Although all blood vessels are susceptible to this serious degenerative condition, the aorta and the coronary arteries serving the heart are most often affected. Arteriosclerosis is of profound clinical importance since it can increase the risk of heart attacks, myocardial infarctions, strokes, and aneurysms.  
       [0004] The traditional treatment for arteriosclerotic vessels currently includes vascular recanalization procedures for less-serious blockages and coronary bypass surgery for major blockages. Where possible, vascular recanalization is much preferred to coronary bypass because it is a far less invasive procedure. Vascular recanalization procedures involve using intravascular devices threaded through blood vessels to the obstructed site, including for example, percutaneous transluminal coronary balloon angioplasty (PTCA), also known as balloon angioplasty. Balloon angioplasty uses a catheter with a balloon tightly packed onto its tip. When the catheter reaches the obstruction, the balloon is inflated, and the atherosclerotic plaques are compressed against the vessel wall. A serious shortcoming of this and other intravascular procedures, however, is that in a significant number of treated individuals, some or all of the treated vessels restenose (that is, the vessels again narrow). This generally occurs in a relatively brief time period, roughly less than six months, after treatment. The restenosis is thought to be due in part to mechanical injury to the walls of the blood vessels caused by the balloon catheter or other intravascular device.  
       [0005] The walls of most blood vessels are composed of three distinct layers, or tunics, surrounding a central tubular opening, the vessel lumen. The innermost layer that lines the vessel lumen is called the tunica intima. The middle layer, the tunica media, consists mostly of circularly arranged smooth muscle cells and connective tissue fibers. In a non-injured vessel, the smooth muscle cells are generally not actively dividing. The outmost layer of the blood vessel wall, the tunica adventitia, is composed largely of collagen fibers that protect inner layers and gives the blood vessel structural integrity. Mechanical injury, resulting in damage to the tunica intima, initiates a cascade of events, including the release of chemicals such as platelet-derived growth factors (PDGF). This cascade prompts the migration and proliferation of vascular smooth muscle cells (VSMCs) at the site of injury. The accumulation of VSMCs at the site of injury narrows the diameter of the vessel lumen, thereby again putting the patient in danger of having a heart attack, stroke, etc.  
       [0006] Several methods for inhibiting smooth muscle cell proliferation following the use of an intravascular device have been reported in the patent literature. These include administering anti-proliferative agents such as cell cycle inhibitors and anti-coagulant agents (either by local or systemic delivery systems). Delivery of these agents systemically, however, has required dosages that cause unacceptable side-effects or are prohibitively expensive. Local delivery of agents, for example heparin, as described in U.S. Pat. No. 4,824,436, has proven ineffective in inhibiting restenosis due in part to inadequate residence time of the active agent at the site of injury. Cell cycle inhibitors such as taxol, which do not react covalently and therefore require prolonged residence time for effectiveness, suffer from similar problems. Moreover, prolonging residence times to increase the effectiveness of such treatments is also likely to present increased risks of toxicity.  
       [0007] Other methods reported for inhibiting VSMC proliferation involve local delivery of active agents contained in a sustained-release formulation. For example, U.S. Pat. No. 5,171,217 describes agents contained within a physiologically compatible, biodegradable polymeric microparticle. This formulation is delivered locally to the site of injury such that the agents are released from the arterial wall for 72 hours or more. In contrast, U.S. Pat. No. 6,281,225 describes the local, but non-sustained-release administration of DNA alkylating agents to prevent VSMC proliferation.  
       [0008] Another method for inhibiting smooth muscle cell proliferation involves administering photochemically-activated agents by local delivery systems. For example, U.S. Pat. No. 5,354,774 describes locally delivering 8-methoxypsoralen to the site of injury and then activating a photodynamic reaction using a visible light source.  
       [0009] Yet another approach to prevent proliferation of VSMCs is the use of radiation-emitting catheters or guide wires. These radioactive devices cause damage to nucleic acid, thus inhibiting replication and thereby inhibiting smooth muscle cell proliferation.  
       [0010] All of the above-described methods suffer from certain drawbacks. For example, sustained release formulations require an added level of complexity, namely incorporation of the agent on or within a sustained release formulation. Photodynamic therapy requires both local delivery of the photo-active agent and the use of a complex intravascular light source. Delivery of a radiation dose requires the presence of a radiologist and presents exposure hazards to the attending personnel, as well as material storage, handling, and disposal complications.  
       [0011] Treated coronary stents now on the market or in clinical trials also suffer from the distinct drawback that they inhibit the proliferation of endothelial cells. This contributes to thrombosis in the vicinity of deployed stent. Thrombosis has been observed in human clinical trials when using stents coated with either taxol or rapamycin. To prevent such thrombosis, the clinical patients have had to undergo a two- to three-month duration anti-coagulation treatment.  
       [0012] A need therefore exists for safe, simple, and straightforward method for inhibiting VSMC proliferation at a site of injury following vascular recanalization procedures or other vascular injury, without inhibiting the proliferation of endothelial cells. The ideal solution should be non-radioactive and require little or no retraining of medical personnel to implement.  
       [0013] Cellular signaling has become a major research theme in biology and medicine over the past twenty years. The complex pathways and protein components in signal transduction are emerging only slowly, but with increasing clarity. Over the last 15 years, the protein tyrosine kinases have been identified as key players in cellular regulation. They are involved in immune, endocrine, and nervous system physiology and pathology and thought to be important in the development of many cancers, most notably chronic myeloid leukemia. As such they serve as drug targets for many different diseases. A host of protein tyrosine kinases are known in the art. The attached Sequence List includes a non-exclusive sampling of the amino acid sequences of a number of such kinases.  
       [0014] As used herein, the term protein tyrosine kinases (PTKs) refers to any and all enzymes falling within the enzyme classification EC 2.1.7.112, without limitation. See the Sequence List, attached hereto, for various examples of PTKs. These enzymes catalyze the transfer of the gamma-phosphoryl group from ATP to the tyrosine hydroxyl moiety of a protein substrate. This family of kinases shares amino acid sequence homology with the serine/threonine kinase family. Although the number of tyrosine kinases being discovered is growing exponentially, molecular details pertaining to their substrate recognition, catalytic mechanism, and intra- and intermolecular regulation are still being elucidated.  
       [0015] As described in full below, the present inventors have found that inhibiting the action of PTKs selectively inhibits the proliferation of VSMCs. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0016]FIG. 1 is a graph depicting porcine coronary vascular smooth muscle cell proliferation following stimulation with platelet-derived growth factor (PDGF) in the presence of increasing concentrations of STI-571.  
     [0017]FIG. 2 is a graph depicting porcine aortic endothelial cell proliferation following stimulation with vascular endothelial growth factor (VEGF) in the presence of increasing concentrations of STI-571.  
     [0018]FIG. 3 is a graph depicting inhibition of proliferation of human coronary artery vascular smooth muscle cells (hCASMC) by increasing concentrations of STI-571 (“Glivec”). Cells were counted after stimulation with 10% fetal bovine serum (FBS) for 48 hours, and data for each experiment was normalized to positive control wells containing FBS and no STI-571 (“Glivec”). Each point represents 18 to 21 wells from eight separate experiments, and is presented as the mean +/− the standard deviation.  
     [0019]FIG. 4 is a graph depicting inhibition of DNA synthesis in human coronary artery vascular smooth muscle cells (HCAVSMC) by STI-571 (“Glivec”). DNA synthesis was assayed by incorporation of BrdU after stimulation of coronary artery vascular smooth muscle cells by 10% FBS for 48 hours in the presence or absence (positive control) of STI-571 (“Glivec”). Data points represent 14 to 28 wells from two separate experiments, and are presented as the mean +/− the standard deviation.  
     [0020]FIG. 5 is a graph depicting inhibition of migration of human coronary artery vascular smooth muscle cells in response to STI-571 (“Glivec”). Migration was assayed by counting cells that migrated through a porous membrane (20 μm diameter pores) in 24 hours in response to stimulation with platelet-derived growth factor (PDGF-pp). Data bars represent six membranes, and are presented as means normalized to control membranes (no STI-571) +/− the standard deviation.  
     [0021]FIG. 6 is a graph depicting the lack of any effect of STI-571 (“Glivec”) on the proliferation of human coronary artery endothelial cells (hCAEC). 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
     [0022] Abbreviations and Definitions:  
     [0023] The following abbreviations and definitions are used throughout the specification and claims. Terms not specifically defined herein have their normal and accepted meaning within the field of cardiovascular medicine and/or physiology.  
     [0024] “BrdU”=5-bromo-2′-deoxy-uridine triphosphate.  
     [0025] “DME”=Dulbecco&#39;s modified Eagle&#39;s media.  
     [0026] “FBS”=fetal bovine serum.  
     [0027] “JAK-2”=Janus-activated tyrosine kinases.  
     [0028] “MAPK”=mitogen-activated protein kinases.  
     [0029] “PDGF”=platelet-derived growth factor.  
     [0030] “Pharmaceutically-suitable salt”=any acid or base addition salt whose counter-ions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base or free acid PTK inhibitor are not vitiated by side effects ascribable to the counter-ions. A host of pharmaceutically-suitable salts are well known in the pharmaceutical field. For active ingredients that are bases, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically-suitable salt by ion exchange procedures. Pharmaceutically-suitable acid addition salts include, without limitation, those derived from mineral acids and organic acids, explicitly including hydrohalides, e.g., hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates, quinates, and the like. In analogous fashion, for active ingredients that are acids, pharmaceutically-suitable base addition salts may be used. Base addition salts include, without limitation, those derived from alkali or alkaline earth metal bases or conventional organic bases, such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, and the like.  
     [0031] “PTCA”=percutaneous transluminal coronary balloon angioplasty.  
     [0032] “PTK”=protein tyrosine kinase; expressly defined herein as any and all enzymes falling within the enzyme classification EC 2.1.7.112, without limitation.  
     [0033] “PTK Inhibitor”=any compound or composition that selectively inhibits the catalytic activity of one or more protein tyrosine kinase inhibitors.  
     [0034] “STI-571”=4-{(4-methyl-1-piperazinyl)methyl}-N-{4-methyl-3-{{4-(3-pyrimidinyl}amino}-phenyl}benzamide and pharmaceutically-suitable salts thereof. The methane-sulphonate salt is preferred. This compound has been given the trivial generic name “imatinib.” As used herein, the term “STI-571” designates imatinib as either a free base or any pharmaceutically-suitable salt thereof, the mesylate salt being preferred. In the United States, it is marketed commercially by Novartis AG (Basel, Switzerland) under the registered trademark “Glivec” (U.S. T.M. Registration No. 2,478,196); it is also sold elsewhere around the world under the trademark “Gleevec.” 
     [0035] “VEGF”=vascular endothelial growth factor.  
     [0036] “VSMC”=vascular smooth muscle cells.  
     [0037] Overview:  
     [0038] Treating arteriosclerosis with intravascular devices, including for example, ablative procedures, balloon catheters, or vascular stents is becoming increasingly popular as technology related to intravascular devices continues to improve. Approximately 1 million balloon angioplasty procedures alone are performed on an annual basis globally. These procedures, however, have a major shortcoming. In a significant number of cases the treated vessels re-occlude, or restenose, by six months post-treatment which requires the individual to undergo additional treatment. “Restenosis” refers to the stage at which the vessel lumen has decreased in diameter by about 50% or more as compared to the diameter of the vessel lumnen immediately following a vascular recanalization procedure.  
     [0039] The pathogenesis of restenosis is not well understood. It is believed to be due, in part, to recoil of the wall of the treated vessel. Additionally, it is hypothesized that vascular recanalization procedures used to treat diseases, such as arteriosclerosis, can cause mechanical injury at the site of recanalization. Without being limited to any particular mechanism of action, it is hypothesized that once intimal rupture occurs in the blood vessel a number of events begin to take place including the migration of monocytes to the subendothelial layer of the intima and the release of mitogenic growth factors, including, for example, platelet-derived growth factor (PDGF), macrophage-derived growth factor (MDGF), and endothelial cell-derived growth factor (EDGF). These chemicals, and in particular PDGF, apparently play a role in inducing VSMC proliferation. This in turn produces substantial quantities of intercellular substances that accumulate within the vessel lumen, thereby narrowing its diameter.  
     [0040] A first embodiment of the present invention is therefore directed to a cardiovascular stent, autologous venous/arterial graft, prosthetic venous/arterial graft, vascular catheter or vascular shunt (collectively referred to herein as a “vascular device”) that is coated with one or more compounds that selectively inhibit the proliferation of VSMCs at the point immediately adjacent to and proximal to the point of vascular injury. Specifically, the invention comprises a vascular device that has coated thereon, adsorbed thereto, impregnated therein, or covalently or ionically bonded thereto an amount of a protein tyrosine kinase (PTK) inhibitor. It is preferred that the compound specifically inhibit the Bcr-Abl tyrosine kinase, the constituitive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality found in chronic myeloid leukemia. Preferred PTK inhibitors for use in the invention are also those that specifically or non-specifically inhibit the activity of one or more PTKs selected from the group consisting of receptor tyrosine kinases for platelet-derived growth factor and stem cell factor (SCF), and c-Kit. The amount of the PTK used in conjunction with the vascular device is an amount sufficient to prevent or inhibit proliferation of vascular smooth muscle cells in an area within a blood vessel immediately adjacent to and/or proximal to the vascular device. In the preferred embodiment, the vascular device is coated with 4-{(4-methyl-1-piperazinyl)methyl}-N-{4-methyl-3-{{4-(3-pyrimidinyl}amino}-phenyl}benzamide and/or a pharmaceutically-suitable salt thereof (preferably the methane sulphonate salt).  
     [0041] A second embodiment of the invention is directed to a corresponding method for specifically preventing or inhibiting proliferation of VSMCs. Here, the method comprises coating, adsorbing, impregnating, or covalently or ionically bonding to the vascular device an amount of a PTK inhibitor; the amount being sufficient to prevent or inhibit proliferation of VSMCs in an area within a blood vessel immediately adjacent to and/or proximal to the vascular device when the device is deployed within the lumen of a blood vessel. The preferred PTK inhibitor is 4-{(4-methyl-1-piperazinyl)methyl}-N-{4-methyl-3-{{4-(3-pyrimidinyl}amino}-phenyl}benzamide and/or a pharmaceutically-suitable salt thereof.  
     [0042] A third embodiment of the invention is directed to a systemic method of preventing or inhibiting restenosis of blood vessels following vascular intervention. The method comprises systemically administering an amount of a PTK inhibitor (preferably orally), the amount administered being sufficient to prevent or inhibit proliferation of VSMCs in an area within a blood vessel immediately adjacent to and/or proximal to the area where the vascular intervention took place. Again, the preferred PTK inhibitor for use in this embodiment of the invention is 4-{(4-methyl-1-piperazinyl)methyl}-N-{4-methyl-3-{{4-(3-pyrimidinyl}amino}-phenyl}benzamide and/or a pharmaceutically-suitable salt thereof.  
     [0043] Compounds For Use in the Invention:  
     [0044] Any compound now known or discovered in the future that inhibits the action of PTKs can be used in the subject invention. Specific compounds whose anti-PTK activity has been documented, and thus can be used in the present invention, include (without limitation): pyridopyrimidines, phtalimides, chinolines, chinazolines, flavonoides, and benzothiazoles.  
     [0045] Among the most extensively studied PTK inhibitors are the tyrophostins and quinazoline derivatives. These compounds are currently under investigation as potential anti-cancer drugs. For example, tyrophostins and quinazoline have been shown to synergize with antibodies to EGFR and to established anti-cancer drugs like cisplatin to inhibit the growth of squamous cell carcinoma in vivo and to block the growth of human cancer cells over expressing HER2-ErbB2 (respectively). Tyrophostins are based on the benzylidenemalonitrile structure. Slight permutations in this structure have provided a range of potent inhibitors that selectively target EGFR, ErB-2 and v-Abl. Thus tyrophostins can be used alone or in combination with other PTK inhibitors to suppress VSMC proliferation into the lumen of blood vessels.  
     [0046] The quinazoline family of compounds includes the brominated quinazoline derivative, an early EGFR inhibitor that was found to be more than 3-fold more potent than any other tyrosine kinase inhibitor yet described (with an IC 50  of 29 pM). In addition, it has little affinity for PDGFR, FGFR, insulin receptor, the CSF receptor and Src, even at micromolar concentrations. Because of this extraordinary inhibitory activity and specificity, the quinazoline derivatives are a major focus of research aimed at developing kinase inhibitors as anti-cancer agents. Thus, these compounds can also be used in the present invention, either alone or in combination with other PTK inhibitors.  
     [0047] Another group of PTK inhibitory compounds, dianilinopthalimides, were rationally designed from the natural product PTK inhibitor staurosporine aglycon (see Appendix C). These compounds have been shown to be competitive inhibitors of ATP and to date more than 250 dianilinpthalimide derivatives have been synthesized and evaluated for their biological activity. The derivative CGP5211 has displayed a good amount of specificity towards EGFR (IC 50 =3 mM), but also shows some inhibitory activity towards PKC. This observation led to the design of CGP53353 derivative, which showed lower specificity towards PKC isozymes. Thus, dianilinopthalimides can also be used as a PTK inhibitor in the present invention.  
     [0048] A large number of other compounds are known to be PTK inhibitors. These compounds, all of which can be used in the present invention, include bryostatins, defensins, genistein, H8, herbimycin A, tyrophostins, K-252a, lavendustin A, phorbol esters, staurosporines, and suramin.  
     [0049] The preferred PTK inhibitor for use in the present invention is 4-{(4-methyl-1-piperazinyl)methyl}-N-{4-methyl-3-{{4-(3-pyrimidinyl}amino}-phenyl}benzamide and pharmaceutically-suitable salts thereof (preferably the mesyl salt):  
                 
