Abstract:
The present invention relates to the use of differentially expressed polynucleotide sequences or polypeptides for the characterization of stroke or progression thereof or progression of neurodegenerative processes as consequence thereof, a method for characterizing stroke, a method for identifying therapeutic agents for stroke and the use of such sequences for the development of a medicament.

Description:
RELATED APPLICATION  
       [0001]    This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60/366,353, filed Mar. 20, 2002. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The present invention relates to the use of differentially expressed polynucleotide sequences or polypeptides for the characterization of stroke or progression thereof or progression of neurodegenerative processes as consequence thereof, a method for characterizing stroke, a method for identifying therapeutic agents for stroke and the use of such sequences for the development of a medicament.  
         BACKGROUND OF THE INVENTION  
         [0003]    Stroke is a rather common and potentially harmful event that often leaves patients severely disabled for the rest of their lives. It is the result of either an interruption of blood and therefore oxygen supply to the brain, or bleeding in the brain that occurs when a blood vessel bursts. The reduced oxygen supply leads to shortage of energy in the affected brain regions and results in the death of neurons around the lesion. The degeneration spreads from the site that is affected by the reduced blood supply into regions which have at all times obtained sufficient oxygen.  
           [0004]    Stroke results from a loss of blood flow to the brain caused by thrombosis or haemorrhage. With an incidence of 250-400 in 100.000 and a mortality rate of around 30%, stroke is a major public health problem. About one-half of the stroke survivors suffer from significant persisting neurological impairment and/or physical disability. Thus, the economic costs of stroke amount to many billions of dollars worldwide.  
           [0005]    A stroke occurs when the blood supply to part of the brain is suddenly interrupted or when a blood vessel in the brain bursts. As a consequence, brain cells die when they no longer receive oxygen and nutrients from the blood or when they are damaged by sudden bleeding into the brain. Some brain cells die immediately after interruption of the blood flow into the brain, while others remain at risk for death and stay in a compromised state for hours. These damaged cells make up the so-called “ischemic penumbra”, and with timely treatment these cells could be saved. Stroke ultimately leads to infarction, the death of huge numbers of brain cells, which are eventually replaced by a fluid-filled cavity (or infarct) in the injured brain.  
           [0006]    There are two major forms of stroke: ischemic—blockage of a blood vessel supplying the brain, and hemorrhagic—bleeding into or around the brain. An ischemic stroke can be caused by a blood clot (embolus or thrombus), which is blocking a vessel. It can also be caused by the narrowing of an artery due to the build-up of plaque (a mixture of fatty substances, including cholesterol and other lipids). The underlying pathological process called stenosis is often observed in arteriosclerosis, the most common blood vessel disease. About 80% of all strokes are ischemic strokes. A hemorrhagic stroke is caused by the bursting of an artery in the brain. Subsequently, blood spews out into the surrounding tissue and upsets not only the blood supply but also the delicate chemical balance neurons require to function. Hemorrhagic strokes account for approximately 20% of all strokes.  
           [0007]    A transient ischemic attack (TIA), sometimes called a mini-stroke, starts just like a stroke but then resolves leaving no noticeable symptoms or deficits. The occurrence of a TIA is a warning that the person is at risk for a more serious and debilitating stroke. About one-third of patients who have a TIA will have an acute stroke sometime in the future. The addition of other risk factors compounds a person&#39;s risk for a recurrent stroke. The average duration of a TIA is a few minutes. For almost all TIAs, the symptoms go away within an hour. There is no possibility to distinguish whether symptoms will be just a TIA or persist and lead to death or disability.  
           [0008]    Recurrent stroke is frequent; about 25 percent of people who recover from their first stroke will have another stroke within 5 years. Recurrent stroke is a major contributor to stroke disability and death, with the risk of severe disability or death from stroke increasing with each stroke recurrence. The risk of a recurrent stroke is greatest right after a stroke, with the risk decreasing with time. About 3 percent of stroke patients will have another stroke within 30 days of their first stroke and one-third of recurrent strokes take place within 2 years of the first stroke.  
           [0009]    The most important risk factors for stroke are hypertension, arteriosclerosis, heart disease, diabetes, and cigarette smoking. Others include heavy alcohol consumption, high blood cholesterol levels, illicit drug use, and genetic or congenital conditions, particularly vascular abnormalities. People with multiple risk factors compound the destructive effects of these risk factors and create an overall risk greater than the simple cumulative effect of the individual risk factors.  
           [0010]    Although stroke is a disease of the brain, it can affect the entire body. Depending on the affected brain region and the severity of the attack, post-stroke patients suffer from a variety of different symptoms. Some of the disabilities that can result from stroke include paralysis, cognitive deficits, speech problems, emotional difficulties, daily living problems, and pain. Stroke disability is devastating to the stroke patient and family, but therapies are available to help rehabilitate post-stroke patients. The mortality rate observed in ischemic stroke is around 30%. The time window for a medical treatment is narrow and limited to anticoagulants and thrombolytic agents, which must be given immediately (at latest 3 hours) after having a stroke. Unfortunately, there is no effective neuroprotective medication available, which is able to stop the delayed degeneration of neurons following the initial stroke attack.  
           [0011]    Stroke symptoms appear suddenly. The following acute symptoms can be observed. Sudden numbness of the face, arm or leg, difficulties in talking or understanding speech, trouble seeing in one or both eyes, sudden trouble in walking, loss of balance and coordination. Severe headache with no known cause does also occur. Even more importantly, there is a variety of severe disabilities occurring and persisting in post-stroke patients. Paralysis is a frequent disability resulting from stroke. Cognitive deficits (problems with thinking, awareness, attention and learning) are also commonly observed. Post-stroke patients exhibit language deficits and also emotional deficits (like post-stroke depression). Furthermore, an uncommon type of pain, called central pain syndrome (CPS), can occur after having a stroke.  
           [0012]    Currently the only effective treatment for thrombotic stroke is the use of anticoagulants (e.g. heparin), and thromobolytics (recombinant tissue plasminogen activator). Neuroprotective agents, which are effective in animal models, have generally proved ineffective in the clinic, and none are yet registered for use in stroke.  
           [0013]    A number of experimental models have been developed for global ischemia and focal ischemia. The availability of these different models provides an opportunity to investigate mechanisms of stroke. Finding common features in different models or over several time points within one model should pro-vide better insight into the mechanisms critical for stroke, and comparison of the models should help to understand development, progression and consequences of stroke.  
           [0014]    Most common global ischemia models are:  
           [0015]    a) The Two Vessel Model  
           [0016]    Models of transient global ischemia resulting in patterns of selective neuronal vulnerability are models that attempt to mimic the pathophysiology of cardiac arrest or hemodynamic conditions that result from severe systemic hypotension. Reversible high-grade forebrain ischemia is generated by bilateral common carotid artery (CCA) occlusion. Together with systemic hypo-tension conditions it reduces the blood flow to severe ischemic levels (Smith et al. 1984  Acta Neuropathol  64:319-332). This model of transient global ischemia has the advantage of a one stage surgical preparation, the production of a high-grade forebrain ischemia and the possibility to conduct chronic survival studies in order to assess the potential of neuroprotective drugs.  
           [0017]    b) The Four Vessel Model  
           [0018]    This model results in a high-grade forebrain ischemia but is produced in two stages, one to manipulate each of the CCA, and the second stage 24 h later to produce the forebrain ischemia. The advantage is that the second step can be produced in awake freely moving animals (Pulsinelli et al. 1982  Ann Neurol  11:491-498). Similar pathohistological results could be obtained for both vessel models.  
           [0019]    c) The Cardiac Arrest Model  
           [0020]    Forebrain ischemia models are of value to study cerebral ischemia but these models do not exactly mimic the hemodynamic consequences of a cardiac arrest, which results in a complete ischemia of the brain, spinal cord and extracerebral organs (Katz et al. 1995  J Cereb Blood Flow Metab  15:1032-1039). The initial cardiac arrest models from Safar et al. (1982  Protection of tissue against hypoxia  Elsevier Biomedical Press; 147-170) or Korpaczew et al. (1982  Partol Fizjol Eksp Ter  3:78-80), were developed further by Katz et al. (1989  Resuscitation  17:39-53) and Pluta et al. (1991  Acta Neuropathologica  83:1-11) to models with controllable insult. Katz and colleagues (1995) have reported a reproducible outcome model of cardiac arrest with apneic asphyxia of 8 min, leading to the cessation of circulation at 3-4 min of apnea and resulting in cardiac arrest of 4-5 min. At 72 hr after injury, widespread patterns of ischemic neurons were found in many brain regions, including cerebral cortex, caudate putamen CA1 and CA3 regions of hippocampus, thalamus, cerebellum and brain stem.  
           [0021]    Pluta et al. described a primary mechanical cardiac arrest model whereby global ischemia was induced by cardiac arrest for 3 to 10 min with survival periods of the animals from 3 min to 7 days.  
           [0022]    Although these models have several limitations, they provide a method for studying the mechanisms of neuronal injury resulting from the clinically realistic cerebral insult and screening potential cerebral resuscitation therapies.  
           [0023]    Focal Ischemia Models  
           [0024]    Models of permanent or transient focal ischemia typically giving rise to localized brain infarction have routinely been used to investigate the pathophysiology of stroke. For example, models of middle cerebral artery (MCA) occlusion in a variety of species have gained increased acceptance due to their relevance to the human clinical setting.  
           [0025]    a) the Permanent MCA Occlusion Models  
           [0026]    Tamura and colleagues (1981  J Cereb Blood Flow Metab  1:53-60) developed a subtemporal approach as standard model of proximal MCA occlusion. In models of permanent MCA occlusion, electrocauterization of the MCA proximal to the origin of the lateral lenticulostriate arteries is utilized routinely. In these models, severe reductions in blood flow are seen within the ischemic core, with milder reductions in blood flow within the border or penumbral regions. The addition of moderate arterial hypotension has the effect of enlarging infarct volume.  
           [0027]    b) The Transient MCA Occlusion Models  
           [0028]    In human ischemic stroke, recirculation frequently occurs after focal ischemia. Thus, models of transient MCA occlusions have also been developed, mainly in rats or mice, whereby surgical clip or sutures are introduced to induce a transient ischemic insult.  
           [0029]    Some further animal models for stroke are considered in several reviews like the articles of W. D. Dietrich (1998  Int Review of Neurobiology  42:55-101), Wiebers et al. (1990  Stroke  21:1-3) or Zivin and Grotta (1990  Stroke  21:981-983).  
         SUMMARY OF THE INVENTION  
         [0030]    Object of the present invention is to identify and characterize development, conditions (status which elicits), progression and consequences of stroke on a molecular basis.  
           [0031]    This object is met by the use of polynucleotide sequences selected from the group of sequences SEQ ID NO: 1 to 88 or homologues or fragments thereof or the according polypeptides for the characterization of a) development and/or occurrence of stroke, b) the progression of the pathology of stroke and/or b) the consequences of the pathology of stroke, whereby the characterization is carried out outside of a living body.  
           [0032]    Polynucleotide sequences SEQ ID NO: 1 to 88 are expressed sequence tags (ESTs) representing genes, which are differentially expressed under stroke, particularly under global ischemia in the cardiac arrest model (Pluta et al. 1991  Acta Neuropathol  83:1-11).  
           [0033]    The model is explained in more detail in the literature and in the examples below. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0034]    [0034]FIG. 1 shows changes in expression of SEQ ID NO: 37.  
         [0035]    [0035]FIG. 2 shows changes in expression of SEQ ID NO: 79.  
         [0036]    [0036]FIG. 3 shows changes in expression of SEQ ID NO: 35.  
         [0037]    [0037]FIG. 4 shows changes in expression of SEQ ID NO: 57.  
         [0038]    [0038]FIG. 5 shows changes in expression of SEQ ID NO: 70.  
         [0039]    [0039]FIG. 6 shows changes in expression of SEQ ID NO: 66.  
         [0040]    [0040]FIG. 7 shows changes in expression of SEQ ID NO: 3. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0041]    The term “polynucleotide sequence” or “nucleic acid sequence” designates in the present application any DNA or RNA sequence, independent of the length. Thus this term can describe short sequences like PCR primers or probes for hybridization, as well as whole genes or cDNA of these genes.  
         [0042]    The term “polypeptide” or “amino acid sequence” designates a chain of amino acids, independent of their length, however, in any case more than one amino acid.  
         [0043]    As “homologues” of polynucleotide sequences such polynucleotide sequences are designated which encode the same type of protein as one of the polynucleotide sequences described herein. Accordingly as “homologues” of a polypeptide the polypeptides are designated, which have an amino acid sequence, wherein at least 70%, preferably 80%, more preferably 90% of the amino acids are identical to one of the proteins of the present invention and wherein the replaced amino acids preferably are replaced by homologous amino acids. As “homologous” amino acids are designated those, which have similar features concerning hydrophobicity, charge, steric features etc. Most preferred are amino acid sequences, containing the species- or family-dependent differences of the amino acid sequence. Particularly as “homologues” sequences are designated those, which correspond to one of the cited sequences in another species or individual. For example if in the present invention a rat model is used and the cited polynucleotide sequence encodes the rat protein, the according polynucleotide sequence and protein of a mouse or of a human is designated as “homologue”. Further splice variants and members of gene families are designated as homologues.  
