A Novel Array For Detection of Unstable Tandem Repeats

描述（由申请人提供）：精神分裂症是一种原因不明的破坏性疾病，约占美国人口的1%。现有的治疗方法仍远未达到最佳，病因和发病机制尚不清楚。尽管精神分裂症的遗传性可能高达80%，但发现遗传风险因素已被证明是困难的。在过去的几年中，人们对基因组拷贝数变异（CNV）对正常人类特征和包括精神分裂症在内的疾病的潜在贡献产生了极大的兴趣。使用先进的阵列技术的最新发现表明，高达12%的人类基因组可能会受到拷贝数变化的影响。虽然现在有可能检测全基因组SNP阵列的拷贝数变化，但这些阵列的探针通常被选择以避免重复区域，即使拷贝数变化最有可能恰好发生在这些区域。短串联重复序列已经成为连锁研究的有力标记，也成为引起许多人类疾病的突变。我们假设，较长的串联重复序列（单位长度为50 bp至150 150bp）的多态性，人类基因组中相对未被探索的特征，也可能有助于正常的人类变异和疾病，包括精神分裂症。为了系统地解决这一问题，我们建议开发一种专门用于检测串联重复序列中重复单元数量变化的寡核苷酸阵列。在Specific Aim 1中，我们将与华盛顿大学的Evan Eichler博士和NimbleGen公司的工作人员合作，开发并初步表征针对bbb3000串联重复序列的寡核苷酸阵列。在Specific Aim 2中，我们将初步确定美国异种对照人群和80名精神分裂症患者中这些重复序列的变异程度。我们的总体目标是充分表征串联重复序列，以便将其应用于大量患者（包括但不限于精神分裂症），以检测对疾病有重大影响的罕见突变，以及可能对疾病风险有轻微影响的常见变异。

DESCRIPTION (provided by applicant): Schizophrenia is a devastating disorder of unknown cause that affects about 1% of the U.S. population. The available treatments remain far from optimal, and the etiology and pathogenesis are unknown. Though the hereditability of schizophrenia may be as high as 80%, finding genetic risk factors has proven difficult. Over the past several years, great interest has arisen in the potential contribution of genomic copy number variation (CNV) to normal human traits and to disease, including schizophrenia. Recent findings using advances in array technology have shown that up to 12% of the human genome may be subject to variations in copy number. While it is now possible to detect copy number variations on whole genome SNP arrays, probes for these arrays have generally been selected to avoid repetitive regions, even though copy number variation is most likely to occur in precisely these regions. Short tandem repeats have emerged both as powerful markers for linkage studies and as mutations causing a number of human diseases. We hypothesize that polymorphisms of longer tandem repeats (unit length of 50 bp to >150,000 bp), relatively unexplored features of the human genome, may also contribute to normal human variation and to disease, including schizophrenia. To systematically address this issue, we propose to develop an oligonucleotide array specifically designed to detect changes in the number of repeating units in tandem repeats. In Specific Aim 1, we will work with Dr. Evan Eichler of the Univ of Washington and the staff of NimbleGen, Inc to develop and preliminarily characterize an oligonucleotide array targeting >3000 tandem repeats. In Specific Aim 2, we will preliminarily determine the extent of variation in these repeats in a heterogeneous U.S. control population and in 80 individuals with schizophrenia. Our overall goal is to sufficiently characterize the tandem repeat array so that it can be applied to large populations of patients (including, but not limited to, schizophrenia) to detect rare mutations of major effect on illness, and common variations that may make a minor contribution to disease risk.