 
     [0050] This compound, originally designated STI-571, is marketed commercially in the United States by Novartis under the trademark “Glivec.” It is approved by the U.S. Food and Drug Administration for the treatment of chronic myeloid leukemia. See EP 0 564 409 A and WO 99/03854.  
     [0051] Modes of Administration:  
     [0052] One embodiment of the invention is a method of preventing restenosis of blood vessels following a vascular injury or intervention by systemically administering one or more PTK inhibitors. The preferred route is orally. The PTK inhibitor may also be administered intravenously, intra-arterially, intramuscularly, percutaneously, parenterally, or rectally.  
     [0053] Specifically, systemic or topical administration is accomplished via a pharmaceutical composition comprising an active compound, i.e., a PTK inhibitor or a pharmaceutically-acceptable salt thereof, in combination with an acceptable carrier therefor and optionally in combination with other therapeutically-active ingredients or inactive accessory ingredients. The carrier must be pharmaceutically-acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Suitable pharmaceutical compositions include those suitable for oral, topical (i.e. intra-lumen), rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration.  
     [0054] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term “unit dosage” or “unit dose” is denoted to mean a predetermined amount of the active ingredient sufficient to be effective for treating an indicated activity or condition. Making each type of pharmaceutical composition includes the step of bringing the active compound into association with a carrier and one or more optional accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid or solid carrier and then, if necessary, shaping the product into the desired unit dosage form.  
     [0055] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, boluses or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or in liquid form, e.g., as an aqueous solution, suspension, syrup, elixir, emulsion, dispersion, or the like.  
     [0056] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active compound with any suitable carrier.  
     [0057] Formulations suitable for parenteral administration conveniently comprise a sterile preparation of the active compound in, for example, water for injection, saline, a polyethylene glycol solution and the like, which is preferably isotonic with the blood of the recipient.  
     [0058] Useful formulations also comprise concentrated solutions or solids containing the PTK-inhibitory compound, which upon dilution with an appropriate solvent give a solution suitable for parenteral administration.  
     [0059] Preparations for topical or local applications comprise aerosol sprays, lotions, gels, ointments, suppositories etc., and pharmaceutically-acceptable vehicles therefore such as water, saline, lower aliphatic alcohols, polyglycerols such as glycerol, polyethylene glycerol, esters of fatty acids, oils and fats, silicones, and other conventional topical carriers. In topical formulations, the PTK inhibitors are preferably utilized at a concentration of from about 0.1% to 5.0% by weight.  
     [0060] Compositions suitable for rectal administration, comprise a suppository, preferably bullet-shaped, containing the active ingredient and pharmaceutically-acceptable vehicles therefore such as hard fat, hydrogenated cocoglyceride, polyethylene glycol and the like. In suppository formulations, the PTK inhibitors are preferably utilized at concentrations of from about 0.1% to 10% by weight.  
     [0061] Compositions suitable for rectal administration may also comprise a rectal enema unit containing the active ingredient and pharmaceutically-acceptable vehicles therefore such as 50% aqueous ethanol or an aqueous salt solution which is physiologically compatible with the rectum or colon. The rectal enema unit consists of an applicator tip protected by an inert cover, preferably comprised of polyethylene, lubricated with a lubricant such as white petrolatum and preferably protected by a one-way valve to prevent back-flow of the dispensed formula, and of sufficient length, preferably two inches, to be inserted into the colon via the anus. In rectal formulations, the PTK inhibitors are preferably utilized at concentrations of from about 5.0-10% by weight.  
     [0062] Useful formulations also comprise concentrated solutions or solids containing the active ingredient which upon dilution with an appropriate solvent, preferably saline, give a solution suitable for rectal administration. The rectal compositions include aqueous and non-aqueous formulations which may contain conventional adjuvants such as buffers, bacteriostats, sugars, thickening agents and the like. The compositions may be presented in rectal single dose or multi-dose containers, for example, rectal enema units.  
     [0063] Preparations for topical or local surgical applications for treating a blood vessel within its lumen comprise swabs or catheters suitable for such purposes. In both topical or local surgical applications, the sterile preparations of PTK inhibitor are preferably utilized at concentrations of from about 0.1% to 5.0% by weight applied to a dressing.  
     [0064] Compositions suitable for administration by inhalation include formulations wherein the active ingredient is a solid or liquid admixed in a micronized powder having a particle size in the range of about 5 microns or less to about 500 microns or liquid formulations in a suitable diluent. These formulations are designed for rapid inhalation through the oral passage from a conventional delivery systems such as inhalers, metered-dose inhalers, nebulizers, and the like. Suitable liquid nasal compositions include conventional nasal sprays, nasal drops and the like, of aqueous solutions of the active ingredient(s).  
     [0065] In addition to the aforementioned ingredients, the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, i.e., diluents, buffers, flavoring agents, colorants, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.  
     [0066] The amount of the PTK inhibitor required to be effective for inhibiting VSMC proliferation will, of course, vary with the individual mammal being treated and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, the nature of the formulation, the mammal&#39;s body weight, surface area, age and general condition, and the particular PTK inhibitor to be administered. In general, a suitable effective dose is in the range of about 0.01 to about 500 mg/kg body weight per day of the selected PTK inhibitor. The total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary.  
     [0067] The PTK inhibitors may be administered prophylactically (in the preferred embodiment immediately post-surgery), chronically, or acutely.  
     [0068] Specifically addressing the preferred embodiment, Novartis sells STI-571 in capsules that provide the equivalent of 100 mg of the free base form of STI-571. When administered orally (the preferred route), the preferred amount of STI-571 for use in the present invention is from 100 to 800 mg daily, taken in from one to four equal doses. Considerably larger doses, up to 1,200 mg/m 2 /day, may also be given. Doses above 1,200 mg/m 2 /day are not recommended.  
     [0069] The methods of the present invention include the administration, by local delivery to a site of injury, of compounds that have the ability to inhibit PTK activity. Non-limiting examples of local delivery systems for use in the present invention include intravascular drug delivery catheters, wires, pharmacological stents and endoluminal paving.  
     [0070] In the preferred embodiment using local delivery, the compounds for use in the present invention are administered to the site of recanalization by direct intravascular deposition using intravascular catheters. Catheter systems for use in the present invention, include, for example, pressure-driven catheters, diffusion catheters and mechanical catheters. Pressure-driven catheter systems that can be used in the present invention include porous catheters; microporous catheters, for example, those made by Cordis Corporation; macroporous catheters; transport catheters, for example, those made by Cardiovascular Dynamics/Boston Scientific; channeled balloon catheters, for example, those made by Boston Scientific; and infusion sleeve catheters, for example, those made by LocalMed. See, for example, U.S. Pat. No. 5,279,565.  
     [0071] The PTK inhibitors may also be administered locally via diffusion-based catheter systems, including for example, double balloon, dispatch, hydrogel and coated stent catheters. The methods of the invention also include local administration of the compounds used in the methods of the present invention by mechanical device-based catheter systems, such as iontophoretic balloon catheters.  
     [0072] The compounds for use in the present invention may be administered by local delivery at a time proximal to the recanalization procedure or at a time after the recanalization procedure. The compounds for use in the invention may be delivered in a single dose or delivered in repeat doses.  
     [0073] The ability to deliver the PTK inhibitory compounds used in the present invention may be evaluated in vivo using known animal models, including the porcine coronary model described in the Examples. Thus, for example, a PTK inhibitor to be used in the methods of the present invention is administered by local delivery to a porcine at a site of vascular injury. The porcine is sacrificed and then examined by known cytological, histological, and other methods, including, for example, fluorescence microscopy.  
     [0074] Optimum conditions for delivery of the PTK inhibitory compounds for use in the methods of the invention may vary with the different local delivery systems used, as well as the properties and concentrations of the compounds used. Conditions may be optimized for inhibition of VSMC proliferation at the site of injury such that significant arterial blockage due to restenosis does not occur, as measured, for example, by the proliferative ability of the VSMCs, or by changes in the vascular resistance or lumen diameter. Conditions which may be optimized include, for example, the concentrations of the compounds, the delivery volume, the delivery rate, the depth of penetration of the vessel wall, the proximal inflation pressure, the amount and size of perforations and the fit of the drug delivery catheter balloon.  
     [0075] In a particularly preferred route of administration, the PTK inhibitory compound is coated or adsorbed onto a vascular stent, a prosthetic venous/arterial graft, or an autologous vascular graft. Alternatively, the PTK inhibitor may be impregnated therein, or covalently or ionically bonded thereto.  
     [0076] The preferred application of the PTK inhibitor to the stent, graft, or prosthesis is by conventional methods which are known in the art. These methods include, without limitation, dipping, steeping and spraying the article with the PTK inhibitor. Additional coating and impregnation techniques using pressure to force the coating into the substrate interstices are also contemplated. Multiple layers of the bio-active coating may be applied to the article. The stent, graft or prosthesis may first be coated with a polymeric coating to provide sustained release of the PTK inhibitor over a period of days, week, or months. Preferably, from about 1 to about 10 layers of the PTK inhibitory agent are applied to the surface of the stent, graft, or prosthesis.  
     [0077] Devices and Autologous Grafts According to the Invention:  
     [0078] As noted in the previous paragraph, one preferred route to administer the PTK inhibitory compounds is to adhere them onto a stent, autologous graft, or vascular prosthesis. In the present invention, any such vascular medical device may be used, including catheters, stents, sheets, tubes, balloons, and the like. The term “medical device” as used herein shall generically designate all such vascular medical devices, whether synthetic, semi-synthetic, or autologous tissue or material.  
     [0079] Preferably the medical device of the present invention is an implantable device such as a vascular graft, endoprosthesis or stent, that has been treated, coated, or otherwise manipulated to have coated on at least one surface a compound that inhibits PTK activity. For purposes of this invention, the term “vascular graft” is meant to include all endoprostheses which are generally introduced via catheter. In the preferred embodiment, the medical device is coated with STI-571. Other medical devices may also be coated, such as catheters which are minimally invasive. The vascular graft may include a hollow tubular body having an inner and an outer hydrophobic surface, the outer surface or both surfaces of which are coated with the PTK inhibitory compound.  
     [0080] Most preferably, the device of the present invention is a small caliber vascular stent or graft, made of metal or polymeric material (such as poly(tetrafluoroethylene)). This includes stents made of polymeric materials and coated with distinct materials, such as the polytetrafluoroethylene stent described in U.S. Pat. No. 6,306,165.  
     [0081] Vascular stents, the preferred medical device of the subject invention, are miniature mesh tubes that are implanted in the arteries to keep blocked portions open after angioplasty procedures. Working as scaffolding for the treated artery, stents are flexible yet quite strong, are generally easy (for a skilled physician) to deliver via catheter, and are readily seen on a fluoroscope. Stents are pre-mounted on balloon catheters which are used to deliver the stent to the treatment site and then expand the stent into place after the blockage is cleared.  
     [0082] Any stent now known or developed in the future can be coated with a PTK inhibitor according to the present invention. Perhaps the largest commercial supplier of vascular stents is Medtronic, 710 Medtronic Parkway, Minneapolis, Minn. Medtronic also has facilities located in Tolochenaz, Switzerland; Ontario, Canada; Causeway Bay, Hong Kong; and Gladesville, NSW, Australia. All of Medtronics stents, catheters, balloons, guide catheters, guidewires, and the like can be used in the present invention. Currently, Medtronic markets a very wide range of stents and other vascular medical devices under the “Discrete Technology,” “S7,” “S670,” “S660,” and “BeStent” trademarks.  
     [0083] Vascular stents are available from non-US-based manufacterers as well. For example, Biocompatibles Cardiovascular, of Farnham, United Kingdom, manufactures and sells a range of cardiovascular stents under the trademark “BiodivYsio.” 
     [0084] The PTK inhibitor can be adhered or coated onto the medical device, or it can be chemically bonded, either covalently or ionically to the medical device. The PTK inhibitor may be bonded directly to the medical device, or bonded via a spacer group or linker. For covalent attachment, it is preferred that a polymeric medical device, or a polymer-coated medical device be used and that the PTK inhibitor be covalently bonded to the medical device via a spacer group or linker having a chain length of from 1 to 250 atoms. For example, the spacer group may include an alkyls, alkylamines, oxygenated polyolefins, aliphatic polyesters, polyamino acids, polyamines, hydrophilic polysiloxanes, hydrophilic polysilazanes, hydrophilic acrylates, hydrophilic methacrylates, linear and lightly branched polysaccharides, and the like.  
     [0085] In yet another embodiment of the invention, there is provided a surface-modified implantable sheet material whose treated surface when exposed to the intimal layer of a blood vessel exhibits anti-VSMC proliferation activity over extended periods of time. This implantable sheet material includes a hydrophobic substrate material having adhered or bonded thereto a compound that inhibits PTK activity, the preferred compound being STI-571. The sheet can be formed into surgical mesh patches or tubes to repair vascular defects and injuries.  
     EXAMPLES  
     [0086] The following Examples are included solely to provide a more thorough disclosure of the invention claimed herein. The Examples do not limit the invention in any fashion.  
     Example 1  
     Vascular Smooth Muscle Cell Proliferation  
     [0087] Porcine coronary VSMCs were grown to subconfluence in 96-well plates with DME media containing 10% FBS at 37° C. for 3 to 5 days. After synchronization in serum-free DME media for 48 hours, the cells were stimulated with PDGF (20 ng/mL) for 24 hours, in the presence of STI-571 (0.01 to 10 M). BrdU was added to the wells for the last 5 hours of the stimulation period. The cells were subsequently dried for 24 hours at 60° C., fixed and denatured, and BrdU incorporation was determined using a calorimetric assay (ELISA) sold commercially by Roche Molecular Biochemicals (catalog no. 1,647,229), following the manufacturer&#39;s protocol. See “Cell Proliferation ELISA, BrdU (Colorimetric) Instruction Manual,” Version 3, September 2000, available from Roche Molecular Biochemicals. Briefly, the BrdU ELISA is a calorimetric immunoassay for quantification of cell proliferation. It is based on the measurement of BrdU incorporation during DNA synthesis. The calorimetric approach is a non-radioactive alternative to the equivalent  3 H-thymidine incorporation assay. See also Example 4.  
     [0088] The results of this Example are presented graphically in FIG. 1. DNA synthesis was assayed by incorporation of BrdU (in the same fashion as described in Example 4) after stimulation of the cells with platelet-derived growth factor (PDGF-ββ, 20 ng/ml) for 48 in the presence or absence (positive control) of STI-571. Each data point represents 5 to 7 wells, and is expressed as he mean +/− the standard deviation.  
     [0089] As can be seen from the figure, administration of STI-571 inhibited the proliferation of VSMCs in a dose-dependent fashion. This Example demonstrates the utility of the present invention to inhibit the proliferation of VSMCs.  
     Example 2  
     Vascular Endothelial Cell Proliferation  
     [0090] Porcine aortic vascular endothelial cells were grown to subconfluence in 96-well plates with DME media containing 10% FBS at 37° C. for 3 to 5 days. After synchronization in serum-free DME media for 48 hours, the cells were stimulated with VEGF (20 ng/mL) for 24 hours, in the presence of STI-571 (0.01 to 10 M). BrdU was added to the wells for the last 5 hours of the stimulation period. The cells were subsequently dried for 24 hours at 60° C., fixed and denatured, and BrdU incorporation determined using the Roche ELISA described in Example 1.  
     [0091] The results of this Example are presented graphically in FIG. 2. As can be seen from this figure, STI-571 had a very minimal inhibitory effect on the proliferation of aortic vascular endothelial cells.  
     [0092] Taken in conjunction with the results of Example 1, this Example demonstrates the utility of the present invention to inhibit the proliferation of VSMCs selectively, while not having an appreciable inhibitory affect on the proliferation of aortic vascular endothelial cells.  
     Example 3  
     Inhibition of Proliferation of Human Coronary Artery Vascular Smooth Muscle Cells by Increasing Concentrations of STI-571  
     [0093] This Example demonstrates that human coronary artery vascular smooth muscle cells are inhibited in a dose-dependent fashion by STI-571.  
     [0094] Cyropreserved human coronary artery vascular smooth muscle cells (CC-2583) were purchased commercially from Clonetics (now a wholly-owned subsidiary of Cambrex Bio Science Walkersville, Inc., Walkersville, Md.).  
     [0095] The cells were grown in canted-neck, filtered-cap, 25 cm 2  culture flasks, at an initial seed density of 2500 cells per cm 2 . The cells were grown in “SmGM-2”-brand smooth muscle growth medium (Cambrex, used as delivered from the manufacturer) plus 10% FBS in a humidified 37° C., 5% CO 2  incubator. Media were changed initially after 24 hours, and then every 48 hrs subsequently. The cells were passed at approximately 80% confluency (˜4-6 days). The proliferation assays were performed in 24-well culture plates.  
     [0096] On day 5, growth media were replaced with test media (growth media+STI-571), growth media (positive control, media+FBS), and serum-free media (negative control, the “SmGM-2”-brand media without any added FBS).  
     [0097] Cells were counted manually trypsinizing the cells on day 7, with each condition (3 wells) pooled into one micro-centrifuge tube. The cells were spun at 1.5×g for 10 min. and then resuspended in 60 μl trypsin-neutralizing solution. The cells were then counted on a hemacytometer in quadruplicate.  
     [0098] The results are shown in FIG. 3. In the figure, cells were counted after being stimulated with 10% FBS for 48 hours. The data for each experiment was normalized to positive control wells containing FBS and no STI-571. Each point represents 18 to 21 wells from eight separate experiments. The center of each data point is the mean at each concentration of STI-571, and the error bars are the standard deviation at each concentration level.  
     [0099] The significance of this graph is that it clearly indicates that STI-571 inhibits, in a dose-dependent fashion, the proliferation of human coronary artery vascular smooth muscle cells. Because these cells are responsible for restenosis, this graph demonstrates the effectiveness of the present invention for inhibiting such restenosis.  
     Example 4  
     Inhibition of DNA Synthesis in Human Coronary Artery Vascular Smooth Muscle Cells by STI-571  
     [0100] This example demonstrates that STI-571 inhibits DNA synthesis in human coronary artery vascular smooth muscle cells.  
     [0101] The same cells as described in Example 3 were used. Culture conditions and exposure to the various test concentrations of STI-571 were also the same as in Example 3.  
     [0102] DNA incorporation was measured using a commercially-available BrdU assay (Roche Molecular Biochemicals, catalog no. 1,647,229). The BrDu labeling solution was added on day 6, and the cells then allowed to incubate for another 24 hrs (through day 7). The label solution was then removed and the cells were dried at 60° C. for one hour. The cells were then fixed using “FixDenat” fixing solution for one hour at room temperature. The fixing solution was then removed and anti-BrdU antibody solution added to the cells. The cells were then incubated for 2 hr at 37° C.  
     [0103] The antibody solution was then removed substrate added to the wells. The plates were incubated at room temperature until sufficient color development occurred. The reactions were stopped by adding 1 M H 2 SO 4  to the wells. The absorbance was then measured at 450 nm (reference, 690 nm).  
     [0104] The results are shown in FIG. 4. Each data point represents 14 to 28 wells from two separate experiments, and are expressed as the means +/− the standard deviations. The significance of this Example is that it shows that STI-571 inhibits DNA synthesis in human coronary artery vascular smooth muscle cells. As in the previous Example, this is notable because these types of cells cause restenosis of stented vessels. By inhibiting the growth of such cells, restenosis is inhibited.  
     Example 5  
     Inhibition of Migration of Human Coronary Artery Vascular Smooth Muscle Cells by STI-571  
     [0105] This Example was performed to determine if STI-571 has any effect on the migration of human coronary vascular smooth muscle cells.  
     [0106] The cells described in Example 3 were used. The initial seed density was 4000 cells per filter (0.3 cm 2 ) in test media with 1% BSA and 20 ng/ml PDGF-ββ. The cells were then incubated in a humidified environment at 37° C., 5% CO 2  for 24 hrs. The cells on the top side of the filter were then scraped away. The cells on bottom side of the filters were then fixed with ice-cold methanol for 10 min. The filters were rinsed with PBS and then stained with HarrisAE Hematoxylin stain for 5 min. and again rinsed with PBS.  
     [0107] The cells were then counted manually under high-power magnification (400×) in quadruplicate.  
     [0108] The results are shown in FIG. 5. Data bars represent 6 membranes, and the data are presented as means normalized to control membranes (no STI-571) +/− standard deviations.  
     [0109] The significance of this Example is that it demonstrates that STI-571 inhibits the migration of human coronary vascular smooth muscle cells in a dose-dependent fashion. Because migration of these cells is a major contributor to restenosis after deployment of a stent, this Example demonstrates that the present invention can be used to inhibit this migration and hence inhibit restenosis.  
     Example 6  
     Lack of Inhibitory Effect of STI-571 on Proliferation of Human Coronary Artery Endothelial Cells  
     [0110] This Example demonstrates that the growth of human coronary artery endothelial cells are not inhibited in any fashion by STI-571.  
     [0111] Cyropreserved human coronary artery endothelial cells were purchased commercially from Clonetics (now a wholly-owned subsidiary of Cambrex Bio Science Walkersville, Inc., Walkersville, Md.).  
     [0112] The cells were grown in canted-neck, filtered-cap, 25 cm 2  culture flasks, at an initial seed density of 2500 cells per cm 2 . The cells were grown in “EGM-MV”-brand smooth muscle growth medium (Cambrex, used as delivered from the manufacturer) plus 10% FBS in a humidified 37° C., 5% CO 2  incubator. Media were changed initially after 24 hours, and then every 48 hrs subsequently. The cells were passed at approximately 80% confluency (˜4-6 days). The proliferation assays were performed in 24-well culture plates.  
     [0113] On day 5, growth media were replaced with test media (growth media +STI-571), growth media (positive control, media+FBS), and serum-free media (negative control, the “EGM-MV”-brand media without any added FBS).  
     [0114] Cells were counted manually trypsinizing the cells on day 7, with each condition (3 wells) pooled into one micro-centrifuge tube. The cells were spun at 1.5×g for 10 min. and then resuspended in 60 μl trypsin-neutralizing solution. The cells were then counted on a hemacytometer in quadruplicate.  
     [0115] The results are shown in FIG. 6. As can be seen from the figure, STI-571 did not have a significant effect on the proliferation of human coronary artery endothelial cells at any of the STI-571 concentrations tested. This Example, in conjunction with Examples 3-5, are significant because they show that STI-571 has a profound inhibitory effect on human vascular smooth muscle cells (inhibits proliferation, DNA replication, and cell migration), but does not inhibit the proliferation of endothelial cells. This is notable because the proliferation of endothelial cells around an inserted vascular stent is desirable so that the stent becomes firmly implanted within the vessel wall.  
    