         [0044]    “Fragments” of a polynucleotide sequence are all polynucleotide sequences, which have at least 10 identical base pairs compared to one of the polynucleotide sequences shown in the present application or by the genes represented by these polynucleotide sequences. The term “fragment” encloses therefore such fragments as primers for PCR, probes for hybridization, DNA fragments included in DNA vectors like plasmids, cosmids, BACs or viral constructs, as well as shortened splice variants of the genes identified herein. As a fragment of a protein (polypeptide) amino acid sequences are designated which have at least three amino acids, preferably at least 10 amino acids. Therefore fragments serving as antigens or epitopes are enclosed in this designation.  
         [0045]    In the present application the term “sequence” is used when either a polynucleotide sequence (=nucleic acid sequence) or a polypeptide (=amino acid sequence) or a protein is meant. That means, when it is irrelevant which type of sequence is used the type is not designated particularly, but with the more common term “sequence”.  
         [0046]    In the present application the term “stroke” means the development, occurrence, progression and consequences of the disease state. Several features of the development, occurrence and consequences of this disease are described herein above.  
         [0047]    The basis of the models and methods described in the present application is the examination and determination of the expression of genes, which are differentially expressed during development, conditions, progression and consequences of stroke. Therefore for the examination each sequence can be used which allows the determination of the expression rate of the considered gene. Such a sequence can be at least one of the polynucleotide sequences SEQ ID NO: 1 to 88 or homologues or fragments thereof, as well as the polypeptides encoded thereby, however, just as well polynucleotide sequences and the according polypeptides can be used which are (parts of) the genes represented by the polynucleotide sequences SEQ ID NO: 1 to 88.  
         [0048]    According to the invention it has been found, that the genes represented by the polynucleotide sequences SEQ ID NO: 1 to 88 are differentially expressed in the cardiac arrest model of stroke.  
         [0049]    Therefore the present invention provides sequences, which represent genes, which are differentially expressed under stroke. Such polynucleotide sequences and the according polypeptides allow the determination and examination of stroke. Most of these sequences have not yet been regarded in relation to stroke. Sequences which are known to be differentially expressed in connection with stroke conditions are Apolipoprotein E, herein referred to as SEQ ID NO: 40, (2001  J Cereb Blood Flow Metab  21:1199-1207), β-amyloid precursor protein (APP), herein referred to as SEQ ID NO: 77 (1996  Neuroreport  7:2727-2731), Preproenkephalin, herein referred to as SEQ ID NO: 35 (1997  Brain Res  744:185-187), Cathepsin B, herein referred to as SEQ ID NO: 86 (1997  J Neurosurg  87:716-723).  
         [0050]    For these examinations animal models can be used. As such a model any animal can be used wherein the necessary preparations can be carried out, however mammalian models are preferred, even more preferred are rodents. Most preferred animal models of the present invention are rat and mouse models.  
         [0051]    The sequences of the present invention further can be used for diagnosing stroke of a human outside of the living body by determining the expression levels of at least one of the cited sequences in comparison to the non-disease status. During treatment period of a patient the expression of the presently shown sequences can also be used outside of the body for assessing the efficacy of stroke treatment. In this case blood, cerebrospinal fluid (CSF) or tissue is removed from the patient and expression is determined in the samples.  
         [0052]    For determination and comparison of the expression levels of at least one of the genes identified in the present invention any of the commonly known methods can be used, either on RNA/cDNA level or on protein level. For example PCR, hybridization, micro array based methods, western blot or 2-D protein gel analysis are suitable methods. One preferred method is the digital expression pattern display method (DEPD method), explained in detail in WO99/42610. The method used for determination of expression levels is not restrictive, as long as expressed amounts can be quantified.  
         [0053]    The sequences of the present invention can further be used to develop new animal models for stroke. By examination of the expression levels of at least one of the shown sequences, a procedure might be determined, which is useful for generating a suitable animal model for different interesting conditions. In particular, useful animal models might be transgenic, knock out, or knock in models.  
         [0054]    In such a newly generated animal model as well as in one of the known models the efficacy of compounds can be tested, using techniques known in the art. As well assay systems can be used that are based on the shown sequences. Such assay systems may be in vivo, ex vivo or in vitro assays. In any case the models or assay systems are contacted with the compound(s) to be tested and samples are obtained from these models/systems, wherein expression levels of the sequences are determined and compared to the non-treated model/system.  
         [0055]    Dependent of the model used the samples can be derived from whole blood, CSF or whole tissue, from cell populations isolated from tissue or blood or from single cell populations (i.e. cell lines).  
         [0056]    In one embodiment of the invention cellular assays can be used. Preferred cells for cellular assays are eukaryotic cells, more preferably mammalian cells. Most preferred are neuronal-like cells, like SHSY5Y (neuroblastoma cell line), hippocampal murine HT-22 cells, primary cultures from astrocytes, cerebral cortical neuronal-astrocytic co-cultures, mixed neuronal/glial hippocampal cultures, cerebellar granular neuronal cell cultures, primary neuronal cultures derived from rat cortex (E15-17), or COS cells (African green monkey, kidney cells); CHO cells (Chinese hamster ovary), or HEK-293 cells (human embryonic kidney).  
         [0057]    Whereas the comparison of the expression levels (disease/non-disease status) of at least one of the provided sequences might give information about the examined disease status, it is preferred to determine the expression levels of more than one of the sequences simultaneously. Thus several combinations of the sequences can be used at different time points. By combination of several sequences a specific expression pattern can be determined indicating and/or identifying the conditions of the disease. The more expression rates are determined simultaneously, the more specific the result of the examination might be. However, good results also can be obtained by combination of only a few sequences. Therefore for the present invention it is preferred to compare the expression rates of at least two of the sequences provided herein, more preferred of at least 4, further more preferred of at least 6 of the sequences.  
         [0058]    Since the presently provided sequences represent genes, which are differentially expressed, the expression rates of the single genes can be increased or decreased independently from each other. “Independently” in this context means that the expression rate of each of the genes can but need not be influenced by each other. In any case expression levels different from the non-disease status might be a hint to the disease status, which is examined.  
         [0059]    The disease status, which is considered in the present invention, is stroke. The preferred types of stroke are ischemic and hemorrhagic stroke. Consequences, which might be related to stroke, are among others severe headache, paralysis, cognitive deficits, speech problems, emotional difficulties, daily living problems, and central pain syndrome.  
         [0060]    Independent whether stroke is diagnosed or characterized, a model for stroke is characterized, the efficacy of stroke treatment or the efficiency of a compound in a model shall be examined, the determination of the expression levels of at least one of the sequences is carried out outside of a living body. A method to obtain such results comprises: providing a sample comprising cells or body fluids expressing one or more genes represented by polynucleotide sequences selected from the group of SEQ ID NO: 1 to 88 or homologues or fragments thereof; detecting expression of one or more of the genes in said cells; comparing the expression of the genes in the test cells to the expression of the same genes in reference cells whose expression stage is known; and identifying a difference in expression levels of the considered sequences, if present, in the test cell population and the reference cell population.  
         [0061]    As mentioned above, detection of the expression of the genes can be carried out by any method known in the art. The method of detection is not limiting the invention.  
         [0062]    Expression levels can be detected either on basis of the polynucleotide sequences or by detecting the according polypeptide, encoded by said polynucleotide sequence.  
         [0063]    Preferred methods for detection and determination of the gene expression levels are PCR of cDNA, generated by reverse transcription of expressed mRNA, hybridization of polynucleotides (Northern, Southern Blot systems, In situ hybridization), DNA-microarray based technologies, detection of the according peptides or proteins via, e.g., Western Blot systems, 2-dimensional gel analysis, protein micro-array based technologies or quantitative assays like e.g. ELISA tests.  
         [0064]    The most preferred method for quantitative analysis of the expression levels is the digital expression pattern display method (DEPD), described in detail in WO99/42610.  
         [0065]    The sequences of the present invention can further be used for identifying therapeutic agents and their efficacy for treating stroke. For example a method can be used comprising: providing a test cell population comprising cells capable of expressing one or more genes represented by nucleic acid sequences selected from the group consisting of SEQ ID NO: 1 to 88 or homologues or fragments thereof; contacting said test cell population with the test therapeutic agent; detecting the expression of one or more of the genes in said test cell population; comparing the expression of the gene(s) in the test cell population to the expression of the gene(s) in a reference cell population whose disease stage is known; and identifying a difference in expression levels of the considered sequences, if present, in the test cell population and the reference cell population, thereby identifying a therapeutic agent for treating stroke.  
         [0066]    Test cells can be obtained from a subject, an animal model or cell cultures of fresh cells or cell lines. Further in vitro assays may be used.  
         [0067]    A method examining the different expression patterns of the differentially expressed gene(s) therefore can be used for testing agents and compounds for their efficiency for treatment of stroke. Which model is used is not relevant, as long as the model allows the determination of differences in expression amounts.  
         [0068]    In such a model cells are contacted with the interesting agent or compound and expression of at least one of the genes considered in the present invention is determined in comparison to the expression of the same gene in cells which never have been contacted to the according agent/compound. Contacting the cells either can be affected by administering the agent/compound to an animal or by contacting isolated cells of tissue, CSF, or blood or cells of cell lines in culture with the agent/compound.  
         [0069]    By examination of the influence the considered agent(s)/compound(s) have on the expression of at least one of the genes, the efficacy of the agent(s)/compound(s) can be estimated. This allows the decision whether it is worthwhile to develop a medicament containing such an agent or compound.  
         [0070]    Whether the expression is determined on basis of mRNA generation or on basis of protein generation is not relevant, as long as the difference of the expression rate can be determined. Therefore both, the polynucleotide sequences, and the polypeptides or proteins shown in the present application can be used for the development or the identification of a medicament.  
         [0071]    The development of a medicament can be desirable for example if the considered compound/agent has any influence on the regulation of the expression rate or on the activity of any polynucleotide sequence or polypeptide/protein of the present invention. Said influence can be for example acceleration, promotion, increase, decrease or inhibition of the expression or activity.  
         [0072]    Said influence of a compound or agent can be examined by a method comprising contacting a sample comprising one of the nucleic acid sequences or of the polypeptides of the present invention with a compound that binds to said sequence in an amount sufficient to determine whether said compound modulates the activity of the polynucleotide or polypeptide/protein sequence.  
         [0073]    By such a method a compound or agent modulating the activity of any of the nucleic acid sequences or any polypeptides of the present invention can be determined.  
         [0074]    Furthermore the sequences itself can be used as a medicament.  
         [0075]    An example for such a use is the use of a polynucleotide sequence as an antisense agent. Antisense agents, including but not limited to ribonucleotide or desoxyribonucleotide oligomers, or base-modified oligomers like phosphothioates, methylated nucleotides, or PNAs (peptide nucleic acids), can hybridize to DNA or mRNA, inhibiting or decreasing transcription or translation, respectively. Thus, polynucleotide sequences of a gene, which is increased in expression rate under stroke, can be used as antisense agents to decrease the expression rates of said gene. Further such polynucleotide sequences can be used for gene therapy.  
         [0076]    Another example for such a use is the use of a polypeptide or a protein as a medicament. In case that the expression of a gene is decreased under stroke and therefore not “enough” protein is provided by the body to maintain natural (healthy) conditions, said protein can be administered as a medicament. In case a gene is increased under stroke, representing a protective beneficial or adaptive response of the brain, this effect can be further strengthened by adding even more of the corresponding protein as medicament.  
         [0077]    A pharmaceutical composition comprising a polynucleotide sequence or a polypeptide according to the present invention can be any composition, which can serve as a pharmaceutical one. Salts or aids for stabilizing the sequences in the composition preferably are present.  
         [0078]    For the determination of the expression of the relevant genes the generated sequences have to be detected. Therefore several reagents can be used, which are for example specific radioactive or non-radioactive (e.g., biotinylated or fluorescent) probes to detect nucleic acid sequences by hybridization, e.g., on DNA microarrays, primer sets for the detection of one or several of the nucleic acid sequences by PCR, antibodies against one of the polypeptides, or epitopes, or antibody- or protein-microarrays. Such reagents can be combined in a kit, which can be sold for carrying out any of the described methods.  
         [0079]    Further the sequences defined in the present invention can be used to “design” new transgenic animals as model for stroke. Therefore the animals are “created” by manipulating the genes considered in the present application in a way that their expression in the transgenic animal differs from the expression of the same gene in the wild-type animal. In which direction the gene expression has to be manipulated (up- or down-regulation) depends on the gene expression shown in the present application. Methods of gene manipulation and methods for the preparation of transgenic animals are commonly known to those skilled in the art.  