     
       
         1 
         
           
             25  
           
           
             1  
             3000  
             DNA  
             Homo sapiens  
           
            1 

atggggccgg ccccgctgcc gctgctgctg ggcctcttcc tccccgcgct ctggcgtaga     60 

gctatcactg aggcaaggga agaagccaag ccttacccgc tattcccggg accttttcca    120 

gggagcctgc aaactgacca cacaccgctg ttatcccttc ctcacgccag tgggtaccag    180 

cctgccttga tgttttcacc aacccagcct ggaagaccac atacaggaaa cgtagccatt    240 

ccccaggtga cctctgtcga atcaaagccc ctaccgcctc ttgccttcaa acacacagtt    300 

ggacacataa tactttctga acataaaggt gtcaaattta attgctcaat caatgtacct    360 

aatatatacc aggacaccac aatttcttgg tggaaagatg ggaaggaatt gcttggggga    420 

catcatcgaa ttacacagtt ttatccagat gatgaagtta cagcaataat cgcttccttc    480 

agcataacca gtgtgcagcg ttcagacaat gggtcgtata tctgtaagat gaaaataaac    540 

aatgaagaga tcgtgtctga tcccatctac atcgaagtac aaggacttcc tcactttact    600 

aagcagcctg agagcatgaa tgtcaccaga aacacagcct tcaacctcac ctgtcaggct    660 

gtgggcccgc ctgagcccgt caacattttc tgggttcaaa acagtagccg tgttaacgaa    720 

cagcctgaaa aatcccccgg cgtgctaact gttccaggcc tgacggagat ggcggtcttc    780 

agttgtgagg cccacaatga caaagggctg accgtgtccc agggagtgca gatcaacatc    840 

aaagcaattc cctccccacc aactgaagtc agcatccgta acagcactgc acacagcatt    900 

ctgatctcct gggttcctgg ttttgatgga tactccccgt tcaggaattg cagcattcag    960 

gtcaaggaag ctgatccgct gggtaatggc tcagtcatga tttttaacac ctctgcctta   1020 

ccacatctgt accaaatcaa gcagctgcaa gccctggcta attacagcat tggtgtttcc   1080 

tgcatgaatg aaataggctg gtctgcagtg agcccttgga ttctagcaag cacgactgaa   1140 

ggagccccat cagtagcacc tttaaatgtc actgtgtttc tgaatgaatc tagtgataat   1200 

gtggacatca gatggatgaa gcctccgact aagcagcagg atggagaact ggtgggctac   1260 

cggatatccc acgtgtggca gagtgcaggg atttccaaag agctcttgga ggaagttggc   1320 

cagaatggca gccgagctcg gatctctgtt caagtccaca atgctacgtg cacagtgagg   1380 

attgcagccg tcaccagagg gggagttggg cccttcagtg atccagtgaa aatatttatc   1440 

cctgcacacg gttgggtaga ttatgccccc tcttcaactc cggcgcctgg caacgcagat   1500 

cctgtgctca tcatctttgg ctgcttttgt ggatttattt tgattgggtt gattttatac   1560 

atctccttgg ccatcagaaa aagagtccag gagacaaagt ttgggaatgc attcacagag   1620 

gaggattctg aattagtggt gaattatata gcaaagaaat ccttctgtcg gcgagccatt   1680 

gaacttacct tacatagctt gggagtcagt gaggaactac aaaataaact agaagatgtt   1740 

gtgattgaca ggaatcttct aattcttgga aaaattctgg gtgaaggaga gtttgggtct   1800 

gtaatggaag gaaatcttaa gcaggaagat gggacctctc tgaaagtggc agtgaagacc   1860 

atgaagttgg acaactcttc acatcgggag atcgaggagt ttctcagtga ggcagcgtgc   1920 

atgaaagact tcagccaccc aaatgtcatt cgacttctag gtgtgtgtat agaaatgagc   1980 

tctcaaggca tcccaaagcc catggtaatt ttacccttca tgaaatacgg ggacctgcat   2040 

acttacttac tttattcccg attggagaca ggaccaaagc atattcctct gcagacacta   2100 

ttgaagttca tggtggatat tgccctggga atggagtatc tgagcaacag gaattttctt   2160 

catcgagatt tagctgctcg aaactgcatg ttgcgagatg acatgactgt ctgtgttgcg   2220 

gacttcggcc tctctaagaa gatttacagt ggcgattatt accgccaagg ccgcattgct   2280 

aagatgcctg ttaaatggat cgccatagaa agtcttgcag accgagtcta cacaagtaaa   2340 

agtgatgtgt gggcatttgg cgtgaccatg tgggaaatac gtacgcgggg aatgactccc   2400 

tatcctgggg tccagaacca tgagatgtat gactatcttc tccatggcca caggttgaag   2460 

cagcccgaag actgcctgga tgaactgtat gaaataatgt actcttgctg gagaaccgat   2520 

cccttagacc gccccacctt ttcagtattg aggctgcagc tagaaaaact cttagaaagt   2580 

ttgcctgacg ttcggaacca agcagacgtt atttacgtca atacacagtt gctggagagc   2640 

tctgagggcc tggcccaggg ccccaccctt gctccactgg acttgaacat cgaccctgac   2700 

tctataattg cctcctgcac tccccgcgct gccatcagtg tggtcacagc agaagttcat   2760 

gacagcaaac ctcatgaagg acggtacatc ctgaatgggg gcagtgagga atgggaagat   2820 

ctgacttctg ccccctctgc tgcagtcaca gctgaaaaga acagtgtttt accgggggag   2880 

agacttgtta ggaatggggt ctcctggtcc cattcgagca tgctgccctt gggaagctca   2940 

ttgcccgatg aacttttgtt tgctgacgac tcctcagaag gctcagaagt cctgatgtga   3000 

 
           
             2  
             1353  
             DNA  
             Homo sapiens  
           
            2 

atgtcagcaa tacaggccgc ctggccatcc ggtacagaat gtattgccaa gtacaacttc     60 

cacggcactg ccgagcagga cctgcccttc tgcaaaggag acgtgctcac cattgtggcc    120 

gtcaccaagg accccaactg gtacaaagcc aaaaacaagg tgggccgtga gggcatcatc    180 

ccagccaact acgtccagaa gcgggagggc gtgaaggcgg gtaccaaact cagcctcatg    240 

ccttggttcc acggcaagat cacacgggag caggctgagc ggcttctgta cccgccggag    300 

acaggcctgt tcctggtgcg ggagagcacc aactaccccg gagactacac gctgtgcgtg    360 

agctgcgacg gcaaggtgga gcactaccgc atcatgtacc atgccagcaa gctcagcatc    420 

gacgaggagg tgtactttga gaacctcatg cagctggtgg agcactacac ctcagacgca    480 

gatggactct gtacgcgcct cattaaacca aaggtcatgg agggcacagt ggcggcccag    540 

gatgagttct accgcagcgg ctgggccctg aacatgaagg agctgaagct gctgcagacc    600 

atcgggaagg gggagttcgg agacgtgatg ctgggcgatt accgagggaa caaagtcgcc    660 

gtcaagtgca ttaagaacga cgccactgcc caggccttcc tggctgaagc ctcagtcatg    720 

acgcaactgc ggcatagcaa cctggtgcag ctcctgggcg tgatcgtgga ggagaagggc    780 

gggctctaca tcgtcactga gtacatggcc aaggggagcc ttgtggacta cctgcggtct    840 

aggggtcggt cagtgctggg cggagactgt ctcctcaagt tctcgctaga tgtctgcgag    900 

gccatggaat acctggaggg caacaatttc gtgcatcgag acctggctgc ccgcaatgtg    960 

ctggtgtctg aggacaacgt ggccaaggtc agcgactttg gtctcaccaa ggaggcgtcc   1020 

agcacccagg acacgggcaa gctgccagtc aagtggacag cccctgaggc cctgagagag   1080 

aagaaattct ccactaagtc tgacgtgtgg agtttcggaa tccttctctg ggaaatctac   1140 

tcctttgggc gagtgcctta tccaagaatt cccctgaagg acgtcgtccc tcgggtggag   1200 

aagggctaca agatggatgc ccccgacggc tgcccgcccg cagtctatga agtcatgaag   1260 

aactgctggc acctggacgc cgccatgcgg ccctccttcc tacagctccg agagcagctt   1320 

gagcacatca aaacccacga gctgcacctg tga                                1353 

 
           
             3  
             3768  
             DNA  
             Homo sapiens  
           
            3 

atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc     60 

gcgagcaccc aagtgtgcac cggcacagac atgaagctgc ggctccctgc cagtcccgag    120 

acccacctgg acatgctccg ccacctctac cagggctgcc aggtggtgca gggaaacctg    180 

gaactcacct acctgcccac caatgccagc ctgtccttcc tgcaggatat ccaggaggtg    240 

cagggctacg tgctcatcgc tcacaaccaa gtgaggcagg tcccactgca gaggctgcgg    300 

attgtgcgag gcacccagct ctttgaggac aactatgccc tggccgtgct agacaatgga    360 

gacccgctga acaataccac ccctgtcaca ggggcctccc caggaggcct gcgggagctg    420 

cagcttcgaa gcctcacaga gatcttgaaa ggaggggtct tgatccagcg gaacccccag    480 

ctctgctacc aggacacgat tttgtggaag gacatcttcc acaagaacaa ccagctggct    540 

ctcacactga tagacaccaa ccgctctcgg gcctgccacc cctgttctcc gatgtgtaag    600 

ggctcccgct gctggggaga gagttctgag gattgtcaga gcctgacgcg cactgtctgt    660 

gccggtggct gtgcccgctg caaggggcca ctgcccactg actgctgcca tgagcagtgt    720 

gctgccggct gcacgggccc caagcactct gactgcctgg cctgcctcca cttcaaccac    780 

agtggcatct gtgagctgca ctgcccagcc ctggtcacct acaacacaga cacgtttgag    840 

tccatgccca atcccgaggg ccggtataca ttcggcgcca gctgtgtgac tgcctgtccc    900 

tacaactacc tttctacgga cgtgggatcc tgcaccctcg tctgccccct gcacaaccaa    960 

gaggtgacag cagaggatgg aacacagcgg tgtgagaagt gcagcaagcc ctgtgcccga   1020 

gtgtgctatg gtctgggcat ggagcacttg cgagaggtga gggcagttac cagtgccaat   1080 

atccaggagt ttgctggctg caagaagatc tttgggagcc tggcatttct gccggagagc   1140 

tttgatgggg acccagcctc caacactgcc ccgctccagc cagagcagct ccaagtgttt   1200 

gagactctgg aagagatcac aggttaccta tacatctcag catggccgga cagcctgcct   1260 

gacctcagcg tcttccagaa cctgcaagta atccggggac gaattctgca caatggcgcc   1320 

tactcgctga ccctgcaagg gctgggcatc agctggctgg ggctgcgctc actgagggaa   1380 

ctgggcagtg gactggccct catccaccat aacacccacc tctgcttcgt gcacacggtg   1440 

ccctgggacc agctctttcg gaacccgcac caagctctgc tccacactgc caaccggcca   1500 

gaggacgagt gtgtgggcga gggcctggcc tgccaccagc tgtgcgcccg agggcactgc   1560 

tggggtccag ggcccaccca gtgtgtcaac tgcagccagt tccttcgggg ccaggagtgc   1620 

gtggaggaat gccgagtact gcaggggctc cccagggagt atgtgaatgc caggcactgt   1680 

ttgccgtgcc accctgagtg tcagccccag aatggctcag tgacctgttt tggaccggag   1740 

gctgaccagt gtgtggcctg tgcccactat aaggaccctc ccttctgcgt ggcccgctgc   1800 

cccagcggtg tgaaacctga cctctcctac atgcccatct ggaagtttcc agatgaggag   1860 

ggcgcatgcc agccttgccc catcaactgc acccactcct gtgtggacct ggatgacaag   1920 

ggctgccccg ccgagcagag agccagccct ctgacgtcca tcgtctctgc ggtggttggc   1980 

attctgctgg tcgtggtctt gggggtggtc tttgggatcc tcatcaagcg acggcagcag   2040 

aagatccgga agtacacgat gcggagactg ctgcaggaaa cggagctggt ggagccgctg   2100 

acacctagcg gagcgatgcc caaccaggcg cagatgcgga tcctgaaaga gacggagctg   2160 

aggaaggtga aggtgcttgg atctggcgct tttggcacag tctacaaggg catctggatc   2220 

cctgatgggg agaatgtgaa aattccagtg gccatcaaag tgttgaggga aaacacatcc   2280 

cccaaagcca acaaagaaat cttagacgaa gcatacgtga tggctggtgt gggctcccca   2340 

tatgtctccc gccttctggg catctgcctg acatccacgg tgcagctggt gacacagctt   2400 

atgccctatg gctgcctctt agaccatgtc cgggaaaacc gcggacgcct gggctcccag   2460 

gacctgctga actggtgtat gcagattgcc aaggggatga gctacctgga ggatgtgcgg   2520 

ctcgtacaca gggacttggc cgctcggaac gtgctggtca agagtcccaa ccatgtcaaa   2580 

attacagact tcgggctggc tcggctgctg gacattgacg agacagagta ccatgcagat   2640 

gggggcaagg tgcccatcaa gtggatggcg ctggagtcca ttctccgccg gcggttcacc   2700 

caccagagtg atgtgtggag ttatggtgtg actgtgtggg agctgatgac ttttggggcc   2760 

aaaccttacg atgggatccc agcccgggag atccctgacc tgctggaaaa gggggagcgg   2820 

ctgccccagc cccccatctg caccattgat gtctacatga tcatggtcaa atgttggatg   2880 

attgactctg aatgtcggcc aagattccgg gagttggtgt ctgaattctc ccgcatggcc   2940 

agggaccccc agcgctttgt ggtcatccag aatgaggact tgggcccagc cagtcccttg   3000 

gacagcacct tctaccgctc actgctggag gacgatgaca tgggggacct ggtggatgct   3060 

gaggagtatc tggtacccca gcagggcttc ttctgtccag accctgcccc gggcgctggg   3120 

ggcatggtcc accacaggca ccgcagctca tctaccagga gtggcggtgg ggacctgaca   3180 

ctagggctgg agccctctga agaggaggcc cccaggtctc cactggcacc ctccgaaggg   3240 

gctggctccg atgtatttga tggtgacctg ggaatggggg cagccaaggg gctgcaaagc   3300 

ctccccacac atgaccccag ccctctacag cggtacagtg aggaccccac agtacccctg   3360 

ccctctgaga ctgatggcta cgttgccccc ctgacctgca gcccccagcc tgaatatgtg   3420 

aaccagccag atgttcggcc ccagccccct tcgccccgag agggccctct gcctgctgcc   3480 

cgacctgctg gtgccactct ggaaagggcc aagactctct ccccagggaa gaatggggtc   3540 

gtcaaagacg tttttgcctt tgggggtgcc gtggagaacc ccgagtactt gacaccccag   3600 

ggaggagctg cccctcagcc ccaccctcct cctgccttca gcccagcctt cgacaacctc   3660 

tattactggg accaggaccc accagagcgg ggggctccac ccagcacctt caaagggaca   3720 

cctacggcag agaacccaga gtacctgggt ctggacgtgc cagtgtga                3768 

 
           
             4  
             3429  
             DNA  
             Homo sapiens  
           
            4 

atggctttct gtgctaaaat gaggagctcc aagaagactg aggtgaacct ggaggcccct     60 

gagccagggg tggaagtgat cttctatctg tcggacaggg agcccctccg gctgggcagt    120 

ggagagtaca cagcagagga actgtgcatc agggctgcac aggcatgccg tatctctcct    180 

ctttgtcaca acctctttgc cctgtatgac gagaacacca agctctggta tgctccaaat    240 

cgcaccatca ccgttgatga caagatgtcc ctccggctcc actaccggat gaggttctat    300 

ttcaccaatt ggcatggaac caacgacaat gagcagtcag tgtggcgtca ttctccaaag    360 

aagcagaaaa atggctacga gaaaaaaaag attccagatg caacccctct ccttgatgcc    420 

agctcactgg agtatctgtt tgctcaggga cagtatgatt tggtgaaatg cctggctcct    480 

attcgagacc ccaagaccga gcaggatgga catgatattg agaacgagtg tctagggatg    540 

gctgtcctgg ccatctcaca ctatgccatg atgaagaaga tgcagttgcc agaactgccc    600 

aaggacatca gctacaagcg atatattcca gaaacattga ataagtccat cagacagagg    660 

aaccttctca ccaggatgcg gataaataat gttttcaagg atttcctaaa ggaatttaac    720 

aacaagacca tttgtgacag cagcgtgtcc acgcatgacc tgaaggtgaa atacttggct    780 

accttggaaa ctttgacaaa acattacggt gctgaaatat ttgagacttc catgttactg    840 

atttcatcag aaaatgagat gaattggttt cattcgaatg acggtggaaa cgttctctac    900 

tacgaagtga tggtgactgg gaatcttgga atccagtgga ggcataaacc aaatgttgtt    960 

tctgttgaaa aggaaaaaaa taaactgaag cggaaaaaac tggaaaataa agacaagaag   1020 

gatgaggaga aaaacaagat ccgggaagag tggaacaatt tttcattctt ccctgaaatc   1080 

actcacattg taataaagga gtctgtggtc agcattaaca agcaggacaa caagaaaatg   1140 

gaactgaagc tctcttccca cgaggaggcc ttgtcctttg tgtccctggt agatggctac   1200 

ttccggctca cagcagatgc ccatcattac ctctgcaccg acgtggcccc cccgttgatc   1260 

gtccacaaca tacagaatgg ctgtcatggt ccaatctgta cagaatacgc catcaataaa   1320 

ttgcggcaag aaggaagcga ggaggggatg tacgtgctga ggtggagctg caccgacttt   1380 

gacaacatcc tcatgaccgt cacctgcttt gagaagtctg agcaggtgca gggtgcccag   1440 

aagcagttca agaactttca gatcgaggtg cagaagggcc gctacagtct gcacggttcg   1500 

gaccgcagct tccccagctt gggagacctc atgagccacc tcaagaagca gatcctgcgc   1560 

acggataaca tcagcttcat gctaaaacgc tgctgccagc ccaagccccg agaaatctcc   1620 

aacctgctgg tggctactaa gaaagcccag gagtggcagc ccgtctaccc catgagccag   1680 

ctgagtttcg atcggatcct caagaaggat ctggtgcagg gcgagcacct tgggagaggc   1740 

acgagaacac acatctattc tgggaccctg atggattaca aggatgacga aggaacttct   1800 

gaagagaaga agataaaagt gatcctcaaa gtcttagacc ccagccacag ggatatttcc   1860 

ctggccttct tcgaggcagc cagcatgatg agacaggtct cccacaaaca catcgtgtac   1920 

ctctatggcg tctgtgtccg cgacgtggag aatatcatgg tggaagagtt tgtggaaggg   1980 

ggtcctctgg atctcttcat gcaccggaaa agtgatgtcc ttaccacacc atggaaattc   2040 

aaagttgcca aacagctggc cagtgccctg agctacttgg aggataaaga cctggtccat   2100 

ggaaatgtgt gtactaaaaa cctcctcctg gcccgtgagg gaatcgacag tgagtgtggc   2160 

ccattcatca agctcagtga ccccggcatc cccattacgg tgctgtctag gcaagaatgc   2220 

attgaacgaa tcccatggat tgctcctgag tgtgttgagg actccaagaa cctgagtgtg   2280 

gctgctgaca agtggagctt tggaaccacg ctctgggaaa tctgctacaa tggcgagatc   2340 

cccttgaaag acaagacgct gattgagaaa gagagattct atgaaagccg gtgcaggcca   2400 

gtgacaccat catgtaagga gctggctgac ctcatgaccc gctgcatgaa ctatgacccc   2460 

aatcagaggc ctttcttccg agccatcatg agagacatta ataagcttga agagcagaat   2520 

ccagatattg tttccagaaa aaaaaaccag ccaactgaag tggaccccac acattttgag   2580 

aagcgcttcc taaagaggat ccgtgacttg ggagagggcc actttgggaa ggttgagctc   2640 

tgcaggtatg accccgaaga caatacaggg gagcaggtgg ctgttaaatc tctgaagcct   2700 

gagagtggag gtaaccacat agctgatctg aaaaaggaaa tcgagatctt aaggaacctc   2760 

tatcatgaga acattgtgaa gtacaaagga atctgcacag aagacggagg aaatggtatt   2820 

aagctcatca tggaatttct gccttcggga agccttaagg aatatcttcc aaagaataag   2880 

aacaaaataa acctcaaaca gcagctaaaa tatgccgttc agatttgtaa ggggatggac   2940 

tatttgggtt ctcggcaata cgttcaccgg gacttggcag caagaaatgt ccttgttgag   3000 

agtgaacacc aagtgaaaat tggagacttc ggtttaacca aagcaattga aaccgataag   3060 

gagtattaca ccgtcaagga tgaccgggac agccctgtgt tttggtatgc tccagaatgt   3120 

ttaatgcaat ctaaatttta tattgcctct gacgtctggt cttttggagt cactctgcat   3180 

gagctgctga cttactgtga ttcagattct agtcccatgg ctttgttcct gaaaatgata   3240 

ggcccaaccc atggccagat gacagtcaca agacttgtga atacgttaaa agaaggaaaa   3300 

cgcctgccgt gcccacctaa ctgtccagat gaggtttatc agcttatgag aaaatgctgg   3360 

gaattccaac catccaatcg gacaagcttt cagaacctta ttgaaggatt tgaagcactt   3420 

ttaaaataa                                                           3429 

 
           