         [0080]    For further examinations or experiments it might be desirable to include any of the nucleic acids of the present invention into a vector or a host cell. By including the sequences in a host cell for example cellular assays can be developed, wherein the genes, polynucleotide sequences and the according proteins/polypeptides further can be used or examined. Such vectors, host cells and cellular assays therefore shall be considered as to fall under the scope of the present invention.  
         [0081]    The following examples are provided for illustration and are not intended to limit the invention to the specific example provided.  
       EXAMPLE 1  
     Preparation of Rat Cardiac Arrest Model  
       [0082]    Cardiac arrest was performed in female Lewis-rats at 3 months of age (150-220 g), resulting in total cessation of blood flow leading to global cerebral ischemia. After 10 min of ischemia, the animals were resuscitated by external heart massage and ventilation. The group size was 2×3 animals.  
         [0083]    For induction of cardiac arrest, a special blunt-end, hook-like probing device was inserted into the right parasternal line across the third intracostal spaces into the chest cavity. Next, the probe was gently pushed down the vertebral column until a slight resistance from the presence of the right pulmonary veins was detected. The probe then was tilted 10-20° caudally. Then, the probe was rotated in a counter-clockwise direction about 135-140° under the inferior vena cava. At this position, the occluding part of the device was positioned right under the heart vessel bundle (inferior vena cava, superior right and left vena cava, ascending aorta, and pulmonary trunk). The pulmonary veins (left and right) were closed by the rotation of the occluding part of the hook. In the last step, the probe was pulled up with concomitant compression of the heart vessel bundle against the sternum. The end of the occluding portion of the hook was then positioned in the left parasternal line in the second intercostal space. To prevent upward movement of the chest and to insure complete ligation of the vessels, simple finger pressure was applied downward the sternum, producing total hemostasis and subsequent ventricular arrest. The effect of the whole procedure is total cessation of both arterial and venous blood flow, it essentially represents the onset of clinical death. After 2.5-3.5 min, the probe was released and removed from the chest by reverse procedural succession, and the animals remained in this position until the beginning of resuscitation.  
         [0084]    The resuscitation procedure consisted of external heart massage until spontaneous heart function was recovered and controlled respiration occurred. During this time, air was pumped through a polyethylene tube inserted intratracheally that was connected to a respirator. External heart massage was produced by the index and middle fingers rapidly striking against the chest (sternum) for 1-2 min at the level of the fourth intracostal area with a frequency of 150-240/min in continuous succession. The ratio of strikes to frequency of ventilation was 6:1 or 8:1.  
         [0085]    An electrocardiogram (lead II-EEG) was recorded continuously during the course of the experiment. Moreover, heart activity was monitored using a loud speaker connected to the output lead of the electroencephalograph. Additionally, the cranial bones were exposed at the sagittal and coronal sutures, where silver-needle electrodes were attached for recording on an electrocorticogram (ECoG). All measurements were registered on a ten-channel electroencephalogram (Accutrace-100A, Beckmann).  
         [0086]    2×3 sham operated animals served as controls. These animals were treated similarly to the experimental group with one major exception. Under anesthesia, the probe was inserted through the chest wall into the plural cavity as has already been described above but without further manipulation and torsion of the probe. The probe remained in the chest for essentially the same time period (3.5 min) as in the experimental group. The control animals were then returned to their cages for recovery.  
         [0087]    Tissue preparation occurred 0.5 hr, 1 hr, 6 hrs, 3 days, 7 days and 2 years after surgery. Tissues were frozen on liquid nitrogen prior to RNA preparation.  
         [0088]    FIGS.  1  to  7  show results of several transcripts differentially expressed in the cardiac arrest model over several time points. Each sequence is examined in their expression levels over a time period of 0.5 hrs after cardiac arrest to 2 years after surgery and compared to sham operated controls. Genes are described as differentially expressed when the sequence is up- or down-regulated at one or more time points with a certain statistical relevant significance value. Over time the expression pattern can be determined as up-regulated in one to seven time points; as down regulated in one to seven time points or as mixed regulated if the type of regulation changes between up- and down-regulation at different time points.  
         [0089]    X-axis describes the time points analyzed by DEPD, 0.5 h=0.5 hrs post operation, 1 h+1 hr post operation, 3 h=3 hrs post operation, 6 h=6 hrs post operation, 3 d=day 3 post operation, 7 d=day 7 post operation, 2 y=2 years post operation.  
         [0090]    The Y-axis shows delta h, which represents the normalized difference of expression (peak height) of a certain transcript between a control group and a treated group. x-fold difference in gene expression is calculated by:  
         1+delta h/1−delta h  
         [0091]    0=no change to control, +=up regulation, −=down regulation; (0.2=1.5 fold; 0.3=1.86 fold; 0.4=2.33 fold; 0.5=3 fold).  
       EXAMPLE 2  
     Determination of Expression Levels  
       [0092]    Gene expression profiling by DEPD-analysis starts with the isolation of 5-10 μg total RNA. In a second step, double-stranded cDNA is synthesized. Through an enzymatic digest of the cDNA with three different type IIS restriction enzymes, three pools with short DNA-fragments containing single-stranded overhangs are generated. Afterwards, specific DNA-adaptor-molecules are ligated and in two subsequent steps 3.072 PCR reactions are performed by using 1024 different unlabelled 5′ primer and a common FAM-fluorescent-labelled 3′-primer in the last PCR step. Subsequently, the 3072 PCR pools are analyzed on an automatic capillary electrophoresis sequencer.  
         [0093]    Differential gene expression pattern of single fragments are determined by comparison of normalized chromatogram peaks from the control groups and corresponding operated animals.  
       EXAMPLE 3  
     Sequencing and Databank Analysis of the Obtained Sequences  
       [0094]    Differentially expressed peaks are confirmed on polyacrylamide gels by using radioactive labelled 3′ primer instead of the FAM fluorescent primer. Differentially expressed bands are cut from the gel. After an elution step of up to 2 hrs in 60 μl 10 mM Tris pH 8, fragments are re-amplified by PCR using the same primer as used in the DEPD analysis. Resulting PCR products are treated with a mixture of Exonuclease I and shrimp alkaline phosphatase prior to direct sequencing. Sequencing reactions are performed by using DYEnamic-ET-dye terminator sequencing kit (Amersham) and subsequently analyzed by capillary electrophoresis (Megabace 1000, Amersham).  
         [0095]    Prior to a BLAST sequence analysis (Altschul et al. 1997  Nucleic Acids Res  25:3389-3402) against GenBank (Release No. 126), all sequences are quality verified and redundant sequences or repetitive motifs are masked.  
                                                                     SEQ-   accession       fragment           ID   number   name   length [bp]                                1   Z99755   Human DNA sequence from clone CTA-714B7 on   220                   chromosome 22q12.2-13.2 Contains pseudogene               similar to part of COX7B (Cytoclirome c oxidase               subunit VIIb)       2       no hit found in DB   296       3   BF418899   UI-R-BJ2-bqk-c-03-0-UI.s1 UI-R-BJ2  Rattus     287                 norvegicus  cDNA clone UI-R-BJ2-bqk-c-03-0-UI 3′,               mRNA sequence       4       no hit found in DB   91       5   AB023781     Rattus norvegicus  mRNA for cathepsin Y, partial cds   258       6   BF420410   UI-R-BJ2-bqb-g-04-0-UI.s1 UI-R-BJ2  Rattus     200                 norvegicus  cDNA clone UI-R-BJ2-bqb-g-04-0-UI 3′,               mRNA sequence       7   M35826   Rat mitochondrial NADH-dehydrogenase (NDI) gene,   347               complete cds       8   AK019199     Mus musculus  11 days embryo cDNA, RIKEN full-   183               length enriched library, clone:2700005I17, full insert               sequence       9   BF413204   UI-R-BT1-bny-a-04-0-UI.s1 UI-R-BT1  Rattus     214                 norvegicus  cDNA clone UI-R-BT1-bny-a-04-0-UI 3′,               mRNA sequence       10   X16555   Rat PRPS2 mRNA for phosphoribosylpyrophosphate   159               synthetase subunit II       11   AK017685     Mus musculus  8 days embryo cDNA, RIKEN full-   195               length enriched library, clone:5730466L18, full insert               sequence       12       no hit found in DB   164       13   Y00964     M. musculus  mRNA for beta-hexosaminidase   181       14       no hit found in DB   110       15   L17127     Rattus norvegicus  proteasome RN3 subunit mRNA,   274               complete cds       16       no hit found in DB   132       17   BG380139   UI-R-CS0-btp-e-04-0-UI.s1 UI-R-CS0  Rattus     139                 norvegicus  cDNA clone UI-R-CS0-btp-e-04-0-UI 3′,               mRNA sequence       18   D86215     Rattus norvegicus  mRNA for NADH:ubiquinone   276               oxidoreductase, complete cds       19   AK005320     Mus musculus  adult male cerebellum cDNA, RIKEN   129               full-length enriched library, clone:1500031J01, full               insert sequence       20       no hit found in DB   118       21       no hit found in DB   154       22       no hit found in DB   103       23       no hit found in DB   73       24       no hit found in DB   107       25   BI287855   UI-R-CW0s-ccm-a-07-0-UI.s1 UI-R-CW0s  Rattus     217                 norvegicus  cDNA clone UI-R-CW0s-ccm-a-07-0-UI 3′,               mRNA sequence       26       no hit found in DB   151       27       no hit found in DB   200       28   AC016673     Homo sapiens  BAC clone RP11-17N4 from 2,   217               complete sequence       29   AB071989     Mus musculus  mRNA for Spop, partial cds   310       30       no hit found in DB   211       31   AF178845     Rattus norvegicus  calmodulin mRNA, complete cds   410       32   J02701   Rat Na+, K+-ATPase beta subunit protein mRNA,   341               complete cds       33   X12553   Rat mRNA for liver Cytochrome c oxidase subunit VIa   411       34       no hit found in DB   118       35   Y07503   Rat mRNA for preproenkephalin (A)   186       36   X14876   Rat mRNA for transthyretin   205       37       no hit found in DB   202       38   AI54730   UI-R-C3-sr-b-11-0-UI.s1 UI-R-C3  Rattus norvegicus     200               cDNA clone UI-R-C3-sr-b-11-0-UI 3′, mRNA               sequence       39   M27315     Rattus norvegicus  Cytochrome c oxidase subunit II (Co   146               II) gene       40   J02582   Rat apolipoprotein E gene, complete cds   139       41       no hit found in DB   234       42   U65579   Human mitochondrial NADH dehydrogenase-   291               ubiquinone Fe-S protein 8, 23 kDa subunit precursor               (NDUFS8) nuclear mRNA encoding mitochondrial               protein, complete cds       43   AF173082     Mus musculus  LIN-7 homolog 2 (MALS-2) mRNA,   113               complete cds       44       no hit found in DB   197       45   U70268     Rattus norvegicus  mud-7 mRNA, 3′ UTR   206       46   X96997   O.aries SOX-2 gene   146       47   AK020957     Mus musculus  adult male corpora quadrigemina   181               cDNA, RIKEN full-length enriched library,               clone:B230104P22, full insert sequence       48       no hit found in DB   272       49   BC012314     Mus musculus,  Similar to ferritin heavy chain, clone   73               MGC:19422 IMAGE:3488821, mRNA, complete cds       50   BB452941   BB452941 RIKEN full-length enriched, 12 days   125               embryo spinal ganglion  Mus musculus  cDNA clone               D130020J05 3′, mRNA sequence       51   AK019418     Mus musculus  13 days embryo head cDNA, RIKEN   365               full-length enriched library, clone:3110018K01, full               insert sequence       52   J01435     Rattus norvegicus  mitochondrial ATPase subunit 6   175               gene       53   BF387893   UI-R-CA1-bbw-a-03-0-UI.s1 UI-R-CA1  Rattus     182                 norvegicus  cDNA clone UI-R-CA1-bbw-a-03-0-UI 3′,               mRNA sequence       54   AB033713     Rattus norvegicus  mitochondrial gene for Cytochrome   101               b, partial cds       55       no hit found in DB   123       56   U53513     Rattus norvegicus  glycine-, glutamate-,   76               thienylcyclohexylpiperidine-binding protein mRNA,               complete cds       57   AK004546     Mus musculus  adult male lung cDNA, RIKEN full-   261               length enriched library, clone:1200002H13, full insert               sequence       58       no hit found in DB   269       59   AY004290     Rattus norvegicus  scg10-like-protein mRNA, complete   277               cds       60       no hit found in DB   228       61       no hit found in DB   119       62   BF544005   UI-R-E0-ce-c-04-0-UI.r1 UI-R-E0  Rattus norvegicus     117               cDNA clone UI-R-E0-ce-c-04-0-UI 5′, mRNA               sequence       63       no hit found in DB   217       64       no hit found in DB   269       65       no hit found in DB   162       66   BC011132     Mus musculus,  Similar to special AT-rich sequence   200               binding protein 1, clone MGC:18461               IMAGE:4164993, mRNA, complete cds       67   AJ278701     Rattus norvegicus  mRNA for cytosolic branched chain   182               aminotransferase (Bcatc gene)       68   M14512   Rat Na + ,K + -ATPase alpha(+) isoform catalytic subunit   207               mRNA, complete cds       69   U42975     Rattus norvegicus  Shal-related potassium channel   268               Kv4.3 mRNA, complete cds       70   BC004706     Mus musculus,  heterogeneous nuclear   285               ribonucleoprotein C, clone MGC:5715               IMAGE:3499283, mRNA, complete cds       71   BE101398   UI-R-BJ1-aud-e-10-0-UI.s1 UI-R-BJ1  Rattus     158                 norvegicus  cDNA clone UI-R-BJ1-aud-e-10-0-UI 3′,               mRNA sequence       72   AF073297     Mus musculus  small EDRK-rich factor 2 (Serf2)   144               mRNA, complete cds       73   D32249     Rattus norvegicus  mRNA for neurodegeneration   250               associated protein 1, complete cds       74   BF391228   UI-R-CA1-bcq-g-07-0-UI.s1 UI-R-CA1  Rattus     122                 norvegicus  cDNA clone UI-R-CA1-bcq-g-07-0-UI 3′,               mRNA sequence       75   BE109851   UI-R-CA0-axi-b-04-0-UI.s1 UI-R-CA0  Rattus     157                 norvegicus  cDNA clone UI-R-CA0-axi-b-04-0-UI 3′,               mRNA sequence       76       no hit found in DB   107       77   AY011335     Rattus norvegicus  amyloid beta precursor protein   254               (App) gene, partial cds       78   BC013540     Mus musculus,  Similar to retinal short-chain   208               dehydrogenase/reductase 1, clone MGC:19224               IMAGE:4241608, mRNA, complete cds       79   X52311   Rat unr mRNA for unr protein with unknown function   300       80   M29358   Rat ribosomal protein S6 mRNA, complete cds   192       81   AC068987   UI-R-CA0-bkh-f-06-0-UI.s1 UI-R-CA0  Rattus     300                 norvegicus  cDNA clone UI-R-CA0-bkh-f-06-0-UI 3′,               mRNA sequence       82   AC068987   UI-R-BO1-aqb-b-02-0-UI.s1 UI-R-BO1  Rattus     328                 norvegicus  cDNA clone UI-R-BO1-aqb-b-02-0-UI 3′,               mRNA sequence       83       no hit found in DB   186       84   M23953   UI-R-BJ0p-aio-h-09-0-UI.s1 UI-R-BJ0p  Rattus     370                 norvegicus  cDNA clone UI-R-BJ0p-aio-h-09-0-UI 3′,               mRNA sequence       85   AK018721     Mus musculus  adult male kidney cDNA, RIKEN full-   441               length enriched library, clone:0610007M20, full insert               sequence       86   X82396     R. norvegicus  mRNA for cathepsin B   412       87       no hit found in DB   149       88   X82550     R. norvegicus  mRNA for ribosomal protein L41   207                          
 
       EXAMPLE 4  
     Comparison of Differentially Expressed Sequences Over Several Time Points in the Cardiac Arrest Model  
       [0096]    0.5 hr, 1 hr, 3 hrs, 6 hrs, 3 days, 7 days, and 2 years survival time of the animals were chosen as time points for gene expression profiling of the cardiac arrest model. After DEPD analysis peaks obtained as differentially expressed at least at one time point were compared over time to control within the cardiac arrest stroke model. Results are shown in Table 2.  
                                     TABLE 2                       SEQ-ID               No.   Regulation                                1   down 7d           2   down 7d       3   down 7d       4   down 7d       5   up 3d/up 7d       6   up 3d       7   up 3d       8   down 3d       9   down 3d       10   up 3d       11   down 3d       12   up 3d       13   up 3d       14   up 7d       15   up 7d       16   up 3d       17   down 7d       18   up 7d       19   down 7d       20   down 7d       21   up 7d       22   up 3d/down 7d       23   up 3d       24   down 3d       25   down 7d       26   up 3d       27   down 3d       28   up 3d       29   down 3d       30   down 3d       31   down 7d       32   up 3d       33   up 7d       34   up 3d       35   up 3d/up 7d       36   up 7d       37   up 7d       38   down 7d       39   up 7d       40   up 7d       41   down 7d       42   up 7d       43   up 7d       44   down 7d       45   down 7d       46   up 7d       47   up 7d       48   down 7d       49   up 3d       50   down 7d       51   down 7d       52   up 7d       53   up 3d       54   up 3d       55   up 3d       56   up 3d       57   down 3d       58   down 3d       59   down 3d       60   down 3d       61   up 3d       62   down 3d       63   up 3d       64   up 3d       65   up 3d       66   up 3d/down 7d       67   up 3d       68   up 3d       69   down 3d       70   down 3d/down           7d       71   up 3d       72   up 3d       73   up 3d       74   down 3d       75   down 2y       76   up 2y       77   up 2y       78   down 2y       79   down 2y       80   down 2y       81   up 2y       82   up 2y       83   up 2y       84   up 2y       85   up 2y       86   down 2y       87   up 2y       88   up 2y                  
 