             5  
             3399  
             DNA  
             Homo sapiens  
           
            5 

atgggaatgg cctgccttac gatgacagaa atggagggaa catccacctc ttctatatat     60 

cagaatggtg atatttctgg aaatgccaat tctatgaagc aaatagatcc agttcttcag    120 

gtgtatcttt accattccct tgggaaatct gaggcagatt atctgacctt tccatctggg    180 

gagtatgttg cagaagaaat ctgtattgct gcttctaaag cttgtggtat cacacctgtg    240 

tatcataata tgtttgcttt aatgagtgaa acagaaagga tctggtatcc acccaaccat    300 

gtcttccata tagatgagtc aaccaggcat aatgtactct acagaataag attttacttt    360 

cctcgttggt attgcagtgg cagcaacaga gcctatcggc atggaatatc tcgaggtgct    420 

gaagctcctc ttcttgatga ctttgtcatg tcttacctct ttgctcagtg gcggcatgat    480 

tttgtgcacg gatggataaa agtacctgtg actcatgaaa cacaggaaga atgtcttggg    540 

atggcagtgt tagatatgat gagaatagcc aaagaaaacg atcaaacccc actggccatc    600 

tataactcta tcagctacaa gacattctta ccaaaatgta ttcgagcaaa gatccaagac    660 

tatcatattt tgacaaggaa gcgaataagg tacagatttc gcagatttat tcagcaattc    720 

agccaatgca aagccactgc cagaaacttg aaacttaagt atcttataaa tctggaaact    780 

ctgcagtctg ccttctacac agagaaattt gaagtaaaag aacctggaag tggtccttca    840 

ggtgaggaga tttttgcaac cattataata actggaaacg gtggaattca gtggtcaaga    900 

gggaaacata aagaaagtga gacactgaca gaacaggatt tacagttata ttgcgatttt    960 

cctaatatta ttgatgtcag tattaagcaa gcaaaccaag agggttcaaa tgaaagccga   1020 

gttgtaacta tccataagca agatggtaaa aatctggaaa ttgaacttag ctcattaagg   1080 

gaagctttgt ctttcgtgtc attaattgat ggatattata gattaactgc agatgcacat   1140 

cattacctct gtaaagaagt agcacctcca gccgtgcttg aaaatataca aagcaactgt   1200 

catggcccaa tttcgatgga ttttgccatt agtaaactga agaaagcagg taatcagact   1260 

ggactgtatg tacttcgatg cagtcctaag gactttaata aatatttttt gacttttgct   1320 

gtcgagcgag aaaatgtcat tgaatataaa cactgtttga ttacaaaaaa tgagaatgaa   1380 

gagtacaacc tcagtgggac aaagaagaac ttcagcagtc ttaaagatct tttgaattgt   1440 

taccagatgg aaactgttcg ctcagacaat ataattttcc agtttactaa atgctgtccc   1500 

ccaaagccaa aagataaatc aaaccttcta gtcttcagaa cgaatggtgt ttctgatgta   1560 

ccaacctcac caacattaca gaggcctact catatgaacc aaatggtgtt tcacaaaatc   1620 

agaaatgaag atttgatatt taatgaaagc cttggccaag gcacttttac aaagattttt   1680 

aaaggcgtac gaagagaagt aggagactac ggtcaactgc atgaaacaga agttctttta   1740 

aaagttctgg ataaagcaca cagaaactat tcagagtctt tctttgaagc agcaagtatg   1800 

atgagcaagc tttctcacaa gcatttggtt ttaaattatg gagtatgtgt ctgtggagac   1860 

gagaatattc tggttcagga gtttgtaaaa tttggatcac tagatacata tctgaaaaag   1920 

aataaaaatt gtataaatat attatggaaa cttgaagttg ctaaacagtt ggcatgggcc   1980 

atgcattttc tagaagaaaa cacccttatt catgggaatg tatgtgccaa aaatattctg   2040 

cttatcagag aagaagacag gaagacagga aatcctcctt tcatcaaact tagtgatcct   2100 

ggcattagta ttacagtttt gccaaaggac attcttcagg agagaatacc atgggtacca   2160 

cctgaatgca ttgaaaatcc taaaaattta aatttggcaa cagacaaatg gagttttggt   2220 

accactttgt gggaaatctg cagtggagga gataaacctc taagtgctct ggattctcaa   2280 

agaaagctac aattttatga agataggcat cagcttcctg caccaaagtg ggcagaatta   2340 

gcaaacctta taaataattg tatggattat gaaccagatt tcaggccttc tttcagagcc   2400 

atcatacgag atcttaacag tttgtttact ccagattatg aactattaac agaaaatgac   2460 

atgttaccaa atatgaggat aggtgcccta gggttttctg gtgcctttga agaccgggat   2520 

cctacacagt ttgaagagag acatttgaaa tttctacagc aacttggcaa gggtaatttt   2580 

gggagtgtgg agatgtgccg gtatgaccct ctacaggaca acactgggga ggtggtcgct   2640 

gtaaaaaagc ttcagcatag tactgaagag cacctaagag actttgaaag ggaaattgaa   2700 

atcctgaaat ccctacagca tgacaacatt gtaaagtaca agggagtgtg ctacagtgct   2760 

ggtcggcgta atctaaaatt aattatggaa tatttaccat atggaagttt acgagactat   2820 

cttcaaaaac ataaagaacg gatagatcac ataaaacttc tgcagtacac atctcagata   2880 

tgcaagggta tggagtatct tggtacaaaa aggtatatcc acagggatct ggcaacgaga   2940 

aatatattgg tggagaacga gaacagagtt aaaattggag attttgggtt aaccaaagtc   3000 

ttgccacaag acaaagaata ctataaagta aaagaacctg gtgaaagtcc catattctgg   3060 

tatgctccag aatcactgac agagagcaag ttttctgtgg cctcagatgt ttggagcttt   3120 

ggagtggttc tgtatgaact tttcacatac attgagaaga gtaaaagtcc accagcggaa   3180 

tttatgcgta tgattggcaa tgacaaacaa ggacagatga tcgtgttcca tttgatagaa   3240 

cttttgaaga ataatggaag attaccaaga ccagatggat gcccagatga gatctatatg   3300 

atcatgacag aatgctggaa caataatgta aatcaacgcc cctcctttag ggatctagct   3360 

cttcgagtgg atcaaataag ggataacatg gctggatga                          3399 

 
           
             6  
             1584  
             DNA  
             Homo sapiens  
           
            6 

atggcggggc gaggctctct ggtttcctgg cgggcatttc acggctgtga ttctgctgag     60 

gaacttcccc gggtgagccc ccgcttcctc cgagcctggc acccccctcc cgtctcagcc    120 

aggatgccaa cgaggcgctg ggccccgggc acccagtgta tcaccaaatg cgagcacacc    180 

cgccccaagc caggggagct ggccttccgc aagggcgacg tggtcaccat cctggaggcc    240 

tgcgagaaca agagctggta ccgcgtcaag caccacacca gtggacagga ggggctgctg    300 

gcagctgggg cgctgcggga cggggaggcc ctctccgcag accccaagct cagcctcatg    360 

ccgtggttcc acgggaagat ctcgggccag gaggctgtcc agcagctgca gcctcccgag    420 

gatgggctgt tcctggtgcg ggagtccgcg cgccaccccg gcgactacgt cctgtgcgtg    480 

agctttggcc gcgacgtcat ccactaccgc gtgctgcacc gcgacggcca cctcacaatc    540 

gatgaggccg tgttcttctg caacctcatg gacatggtgg agcattacag caaggacaag    600 

ggcgctatct gcaccaagct ggtgagacca aagcggaaac acgggaccaa gtcggccgag    660 

gaggagctgg ccagggcggg ctggttactg aacctgcagc atttgacatt gggagcacag    720 

atcggagagg gagagtttgg agctgtcctg cagggtgagt acctggggca aaaggtggcc    780 

gtgaagaata tcaagtgtga tgtgacagcc caggccttcc tggacgagac ggccgtcatg    840 

acgaagatgc aacacgagaa cctggtgcgt ctcctgggcg tgatcctgca ccaggggctg    900 

tacattgtca tggagcacgt gagcaagggc aacctggtga actttctgcg gacccggggt    960 

cgagccctcg tgaacaccgc tcagctcctg cagttttctc tgcacgtggc cgagggcatg   1020 

gagtacctgg agagcaagaa gcttgtgcac cgcgacctgg ccgcccgcaa catcctggtc   1080 

tcagaggacc tggtggccaa ggtcagcgac tttggcctgg ccaaagccga gcggaagggg   1140 

ctagactcaa gccggctgcc cgtcaagtgg acggcgcccg aggctctcaa acacgggttc   1200 

accagcaagt cggatgtctg gagttttggg gtgctgctct gggaggtctt ctcatatgga   1260 

cgggctccgt accctaaaat gtcactgaaa gaggtgtcgg aggccgtgga gaaggggtac   1320 

cgcatggaac cccccgaggg ctgtccaggc cccgtgcacg tcctcatgag cagctgctgg   1380 

gaggcagagc cgcccgccgg ccacccttcc gcaaactggc cgagaagctg gcccgggagc   1440 

tacgcagtgc aggtgcccca gcctccgtct cagggcagga cgccgacggt ccacctcgcc   1500 

ccgaagccag gagccctgac cccacccggt ggcccttggc cccagaggac cgagagagtg   1560 

gagagtgcgg cgtgggggca ctga                                          1584 

 
           
             7  
             2544  
             DNA  
             Homo sapiens  
           
            7 

atggagccct tgaagagcct cttcctcaag agccctctag ggtcatggaa tggcagtggc     60 

agcgggggtg gtgggggcgg tggaggaggc cggcctgagg ggtctccaaa ggcagcgggt    120 

tatgccaacc cggtgtggac agccctgttc gactacgagc ccagtgggca ggatgagctg    180 

gccctgagga agggtgaccg tgtggaggtg ctgtcccggg acgcagccat ctcaggagac    240 

gagggctggt gggcgggcca ggtgggtggc caggtgggca tcttcccgtc caactatgtg    300 

tctcggggtg gcggcccgcc cccctgcgag gtggccagct tccaggagct gcggctggag    360 

gaggtgatcg gcattggagg ctttggcaag gtgtacaggg gcagctggcg aggtgagctg    420 

gtggctgtga aggcagctcg ccaggacccc gatgaggaca tcagtgtgac agccgagagc    480 

gttcgccagg aggcccggct cttcgccatg ctggcacacc ccaacatcat tgccctcaag    540 

gctgtgtgcc tggaggagcc caacctgtgc ctggtgatgg agtatgcagc cggtgggccc    600 

ctcagccgag ctctggccgg gcggcgcgtg cctccccatg tgctggtcaa ctgggctgtg    660 

cagattgccc gtgggatgca ctacctgcac tgcgaggccc tggtgcccgt catccaccgt    720 

gatctcaagt ccaacaacat tttgctgctg cagcccattg agagtgacga catggagcac    780 

aagaccctga agatcaccga ctttggcctg gcccgagagt ggcacaaaac cacacaaatg    840 

agtgccgcgg gcacctacgc ctggatggct cctgaggtta tcaaggcctc caccttctct    900 

aagggcagtg acgtctggag ttttggggtg ctgctgtggg aactgctgac cggggaggtg    960 

ccataccgtg gcattgactg ccttgctgtg gcctatggcg tagctgttaa caagctcaca   1020 

ctgcccatcc catccacctg ccccgagccc ttcgcacagc ttatggccga ctgctgggcg   1080 

caggaccccc accgcaggcc cgacttcgcc tccatcctgc agcagttgga ggcgctggag   1140 

gcacaggtcc tacgggaaat gccgcgggac tccttccatt ccatgcagga aggctggaag   1200 

cgcgagatcc agggtctctt cgacgagctg cgagccaagg aaaaggaact actgagccgc   1260 

gaggaggagc tgacgcgagc ggcgcgcgag cagcggtcac aggcggagca gctgcggcgg   1320 

cgcgagcacc tgctggccca gtgggagcta gaggtgttcg agcgcgagct gacgctgctg   1380 

ctgcagcagg tggaccgcga gcgaccgcac gtgcgccgcc gccgcgggac attcaagcgc   1440 

agcaagctcc gggcgcgcga cggcggcgag cgtatcagca tgccactcga cttcaagcac   1500 

cgcatcaccg tgcaggcctc acccggcctt gaccggagga gaaacgtctt cgaggtcggg   1560 

cctggggatt cgcccacctt tccccggttc cgagccatcc agttggagcc tgcagagcca   1620 

ggccaggcat ggggccgcca gtccccccga cgtctggagg actcaagcaa tggagagcgg   1680 

cgagcatgct gggcttgggg tcccagttcc cccaagcctg gggaagccca gaatgggagg   1740 

agaaggtccc gcatggacga agccacatgg tacctggatt cagatgactc atccccctta   1800 

ggatctcctt ccacaccccc agcactcaat ggtaaccccc cgcggcctag cctggagccc   1860 

gaggagccca agaggcctgt ccccgcagag cgcggtagca gctctgggac gcccaagctg   1920 

atccagcggg cgctgctgcg cggcaccgcc ctgctcgcct cgctgggcct tggccgcgac   1980 

ctgcagccgc cgggaggccc aggacgcgag cgcggggagt ccccgacaac accccccacg   2040 

ccaacgcccg cgccctgccc gaccgagccg cccccttccc cgctcatctg cttctcgctc   2100 

aagacgcccg actccccgcc cactcctgca cccctgttgc tggacctggg tatccctgtg   2160 

ggccagcggt cagccaagag cccccgacgt gaggaggagc cccgcggagg cactgtctca   2220 

cccccaccgg ggacatcacg ctctgctcct ggcaccccag gcaccccacg ttcaccaccc   2280 

ctgggcctca tcagccgacc tcggccctcg ccccttcgca gccgcattga tccctggagc   2340 

tttgtgtcag ctgggccacg gccttctccc ctgccatcac cacagcctgc accccgccga   2400 

gcaccctgga ccttgttccc ggactcagac cccttctggg actccccacc tgccaacccc   2460 

ttccaggggg gcccccagga ctgcagggca cagaccaaag acatgggtgc ccaggccccg   2520 

tgggtgccgg aagcggggcc ttga                                          2544 

 
           
             8  
             2640  
             DNA  
             Homo sapiens  
           
            8 

atgagtgatt actgggttgt tggaaagaag tctaactatg aagtattaga aaaagatgtt     60 

ggtttaaagc gattttttcc taagagttta ctggattctg tcaaggccaa aacactaaga    120 

aaactgatcc aacaaacatt tagacaattt gccaacctta atagagaaga aagtattctg    180 

aaattctttg agatcctgtc tccagtctac agatttgata aggaatgctt caagtgtgct    240 

cttggttcaa gctggattat ttcagtggaa ctggcaatcg gcccagaaga aggaatcagt    300 

tacctaacgg acaagggctg caatcccaca catcttgctg acttcactca agtgcaaacc    360 

attcagtatt caaacagtga agacaaggac agaaaaggaa tgctacaact aaaaatagca    420 

ggtgcacccg agcctctgac agtgacggca ccatccctaa ccattgcgga gaatatggct    480 

gacctaatag atgggtactg ccggctggtg aatggaacct cgcagtcatt tatcatcaga    540 

cctcagaaag aaggtgaacg ggctttgcca tcaataccaa agttggccaa cagcgaaaag    600 

caaggcatgc ggacacacgc cgtctctgtg tcagaaacag atgattatgc tgagattata    660 

gatgaagaag atacttacac catgccctca accagggatt atgagattca aagagaaaga    720 

atagaacttg gacgatgtat tggagaaggc caatttggag atgtacatca aggcatttat    780 

atgagtccag agaatccagc tttggcggtt gcaattaaaa catgtaaaaa ctgtacttcg    840 

gacagcgtga gagagaaatt tcttcaagaa gcctgccatt acacatcttt gcactggaat    900 

tggtgcagat atataagtga tcctaatgtt gatgcctgcc cagaccccag gaatgcagag    960 

ttaacaatgc gtcagtttga ccatcctcat attgtgaagc tgattggagt catcacagag   1020 

aatcctgtct ggataatcat ggagctgtgc acacttggag agctgaggtc atttttgcaa   1080 

gtaaggaaat acagtttgga tctagcatct ttgatcctgt atgcctatca gcttagtaca   1140 

gctcttgcat atctagagag caaaagattt gtacacaggg acattgctgc tcggaatgtt   1200 

ctggtgtcct caaatgattg tgtaaaatta ggagactttg gattatcccg atatatggaa   1260 

gatagtactt actacaaagc ttccaaagga aaattgccta ttaaatggat ggctccagag   1320 

tcaatcaatt ttcgacgttt tacctcagct agtgacgtat ggatgtttgg tgtgtgtatg   1380 

tgggagatac tgatgcatgg tgtgaagcct tttcaaggag tgaagaacaa tgatgtaatc   1440 

ggtcgaattg aaaatgggga aagattacca atgcctccaa attgtcctcc taccctctac   1500 

agccttatga cgaaatgctg ggcctatgac cccagcaggc ggcccaggtt tactgaactt   1560 

aaagctcagc tcagcacaat cctggaggaa gagaaggctc agcaagaaga gcgcatgagg   1620 

atggagtcca gaagacaggc cacagtgtcc tgggactccg gagggtctga tgaagcaccg   1680 

cccaagccca gcagaccggg ttatcccagt ccgaggtcca gcgaaggatt ttatcccagc   1740 

ccacagcaca tggtacaaac caatcattac caggtttctg gctaccctgg ttcacatgga   1800 

atcacagcca tggctggcag catctatcca ggtcaggcat ctcttttgga ccaaacagat   1860 

tcatggaatc atagatctca ggagatagca atgtggcagc ccaatgtgga ggactctaca   1920 

gtattggacc tgcgagggat tgggcaagtg ttgccaaccc atctgatgga agagcgtcta   1980 

atccgacagc aacaggaaat ggaagaagat cagcgctggc tggaaaaaga ggaaagattt   2040 

ctgattggaa accaacatat atatcagcct gtgggtaaac cagatcctgc agctccacca   2100 

aagaaaccgc ctcgccctgg agctcccggt catctgggaa gccttgccag cctcagcagc   2160 

cctgctgaca gctacaacga gggtgtcaag cttcagcccc aggaaatcag cccccctcct   2220 

actgccaacc tggaccggtc gaatgataag gtgtacgaga atgtgacggg cctggtgaaa   2280 

gctgtcatcg agatgtccag taaaatccag ccagccccac cagaggagta tgtccctatg   2340 

gtgaaggaag tcggcttggc cctgaggaca ttattggcca ctgtggatga gaccattccc   2400 

ctcctaccag ccagcaccca ccgagagatt gagatggcac agaagctatt gaactctgac   2460 

ctgggtgagc tcatcaacaa gatgaaactg gcccagcagt atgtcatgac cagcctccag   2520 

caagagtaca aaaagcaaat gctgactgcc gctcacgccc tggctgtgga tgccaaaaac   2580 

ttactcgatg tcattgacca agcaagactg aaaatgcttg ggcagacgag accacactga   2640 

 
           