         [0097]    For each DNA fragment, gene expression patterns are obtained in the stroke model compared over several time points. “Up”, “down”, and “mixed” is defined as time dependent expression at one or more time points in the cardiac arrest model compared to the non-disease model.  
     
       
       
         1 
         
           
             88  
           
           
             1  
             220  
             DNA  
             Rattus norvegicus  
           
            1 

gggagtcaat aaatcttatt agacataaca ggtacccaag gacgacagtc tactctaagc     60 

tagctaccat atgcgtatca atgttgcaat ctcgttatgt ccagctgagg atcagaagcc    120 

tgactattag atccgctata ccaggatata cctacgatcc cgtaggtgtc atgacgtatc    180 

ataactagta ctgagacggg aaactgcaca taaaaaaaaa                          220 

 
           
             2  
             296  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(296)  
               n = A,T,C or G  
             
           
            2 

tgaatcctag gatggatgag cgtgtctcat attataaccg tatacatcgt cattactcat     60 

tgancgaaca gtataggtcg cgagaggagt ggtgctacca actatcaggc gcgttacttg    120 

aggtgtcgat acgtctgcag ctcccgtagc ccgcagaatt atggtacatg aatcatatgt    180 

attcgctaag gttctatccg tactggtaga ccagggctct ggaccatagt ctcatactca    240 

aagtactaca tagactcaaa tgacagttca tgacgaacaa gtacacaaac aacaaa        296 

 
           
             3  
             287  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(287)  
               n = A,T,C or G  
             
           
            3 

gtgggcgcaa ngaccantnc cccctaaaat ttntaaaacc ngnagggatt anatttnatt     60 

cttctcagac aggtgaggnc ccactaagtc ctcggaagca aatagctgcg gtctcagaga    120 

gcacangatc gttggccttg nattcatggc tgttgacagc tgtccatgcc atgatcatga    180 

tttcgatatc aatgcttttc atnttagaat atgtanacat accgaagtga gtttgtgaca    240 

ctattttaac ataaaatttc taacactcaa caaaaaaaaa aaaaaaa                  287 

 
           
             4  
             91  
             DNA  
             Rattus norvegicus  
           
            4 

tactcttcca tacaagtcct atacacactt ttatgtacca ttgattgatc ctactgccct     60 

tcttactttt cactcaaaaa aaaaaaaaaa a                                    91 

 
           
             5  
             258  
             DNA  
             Rattus norvegicus  
           
            5 

gtggaggctg agtgctacct atgatgtctt gaagtatatc acaattatct gtaatcctca     60 

tcttcagact gcttccctcc accgtagact gtgcttcctc ctccagcgtg ccctgcatgg    120 

cctagctcca gacgtcgaga gaggacagct atcgtctagg acagttctgg tgttaccctg    180 

gagtccacgg gaggtgaact agtccagact gcctgagatg agtacagtat ctggcgtcac    240 

caaaaaaaaa aaaaaaaa                                                  258 

 
           
             6  
             200  
             DNA  
             Rattus norvegicus  
           
            6 

ttctcgcctc gtactttgct ggcttcctct cattcacaat ctgtcttatt gtgacccatc     60 

tgagatttcc agtagtagtc tcattacaac agcgagatga cattcgtatc ctcatagata    120 

taatgagtca caattctggt aatcatctaa attcacacag ttctcttact aaagtctctc    180 

aatctcaaaa aaaaaaaaaa                                                200 

 
           
             7  
             347  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(347)  
               n = A,T,C or G  
             
           
            7 

caagcggagg acatcgtcct catcttcata ggccgagcta caccaacatt attctatcta     60 

atcgccctaa catctatcgt attcctaggc cccttatatc atatcaagtt accctgaatt    120 

atactcaagc agcttcataa gcagaaacac atacttctat ccacacactt tcctactgaa    180 

tcgcgagcat cctaccgccg cggtggcgag tatgaccaac tggatgcacc tccgtatgga    240 

gaaaatttcc tcccacntaa cacgtagcat tctcgcagta tgatacattt gcgctgggca    300 

atttgccagt agcagtgaac ttccatgcct acaggtataa aaaaaaa                  347 

 
           
             8  
             183  
             DNA  
             Rattus norvegicus  
           
            8 

caaggcctca ctgtctgacg tcctccacag gtcctagctt cagctgaaat gttgcttctg     60 

cagttttgtg tgcagttccc aactttctgc acagggacga tctttgtccc tgatcctgaa    120 

gagtagaaat ggttcttaga aaagatttca aataaagtct gcacatcaaa aaaaaaaaaa    180 

aaa                                                                  183 

 
           
             9  
             214  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(214)  
               n = A,T,C or G  
             
           
            9 

ggggggcggc agaggcaatt gtactactga tgttttatct agcttnagcc tgtgcccact     60 

ctgatttgct cctgcaacca tacagctgtg gcatgtaatg aagtcctgtt gtgtgtccga    120 

tgccccgagc ctctacattc aagcagcgaa tagagtgtga gagcaaggcc ttgtgaatca    180 

gatgaaggat cgaagtgaaa aaaaaaaaaa caaa                                214 

 
           
             10  
             159  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(159)  
               n = A,T,C or G  
             
           
            10 

gtatctttct ctcancttac tgtcctatat ttcaatgaaa caacaaggca cttctctatt     60 

tcatcattaa aagtggacaa cctatcattt tccttctcac caagaagagg atttgcctgt    120 

gtacctaaag cttaggaatg ctaacaaaaa aaaaaaaaa                           159 

 
           
             11  
             195  
             DNA  
             Rattus norvegicus  
           
            11 

aagtgcgagt gtaacattta gcatgacagt ctgtacctga tcactgtact gctcttacac     60 

agtctggtca cagaatggga ggctagggtt gttgactgat ccagacccca actggcaact    120 

tcatgtatgt tttcaaccat ccccttagtg gttctacttc aaaatagaag aaagacaaca    180 

aaaaaaaaaa aaaaa                                                     195 

 
           
             12  
             164  
             DNA  
             Rattus norvegicus  
           
            12 

ataccttgtg tcgcagctag tacgcttcta gacttcagag tctggatctc tatgcatccg     60 

ctggtagagc tgtgcttgat agtacctcat aggctgcgta cgatcacgct ggccgcaagc    120 

atatctgtca ttagatagga ggaatccaag aaaaaaaaaa aaaa                     164 

 
           
             13  
             181  
             DNA  
             Rattus norvegicus  
           
            13 

aaacgctgcg aaccttctca ctccttacct acttttatct acgatcatac ttggaccacg     60 

tgacataagt ctacagcact acagctctaa tcatgttgct tctgaacatc atgtacatta    120 

atatttgtta ggcaattaat taaaataaac aatcttttta tgcgactaaa aaaaaaataa    180 

a                                                                    181 

 
           
             14  
             110  
             DNA  
             Rattus norvegicus  
           
            14 

ccgtcttgga tgtgctgtct gactttctct ctatgtgaat agtcttactg ttcatctaca     60 

tacattaaat taaaatgaag attcttatga ctcaacaaaa aaaaacaaaa               110 

 
           
             15  
             274  
             DNA  
             Rattus norvegicus  
           
            15 

atggagcgcg cgtcaacatg ctggtctatc gattacgctc gttcgtataa tccggtttca     60 

ggttgctact gttacttaaa ctaggtcgtg gacgatagaa ggaccactgt cagcacagac    120 

caactgggac attgctcaca tgatcagtgg ctttgaatga aatccagatc aagtgtccta    180 

gagttgacgc ttggcccttg tgaacgtgac tgtagctggc tcaaaggcag acttttgtga    240 

tcctaaatca gtccttcgaa ctgaaaaaaa aaaa                                274 

 
           
             16  
             132  
             DNA  
             Rattus norvegicus  
           
            16 

cctcgacgcg gggcaaccga ccggcgccgt cagacctaga ataatgtcca ggttactctt     60 

ctactagcag tactgtcata gctaggctct agctcaatta agaaatgtag gcgatgagaa    120 

aaaaaaaaaa aa                                                        132 

 
           
             17  
             139  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(139)  
               n = A,T,C or G  
             
           
            17 

ctccggtcgc tctcccgaaa tactagcctc tatgttttga aactacgaga ncagangaca     60 

ctaccaaagc acatgtagag gttctcgaaa cgataatgaa ataaacggta atgacttctt    120 

cacacaaaaa aaaaaaaaa                                                 139 

 
           
             18  
             276  
             DNA  
             Rattus norvegicus  
           
            18 

aaaagataca gtgagaagct ggagttggtc aattggaacc agatgttaaa aaattagaaa     60 

acttgcttca gggtggtgaa gtagaagagg tgattcttca ggctgaaaaa gaactaagtc    120 

tggcaagaaa aatgttgcag tggaagccct gggagccact ggtggaggag ccccctgcta    180 

accagtggaa gtggccaata taatccccgt gtctgatgat ggatgtggat ctaatgtgca    240 

attaaatgtt ctgtgatgct aaaaaaaaaa aaaaaa                              276 

 
           
             19  
             129  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(129)  
               n = A,T,C or G  
             
           
            19 

ccgtggagng gtacggaccg gagtccaaac tttntagttg gctgtntnca ttagatatgg     60 

atcaccctga atgctcctaa taaacgtcgg aaagcctana ttatcacaac tccaaaaaaa    120 

aaaaaaaaa                                                            129 

 
           
             20  
             118  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(118)  
               n = A,T,C or G  
             
           
            20 

cctacnaaac gagcgcggca cgtcgtgtcc tagtgtgtat tgtggctgtc ctctgagttg     60 

gacatacttg tatcgtcttc aatcaagaca tgtctgtgta cactaaaaaa aaaaaaaa      118 

 
           
             21  
             154  
             DNA  
             Rattus norvegicus  
           
            21 

gctgctgcag cgactagtca ggactggaca tatagacagg gtgcgggtcc caatcgctcc     60 

tgtgactgca ctggggcagc tgaagtgcag gaccttgcga ctagattgaa cgtcgtgatg    120 

agactagtct cgtccttaaa taaaaaaaaa aaaa                                154 

 
           
             22  
             103  
             DNA  
             Rattus norvegicus  
           
            22 

gggtggccgc cgcctcggat ctcatccttt tctctgacta catcattgca tttagcggta     60 

gccgatgtag tatactaata ggcagacaac aaaaaaaaaa aaa                      103 

 
           