             9  
             3213  
             DNA  
             Homo sapiens  
           
            9 

atgggagctg cgcggggatc cccggccaga ccccgccggt tgcctctgct cagcgtcctg     60 

ctgctgccgc tgctgggcgg tacccagaca gccattgtct tcatcaagca gccgtcctcc    120 

caggatgcac tgcaggggcg ccgggcgctg cttcgctgtg aggttgaggc tccgggcccg    180 

gtacatgtgt actggctgct cgatggggcc cctgtccagg acacggagcg gcgtttcgcc    240 

cagggcagca gcctgagctt tgcagctgtg gaccggctgc aggactctgg caccttccag    300 

tgtgtggctc gggatgatgt cactggagaa gaagcccgca gtgccaacgc ctccttcaac    360 

atcaaatgga ttgaggcagg tcctgtggtc ctgaagcatc cagcctcgga agctgagatc    420 

cagccacaga cccaggtcac acttcgttgc cacattgatg ggcaccctcg gcccacctac    480 

caatggttcc gagatgggac ccccctttct gatggtcaga gcaaccacac agtcagcagc    540 

aaggagcgga acctgacgct ccggccagct ggtcctgagc atagtgggct gtattcctgc    600 

tgcgcccaca gtgcttttgg ccaggcttgc agcagccaga acttcacctt gagcattgct    660 

gatgaaagct ttgccagggt ggtgctggca ccccaggacg tggtagtagc gaggtatgag    720 

gaggccatgt tccattgcca gttctcagcc cagccacccc cgagcctgca gtggctcttt    780 

gaggatgaga ctcccatcac taaccgcagt cgccccccac acctccgcag agccacagtg    840 

tttgccaacg ggtctctgct gctgacccag gtccggccac gcaatgcagg gatctaccgc    900 

tgcattggcc aggggcagag gggcccaccc atcatcctgg aagccacact tcacctagca    960 

gagattgaag acatgccgct atttgagcca cgggtgttta cagctggcag cgaggagcgt   1020 

gtgacctgcc ttccccccaa gggtctgcca gagcccagcg tgtggtggga gcacgcggga   1080 

gtccggctgc ccacccatgg cagggtctac cagaagggcc acgagctggt gttggccaat   1140 

attgctgaaa gtgatgctgg tgtctacacc tgccacgcgg ccaacctggc tggtcagcgg   1200 

agacaggatg tcaacatcac tgtggccact gtgccctcct ggctgaagaa gccccaagac   1260 

agccagctgg aggagggcaa acccggctac ttggattgcc tgacccaggc cacaccaaaa   1320 

cctacagttg tctggtacag aaaccagatg ctcatctcag aggactcacg gttcgaggtc   1380 

ttcaagaatg ggaccttgcg catcaacagc gtggaggtgt atgatgggac atggtaccgt   1440 

tgtatgagca gcaccccagc cggcagcatc gaggcgcaag cccgtgtcca agtgctggaa   1500 

aagctcaagt tcacaccacc accccagcca cagcagtgca tggagtttga caaggaggcc   1560 

acggtgccct gttcagccac aggccgagag aagcccacta ttaagtggga acgggcagat   1620 

gggagcagcc tcccagagtg ggtgacagac aacgctggga ccctgcattt tgcccgggtg   1680 

actcgagatg acgctggcaa ctacacttgc attgcctcca acgggccgca gggccagatt   1740 

cgtgcccatg tccagctcac tgtggcagtt tttatcacct tcaaagtgga accagagcgt   1800 

acgactgtgt accagggcca cacagcccta ctgcagtgcg aggcccaggg ggaccccaag   1860 

ccgctgattc agtggaaagg caaggaccgc atcctggacc ccaccaagct gggacccagg   1920 

atgcacatct tccagaatgg ctccctggtg atccatgacg tggcccctga ggactcaggc   1980 

cgctacacct gcattgcagg caacagctgc aacatcaagc acacggaggc ccccctctat   2040 

gtcgtggaca agcctgtgcc ggaggagtcg gagggccctg gcagccctcc cccctacaag   2100 

atgatccaga ccattgggtt gtcggtgggt gccgctgtgg cctacatcat tgccgtgctg   2160 

ggcctcatgt tctactgcaa gaagcgctgc aaagccaagc ggctgcagaa gcagcccgag   2220 

ggcgaggagc cagagatgga atgcctcaac ggtgggcctt tgcagaacgg gcagccctca   2280 

gcagagatcc aagaagaagt ggccttgacc agcttgggct ccggccccgc ggccaccaac   2340 

aaacgccaca gcacaagtga taagatgcac ttcccacggt ctagcctgca gcccatcacc   2400 

acgctgggga agagtgagtt tggggaggtg ttcctggcaa aggctcaggg cttggaggag   2460 

ggagtggcag agaccctggt acttgtgaag agcctgcaga gcaaggatga gcagcagcag   2520 

ctggacttcc ggagggagtt ggagatgttt gggaagctga accacgccaa cgtggtgcgg   2580 

ctcctggggc tgtgccggga ggctgagccc cactacatgg tgctggaata tgtggatctg   2640 

ggagacctca agcagttcct gaggatttcc aagagcaagg atgaaaaatt gaagtcacag   2700 

cccctcagca ccaagcagaa ggtggcccta tgcacccagg tagccctggg catggagcac   2760 

ctgtccaaca accgctttgt gcataaggac ttggctgcgc gtaactgcct ggtcagtgcc   2820 

cagagacaag tgaaggtgtc tgccctgggc ctcagcaagg atgtgtacaa cagtgagtac   2880 

taccacttcc gccaggcctg ggtgccgctg cgctggatgt cccccgaggc catcctggag   2940 

ggtgacttct ctaccaagtc tgatgtctgg gccttcggtg tgctgatgtg ggaagtgttt   3000 

acacatggag agatgcccca tggtgggcag gcagatgatg aagtactggc agatttgcag   3060 

gctgggaagg ctagacttcc tcagcccgag ggctgccctt ccaaactcta tcggctgatg   3120 

cagcgctgct gggccctcag ccccaaggac cggccctcct tcagtgagat tgccagcgcc   3180 

ctgggagaca gcaccgtgga cagcaagccg tga                                3213 

 
           
             10  
             3645  
             DNA  
             Caenorhabditis elegans  
           
            10 

atgggtcatt cacatagtac tgggaaagaa atcaatgaca atgaactctt cacatgtgaa     60 

gatcctgtat tcgatcaacc ggtggcgagt ccgaaatcgg agatttcgag caagttagcc    120 

gaagaaatag aacggagcaa aagtccactc atactcgaga tgttccgtcc aacatttgac    180 

acatttcgac cgccgaacag tgacagctcg actttccgtg gcagccagag cagagaggat    240 

ctagtagcat gtagctcaat gaattcggta aacaacgtgc acgatatgaa tacagtttcc    300 

tcttcatcat catcatctgc accacttttt gtagctctct atgatttcca cggtgtcggc    360 

gaagagcagc tttcgttacg aaagggtgat caggtgcgaa ttctgggtta caacaaaaac    420 

aatgagtggt gtgaggcacg attatactca acgagaaaaa atgatgcgag caatcagcga    480 

aggttaggcg aaattggatg ggtgccaagt aattttattg ctccgtacaa ctctttggat    540 

aagtacacgt ggtatcatgg caaaatctca aggagcgatt ctgaggctat actaggcagt    600 

ggaatcactg gctcattttt ggtacgagaa agtgaaacaa gtataggaca gtatacaatc    660 

tctgttcgcc atgatggtcg agtgtttcac taccggatca atgtagataa tacagaaaag    720 

atgttcatca cacaagaagt caaattccgc acacttggag agttagtgca ccatcatagt    780 

gttcacgctg atgggctgat atgtctttta atgtacccag cgagtaaaaa ggacaaggga    840 

cgtggactgt tctcactgtc gcctaacgcg ccagacgaat gggaactaga tagatccgaa    900 

atcatcatgc ataacaaatt gggcggtgga cagtacggag acgtgtacga gggatactgg    960 

aaacgacatg actgcacaat tgcagtgaaa gcgttgaagg aagatgcaat gccacttcat   1020 

gaatttttag cagaagctgc tatcatgaaa gatttgcacc acaaaaacct tgttcgactg   1080 

cttggagtat gcactcacga ggcaccgttc tatattatca ccgagtttat gtgcaatgga   1140 

aatttgctcg agtacctgag gaggaccgat aaaagcttgc tgccacctat aatccttgtt   1200 

caaatggcta gtcagattgc gtccggcatg tcgtacctgg aagccagaca cttcattcat   1260 

agggatttgg ccgcaaggaa ttgcttagta tccgagcata atattgtaaa aattgccgac   1320 

tttgggttgg caagattcat gaaggaagac acctatacag cacatgctgg agccaagttt   1380 

cctatcaaat ggactgcccc agaggggctt gcattcaaca ccttcagctc taaatctgat   1440 

gtttgggcgt ttggagttct gctctgggaa attgccacgt atggaatggc tccctatcca   1500 

ggcgtcgagc tgtcaaatgt ttatgggctt ttggaaaacg ggttccgtat ggatggcccg   1560 

caagggtgcc ctccatcggt gtatcgcctt atgcttcagt gctggaactg gtctccgtcg   1620 

gatcgtcctc gtttccgaga tattcatttc aacttggaaa atctaatttc aagcaattcc   1680 

ttgaacgacg aggtgcaaaa acaattgaaa aagaataatg ataagaaact ggaaagtgac   1740 

aaaagaaggt ctaacgttag agaacgaagt gactctaaat ccagacattc ttcacatcac   1800 

gaccgtgacc gtgaccggga atctcttcat tctcggaact caaatcctga aattcccaat   1860 

agaagtttta taagaaccga cgacagtgta tcattcttca atccatcaac cacaagtaaa   1920 

gtaacgtcgt ttcgtgctca aggaccaccg ttcccaccac cgccacaaca aaacacaaaa   1980 

ccgaaactat tgaagtcagt tctgaatagt aacgctcgtc atgcatcaga ggagtttgag   2040 

agaaacgaac aagatgacgt ggttcctttg gccgagaaaa atgtgcggaa agcggttacc   2100 

aggctgggtg gaactatgcc gaaaggacaa aggatagatg catatttaga ctcgatgaga   2160 

agggttgaca gttggaaaga aagcactgac gctgacaatg aaggggcggg atcatcatcg   2220 

ctgagcagaa ctgtatcgaa tgattctctt gacacacttc ctctgccaga ttctatgaac   2280 

tcgagtacgt atgttaaaat gcatcctgca tccggcgaga acgttttcct gagacaaatt   2340 

cgttcaaaac tgaagaaacg aagtgagaca ccagagttgg atcatattga ttcagatact   2400 

gccgatgaaa caacaaaatc ggaaaagtca ccctttggat ctttgaataa atcttctatc   2460 

aaatatccaa ttaaaaacgc gcccgaattt agtgagaatc actctagagt cagccctgtc   2520 

ccggtgccac catctcgtaa cgcttctgta agtgtaagac ccgattcgaa agcagaagac   2580 

tcatcggatg agacaacaaa agatgttgga atgtggggtc ctaagcatgc cgtgacgcgg   2640 

aaaattgaaa ttgtcaagaa tgattcgtat ccaaatgtag aaggcgagtt gaaagcaaaa   2700 

attcgaaatt tacgtcatgt acccaaagaa gagagcaaca caagtagtca agaagatttg   2760 

ccacttgatg cgacagacaa cacaaatgac agcatcattg tgattccaag agatgaaaaa   2820 

gcaaaagttc gtcaactggt gacacaaaaa gtatctcctc ttcaacatca tcggccattc   2880 

tcactgcaat gtccaaacaa ttctacaagc tctgcaatat cgcattctga acacgcggat   2940 

agctcagaaa catcttcact ttccggtgtc tatgaggaac gtatgaaacc tgaacttcca   3000 

agaaaacgga gtaatggcga tacaaaagtg gtgccagtaa catggattat caatggagaa   3060 

aaggaaccca atggtatggc tcgaacaaaa tctctacgtg atattacatc aaagttcgaa   3120 

cagcttggaa cagcttccac gattgaaagt aagattgaag aagccgtccc atatcgtgag   3180 

catgcattgg aaaagaaagg aacttcaaaa cgattttcaa tgctggaagg aagtaatgag   3240 

ttgaagcatg ttgtcccacc gcgtaaaaac cgaaaccaag acgaatctgg ctcaattgat   3300 

gaagaaccag tgagcaagga catgattgta tcgttgctca aagtaatcca aaaggaattt   3360 

gtgaatcttt tcaatttggc gagctcagag atcactgatg aaaaactaca acaatttgta   3420 

ataatggctg ataatgtaca aaaacttcat tccacgtgtt ccgtctatgc agaacaaatc   3480 

tcaccgcata gtaaatttcg gttcaaagaa cttctttctc aacttgaaat ctacaatcga   3540 

caaattaaat tttcccacaa ccctcgagcg aagccagttg atgacaaact taaaatggcg   3600 

ttccaggact gtttcgacca aatcatgagg ctggtggatc gctga                   3645 

 
           
             11  
             3672  
             DNA  
             Caenorhabditis elegans  
           
            11 

atggcaagca cgtcaggggc gcttgtcgac gacaacgtcc tcgaagtgct ccgcaaagca     60 

cagttggacg catttattag tcagtttgtc ttcttattca acgtcagaag gtttgatcac    120 

ttttcacatg ttcgagataa agatatgctg gaaattggta tgcaacaagt tcaaattcgg    180 

cagctccgag agcagattct caaaatgtcc agagaaatgt ggaatcggag tgatccgaag    240 

caagtgtaca ttcaagccga tcagtcgatg ccagcacaaa attcgattga cgagaaagca    300 

ctgattccaa atgagcagat taaactgtac gagttgattg gcgagggctc ttttgctgtg    360 

gtgaagcgtg gtacgtggac acagagcaat gggacgcatg tgaatgtcgc tgtcaaaatt    420 

ctccgcgaca tttctccaaa tattatggat gatttgagag tggaagccag tcatttgctc    480 

aagctccagc acccgtcttt gattcgcctt tacggaattg ttcgccagcc agcgatgatg    540 

gtgtttgaac tctgtgaagg tggttcactg ctcgacagac tacgagatga caaaaaggca    600 

attcttctgg tgtcacggct tcatgactat tgtatgcaaa ttgcgaaggc tttgcagttt    660 

ttggagtcaa aacactgtgt acacagagat gtggcagcaa ggaatatttt gttggctaga    720 

gacgaaagga cagtcaagat ctgtgatttt ggactcatgc gagcactaaa agaaaatgag    780 

caaatgtaca ctatggctcc acaaaagaaa gtcccatttg cctggtgccc tccggaagca    840 

cttcgtcatc gcaagttctc tcatgcttcc gacgtctggt cgtacggagt caccatctgg    900 

gaggtgttca catttggcga ggagccatgg gtcggctgtc gagccatcga tgtgctcaaa    960 

aacattgacg ccggcgagag gctggagaag cccaagtact gctcggagcg aatttatcaa   1020 

atcatgaaga attgttggaa attcaatccg gcagagcgat gcaaatttgg tgcaattcga   1080 

gaggacttgg tggcggccat gtttttggat gcagtggcaa gggagacgta caactctatt   1140 

caaccgggcg cactacaatt gacaaaaggg gatgaagttg ttgtggtgga gaacacaggc   1200 

caagactggt ttggtcagaa caagaagaac caaaagtttg gcacattccc ccgatcagtt   1260 

gtgtttgcgc agacgaacaa cgcggttgcg gcagcgacgg cggttacccc acagaaagtt   1320 

ccaacggcgc caacgatcag aattccaccg tcacacccac ccccagcccc gctgaaacca   1380 

ttgaacaata atacgaaaac ttcgctgaac gaccgcacgt caaaaatttc aatgcctgtg   1440 

gcaggttctt tcatccatac cggtcacgga gacccactag gaggccaatc atggggtaac   1500 

ccagctacga ttgcggacat gtatctcaag aatccagtga acggcgctcc attgtctagt   1560 

atgtcgagtg gtgcggaaat tatcgccagt aaggagttgc tcaccaatgg cggccggagc   1620 

acacaccaac ctgctgctcc atcgcctgcc gtcatgtcca agattcgagg tctttcgctt   1680 

gatttgccag aatatgatga tttcgatcga gcattcgatg atgggttttc tccgtcgaag   1740 

atcgagctgc ccagagagtt ttgtggcaat gacagcgtaa tcagtggtgg gtcgaacagc   1800 

atcggcttgg ctaacactta tgtcatggaa ccgcccaagc aggcatttga tattcgagga   1860 

aatcgagtgc tcccgccaac gaacaaggcg cctgtgctca ttccaactaa cccggcgcca   1920 

agtgtcatct cgagcacagc ttctgcagga atcacacttt ctacgaacag ttctcagatg   1980 

tttaccagtc aagaccgcca ttcgaatatg cccgcaaatc ttttccccga gcttcaacac   2040 

cgcctcaatc aaggaagttc aacgggaaat ggcgtccgac ctcggccagc ttcctcgatt   2100 

ggaattcaaa acaatgattt gagcatgctc aaccctcaac aaccagcgaa tattccgtgc   2160 

ctggttccaa ctccggctcc accagctcca gcacactttt ctcaaccggt gtcttcccag   2220 

agagttgcac aacaacaaca gaacactttg caaaaagcgc tgaacgatga actcaaagga   2280 

aatctgaaca aaagacctac tggcacgacg gcaccaccgt caaatgggtt caatgctcca   2340 

cgagcagacg ttgcaccggt ccaacagcga ccgatctcat cggcatctat tccagcgctc   2400 

caaccacaac ccattcaaca cattcagaag cctatccaac cgcaacaagt tcgtataccg   2460 

ccatcaacag ctcccgttca gaaaccagtt caagtctcag ctcctaccca tagtaatgtg   2520 

gcacccacaa cttcatctca agcgtctgca gatgcacgca atccgctacc tccaaaaaca   2580 

agcccaccag ttagcaacac gcctatcaca gttgctcctg ttcacgcggc accaactact   2640 

tcggcaccat caacttcggt ggtaacgaga aggccaactt caaccacagc tcaaatgtcg   2700 

gacgaggaga gacggtcaag aattgccatg gacatcagct ctgcacttcc agctcccagt   2760 

gctttgctct atggatctaa ctccacatca tcacttccgt cagcggcagt gtctacagcg   2820 

tcttctgtgc catcaactgc aagagacaat ccagtggaaa caagaccatc tcaacctcat   2880 

gttaccatgc cacccaaaaa atcttctgag ccgattctct cgtctgaggt gctccaacca   2940 

actcgtctgc catctgccac aacttcgcag gcaaaaccag tgactcaacc aatccgtcac   3000 

ccatcacctc cggtagccac tgttataccg actgcagtgg ttgacaaaaa gccagtttca   3060 

caaaatcaag gaagcaacgt tcctttgttt aacattacca actccagcaa cgggtaccct   3120 

cagttaaatg gatatccaaa ctatggaaac ggttttcagg cgtatggtta tggaatgaac   3180 

tatcatcaag gatatcctgg atatcaagga tacaattcat atggcaacgg aatggggcag   3240 

cttgcactga cccacaacgc cgtcacttct ttgccaccgt tggttccatc agagaacaga   3300 

ttctccggaa cagcccaacc acttggcgag tctgacatta tggagttttt gggaacacag   3360 

caacgtcaag cgggttcttc atcgcgagca gttccacctg catctgcatc cacgtcagca   3420 

gcttctggaa tcacggattt gagtatggca gataagatgg aggtgttgta tagagaagct   3480 

gattttacgc ataaaggaaa ttgtgatacc atggtttctc agtgcaacgg aaacaccgaa   3540 

caggcgttga agcttctcaa acaacaacac ttggtggata tggaacttgc aatgtcaacg   3600 

gagaccgccc gacaagcact cgaggccaga cagtatgatc tccctgcagc cgccaacatg   3660 

ttgctcggct ga                                                       3672 

 
           
             12  
             1335  
             DNA  
             Caenorhabditis elegans  
           
            12 

atgtcaatta attctctttc gaacgaaacg cccactccaa caatcgagaa agaagcctac     60 

ttccatggat tgatccaacg agaagatgtc ttccagctcc ttgacaataa tggcgactac    120 

gtggtcagac tgtcggatcc aaagcccggc gagcctcgct cctacattct gagcgtcatg    180 

ttcaacaata agctcgatga gaacagttcg gtgaagcact ttgttatcaa ttctgtagag    240 

aacaaatatt ttgtgaacaa caatatgtcg ttcaacacga ttcaacaaat gctcagccac    300 

tatcagaaga gtcgcacgga gattctcgaa gcgtgcaaga ttttgcatcc tgtgcgcaga    360 

caattctggg agttagatca tggcaatatc gtgattgaga agaaactagg cgaaggtgct    420 

tttggtgaag tttcctccgg agttatgaag ttcaagagag gtggaaggct ggtgaaggtt    480 

gctgtgaagc aggtaaaaac cgatggtatc gggaaagatc aaatcaagga tttcctgatg    540 

gaagctcgta ccatgcgaaa cctcggtcat ccaaacatcg taagattcct cggaatcgcc    600 

gtgctgcagg agccgctgtt cctggtgatg gagctcgcga cgggcggcgc tttggatagc    660 

tacttgaagc ataatgagtt gctgccgatt gacaagagac acgagatgct tcttcaagca    720 

gcatggggtc tcgagtacat ccatggaaaa cccatgctgc atagggacat cgccgcgcga    780 

aattgccttt atggagatgg gaaggttaaa atttcggatt tcggcctaac ccgtagagga    840 

accatctacc aattgcatcc ggagacgaag tcaccaattc gatggctggc agttgaaact    900 

atcaggacta tggtttgctc tcagaagact gacgtctggg cttacgggat tctctgctgg    960 

gagatcttca acaacggagc cgagccgtat ccgggactga ctgccaatga ggttgctaag   1020 

caggtgactg atggataccg tatgccacca caccagttgg ctgcgccaga ggttcaagcg   1080 

ttgatgacga gatgctgcgc ggagaacccc aacgatcgtc caacaatgtc ggatgtcgct   1140 

cagatcttgc aacgcgtcac tggtcaagga cgtcccaact ttgcagcgat tgccaagaaa   1200 

gaggctgaag agcttctcat catgaattct cgtagtgcaa ggagaacttc acgacgtaag   1260 

ggcagtaata agaagtcggc aattccaaac ggagttttaa cacctgtcaa tagagctcaa   1320 

gaaattaagc attga                                                    1335 

 
           