             23  
             73  
             DNA  
             Rattus norvegicus  
           
            23 

tatctaagct caacttagct attatgctgt aggatgactg tgatactaca gttgttatca     60 

aaaaaaaaaa aaa                                                        73 

 
           
             24  
             107  
             DNA  
             Rattus norvegicus  
           
            24 

gcgcccgtcg ggtctgctct tcatatatca ttcttcttct ttattagttt taggttcctt     60 

ctagcattca tgatatagct tacaaatatc ggaaacaaaa aaaaaaa                  107 

 
           
             25  
             217  
             DNA  
             Rattus norvegicus  
           
            25 

actgcactaa cacgcactca ccttttgcct tctgccctca gccttcccgt ctgttcccca     60 

tgttctttcc caaggaatct agccttgagt ccagccacca attgtctcac aatacacagt    120 

gtggtattct tatcctctga aagagggctg aagggctgag aatggagtca ataaagcaag    180 

gaagcaaaca tcctgtttct gccaaaaaaa aaaaaaa                             217 

 
           
             26  
             151  
             DNA  
             Rattus norvegicus  
           
            26 

tccccccgag gccctaaggg ggctctgctc tcttctctct cttccttata tttatactcc     60 

tagagcatac aaaaggacac tatctttaaa acaagaaata atatatatcc tatgaacata    120 

tagtatagct aagtgcaaaa acaaaaaaaa a                                   151 

 
           
             27  
             200  
             DNA  
             Rattus norvegicus  
           
            27 

taacactgtg gacaggccaa ggcatatatt gcttcttctt agcattgcct acacacatct     60 

gcagcgttcc tctaagagct ggccctgtga caggggtctg gggatttagc tcagtgttag    120 

agcgcttgcc taggaagcgc aaggccctgg gattcggtcc ccagatctag aaaaaaaaga    180 

acctaaaaaa aaaaaaaaaa                                                200 

 
           
             28  
             217  
             DNA  
             Rattus norvegicus  
           
            28 

ctggctgatg acccaacagg aagaaagacc ctggtgaacg ctactctctg ggacctccct     60 

ttttgtgacc cgaaatgcct gtgcagtttt tcctgtccat cagccaaaaa tccaccccta    120 

gcagagatcc aacaaacaga aagttcacct tgccacgcac tctgtcctct cctcttccat    180 

gcattaaatt atgtttttag aaaaaaaaaa aaaaaaa                             217 

 
           
             29  
             310  
             DNA  
             Rattus norvegicus  
           
            29 

tgtgactgca gtaacgcgcg gtcttgcggt ttactctgtg tcggggagat gtaccatggc     60 

cacccagact ttaacagcac taaataactt agggagctgg gggagggaag ggcccaggac    120 

tcgggccact cagcctaatg aaaccctgtt gctctgtcac cgtgtgccct ttggcctgac    180 

caagtttgac actgggattc agtttaggcg ccagcctcaa gcacatccca gcagtggtac    240 

ttcggagaaa tcagcatctg actgagcaga acaaatcgtc aggtgcctgg agcaaaaaaa    300 

aaaaaaaaaa                                                           310 

 
           
             30  
             211  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(211)  
               n = A,T,C or G  
             
           
            30 

tctcctgcct ttgtcctgtc ttctctctat ccctctctat acgtctctgt atattttacc     60 

ggaccttccc gatcnatgct gtgtacgaaa tacatggtga cgcctaggca attcctatga    120 

tacttctacg tatgctagat gaagcttata cgtacttaga tagataactt acaaaataaa    180 

gtcttgatat cagtagacaa aaaaacaaaa a                                   211 

 
           
             31  
             410  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(410)  
               n = A,T,C or G  
             
           
            31 

gtgactgtga acnggcgtcg tntcgatgca cggtccgtgg natctcttna aggaggaccc     60 

ccctacntat cggactgtcc ncattncagc tggctcctgc ccangtgatt taatataaca    120 

ttcattggnn tgatcgataa tgttanggta caccncgtgg cacattgcat nggagtgaag    180 

tgaacaaggc tgtcaccaaa tcacacacgt tttaataaga aatgtttact aagggagcat    240 

ctttggactc tctgttttaa aaccttgtga accatgactc ggagccagca gagtaggctg    300 

tgtctgtgga cttgagcaca ccatcaacat tgctgttcag gaaattataa tttacgtcca    360 

ttccaagttg taaatgctag tcttttattt tttttttccc aanaaaaaan               410 

 
           
             32  
             341  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(341)  
               n = A,T,C or G  
             
           
            32 

ccaactcact gggacactga aatccntatt gagtgtaagg cgtatggtga gaacattggg     60 

tacagtgaga aagaccgttt tcagggacgc tttgatgtaa aaattgaagt taagagctga    120 

tcacaagcac aaatctttcc cactagccat ttaataagtt gaaagaaaaa gatacacaaa    180 

cctactagtc ttgaacaaac tgtcatacgt atgggaccta cacttaatct ctatgcttta    240 

cactagcttc tgcatttaat aggttagaat gtaaatttaa agtgtagcaa tagcaacaaa    300 

atatttattc tactgtaaat gacaaaagaa aaaaataaaa a                        341 

 
           
             33  
             411  
             DNA  
             Rattus norvegicus  
           
            33 

ggtgactcgt gcgctgccgg tggtgggagt gagcatgctc aacgtttgcc tgaagtcgcg     60 

acacgaagag cacgagagac ccgagttcgt cgcctacccc catctccgca tcaggactaa    120 

gcccttcccc tggggagatg gtaaccatac cctcttccac aatcctcaca tgaacccgct    180 

tccgactggc tatgaagatg agtaaagaga acctggctct tcgcccaggc gacaagggac    240 

cacagcactg atttggaccc tgactcttgt gtgtggacca cgaaagccca ttggatgctc    300 

agctcatctt tcctttatca gatggtgacc attactttgc tcctccatcc ctttgctcgt    360 

aagaggagat ggcttaaata aataacttga actgagaaaa aaaaaaaaaa a             411 

 
           
             34  
             118  
             DNA  
             Rattus norvegicus  
           
            34 

cggacgaata gatcgtaacg acttactctc tgctcttaag gacgaactgc tgtccccacg     60 

cgaactaagt tcaagtaaga gccagccggt agcgatacga acaagaaaca caacaaaa      118 

 
           
             35  
             186  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(186)  
               n = A,T,C or G  
             
           
            35 

cngcnaagct gtgattcagg ggttgctgta ttcttttgag tctggaagct cagtattggt     60 

ctctgtggct atgttgttat catgctgaaa cagtctgtta cctcatccct tctgacaaaa    120 

cgtcaataaa tgcttattng tatataaata ataaacccgt gaacccaact gcaaaaaaaa    180 

aaaaaa                                                               186 

 
           
             36  
             205  
             DNA  
             Rattus norvegicus  
           
            36 

ccccgggaga ctagcacact gctgtcgtca gtacctccag aactgaggga cccagcccag     60 

gaggacagga tcttgccaaa gcagtagctt cccatttgta ctgaaacagt gttcttggct    120 

ctataaaccg tgttagcaac tcgggaagat gccgtgaaac gttcttatta aaccaccttt    180 

atttcattca aaaaaaaaaa aaaaa                                          205 

 
           
             37  
             202  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(202)  
               n = A,T,C or G  
             
           
            37 

gcaggaccgc agctttatga ctgcatgttt ggatgttagc tctcgtctta tgagtcatcc     60 

actgcggatg cacttggata tgcttattgc gtattcctca tctgtacttg tttgtgcgat    120 

atcgttattt cgtgactatg tattccagct cttgtgtctn catcgatnat cgactgttga    180 

acactcaaga aaaaaaaaaa aa                                             202 

 
           
             38  
             200  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(200)  
               n = A,T,C or G  
             
           
            38 

aaagggacta actantgatt attagactgg catttactta gataaagttt gtggggccag     60 

attctttcca gacatgtgat tcacatacag gaatttctta cacatccacc tctcccctcg    120 

tgcagtatgg ccctgatgct taaaatctga gtaactaaga catctttgaa gatttaaacc    180 

aagtaatgca aaaaaaaaaa                                                200 

 
           
             39  
             146  
             DNA  
             Rattus norvegicus  
           
            39 

agccagtaac gacagctatc taggaccaag ctctgaaatt ggcggctcag atcacagctt     60 

catacccatg gtactagaaa tagtgcctct aaaatatttc gaaaactgat cagcttctat    120 

aattcaaacc aaaaaaaaaa aaaaaa                                         146 

 
           
             40  
             139  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(139)  
               n = A,T,C or G  
             
           
            40 

caaaatacgt taatatgaac antcactacg cctttacgta anatcatgac agccaggtgg     60 

ccttgtccca agcaccactc tggccctctg gatggccctt gcttaataaa tgattctcca    120 

agcaaaaaaa aaaaaaaaa                                                 139 

 
           
             41  
             234  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(234)  
               n = A,T,C or G  
             
           
            41 

atacagncca cacttaactc acccttacac tcaaatcatt atgtcgacag atattgactt     60 

accgaagtgc tattagacaa agagtcccgt caaggagagt gcctgaaagg agaaatgatg    120 

aaagtactaa ctagagcaga taattacacc gtcgtacctt ttagctatat atgctattag    180 

acttggatga attcattcat agacaaaatc cattaaacaa agaggctcga aaac          234 

 
           
             42  
             291  
             DNA  
             Rattus norvegicus  
           
            42 

ggacatgaca tgaccagtgt atctactgtg gtttctgcca ggaagcctgc cctgttgacg     60 

ctatcgtgga gggccccaac tttgagttct ccaccgagac gcatgaggag ttgctgtaca    120 

acaaggagaa gctactcaac aatggtgaca agtgggaggc cgagatcgcg gccaacatcc    180 

aggctgacta cctgtatcgg tgaccgggcc accggtgacc ttgccacctg gccagccttg    240 

tggcccctat agcccataaa gaaactctga tcccaaaaaa aaaaaaaaaa a             291 

 
           
             43  
             113  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(113)  
               n = A,T,C or G  
             
           
            43 

cggttnccgc gggctgtagc gaactcgagc ggaccgtctc tcccggtaca gttattattt     60 

atgtcactgg ctccttatta aagatcttta accctcaaaa aaaaaaaaaa aaa           113 

 
           
             44  
             197  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(197)  
               n = A,T,C or G  
             
           
            44 

tggggntcat tggcaataat gacctaggtn ttaacagtct tcctaagcat anaatttang     60 

ctaaagcaag cccgacacct aanatcgacg tctatcgtaa nccantcacn cgtttcagng    120 

acnctcaacn cgtactactt agacncaata gncgggnctc gatcgtntca ggatagcgtg    180 

gtcanncgcg tatcacn                                                   197 

 
           