             13  
             1689  
             DNA  
             Caenorhabditis elegans  
           
            13 

atgttcatca gcaaagagga aatgaatcgt acttttggtg tcaaagctga gctgaattac     60 

attgaaatgg ggaatgttag ctcgtactct acaaagtttc actacagagt tatggcaaac    120 

atcgactacc tctcgttcac atggaatgct gttggaattg tacactatga agtttacgtc    180 

gaatctgatg actcttctgt gcttcctatt gttcgaattc cattgaaagg aacggtgcca    240 

gaatctttgc aggacttcac cgttgaatac agatgtgccg gacaccgatc cggacaattt    300 

gctgtcagtc tatatttcac attcaaatat ggtaataagg agccgttgaa agtgaaattg    360 

cgacaggaga agatctgcgc ttcaagggac ggacgtcgag gtctgaacgg aggctacgag    420 

ggtcatgaag tcgacgacac tgactcaata gacaaggcat tttttgttat catttgcatt    480 

gctgcggcat tcctacttat tgtggcagca acgttgatct gttatttcaa gcgctctaaa    540 

aaagaagaca tgattccgac tcgacttcca acgtcttttc ggaattcttt gaaatctaca    600 

aaaagcgcgc agccttttct tctgagcaca ccgcgagatg gacctccgac tctttccgct    660 

atttcaagcg ctccttgttc ttcgtcgtct gcgtcgggaa attcgataat cccgagcaag    720 

ccaagaaaca ttgacgtgag acgtgcattg ttacaactct atcaagatcg agatgctttt    780 

caatctctac ctctagatat ggagggaaca tttggagaag tgagatatgc aatttggcgt    840 

caagtagatg acgtactgaa cggagatgtt gacgacgaag aagacacatt ctgtaaccag    900 

gaagctgttt acaccaaaac gttgaaaaat aatgcctcac caattcagct ggatcggttt    960 

ttgtccgacg cccttctatt ttacaacatc acacctcacc aaaacttgtc tcaagtggca   1020 

tgtgtggctt ccttcggaag attcgaccgc ccggaaactg tcacagattt tccacttgtt   1080 

tgttacagac accaaggctt tggaaacctg aagaagttcc tcaccatctg ccgacatggt   1140 

gataaaacta aaggagctca aactctccga actcatcaac tcgtctctct ggccacacaa   1200 

gtatcttctg cagtagctca tatacacaaa tatagaatag tgcataacga cattgccgct   1260 

agaaactgct tgatcgcaga agtgaatggg cgactccaag tgcaattatg cgactcggcg   1320 

ctgtcccgcg atctgttccc agctgattat cactgcttgg gtgacaatga gaacagacca   1380 

ttgaaatgga tgtctccaga agctattgca aatgagctgt actcatcggc cgctgatgtt   1440 

tggtcactgg gagttctact gtgggagctc atgtcgctag gaggatctcc acacgctgaa   1500 

atagaccctg aggaagtgta cacaatgatt ctcaaaggaa agcgtctgca acagccgaac   1560 

aattgtccgg atcaattata cgaagtcatg ctgtgctgtt ggagggtact cagcgaagat   1620 

cgtcctagca gtgagcaggt agttcatgga cttcgagact ttaacattca actcagtcaa   1680 

tacatctaa                                                           1689 

 
           
             14  
             3603  
             DNA  
             Drosophila melanogaster  
           
            14 

atgaacaccg cgggagccac cagtcaaccg ccgcccacta aaaatgagat taactccgag     60 

gagtatctca tccacgtgca tatgccgaac aagagcttca aggctgttcg gtttaatgtc    120 

aaggagaccg ttttccatgt gatccggcgc actgtcgagg atctgggcac ggatggacgg    180 

acgcccagca ttcagcgata tgcctgccgc atgcttaaca tgatcaccaa ggaggtgatt    240 

tggctggcta gaagcacttc aatgcagaag gttctctcgc acatcctgac gcccggctgc    300 

tccaacgttg actgtcccaa caaccagtcg gagttggatg aggttctatt ggagcacgga    360 

agaaggatca ccgataatag ggtgtggcga gtggagctca gagtgcgcta cgtgccaaat    420 

aatattcaag agctcttcga ggaggacaag gccacatgct tctattattt caatcaggtg    480 

aaagaggact ttatccaagc caatgtcaca gccatcgaca ctgaagtggc ggtgcaactg    540 

tgctgtctgg gcattcgtca ttatttcaag aacatcaccg tgaaagcacc tgacaaaaag    600 

cagcacattg actacattga aaaggaaatc ggatttaaaa gttttcttcc acaatctgtg    660 

atagccacat caaagccaaa gaatcttaag aaactgatcc aagtcggtta caaaaaggtc    720 

tacaattaca acgacattga gtacttgacg cggttctttg atcttctgaa gaatatttat    780 

ttaacgaact tcgagcagtt ctcggtaacc ctgagctcgg cgtggaatat ttctggaatt    840 

ctacacgtcg gccctcacat tggaatctcg taccagactc atcctcaggc cagcttgaag    900 

aacgtggctc agtttaaaga tgtggtctct attaaaacgt gcactttacc aaaggaaaaa    960 

ctgtccaagt ctggggagaa taccacagaa ccagagcttc agaattttaa ttgcaactgc   1020 

cagaagatta aaacccaaat aaaaatatcc gcttccaaca atgtggaaga tttggttata   1080 

acgtgcaatg gtattaatac cgctgagagt attgctgacc taattgacgg ttactgccgg   1140 

ctgttatcaa aagacctaga gttcacgatt tggcatcgag agacaaacgc gtcgaacgaa   1200 

gatagcgcaa aagcattgcc caatgatgcg acgctggggt ccaataaatc aacttcaagt   1260 

cagggaaaac cgatgctgac cgatgattat gccgagattg gtttattgga gggcgagggc   1320 

gactactcta cgcccaccgt tcgaaattat gagttggaca gagccctcat aacgccgagc   1380 

gccaaaattg gtgtgggaca gtttggtgat gtgtatgtag gcacgtatac gcttccgaaa   1440 

ctgggcaagg gcaagaactt agcaggaaat ggaaaaaata gtaatagtga ccaaagaaat   1500 

gccgattcaa ggccagatgt tatacaagtg gcgataaaga catgtaaagc taacgacgat   1560 

cctgaaaaaa ccgaaaattt tcttgccgaa gcttatatta tgcaaaaatt cgatcatccc   1620 

catattatac gcttaatcgg catttgcagc gtaatgccca tttggatagt tatggaattg   1680 

gccaaactgg gtgaattgcg tgcgtactta aagacaaaca gcgaaagatt aagccacggt   1740 

actttactga agtattgcta tcagctatcg actgctctta gttatttgga atccaaaaag   1800 

tttgttcacc gagatatagc ggcgcgtaat gtactagtca gctcaccaac gtgtgttaag   1860 

ttggctgatt ttggattatc acgttgggtt tccgatcagt cgtattatca ctcaacaccc   1920 

acagttgccc tacccattaa atggatgtcc cccgagtcaa taaactttag aagatttacc   1980 

actgctagtg atgtttggat gtttggtgtc tgcatttggg aaatactcat gctcggtgta   2040 

aagcctttcc aaggcgtcaa gaacagcgat gttatattga agctcgaaaa cggagagcgt   2100 

ctgccattgc ctcccaactg cccacctagg ttatattcgt taatgtccca atgctgggcg   2160 

tacgagccac ttaaacgacc gaatttcaag cggatcaagg aaactctgca tgaaattctg   2220 

attgaagaca gcattaattc atcggagaca ctgaagcggg agcaacgaaa agtggcttcc   2280 

atgtcctgga ttggcagtga tgacatcgac attccgccat cgaaaccttc aagggtgatg   2340 

cacgatcctg acatcactgg cttaatgcct gaaacaacgg ggctacctca gacctatatt   2400 

attgcacaaa atcccgcggt gctggccaaa ctgatgatgg agaaccaaaa acgaggcata   2460 

aatccagcgg cgtacaccac accagcttcg ggcattcaca atgttttggg cgaaaaacta   2520 

cgacaacagc aaaaggatag caacagcgac agcgaatggt taattcaaga agaattgcta   2580 

cggcagagat cctgctcaat acctcaagga tcgctcaatg atcatcaggc tcaaatgttt   2640 

aagcttgact tcatgtcagc tggtccttcc agtttgccgg actgctcgaa ctccagttct   2700 

cgacctatga caccaaatgc caatctttct tcactgaagt cgaaccactc atcggcggat   2760 

catttgtcca gcttgacatc tgcagaagaa cagatgggtt caaatgcacg aaacctgggc   2820 

agtgcagttc caagtcgacc acctaaccgc gcagatgacg aagtttattg cgccaccaca   2880 

ctggtggtca aatcaataat ggcgctgtca caaggtgtgg agaaagcgaa taccgagggt   2940 

tacttggaat tggttaagaa cgtgggcgtc aagttgagaa acttgctaac atcggtggac   3000 

aaaatatcta taatatttcc agcacaggcc ctcaaggaag tgcaaatggc acatcaggta   3060 

ctttcaaaag acatgcacga attggtctca gcgatgcgat tggctcaaca atatagtgac   3120 

acaacgctgg attgtgaata tcgcaagagt atgctgtctg ctgcccacgt tttggctatg   3180 

gacgccaaaa acctgtttga tgttgtcgat tcgatacgtc aacgttatca gcatctattc   3240 

ccgccatccg ccacaaaaga aacaagttgt tcgtcaagtt tcgagtcgac ttctggatct   3300 

attgtcgcag agccagttaa tgaccttggt ggttatatca agactagcac ttctggagat   3360 

ttgcttcaaa acacaggaat atatgataat gatttgcatc atagcttcaa ctcgcaattg   3420 

cagttgcaaa acccaaaagc cagcatcgac ttaagcggcg gtggtagtct acagcgaggg   3480 

atgagccttg gcttggacac aaccaggtcg acaaacgaac cgttgcgaat tgttgaggag   3540 

accctgggca gcccgggtga acatatgtac tgcaatacgt ccgccttgca cggccacgcg   3600 

taa                                                                 3603 

 
           
             15  
             2772  
             DNA  
             Drosophila melanogaster  
           
            15 

atgcttattt tctacgcgaa gtacgcattt atcttctggt ttttcgtggg aagcaatcaa     60 

ggtgaaatgt tgctaatgga caaaatctct cacgataaga cgcttctcaa cgtcaccgct    120 

tgcacccaga attgtctgga aaagggccag atggatttcc gaagctgttt aaaggactgc    180 

aggattaatg gaacatttcc cggggctctg cgcaaggtgc aggaaaacta ccagatgaac    240 

atgatctgcc gcacggagtc ggaaatcgtt ttccaaatag attgggtgca gcacagcagg    300 

ggaaccgagc cggctccaaa tgccacctac ataatccggg tggatgctgt caaggacgac    360 

aacaaagaaa ctgcgcttta cctgtctgat gacaactttc tcatcctgcc gggattggag    420 

tccaactcta cccacaacat caccgccctg gcgatgcacg gagatggcag ctactccttg    480 

atagcaaagg accagacctt cgccaccctc atccgaggct atcagcccag caaaatggga    540 

gcggtgaatc tgctgcggtt tgtcccccaa ccagacgacc tgcatcacat tgctgccgaa    600 

atcgagtgga agccatcggc ggagagcaac tgctatttcg acatggtgtc gtattcaacc    660 

aacagcgtga atatggacga gccactggag gtgcagttcc gggatcgcaa aaagctgtac    720 

aggcacacgg tggacaactt ggagtttgac aaacagtatc acgttggcgt aagaacggtg    780 

aacataatga atcgactgga gagcgatctg cagtggctgc caatcgctgt tccaagctgc    840 

ttggattggt atccctataa ctacacactc tgcccacccc ataagccaga gaatcttact    900 

gtgacccaga agcagtatct gccaaatatt ttggccctga acatcacctg ggcgcgtccc    960 

agatacctgc cggataacta tacacttcac atctttgatc tattcaaagg aggtacggag   1020 

ctaaactata cacttgacca aaacaggagc cacttctatg tacccaagat cacggtactg   1080 

ggttcccatt tcgaagtaca tttggtggcc cagtcggcag gcggaaaaaa cgtatccggt   1140 

ttgacgttgg acaaggttca tcgaggtgtg ttgctgagcg agggcaacat ggtcaagttg   1200 

gtactcttta ttatcgtgcc catatgctgc attttgatgc tgtgctccct gacgttctgc   1260 

agacgaaatc gttcggaggt tcaggcgctg caaatggacg ctaaggacgc gaaggccagt   1320 

gaatttcatc tctccctgat ggacagcagt ggcctgctgg tcaccctctc ggccaacgag   1380 

agtctggaag taatggacga gctggaggtg gagccacact cggtgctcct tcaggatgtc   1440 

ctcggcgaag gagcctttgg cttggtgcga cgtggagttt acaagaaacg ccaagtggcc   1500 

gtcaagttgc tgaaagatga accaaacgac gaggacgtat atgcgttcaa gtgcgaaatt   1560 

cagatgctca aggccgtggg caagcatcca aatattgtgg gtatcgtggg atactccact   1620 

cgttttagca accagatgat gttgctaatt gaatactgca gccttggaag cctgcagaac   1680 

tttttacgtg aggagtggaa gttcaggcag gagcaaaatg caattggact taagaagaac   1740 

cttgaacaga acgtggacaa ccgacggttt aaccgactcc ctagaaattc catccatgat   1800 

cgcatagagg atatcaacaa ctcgatgctg tccactgtgg aagaggagag tgaatcggat   1860 

cagacacact caagtcgatg tgagacctac accctcactc gaataaccaa tgcagccgac   1920 

aacaagggct atggcctgga ggacattgaa aacatcggtg ggagttacat tcccaaaacc   1980 

gctgaagctc caaaggatcg gccaaaacgg aagctgaagc cgcagcccaa gaaagactcg   2040 

aagcaggatt tcaaatcgga caacaagaag cgaatctttg agaacaagga atactttgat   2100 

tgcctcgact catcggatac caagccccga ataccactga aatatgcaga tttgctagac   2160 

atcgcccaac aggtggcggt gggaatggaa tttctggccc aaaacaaagt agtgcatagg   2220 

gatctggctg cccggaatgt tctaatctcc gtagatcgca gcatcaagat agcagatttt   2280 

gggctgagtc gagatgtgta tcatgagaac gtgtaccgaa agtccggagg aagtggcaag   2340 

ctgcccatca agtggctcgc gctggagtcc ctcacccacc aggtgtacac cagtcagagc   2400 

gatgtttggt cctttggtgt gctgctctat gagatcacca ctctcggtgg aatgccatat   2460 

ccgtcggtgt ctcccagtga tctcttgcag ctactgcgac aaggtcatcg gatgaagcga   2520 

ccggagggat gtacgcaaga aatgttttcc ctgatggaaa gctgctggag ctccgtgcca   2580 

tcacacaggc caacattttc cgcccttaaa cacagacttg gtggcatgat tttggccact   2640 

aacgatgttc cagaaaggct gaaacaactg caagctgcaa ccgagtcaaa attaaagtca   2700 

tgtgacggtc taaacagtaa agtggagcaa gtgccatgcg aggaagagct atacctagaa   2760 

cctttgaatt aa                                                       2772 

 
           