             45  
             206  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(206)  
               n = A,T,C or G  
             
           
            45 

cacgttannt atggagcgcg ncgtactgac ttactcagtt tgcgttccct ttcctcgtta     60 

tgccttactg aactatgtac ttgacatgta gtgctacact tgggagagtt gttagcgctc    120 

tgctcccact ctctgtctac tcttcttgca tgtgtgggta ataaaggcgc ccggagaggg    180 

caagtgacta aaaaaaaaaa aaaaaa                                         206 

 
           
             46  
             146  
             DNA  
             Rattus norvegicus  
           
            46 

tccaacttac gttactactc catttatgca caggttcgag ataaattaat ttttgtaata    120 

tggacactga aaaaaaaaaa aaaaaa                                         146 

 
           
             47  
             181  
             DNA  
             Rattus norvegicus  
           
            47 

cagagacgcc gttcttgatt tattctcgcc cttcattccc atggcctgct gtctatgagt     60 

acaaatagta atggtggacg tgactgcttg ttgccaaact ggaacatgtt ctgtaggggt    120 

ttactggcat ggtatcattc ctaggaagaa gaagagggaa aaaaaagagg aaaaaaaaaa    180 

a                                                                    181 

 
           
             48  
             272  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(272)  
               n = A,T,C or G  
             
           
            48 

cagccagcag gaccaaactc aatcacagta gataaatact atgtccctcc acgatgcgtt     60 

gtcacgcgat gaggacaaga gaaatcgacg cgaccgaagt catgacagcg cgcgaacagc    120 

ccaacgcgtg cacgcgaccc gacgccagga cgagagccga caagctgatc accaggagag    180 

acacggagat aggatgcgcc aaggcagagc gaggacggcc agcaccagaa ggaagcgtgc    240 

gcggtaggag tgactatgag cactgtagna gt                                  272 

 
           
             49  
             73  
             DNA  
             Rattus norvegicus  
           
            49 

atctgcttaa agtctttaat ttgtactatt tcttcaaata aagaattttg gtacccaaaa     60 

aaaaaaaaaa aaa                                                        73 

 
           
             50  
             125  
             DNA  
             Rattus norvegicus  
           
            50 

tccaaaatat ttctgtgaag ctcagtcctc tgttcctctt ttttattttt ttttgttcct     60 

ctgtagacat gatggaggag tttactagaa aataacgtga gatgggagca ggaaaaaaaa    120 

aaaaa                                                                125 

 
           
             51  
             365  
             DNA  
             Rattus norvegicus  
           
            51 

aaacatggcg acgatgcaca gaccgaataa ctgtgtctta atcagagacc ctccctctag     60 

cacccagcgt gccatctcct acctaggaac gagcaacttg ctcaaaggcg taggtgactt    120 

gtgggccatt catctacaag tcctgatgga acaaggccca agactaaggg atgtaagaac    180 

gacccattga tataacgtta ttagtcccag ccaatgtctt cggtgatatt cccagttgca    240 

cttccctacg ttcgagaaca atccaacgag acactccaga ctcggtctgt gttaatgtcg    300 

catagctccc cttttgtaca acataaacat tatactgtga tgtgaacaac taaaacaaaa    360 

aaaaa                                                                365 

 
           
             52  
             175  
             DNA  
             Rattus norvegicus  
           
            52 

tggaggagta cctagtatta ttgacatcag tccgccaggc gcaacaatta catttgttat     60 

tctactgcgt acttacaggt acttgaattg gtcgaagtcc ttaattcaat gcctatgtat    120 

tcacccttct agtaagcctg tagctacatg actcacacat acaaaaaaaa aaaaa         175 

 
           
             53  
             182  
             DNA  
             Rattus norvegicus  
           
            53 

cacagcgcct ctctgttcac cacggcgtag ttacgatata tctctagcta gttcttttac     60 

attagttgac gtgtacttcc tcttgtgcag actgccgctg tccttgctcc actgatgggc    120 

ctgagcagtg ggtaagaact ccgtatgtaa ttgccgatac taaccagcaa aaaaaaaaaa    180 

aa                                                                   182 

 
           
             54  
             101  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(101)  
               n = A,T,C or G  
             
           
            54 

gggacgagcn canacgcgat ttccacgtta tcctcattct cataccagtc tctggcaata     60 

gtagaagacc agatgttaca atgaaattaa taaaaaaaaa a                        101 

 
           
             55  
             123  
             DNA  
             Rattus norvegicus  
           
            55 

ccgtccgtgg ggacgactat tatattttat tctttatctt ttctttctct ccagagacga     60 

tgcggccgag agaactggag cctcctatat cagtaagtgc tcgcagccca aaaacaaaaa    120 

aaa                                                                  123 

 
           
             56  
             76  
             DNA  
             Rattus norvegicus  
           
            56 

ctacgaaagg acaagagaat tggagcctcc ttaccataag tgctcccaac caatttatga     60 

aaaaaaaaaa aaaaaa                                                     76 

 
           
             57  
             261  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(261)  
               n = A,T,C or G  
             
           
            57 

ccgngaaacg gctgatgtgt catctttgct tcctcaggta ataagtctta acaggcccgc     60 

catcgttggt ctcatcaggt cctgctctct agaagtcgga tcagaaacag acttgaaaat    120 

gtgccgaaga attgcatctt agggtccgac gaaaaatgta tatagttgct gagtcctgag    180 

actcatgtgt gtgcacaaga aaacctggtt ttcccttaga atttacaact aaaggaagta    240 

acaagaaaac aaaaaaaaaa a                                              261 

 
           
             58  
             269  
             DNA  
             Rattus norvegicus  
           
            58 

tctgcggtgc ccaccagtat actggagacg tacttgtaac agggcccagg catactctag     60 

gtcctccatc acggacctgc ttctctcaga acgtcgagat cagaaacacg acttgaaaag    120 

tgtgccggaa gaatttgcat cttagaggtc cgacaaaaaa tgtatatacg tttctgagct    180 

cctgacgact catagtgtgt gcacaacgaa aacctggatt ttcccattag tatcctacac    240 

ataaaggcaa gtaagcaaga acaaaaaaa                                      269 

 
           
             59  
             277  
             DNA  
             Rattus norvegicus  
           
            59 

cggggtgttt gtttcattct gtctaatgtg aattttgtgc ctgctcctat ctgctcccct     60 

gtacccccag cttcctgctt ttctcccaca ttctgaactg tccagtcctg tgatgtgtct    120 

gaccttggac tcttcctgaa ggagctccct aggcaggaat atggtcccct attcagacac    180 

taggccaggt gtgactgggg ctctcttagt ggccctctta gtggatgtgt tggcaacctt    240 

aataaatcta gtggcagtgg caaaaaaaaa aaaaaaa                             277 

 
           
             60  
             228  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(228)  
               n = A,T,C or G  
             
           
            60 

cgggctgcat gacatatnga ctatccttga ctgcatctgt tccatcagca taatggaggt     60 

catccccagg catggatccc acctttacac taggtcttaa cctagttacg tatacctact    120 

cacgttatca cacctagtac ctcacgtagc taatacaagt ttgatactac atgacgcgtc    180 

ccatatcttn tnatacgctt aggcncntct cggtcngagt agatcaaa                 228 

 
           
             61  
             119  
             DNA  
             Rattus norvegicus  
           
            61 

gtttgtcttt ctttcctttc cttctgtttc ttttatccta ctgtgaccca cttatgcaaa     60 

accacaggta tactcactac tatctcatat ttctagcgct acgaaaaaaa aaaaaaaaa     119 

 
           
             62  
             117  
             DNA  
             Rattus norvegicus  
           
            62 

aagaaacgga gggagaccgg agagctgccc gctactgtcg gtaatctatc tcagtgtgga     60 

caagatatgt agggtagtgt gtagtatgct agtgtactag gccaaaaaaa aaaaaaa       117 

 
           
             63  
             217  
             DNA  
             Rattus norvegicus  
           
            63 

agcactcctc cacacaccac gactccgtct ttaagccgac gttctagcac cagtatccca     60 

aactcaccct actcatagag tcatagaagc caatgcctaa tcccattctg agcaacatat    120 

acactagaac agtctatatc tccgccacag tcattagatg aacaaaggct aatactgaga    180 

ttagatagac cttgtcaagg ggttggcaaa acaaaaa                             217 

 
           
             64  
             269  
             DNA  
             Rattus norvegicus  
           
            64 

cccagtttcg ttcgattaag tcagcgcacg ttcggagggt agtactatct acccagtaga     60 

gatcctatgt gcaatgcagg aagaactata gctgctgtag tgtagcgtgt acttcagtat    120 

acatcctgca taccacaaca accccaccac gcacccccgc ggttcataac acccgagggt    180 

caccgtggcc acaacttcgt gtcacgctat tcttgttaca tctggccaac attactcacc    240 

ccaccatata caactcgtta tccccacaa                                      269 

 
           
             65  
             162  
             DNA  
             Rattus norvegicus  
           
            65 

tctgtatacc gcattagagg cttgtagtat ccatccctct gtcacactta gtattcacat     60 

ggtgcgtact ttcgtgtata ttcaaactct ctgttaccct gacaaaatcc aaacttttgc    120 

tgttcacatc acatatgatg cacaattcaa aacaaaaaaa aa                       162 

 
           
             66  
             200  
             DNA  
             Rattus norvegicus  
           
            66 

cggggaagaa agcaggctgc caggtgtgtc ctgtctcatg atacagaaat ggtttccttt     60 

cggttattat tctggagcct caaatagcat tataacgttc tgtgattatg attgccttta    120 

tctttaatta tttctgtaac actccacact agtcttggga aaccggcccc ttattttaga    180 

gagaaaaaaa aaaaaaaaaa                                                200 

 
           
             67  
             182  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(182)  
               n = A,T,C or G  
             
           
            67 

tggtgnttct gtcctggact cctccagaca gcatggagga attctgtttt aagattatct     60 

tggagtttaa gtgattgccc tggaaaaatg aaatgtacca accatgtgga aatgacagct    120 

acgtgtacat tatgtatgaa atgccaaata gagggacaag ttgggagata aaaaaaaaaa    180 

aa                                                                   182 

 
           
             68  
             207  
             DNA  
             Rattus norvegicus  
           
            68 

cgtgagttaa tgagcttcga gccttaccac tctcccttta aatcaggaag tgcataggct     60 

aattactatc agtcccgata tatttgttaa aggaacacct acaagatcct tactggtgac    120 

cttctgtgag acactagttt gaggcactac atgtgtactt gaaaataata aagttgcatt    180 

tctttatgaa taaaaaaaaa aaaaaaa                                        207 

 
           
             69  
             268  
             DNA  
             Rattus norvegicus  
           
            69 

gtgtgtgatg agattatgtg atggggaggc tgaacacagt tctatatttt agtatttttt     60 

agtaatttgt actgtatttt tccttgcaga tattgaagtt atgaaccatt tactttgtgt    120 

tctactgagt aagatgactt gttgactgtg aaagtgaatt ttcttgctgt gttgaacaat    180 

caggactgcg ttcacttgag atccttgtag aataagcaca ggccgttttt cactttggta    240 

ttgatacaat gtaaaaaaaa aaaaaaaa                                       268 

 
           
             70  
             285  
             DNA  
             Rattus norvegicus  
           
            70 

gacatacttc acgcgaatat atgactggat gtacagttac ccagcacgtg ttcctcctcc     60 

tcctcccatt gctcgagctg tggtgccttc caaacgccag cgtgtgtcgg ggaacacctc    120 

acgaaggggc aaaagtggat tcaattcaaa gagtggacaa cggggatctt cttccaaatc    180 

tggaaagttg aaaggtgatg accttcaggc cattaaaaag gagctgactc agataaaaca    240 

aaaagtggat tctctgctgg aaagcctgga aaaaaaaaaa aaaaa                    285 

 
           
             71  
             158  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(158)  
               n = A,T,C or G  
             
           
            71 

atggacgacg gtgaatgcag gactgggctg tcgtgtagca tcaccaccac cttcacatag     60 

taaccccatc gttggagcac agaggaagga agatcatcag ngcagcttgg gctacttagc    120 

agaccctgtt ccaaaaaaaa aaaaaaaaca caccacag                            158 

 
           
             72  
             144  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(144)  
               n = A,T,C or G  
             
           
            72 

gagccgaggt gatgcctcgt agtctctctc tctgttgntc tcttctggtg gtgacggggt     60 

tatcccttcc cagttgtatt atattcctgt ggggcacatc ccaaagtatt aaaagtagct    120 

tagtaattca aaaaaaaaaa aaaa                                           144 

 
           
             73  
             250  
             DNA  
             Rattus norvegicus  
           
            73 

aggcgcacta gagatcagaa ttacgctctc ctttccacat cagatgtgaa aactgtgatc     60 

acaacagtag tacagtttgg tttcattgaa aataaactga attctaaagc atgctttttc    120 

actggtccct ttgcttttgc tacttcgaga cctcttggtt tatataacac tgaggttaag    180 

attaaagctt ttcagaatgc caggcaaaga ctagagtttt gacccgaaca cacacacaaa    240 

aaaaaaaaaa                                                           250 

 
           
             74  
             122  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(122)  
               n = A,T,C or G  
             
           
            74 

ggaaagtagt ggtggtagcg tgtanttctt atattatgtg ttacatatgt gtcgtctata     60 

tatataagta catcccttag aactgctagg accatctcag aactgcacaa aaaaaaaaaa    120 

aa                                                                   122 

 
           
             75  
             157  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(157)  
               n = A,T,C or G  
             
           
            75 

ggtccanngg taatannttt acctngtgtt tattgnngta tatagctcac tccgttacgt     60 

tcttgtctag gcgtggccct anacggggac ttgagtaaat caccgtgatg ctcatgcccg    120 

atgtaaggga taagagatgt acaaaaaaaa acaacaa                             157 

 
           
             76  
             107  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(107)  
               n = A,T,C or G  
             
           
            76 

gggattggtg tggcttcttg tntaatctgt ctattcttct ggtggtgatg tgttgtgtag     60 

tatatgttac gcagtcatta gcacgggagg taagcaaaaa aaaaaaa                  107 

 
           
             77  
             254  
             DNA  
             Rattus norvegicus  
           
            77 

tgcgacgtga gacacctgct ccctctctgg tgtatttata catacgtgga cagaaacaac     60 

tcgtctgttt attgactcac cctcggtctg agacagcggt gctgtaacag aagtagatgc    120 

ctgaactcga gtcaatatac aaatcaataa tgtatgctct ctttctctct ttacattctg    180 

gtcactacac tacagttatg aaatgggatg ctagtgtctt ggacagccca aaaaattggc    240 

cgctcgtaac aaaa                                                      254 

 
           
             78  
             208  
             DNA  
             Rattus norvegicus  
           
            78 

aggcatccta tctgctaggc tactgtgaat ttgctctcca gtctacctgc ctgagcagtg     60 

tgcatctact attgacagga gagtctgctc ccagacactc tgcctttccc tccacaatcc    120 

tcgtcattcc gcatcctcat ggtaaactag gtcacgacgg cagtgcaatg cgtaaataac    180 

cgaggtggac tttcgaatgt acaaacaa                                       208 

 
           
             79  
             300  
             DNA  
             Rattus norvegicus  
           
            79 

aacggtagtt gaccagtacg gattgactga tccttgtgtt ttcctcttgc aattggcccc     60 

aaacatgtcc ctggcaagtg gagtgaaggc tttttgtcta aagatgacta gggtcagctc    120 

aggagttgtg ggggagggcg ttttcatctt ccccgttgtc acttagaggt ttcgaactct    180 

ggtgtaaaga ggccgtttat ctttgtaaac acaaaacatt tttgctttct ccggtttcat    240 

gttaatggcg aaagaatgga agcgaataaa cgtttcactg actttttgaa acaaaaaaaa    300 

 
           
             80  
             192  
             DNA  
             Rattus norvegicus  
           
            80 

cacgagagga gaacatttaa cttttggtca gcagaatgaa ggaagcaaag agaagcgcca     60 

ggaacagatt gtcaagagca cgtaggctgt cttcgctgag agcttctact tctaaatctg    120 

agtccagtca aaaataagtc tttaaagagt caacaaataa ataatgagca ccttgaaaaa    180 

aaaaaaaaaa aa                                                        192 

 
           
             81  
             300  
             DNA  
             Rattus norvegicus  
           
            81 

gcaaaataac tgactgctca cccccgcttc tcatcaccag gacagcaggt cgagaaatgt     60 

ctttccttgc acttgcttct ggggtttgtg attcttctaa ttttccccct tgctgtatct    120 

ccctccttac cccctccact cgttccctgt ttctgtttat gcggaaatgg cagaaacgct    180 

tgagaaatgc gaatgtgtaa gtggactgga agtttatagt ctggattttc aattttactt    240 

tgtactgtac atctttttac tttagaattt gcaataaagg gttacgtcaa aaaaaaaaaa    300 

 
           
             82  
             328  
             DNA  
             Rattus norvegicus  
           
            82 

ggtatcgtga gagcaaaata aactgtactg ctccacccac cgcttctcat caccaggaca     60 

gcaggtcgag aaatgtcttt ccttgcactt gcttctgggg tttgtgattc ttctaatttt    120 

cccccttgct gtatctccct ccttaccccc tccactcgtt ccctgttctg tttatgcgga    180 

aatggcagaa acgcttgaga aatgcgaatg tgtaagtgga ctggaagttt atagtctgga    240 

ttttcaattt tactttgtac tgtacatctt tttactttag aatttgcaat aaagggttac    300 

gtcaatcttg tttccaaaaa aaaaaaaa                                       328 

 
           
             83  
             186  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(186)  
               n = A,T,C or G  
             
           
            83 

aacgcanaag agctancgag caacccgant gtacttcacc ggagactggg tgaccggacc     60 

tcactgcggc atttctgcag ggccatctgg acatggcgcc taggtcagcg aggtgcagca    120 

caggcttgac gtattcgagc gattgcccta taagtccgac ggctcaatta aacacacaaa    180 

caaaaa                                                               186 

 
           
             84  
             370  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(370)  
               n = A,T,C or G  
             
           
            84 

ctggcggtat acgtctcaat cccttagtta tnttatctaa gtctgggtgt gtacctagtg     60 

tcacacatga ctagcatatg acctaactgt atgggcagtc tatggatttc ggacttccgc    120 

tcctccctcc ctcctgatcc ctcgctggtt cgtggcatga tccgtaatag actctggtta    180 

aaatccatcg tcggtggttg cagcttcctc atatacgcga gctgtgagtg gtattaggtc    240 

atgcacccct cacagtgcat ggtcgcgata ctctacgcta atccatcata ggcttcggga    300 

ttaacagctt cttcacgttg ctgagacagc aagaaacaaa caatatggct cctctcccaa    360 

aaaacaacac                                                           370 

 
           
             85  
             441  
             DNA  
             Rattus norvegicus  
           
            85 

cgaatacatc atggcgtctc tcatagagtt tgatggcgaa gacatcacga ctagaatcat     60 

gaactacaaa accgcccgct ttgacagccg cttccaaacc agaaccagac taagaactgc    120 

tggcagaact acctggactt ccaccgctgt gagaaggcaa tgacggcaaa gggcggtgac    180 

gtctccgatg tgcgagtggt accggcgagt gtacaagtcc ctctgccccg tctcatgggt    240 

ctcagcctgg gatgaccgca tagcagaagg cacatttcct gggaagatct gacctggctc    300 

cgcccacctc tcctctgctc tttgaccttc tccccgatag aaaaggggga cctcagtata    360 

tgatggtccc tatcctggga ccctgaatca tgatgcaact actaataaaa actcactgga    420 

aaggttacaa aaaaaaaaaa a                                              441 

 
           
             86  
             412  
             DNA  
             Rattus norvegicus  
           
            86 

gtgcagctag tcacttctag cgactgtggc aggctttgat ggcccaatgc agttctctgg     60 

agaaaactac ctttccccaa ggcatctgca cccattgaca atggtaatgt gcccatctct    120 

ccttggtcct gccctcaacc gatgcttttc cagtcagggt tttgtttttt gttttgtttt    180 

gtgtacctca actgagttat gaagatttgt actggtttta cagatcatct catcgtatgg    240 

attagaacaa gcttcgtggt cagtttgctg ggtgaccggc agacaccaca atcaaactag    300 

tctgggaaaa acctgctttt ttgttgtagg tgccacgtaa ccctgtcagt ttaacaagga    360 

atgaccgtgc caataaacca attctccctc tgcttgaaaa aaaaaaaaaa aa            412 

 
           
             87  
             149  
             DNA  
             Rattus norvegicus  
           
            87 

cgttaggcgc agtcgtacag gcgtactgtt tctctatcta cttgctgctc gggtcagatg     60 

cgacttcaaa tctagatggg acgccgtagg tccatgtatg ctaatgaggg gtgagctagt    120 

attacttatt atcaggaagc aaaaaaaaa                                      149 

 
           
             88  
             207  
             DNA  
             Rattus norvegicus  
             
               misc_feature  
               (1)...(207)  
               n = A,T,C or G  
             
           
            88 

actagtagag ttcgaantag tctcgttaga tccggaatgt acctcgccga gatcagactg     60 

ggaaaatgac tacctttctc acaacgaaaa cagtcccggt ggccctctgc cctggacctt    120 

tgggattctg ggactagttc tgttctctag tggccaattg taactcgtgt acaataaacc    180 

ctcttgctgt caaaaaaaaa aaaaaaa                                        207