             16  
             5229  
             DNA  
             Drosophila melanogaster  
           
            16 

atgttcaata tgccacgggg agtgacaaaa agtaaatcca agcgtgggaa aattaagatg     60 

gaaaacgata tggcagcagc agcaacaaca acagcctgca cgcttggaca catttgtgtt    120 

ttgtgccggc aagaaatgtt gctggataca tgttgctgcc ggcaagcagt agaagcagtt    180 

gacagccccg caagcagtga agaagcgtat agcagtagca acagcagcag ctgtcaagca    240 

agcagtgaaa tcagtgcgga ggaggtctgg tttctcagtc atgatgatat cgtactgtgc    300 

cgcagaccaa aatttgacga agtggagacg acgggtaaaa agagggacgt taaatgcagc    360 

gggcatcagt gcagcaatga atgcgacgat ggcagcacga aaaacaatcg acaacagcgc    420 

gaaaacttca atatctttag caactgtcac aatattttgc gaacattgca atcgctgctg    480 

ctgctcatgt tcaattgcgg cattttcaac aagcgacgca ggcggcagca tcagcagcag    540 

catcatcatc attatcagca tcatcatcag cagcatcatc agcagcatca tcagcggcag    600 

caagccaatg ttagttacac aaaattccta ttgctgctac aaacactggc agcagcaacc    660 

acaagactga gtttaagccc taaaaactac aaacaacaac aacaactaca gcataaccaa    720 

cagctgccac gtgccacacc gcaacaaaag caacaagaga aagataggca taagtgcttt    780 

cactacaagc acaattactc ttactcgcct ggcattagcc ttctactctt tatcctactg    840 

gccaacacat tggccatcca agcggtcgtg ttgccagcac atcagcagca cctgctgcac    900 

aatgatatag ccgatggact ggataaaaca gcgctttcgg tgtcggggac gcaatcgcga    960 

tggacaagga gcgaatcaaa cccaacaatg cgactgtcac aaaatgtaaa accttgcaaa   1020 

tccatggaca tcaggaacat ggtgtcgcac ttcaatcagc tggagaactg cacggtcatc   1080 

gagggcttcc tgctgatcga tttgataaac gacgccagcc ctctgaacag aagctttcca   1140 

aaactgaccg aggtcacaga ttatatcata atctaccgtg tgactggatt gcactcgctg   1200 

tcaaagatct ttcccaatct gagcgtcatt aggggaaaca agctgttcga cggatatgcc   1260 

ttggtcgtct actcgaattt cgacctcatg gatttgggac ttcacaagct acgatccata   1320 

accagaggcg gtgtgcggat tgagaagaat cataagctgt gctatgatag gaccatcgat   1380 

tggctggaaa ttctggcgga aaacgaaacc caactggtgg tgctgacaga gaacggcaag   1440 

gagaaggagt gcaggctttc caagtgcccg ggggagatca gaattgagga ggggcacgat   1500 

accacggcta ttgagggaga gcttaatgcc agttgtcagc tgcacaataa taggcgcctg   1560 

tgctggaaca gcaaactctg ccagacgaaa tgccctgaaa agtgcagaaa taactgcatc   1620 

gatgagcaca cctgctgcag ccaggattgt ttgggtggat gcgtgatcga taagaatggg   1680 

aatgagagct gcatctcctg tcgaaatgtg tctttcaaca acatctgtat ggactcctgt   1740 

ccgaaaggct attatcagtt cgacagccgc tgcgtaacgg cgaacgagtg catcacactg   1800 

acaaagtttg aaacgaacag tgtgtattcc ggtattccat acaacggaca atgtatcacc   1860 

cactgtccaa cggggtacca gaagtcagag aacaagcgca tgtgcgaacc ttgtccgggc   1920 

ggcaagtgtg acaaggagtg ctcctccggt cttatcgaca gtttggagcg tgctcgggag   1980 

ttccacggct gcaccattat aaccggaacc gagcccctta ccatcagcat taaacgtgaa   2040 

agcggcgctc acgtcatgga tgaattaaaa tatggcctgg ctgccgtcca taaaattcag   2100 

tcgtccctaa tggttcattt gacctacgga ttgaagtcct tgaaattctt tcaatcccta   2160 

actgaaatta gcggcgatcc gccgatggac gcggataaat atgctttgta tgtgcttgat   2220 

aatcgcgatc tagatgagct ctggggaccc aaccaaacgg tgttcattag gaagggcggc   2280 

gtcttctttc atttcaaccc aaaactatgt gtgtccacca ttaaccagtt gctgcccatg   2340 

ctggcctcca agccaaagtt ttttgaaaag tcagatgtgg gcgcagactc gaatggaaac   2400 

cgcggatcat gtggaacagc cgttctcaat gtcacattac aatcagtggg agcaaactcc   2460 

gctatgctga acgtcacgac aaaagttgaa ataggagagc cccaaaagcc gagcaatgct   2520 

acaattgttt ttaaggatcc gcgcgccttc atcggtttcg tgttttatca tatgatcgat   2580 

ccgtacggga actcaactaa aagcagtgac gatccatgcg atgatcgctg gaaggttagc   2640 

tctccggaaa agagcggggt catggtatta agcaatttga ttccgtacac taactactcc   2700 

tactacgttc ggaccatggc tatatcctcg gaattgacaa acgcggagag cgacgtgaag   2760 

aactttagga cgaatcccgg acgaccgtca aaggttacgg aggtggtagc aaccgccatt   2820 

tcagattcga aaattaacgt aacatggagc tacctagata agccttatgg cgtgctaacg   2880 

cgctatttta taaaagccaa acttataaat cggcctactc gaaacaataa ccgggattac   2940 

tgtactgaac ctctcgtcaa ggccatggaa aatgacctgc cagccacaac gcctaccaag   3000 

aaaatatcag atcctttagc aggcgactgt aagtgcgtgg agggttcgaa gaagactagc   3060 

agtcaggaat acgatgatcg taaagttcaa gcgggcatgg agtttgagaa cgcgttgcaa   3120 

aactttatat ttgttccaaa cattcggaaa agcaagaatg gatcgtctga caaatcagac   3180 

ggagcggaag gtgcagctct cgattctaat gctattccaa atggaggagc tactaaccct   3240 

tcacgtagaa ggagagacgt tgcgctcgag ccagagctcg acgatgtaga gggcagtgta   3300 

cttctacgcc atgtgcgctc catcacagac gataccgatg catttttcga aaaggacgac   3360 

gaaaatacct ataaagacga agaagacttg tcctccaaca aacaattcta tgaggtgttt   3420 

gccaaggaat tgccaccaaa tcaaacacat tttgtctttg aaaaactgcg ccacttcacc   3480 

cgctacgcta tcttcgtggt agcctgtaga gaagaaatcc ccagcgaaaa attaagggac   3540 

accagtttta agaagtcgct ctgcagcgat tatgacaccg ttttccaaac tacaaagaga   3600 

aagaaatttg ccgacatagt catggaccta aaagtagatt tagaacacgc caacaacacc   3660 

gagtccccag tacgggttcg ctggacgcca ccagtagatc ccaacggaga aattgtcacc   3720 

tatgaagtgg cctacaagtt gcaaaaaccc gatcaagtgg aagaaaagaa gtgcattccg   3780 

gctgctgact tcaaccagac tgccggttat ttaataaagc tcaacgaggg cctttacagc   3840 

ttcagggtgc gagccaattc aatagcggga tacggcgatt tcacggaagt cgaacatata   3900 

aaagttgagc ctccgccgag ctatgctaag gtctttttct ggctactggg aatcggccta   3960 

gcgttcctga tcgtttccct gttcggctat gtctgttacc tgcacaagag gaaggttccc   4020 

tctaatgacc ttcatatgaa cacagaggtg aatccgttct atgcgagcat gcaatacatc   4080 

ccagacgatt gggaggtgct gcgagagaac atcattcagt tggctccact aggccaggga   4140 

tcctttggca tggtgtatga gggtatcctg aagtcctttc cacccaatgg cgtggatcgc   4200 

gagtgtgcca ttaagactgt caacgaaaat gctacggatc gcgagcgaac caatttcctg   4260 

agcgaggcga gcgtcatgaa ggagttcgat acgtatcatg tcgtaagatt gctcggtgtt   4320 

tgctccaggg gtcagccggc tctggtggtc atggagctaa tgaagaaggg tgatcttaag   4380 

tcctatttgc gtgcccatcg tcccgaggag cgggatgagg ccatgatgac gtatcttaat   4440 

cgcatcggag tgactggtaa tgtgcagcct cctacttatg gaagaatcta ccagatggcc   4500 

attgagattg cggatggcat ggcatatttg gccgccaaga agttcgtcca tcgtgatctt   4560 

gcagctcgaa attgcatggt tgctgatgat ttgacggtga aaattggtga ctttggaatg   4620 

acccgtgaca tctatgagac ggattactat cggaagggca ctaaagggct gctgccagtt   4680 

cgctggatgc caccggagag cttgcgagat ggtgtctact ctagtgccag tgatgtattc   4740 

agctttggag tggttctctg ggaaatggcc accttagcgg ctcagccata ccagggactt   4800 

tccaacgagc aagtcctgcg ttacgtcatc gatggcggtg ttatggagag gccggaaaat   4860 

tgtcctgatt ttctgcataa actaatgcaa aggtgctggc atcataggtc ttcggcgaga   4920 

cccagttttc tggatatcat tgcgtatctc gaaccacaat gccccaattc acaatttaag   4980 

gaagtatcct tctatcactc agaggcaggt ctgcagcatc gggaaaagga gcgcaaggaa   5040 

cgcaatcagc tagatgcatt cgcggcagtc cccttggatc aagatctgca ggatcgggaa   5100 

cagcaggagg atgctaccac acctttacga atgggcgatt atcagcagaa ctcctcgttg   5160 

gatcaaccgc ccgaaagccc catcgccatg gttcctgcca tccggattca ttgcgagcag   5220 

tactcctga                                                           5229 

 
           
             17  
             2058  
             DNA  
             Drosophila melanogaster  
           
            17 

atgaacaaat actcggcatt tatagtctgc atttcgctcg tgcttttatt tacaaaaaag     60 

gatgtgggga gccataatgt ggactcaaga atatatggtt tccagcaatc atcaggtatt    120 

tgccatattt acaatggcac catttgtcgc gatgtcttga gcaatgccca tgttttcgta    180 

tcccccaatc tcaccatgaa cgatttggag gagcgattaa aggcagctta tggagtaatc    240 

aaggaatcca aggatatgaa cgcaaattgc cgcatgtacg ctttgcccag cttgtgtttc    300 

agttcaatgc caatttgccg gactccagag cgcacgaatc tcttgtactt cgccaacgtg    360 

gccacaaatg ccaagcaact gaagaacgtc agcattcgac ggaagagaac caagtccaag    420 

gacattaaga acataagcat attcaagaag aagtccacca tctacgagga tgtgttcagc    480 

acagacatat cgagtaaata cccaccaacc agagagtctg agaacctaaa acgcatttgc    540 

cgcgaagagt gcgaacttct ggagaacgag ctgtgccaga aggaatatgc cattgccaag    600 

cgacatcccg tcatcgggat ggtgggtgtg gaggattgcc aaaagttgcc gcagcacaag    660 

gactgcctat ccttgggcat caccatcgag gtggataaga cggagaattg ttactgggag    720 

gatggatcga catatagagg agtggccaac gtctccgcat ccggaaagcc atgtttgcga    780 

tggtcatggc tgatgaagga aatctccgat ttccctgaac tcatcggtca gaattattgc    840 

agaaatcctg gaagcgttga aaatagtcct tggtgttttg tggactcctc acgtgaacgc    900 

ataatcgaac tttgtgatat tccaaaatgt gcggacaaaa tatggattgc cattgtcgga    960 

acgactgcag ccattattct aatattcata attatatttg cgataatact tttcaaaagg   1020 

agaacaatca tgcactatgg aatgaggaat attcataata tcaacacacc cagcgccgat   1080 

aaaaatatct acggaaattc gcagcttaat aacgcacaag atgctggcag gggaaatctg   1140 

ggaaatctat ccgatcacgt tgctttgaac tccaaactta tcgaaagaaa tactctgctg   1200 

aggataaacc attttacgct gcaggatgtt gagtttctgg aggagctggg cgaaggagct   1260 

tttggaaaag tctacaaggg acagctcctg cagccgaaca aaaccaccat aacagttgcc   1320 

atcaaggcgt tgaaggaaaa cgcctcggtg aaaacgcagc aggactttaa gcgcgaaatc   1380 

gaactaatct cggatctaaa gcatcagaat atagtgtgca tattgggcgt agtgctcaat   1440 

aaggagccct actgcatgct gttcgagtac atggccaatg gtgatctgca cgaattccta   1500 

atctcaaact cacccaccga aggcaagtcg ctgtcgcagt tggaattcct gcaaatagct   1560 

ctacaaatca gcgaaggaat gcagtatctg tcggcccatc attacgtaca tcgcgacttg   1620 

gcagctcgga attgcctggt aaacgagggt ctggttgtga agatatccga ttttggacta   1680 

tccagagaca tttacagctc agattattat cgagttcagt caaagtcgct attgcctgta   1740 

aggtggatgc cctcggaatc gatattgtat ggaaagttta cgaccgagag cgatgtttgg   1800 

tcctttggag tcgttctttg ggaaatatac agctatggaa tgcagccata ctacggtttt   1860 

agcaatcagg aagtaatcaa tctcatccgt tcacggcaac tgctctccgc tccggaaaac   1920 

tgtcccactg ctgtctactc gctaatgatc gagtgctggc atgagcagtc agtaaaacgt   1980 

ccaacattca cagatatttc gaaccgtctc aaaacttggc acgagggcca ctttaaggcc   2040 

agtaatccag aaatgtaa                                                 2058 

 
           
             18  
             1554  
             DNA  
             Drosophila melanogaster  
           
            18 

atgggtaact gcctcaccac acagaagggc gaacccgaca agcccgcaga tcgaatcaag     60 

ctggacgacc cgcccaccat cggagtcgga gtgggcgtgc cacaaatccc catgccctca    120 

cacgccggac agccaccgga gcagatacgt ccggttcccc agatcccgga gagcgaaacg    180 

gcaggtgcca acgccaagat ttttgtcgcc ctctacgact acgacgcccg caccgacgag    240 

gatttgagct tccgcaaggg agagcacttg gagatactga atgacacgca gggtgactgg    300 

tggctggcgc ggagcaagaa gacacgttcg gaaggctaca ttccatccaa ttatgtggcc    360 

aagttgaaat caatcgaagc agaaccgtgg tacttccgca aaatcaaacg cattgaggct    420 

gagaaaaaac ttctactgcc agagaacgag cacggtgcat ttttaattcg cgattccgaa    480 

agccgtcaca acgactactc gctatcagtg cgcgatggcg atacggttaa gcattatcgc    540 

atcagacaat tggacgaagg cggcttcttc atcgccaggc gcacgacatt cagaaccctt    600 

caggagctgg tggaacacta ttcgaaggac tctgatggcc tatgcgtcaa cctctgcaag    660 

ccgtgtgtcc agatcgagaa gcctgtaact gaggggcttt cgcaccgcac tcgcgatcag    720 

tgggagatcg acagaacgtc tttgaaattc gtgcgcaaac tgggctccgg acagtttggc    780 

gatgtctggg agggattgtg gaacaacaca acacctgtgg caattaaaac tctgaaatct    840 

ggtacaatgg accccaagga tttcttagcg gaagcccaga tcatgaagaa actgcgccac    900 

accaagctta tacagttgta cgctgtctgc actgttgagg agcctatcta tattatcaca    960 

gagttaatga agcacggttc actgttggaa tatctccaag ccattgcagg caagggtcgt   1020 

agccttaaaa tgcaaactct gattgatatg gcagcgcaaa tagctgctgg catggcttac   1080 

ttggagtccc agaattatat tcatagggat ttagcggcgc gcaatgtact ggtaggcgat   1140 

ggaaacatcg tcaaaatcgc cgactttggt ttagctaggc tcatcaagga ggacgaatac   1200 

gaggcgcggg taggcgccag atttcccata aaatggaccg ctccagaggc tgctaactac   1260 

agcaaattct caataaaatc ggatgtttgg agctttggca ttcttctcac agaactggtc   1320 

acctacggac gcataccata tccaggcatg accaacgctg aggtgctaac gcaagtggag   1380 

cacggctatc gaatgccgca acctcccaac tgcgagccgc gcctgtatga gattatgctg   1440 

gaatgttggc acaaggaccc catgcgcaga cccacgtttg agacgctaca atggaaactg   1500 

gaagacttct atacatctga tcagagcgac tacaaagagg cgcaggccta ctga         1554 

 
           
             19  
             1779  
             DNA  
             Drosophila melanogaster  
           
            19 

atgatcaagt gcgccctgaa cgaggtggga tgcgaggagc tgccctccgg ttgcgacgat     60 

gacctcaccc tggagcagaa cttcatcgag aatggctata acaacgaaca gcagagcaat    120 

agcaatcaca gtgcctcaca gtccacgata ataacgagca cgatcaccac caccataacg    180 

actacaacta ccacgacgcc gtccaaggaa aactcaagac tgaaattcaa agtgcccaag    240 

atccagaaga aatcaaaggc catccgcaat acattccgct ccaagttgct caatttccag    300 

ttgaagcgct ccaagccgtg caaacagtgc accaagagac gtcgcatcca tcccagcaaa    360 

agtgtctttg attttgccaa agagttcgag gtggaacaac cggctggttc ggcggcggat    420 

gagcaattct gcaactgtcc gccagctggt caaaagcctg ttaagccatc cgtccaaata    480 

tccggccaca aagatcaccc gttcgagtcc agttctggag agctggacga gaactcggat    540 

cgggacatcg acaacgacga ggaggaggag gatagcgcca gtgacgacgt gctcagcatg    600 

aaggatcact gctattgcgt gcccagcctg gcggccagta tatcgctctc cacaaatcgt    660 

ccgctttacg aggaggaatg gttccatggc gttctgccgc gcgaggaagt ggttcgattg    720 

ctgaataacg atggtgactt cctggtccgc gaaacgattc gaaacgagga gagccagatt    780 

gtgctcagtg tctgttggaa tggccataag cacttcattg tccagaccac cggagagggt    840 

aatttccggt tcgagggacc accatttgcc agcatccagg agctgatcat gcatcagtat    900 

cactcggaat tgccagtgac cgtgaaatcg ggagccatac tccgacgacc cgtttgccgg    960 

gagcgctggg agctgagcaa cgatgatgtg gtacttctgg agaggattgg tcggggaaac   1020 

tttggggatg tctacaaggc caaactgaag tccaccaaac tggatgtggc tgtcaaaacc   1080 

tgtcgaatga ccctgcccga cgaacagaag cgtaaattcc tacaggaagg gcgcatcctc   1140 

aagcaatacg atcatccaaa tatcgtaaaa ttgattggca tttgtgtgca gaagcagccc   1200 

atcatgattg tcatggaatt ggtgctcggt ggttcgcttt taacttattt acgcaagaac   1260 

tccaatggcc tcaccactcg ccaacaaatg ggcatgtgca gagatgcggc ggcaggcatg   1320 

cgatatctgg agtccaaaaa ctgcattcat cgcgatctgg cggcgcgtaa ttgtctcgtt   1380 

gacttggagc acagtgtgaa gatctccgat ttcggaatgt ctcgcgagga agaggaatat   1440 

atagtttccg atggcatgaa acaaatacct gtgaagtgga cagctcccga ggccttgaat   1500 

ttcggcaagt acacttcgtt gtgcgatgtg tggtcctatg gcatactgat gtgggagatc   1560 

ttctccaagg gcgacacacc ctactccggc atgaccaact ccagagccag agagcgcatc   1620 

gatacgggat atcgtatgcc aacgccgaag agcacgcccg aggagatgta ccgactgatg   1680 

ctccagtgct gggcagccga cgccgaatcc cgaccgcatt tcgatgagat ctacaatgtg   1740 

gtggatgcac tgattctgcg cctggacaac agccactaa                          1779 

 
           
             20  
             2685  
             DNA  
             Caenorhabditis elegans  
           
            20 

atgcaccatc ccaaagaaac gcttcttatc gattcatcta atccttctta ctcccacctc     60 

accgagtacc gttttgataa cctgaaacgt gaagagtctc gatcgacctc actttttggc    120 

gacaggagaa gagtgatgaa aatcctgagt ggattttccc tcattattat tgtcgttttc    180 

atatttgcta caagtcatga acaggcgctc tctaccactg gagacctcac ttcgagtact    240 

cagagtacta cacatggagg tgttgtcttt acatatccaa ctacaagaaa atctcccggt    300 

aaaggatgtg tcctgaattc gcagagatca acgcctaaaa acttgaaaca gtacactgga    360 

aacatttcag acgcttgttt agccggaata aaatcaagta actgtaagac atggctaatg    420 

acaaatgcgg tgattttgaa atactcagac gatgttgtca gcaattgccc ttcgattttg    480 

gaatttgtga ataaaacatc gttatcatgt tcgggtaaaa gtcagattca atatatgtat    540 

cctcagagtg attctgcgtc aagtgattgc aatcactctt atgacttcaa ctcaaatgct    600 

ctgaacagag caatatataa cttcaactac agcaagacct taatctccac gtcatatgcc    660 

aatactcctg gattcgctat gtatacattt ttgctgaaga ttatgaactg tgtcaacaaa    720 

aacggaataa aacttgacgc cggaattctc aacattttta cggacatgac ctatattgat    780 

ttatgtgaaa gtgatgtttt catgagctcg tttccagata ctctgaacaa gcttattgag    840 

gcggggtata ttgtcaaatt ttatttcctg aatcaaaatt tgcaagatac tcaaaaaaac    900 

gttgaaaacg tactagctgg atgtaaatac atgaattcaa gatcgtactg cgaaattgta    960 

gactggagct atcattcgga aaatcctaat gagtttgaaa tttgcatccc agattcacag   1020 

cccagtggga agaaagaaga ctttaattgg caacttcttc taattattgg tataccttgt   1080 

ataagtttga caatttgctg cattgcattt ttcgtttgtt gcttgaaatg tgctaaactg   1140 

aaaatggcaa tgatgagaat gaatgtattc tcaaatgata ctcaccaaaa tcctgatgaa   1200 

atggagctga aaaagagatg gatcgggatg agaaagaaat tcaataaaga tgttgagaat   1260 

ggaagttgta aagagttaaa cacccaaaaa tggtctcact tcgcatcggc gaacaattac   1320 

atggacatac aagcattggc aaatgctaat aaaaaagata tatgggaaat tgacacaaaa   1380 

aatctgctcg tccaggaaga ccatctcctt ggaaacggtg catttgcaaa cgtctataag   1440 

ggaatcgtaa aaggaaaaat accactacta gttgtaaata atagtctcaa catgaccgta   1500 

gaatcagaaa acaatggtca ctatgaagct gccatcaaga agttaccagc ccatgctgac   1560 

gagcagaacc atttggattt tttccatgaa attgatttta tgaagcgttt gggccatcat   1620 

ccacatgtca tcagcatgtt gggatgtgtg tcaaatccat atgagccatt gatcgtggtg   1680 

gagtattgcg cacgtggtga cctgttgaag tttttgagaa gacataaaga ttatgtgctg   1740 

atgaatcgtg tacatattga attatgtata agtatataca agttcaaatt aaaacttaga   1800 

ccgaacattg agatttcaaa aatcagtttc cagaacaaaa cagacgattg tccaattgaa   1860 

gcagacatgt gtctcagaat caaagatttg gtttctattg cttggcaagt tgccgatgga   1920 

atgtcatacc tggcatcaaa aaactttatt caccgtgatt tagctgcccg taacattctg   1980 

ctcacaaaaa gtttaactgc aaaggttagt gacttcggtc tatgtcggta tatggattca   2040 

gcactttata ccgcaaaggg gggccgtctc cccatcaaat ggatgtctgt agaagcattg   2100 

aaactgtacg aattctccac aaaaactgat gtttggtcgt ttggagtgtt gttgttcgag   2160 

attttctcca tgggagatgt tccgtatcca acaatacaac aagtagatat gctggaacac   2220 

cttctcgctg gtggccgctt gtcacagcca ttgaaatgtc cgaatgagat atttaatatc   2280 

atgcagaaat gttgggccga aaagcctgaa gacagaccag agtttaatga aatgagagga   2340 

gaaatcacag tgatgttgaa cttggacgat gaaagttatg gatatcttag cgtcgagtca   2400 

cagggtggtc caaagtatac acaattaaca atgcaagatt caaaggaaac agctccatgc   2460 

tccactcctg gaggatcaca agatatggac gaagacgggg attatgatag tggctcagaa   2520 

ggccactcgc aaggaacttg tgctcagctc gaccaggttt tgactgagag atttggtgaa   2580 

gaacagaaga aggaaatcaa gcaaatcttt tgtgagatca cttcgaaatc aatgcgaggc   2640 

aaacgccgtc aatcgaattc tacagtcagc acgtatcaat cttga                   2685 

 
           
             21  
             2376  
             DNA  
             Caenorhabditis elegans  
           
            21 

atgtttcagg agaatgcagt caccaattgg gaatgtcaaa tcgaaagatt cgtgatgagc     60 

aaatctcggc gtcttcgagt ttcgacttgc aaagcactgg acctcaacat gctcggtaag    120 

tggtttggga actactcatt tgaaattcgt actacagctc atcaagaatc tggaagtggt    180 

gcctggtgtc cgaagaatca aataaactct ctcagcaaag aatggttgca gatttcgttt    240 

tccgtggata cagtaataac ttctgtggag acccagggac gatttgacga cggacgtgga    300 

atggagtatg cgaccgcatt caaaattcag tactggcgac cttcgctaaa cgcatgggca    360 

tcttataaag acgattttga gctagagaca attcctgcta ataatgacac ggagcacgca    420 

atccggcgac atcttgaccg ggcaatcata gcaagaagaa tcagaattgt tccagtttca    480 

aattccacca gaactgtttg catgagagtt gaagttttcg gatgcccatt tgatgatagt    540 

ctcgtgtttt acaatgtcga tcaaggcgat ttgcaatctg gcatctctta tcacgacttt    600 

tcctacgatg gtaatctcgc caactctcca cacttaaccg gcggtattgg gaagttatac    660 

gacggcgaag tgggaaaaaa caatgtattt gttaatcacc acaaatgggt tggatggaga    720 

cgtaaaagaa atggcaatgt gaagttggca tttgagtttt ccgaattgag aaatatatca    780 

gggattttga ttcatacgtc gaacgagttc aaaaagagcg caaaggcatt ttcctcggct    840 

actgtgctat tttcgataaa tggaaaagac ttctcagaca ccatcgtaca cttcaataat    900 

ccggaagata ccgaatcaga ggtacctcga tggataagga ttccagtgaa caatcggatt    960 

gccaaagttg caaagattcg tcttaacttt ggaactgact ccgactggct gttcatttct   1020 

gaagtgaatt ttgaatcaaa tcacacaaat attgagcttc tcaatgatga cgtggttatt   1080 

cccgattcgg tttcatattt ctccgtaacc gagcacgatg acggaactag catgtttgct   1140 

ttcattatct tcttcttcat gttcctcatc gtggcagtca ttattctgac agttctctac   1200 

cgtaaacgcg agtatcgtgt gaaagcatcg tctccatctc caaatgcgaa acgggaaatt   1260 

ctgttgacaa ttgacggaaa caccatcaag catcacgttt ctccgtcaac ctatcaaatg   1320 

gctcgcgata atcttcagaa tgcgttgatt gagaaaatgc ccatgtcacc gattataagc   1380 

gattacgctg aaccggacat tagtgtttgc tccgatgtca ccgccaacac tccattgctc   1440 

tatggaattg atggtccata tgatacacag aagagaagca accctttgtc atctatggta   1500 

aaatactccg attatggaga ggtttattgc acaacacttc cggaaattgc tcgagacaag   1560 

ttgatttgcg tgagcagaat tgggcaagga gagtttggtg aagtcgattt gtgtcagctt   1620 

gaaaaccgaa aagttgcggt caaaaaactt catggaatca gtcaagccga cgagttttct   1680 

tttcatagag aaattcgagt attaggaagt ctcaaacatc cgaacgtagt tgaagtcgtc   1740 

ggagtatgca ctatacaaaa accaatactc tgtatcatgg aatatatgga aaatggcgac   1800 

ttgaaatcct acattttgaa aaaccctact atacaaacct cccaatgcat ctcaatttgc   1860 

acacagcttg ccgcaggact tgcctatttg gaatcatgta attttgtgca tagagatatt   1920 

gctgctcgaa attgccttgt tgacggagaa ggcaatgtaa aaattgccga tttcggaatg   1980 

gcccgatctc tttattctca agaatattac aaagttgagg gaaagtttgt gctcccgatt   2040 

cgctggatgg catgggaagc tttgctactc ggcaaatttt ccactgccag tgatgtttgg   2100 

ggattcggag ttaccatgtg ggagatcttc tcgctgtgct ccgaaaaacc atactccgat   2160 

atgacagatg atgatgtggt ggagaatctt cagagcatga gctctactgg atcattaaag   2220 

caagttcttt cccgaccaag gatgtgtcca tcaaagttgt acaacgagca aattcttccg   2280 

tgctggaact atgagagcag tcgccgaccc agtttcgaga acgtccatct tcacctccag   2340 

tcattggtgc acacttctcc tcatattcat ttttaa                             2376 

 
           
             22  
             3390  
             DNA  
             Mus musculus  
           
            22 

atgggaatgg cctgccttac aatgacagaa atggaggcaa cctccacatc tcctgtacat     60 

cagaatggtg atattcctgg aagtgctaat tctgtgaagc agatagagcc agtccttcaa    120 

gtgtatctgt accattctct tgggcaagct gaaggagagt atctgaagtt tccaagtgga    180 

gagtatgttg cagaagaaat ttgtgtggct gcttctaaag cttgtggtat tacgcctgtg    240 

tatcataata tgtttgcgtt aatgagtgaa accgaaagga tctggtaccc acccaatcat    300 

gtcttccaca tagacgagtc aaccaggcat gacatactct acaggataag gttctacttc    360 

cctcattggt actgtagtgg cagcagcaga acctacagat acggagtgtc ccgtggggct    420 

gaagctcctc tgcttgatga ctttgtcatg tcttaccttt ttgttcagtg gcggcatgat    480 

tttgtccacg gatggataaa agtacctgtg actcatgaaa ctcaggaaga gtgtcttggg    540 

atggcggtgt tagacatgat gagaatagct aaggagaaag accagactcc actggctgtc    600 

tataactctg tcagctacaa gacattctta ccaaagtgcg ttcgagcgaa gatccaagac    660 

tatcacattt taacccggaa gcgaatcagg tacagatttc gcagattcat tcagcaattc    720 

agtcaatgta aagccactgc caggaaccta aaacttaagt atcttataaa cctggaaacc    780 

ctgcagtctg ccttctacac agaacagttt gaagtaaaag aatctgcaag aggtccttca    840 

ggtgaggaga tttttgcaac cattataata actggaaacg gtggaattca gtggtcaaga    900 

gggaaacata aggaaagtga gacactgaca gaacaggacg tacagttata ttgtgatttc    960 

cctgatatta ttgatgtcag tattaagcaa gcaaaccagg aatgctcaaa tgaaagtaga   1020 

attgtaactg tccataaaca agatggtaaa gttttggaga tagaacttag ctcattaaaa   1080 

gaagccttgt cattcgtgtc attaattgac gggtattaca gactaactgc ggatgcgcac   1140 

cattacctct gcaaagaggt ggctccccca gctgtgctcg agaacataca cagcaactgc   1200 

cacggcccaa tatcaatgga ttttgccatt agcaaactaa agaaggcggg taaccagact   1260 

ggactatatg tgctacgatg cagccctaag gacttcaaca aatactttct gacctttgct   1320 

gttgagcgag aaaatgtcat tgaatataaa cactgtttga ttacgaagaa tgagaatgga   1380 

gaatacaacc tcagcgggac taataggaac ttcagtaacc ttaaggacct tttgaattgc   1440 

taccagatgg aaactgtgcg ctcagacagt atcatcttcc agtttaccaa atgctgcccc   1500 

ccaaagccaa aagataaatc aaaccttctc gtcttcagaa caaatggtat ttctgatgtt   1560 

cagatctcac caacattaca gaggcataat aatgtgaatc aaatggtgtt tcacaaaatc   1620 

aggaatgaag atttaatatt taatgaaagt cttggccaag gtacttttac aaaaattttt   1680 

aaaggtgtaa gaagagaagt tggagattat ggtcaactgc acaaaacgga agttcttttg   1740 

aaagtcctag ataaagcaca taggaactat tcagagtctt tcttcgaagc agcaagcatg   1800 

atgagtcagc tttctcacaa gcatttggtt ttgaattatg gtgtctgtgt ctgtggagag   1860 

gagaacattc tggttcaaga atttgtaaaa tttggatcac tggatacata cctgaagaag   1920 

aacaaaaatt ccataaatat attatggaaa cttggagtgg ctaagcagtt ggcatgggcc   1980 

atgcattttc tagaagaaaa atcccttatt catgggaatg tgtgtgctaa aaatatcctg   2040 

cttatcagag aagaagacag gagaacgggg aacccacctt tcatcaaact tagtgatcct   2100 

ggcattagca ttacagttct accgaaggac attcttcagg agagaatacc atgggtacct   2160 

cctgaatgca ttgagaatcc taaaaatctc aatctggcaa cagacaagtg gagcttcggg   2220 

accactctgt gggagatctg cagtggagga gataagcccc tgagtgctct ggattctcaa   2280 

agaaagctgc agttctatga agataagcat cagcttcctg cacccaagtg gacagagtta   2340 

gcaaacctta taaataattg catggactat gagccagatt tcaggcctgc tttcagagct   2400 

gtcatccgtg atcttaacag cctgtttact ccagattatg aactactaac agaaaatgac   2460 

atgctaccaa acatgagaat aggtgcccta gggttttctg gtgcttttga agacagggac   2520 

cctacacagt ttgaagagag acacttgaag tttctacagc agcttggcaa aggtaacttc   2580 

gggagtgtgg agatgtgccg ctatgacccg ctgcaggaca acactggcga ggtggtcgct   2640 

gtgaagaaac tccagcacag cactgaagag cacctccgag actttgagag ggagatcgag   2700 

atcctgaaat ccttgcagca tgacaacatc gtcaagtaca agggagtgtg ctacagtgcg   2760 

ggtcggcgca acctaagatt aattatggaa tatttaccat atggaagttt acgagactat   2820 

ctccaaaaac ataaagaacg gatagatcac aaaaaacttc ttcaatacac atctcagata   2880 

tgcaagggca tggaatatct tggtacaaaa aggtatatcc acagggacct ggcaacaagg   2940 

aacatattgg tggaaaatga gaacagggtt aaaataggag acttcggatt aaccaaagtc   3000 

ttgccgcagg acaaagaata ctacaaagta aaggagccag gggaaagccc catattctgg   3060 

tacgcacctc aatccttgac ggagagcaag ttttctgtgg cctcagatgt gtggagcttt   3120 

ggagtggttc tatacgaact tttcacatac atcgagaaga gtaaaagtcc acccgtggaa   3180 

tttatgcgaa tgattggcaa tgataaacaa gggcaaatga ttgtgttcca tttgatagag   3240 

ctactgaaga gcaacggaag attgccaagg ccagaaggat gcccagatga gatttatgtg   3300 

atcatgacag agtgctggaa caacaatgtg agccagcgtc cctccttcag ggacctttcg   3360 

ttcgggtgga tcaaatgcgg gacagtatag                                    3390 

 
           
             23  
             3246  
             DNA  
             Mus musculus  
           
            23 

atggcacctc caagtgagga gacacctctg atccctcagc gctcttgcag cctctcatcc     60 

tcagaggcag gagccctgca tgtgctcctt cctccccggg gacctgggcc tccccagcga    120 

ttgtcattct cttttgggga ctacttggct gaggatttat gtgtgcgagc tgccaaggcc    180 

tgtggcatcc tgcctgttta tcattcgctt ttcgctctgg ccactgagga cttctcttgc    240 

tggtttcccc caagccacat cttctgcata gaggacgtgg acactcaagt cttggtctac    300 

aggctacgct tttatttccc tgactggttt gggctggaga catgtcaccg ctttgggctg    360 

cgcaaagatt tgaccagtgc catccttgac ttacatgttt tagaacatct ctttgctcag    420 

caccgcagtg acctggtgag tgggcgcctc ccggtgggcc ttagcatgaa ggagcaggga    480 

gagttcctga gcctggccgt gctggacttg gcccagatgg ctcgtgagca ggcccagcgc    540 

ccaggagagc tgctgaagac ggtcagttac aaagcctgtc tgccgcccag cctgcgcgat    600 

gtgatccagg gccagaactt cgtgacacgc aggcgcatcc gcaggaccgt ggtcttggcg    660 

ctgcgcgtgt ggtcgcctgc caggccgacc gctacggctc atggccaagt atatctggac    720 

ctggagcggc tacatccagc ggccaccacc gagaccttcc gtgtggggct cccgggcgcc    780 

caggaggagc cggggcttct gcgtgtggcg ggggacaacg gcatctcctg gagctccggg    840 

gaccaggagc ttttccagac cttctgtgac tttccggaaa tcgtggatgt cagcatcaag    900 

cagcccacgt gtgggtccgg cagggagcac cggctggtca ctgtcaccag gatggacggc    960 

cacatcctgg aagcggagtt tccggggctg cctgaggcgc tgtctttcgt ggccctcgtg   1020 

gatgggtact tccgcctgat ctgcgactcc aggcattatt tctgcaagga ggtggcggcg   1080 

ccacggctgc tggaggagga ggcggagctg tgccatggac ccatcacgtt agactttgcc   1140 

atccacaagc tgaaggccgc tgcgtccctc ccaggcacct atattctccg ccgcagcccg   1200 

caggactatg acagctttct tcttaccgcc tgcgtccaga ctcctcttgg ccccgactac   1260 

aagggctgcc tcatccgcca ggaccccagc ggggctttct ccctggttgg cctcagcagc   1320 

cccacagaag cctgcgggac gtgcttgcag tgctggaatt ctgggctgcg agtagacggt   1380 

gctgccctga acctaacatc ctgctgcgct cccagaccca aggaaaagtc caatttgatc   1440 

gtggtgcgaa ggggctgcac ccccgcgcct gcccctggct gctccccgtc ctgctgtgcg   1500 

ctgacacagc tgagcttcca cacaattcca acggacagcc tgggacacga gaacctgggt   1560 

cacggttctt ttaccaagat cttccgtggc cgcaggcggg aggtcgtgga tggtgagaca   1620 

catgactcgg aagtcctcct gaaggtcatg gactccagac atcggaactg catggagtct   1680 

tttctggaag ccgcaagctt gatgagccaa gtatcctacc cgcacctggt gttactgcac   1740 

ggcgtctgca tggctggaga cagcatcatg gtgcaggaat ttgtgtatct aggagcaatt   1800 

gacatgtacc tgcgcaagcg tggccacctg gtgtcagcca gctggaaact gcaggtgacc   1860 

aagcagctgg catatgccct taactacttg gaggacaaag gccttcctca cggcaacgtc   1920 

tcagcacgga aggtgctcct ggctcgtgag gggggtgatg ggaatccacc tttcattaag   1980 

ctgagtgatc ctggtgtcag tcccactgtg ctgagcctgg aaatgctcac cgacagaata   2040 

ccctgggtgg cccccgaatg tctccaggag gctcagacac tctgcttgga ggctgacaag   2100 

tggggctttg gagccaccac gtgggaggtg ttcagcgggg gacccgccca catcacctcg   2160 

ctggagcccg ccaaaaagct gaagttctat gaggaccagg gacagctgcc cgctctcaaa   2220 

tggacagaac tggcgggact tatcacacag tgcatggcgt atgatcctgg ccggcgcccc   2280 

tccttccgag ctatcctcag agacctcaac ggcctcatta catcagatta cgagctcctc   2340 

tcagacccca cacctggcat cccgagtcct cgagatgagc tgtgcggtgg cgcccagctc   2400 

tatgcctgcc aggaccccgc catattcgag gagagacacc ttaagtacat ctctttgctg   2460 

ggcaagggca actttggcag cgtggagctg tgccgctatg accccctgga caatacggga   2520 

cccctggtgg cagtgaaaca gctacagcac agcgggccag accagcagag ggacttccag   2580 

cgggagattc agatccttaa ggctctgcac agcgacttca tcgtcaagta ccggggagtc   2640 

agctatgggc caggtcgcca gagcctgcgg ttggtgatgg agtacctgcc cagcggctgc   2700 

ctgcgagact tcctgcagcg ccatcgcgcg gccctgcaca ccgaccgcct actgctgttc   2760 

gcttggcaga tctgcaaggg catggagtac ctgggtgcgc gccgctgcgt acaccgtgac   2820 

ctggctgcgc gcaacatctt ggtggagagc gaggctcatg tgaagatcgc ggactttggc   2880 

ctcgctaagc tgctgcccct gggaaaggac tactacgtgg tccgcgagcc tggccaaagc   2940 

cccatctttt ggtatgcccc ggagtcccta tctgacaaca tcttctcccg ccaatctgac   3000 

gtgtggagct tcggagtggt gttgtacgag ctcttcacct actgcgacaa gagctgcagc   3060 

ccatccgctg agttcctgcg catgatgggg cctgagcgtg aaggaccccc gctctgccgc   3120 

ctcctggagc tgctggcaga gggccgacgc ctcccaccac ctcccacctg ccccaccgag   3180 

gttcaggagc tcatgcagct gtgcgtggcg cccagccgca cgaccggcca gccttcggca   3240 

ccctga                                                              3246 

 
           
             24  
             1518  
             DNA  
             Mus musculus  
           
            24 

atggcaaggc gaagctcccg ggtctcctgg ctggcctttg aaggctggga atctagggac     60 

ctgcctcggg tgagccctag attgttcgga gcttggcacc ccgcgcctgc tgcagctagg    120 

atgccaacgc gctgggcccc tgggactcaa tgcatgacca agtgtgagaa ctctcgcccc    180 

aagcccggtg agctagcctt tcgaaagggt gacatggtga ccatcttgga ggcctgtgag    240 

gacaagagct ggtaccgagc caagcaccat ggcagtgggc aggaagggct gctggcggcc    300 

gctgctctgc gacagcggga ggccctctcc acagacccca agctcagcct catgccatgg    360 

tttcatggca agatctccgg ccaggaagcc atacagcagc tgcagccacc cgaggacggg    420 

ctgttccttg tgagggaatc agctcgtcac cctggagact atgtcttgtg tgtcagtttc    480 

ggccgtgacg tcatccacta ccgtgttttg catcgagatg ggcacctcac catcgatgag    540 

gccgtgtgtt tctgtaacct gatggacatg gtggagcact acaccaagga caagggggcc    600 

atctgcacca agctggtgaa gccaaggagg aaacagggcg caaagtctgc agaggaggag    660 

ctcgccaagg ctggctggct actcgacctg cagcatctga ctctgggagc acagattgga    720 

gagggggagt ttggagccgt cctacagggt gagtacctgg gacagaaggt ggctgtgaag    780 

aatatcaagt gtgatgtgac agcccaggcc ttcctggatg agacggctgt gatgacgaag    840 

ctgcagcaca ggaacctagt gcgactcctg ggtgtgatcc tgcaccacgg cttgtacatt    900 

gtcatggagc acgtgagcaa gggcaacctg gtgaacttcc tgcgcacgcg gggccgtgct    960 

cttgtgagca cctctcagct tctgcagttt gctcttcatg ttgctgaagg catggaatac   1020 

ctggagagca agaagctggt gcaccgggac ctggctgctc ggaacatcct ggtctctgag   1080 

gacttggtgg ccaaggtcag tgactttggc ttagccaagg cagagcgcaa ggggctggac   1140 

tcaagccggc tgccagtcaa gtggacggca cctgaggctc tcaaaaacgg gcggttctcc   1200 

agcaagtcgg atgtctggag ttttggggtg ctgttgtggg aagtcttctc ttatggaaga   1260 

gccccatacc ccaagatgtc gctaaaggag gtttcagagg ctgtggagaa gggttaccgc   1320 

atggagcccc ccgatggctg cccaggctct gtgcacaccc tcatgggtag ctgctgggag   1380 

gcagagcctg cgcgccgacc acccttccgc aaaatagtgg agaagctggg ccgtgagctc   1440 

cgcagtgtgg gtgtctcggc ccccgctggg ggacaggagg ctgagggctc agctcccaca   1500 

cggagccagg acccctga                                                 1518 

 
           
             25  
             1490  
             DNA  
             Mus musculus  
           
            25 

tggagccctt cctcaggaag cggctcactt tcttgtcctt tttctgggat aagatatggc     60 

cagcggatga atcggaggaa gacatcccca ggatccaggg acacgacgac aacccagtgc    120 

cggagcaagc cgctgccgtt gaaccttgta gcttcccagc cccacgcgcc cgactcttcc    180 

gcgcgctcta cgacttcact gctcgatgtg cagaggaact gagcgtcagc ggtggggaca    240 

gactctacgc cctcaaggag gagggggact acatctttgc ccaaaggctc tctggtccac    300 

ccagcaccgg actagttcct gtcacctacc ttgccaaggc taccccggag ccgccctcag    360 

accaaccttg gtacttcagt gggatcagca gggctcaggc ccagcagttg ctcttgtctc    420 

ctgccaatgc accaggggcc ttcctcatcc ggcccagcga aagcagcatc gggggctatt    480 

ctctatcagt cagggcccag gccaaagtct gccactaccg catctgcatg gcacccagtg    540 

gcagcctcta tctgcaggag ggccaactct tccccagcct ggatgcactg ctggcttact    600 

acaagaccaa ctggaagctg atccagaacc ctctgctgca gccctgcata ccccagatac    660 

ccttggttca ggacgagtgg gaacgaccac gttcagaatt tgtcttcgga agaaagctgg    720 

gtgaaggttt cttcggggag gtgtgggaag gcctgtggct gggctctatc cctgtggcag    780 

tgaaggttat caaatcagct gacatgaagc tggcagacct caccaaggag attgaggcac    840 

tgaagagctt gaggcatgag aggctgatcc ggctgcacgc tatatgttcc ctcggtgaac    900 

ctgtgtacat cgttactgaa ctcatgggca agggcaactt gcaagtctac ctgggcagct    960 

ctgagggaaa ggccctgagc ctgccccatc tactgggatt tgcctgccag gtagctgagg   1020 

gcatgagcta cctggaggag cggcgtgtcg tccaccggga cttggctgcc aggaacgtgc   1080 

tggtgggtga tgacctcacc tgcaaggtag ctgattttgg cctggccaga ctgctcaagg   1140 

atgatgtcta ctccccaagc agtggctcca agatccctgt caagtggacg gcacctgagg   1200 

ctgctaatta ccgtgtcttt tcccaaaagt cagatgtctg gtcctttggc atcctgctgt   1260 

atgaggtctt cacttatggc cagtgtccct atgaaggaat gaccaaccat gagacgctac   1320 

agcagattag tcgtggatac cggctgccac gcccagctgt ctgcccagca gaggtctatg   1380 

tgctcatggt agagtgctgg aagggcagcc ctgaggagcg tcccaccttt gccatactga   1440 

gggagaagct gaatgccata aacagacgcc tccatctggg cctcacgtga              1490