Common Chromosomal Inversions and Genomic Variability

描述(由申请人提供)： 最近对人类基因组的研究发现，在特定的染色体区域，有大量几乎相同的序列，约占人类基因组序列的5%。这些平行序列之间的非等位同源重组导致基因组结构的变化，造成倒置和其他类型的染色体重排。染色体结构的变异，如亚显微倒置，在人类基因组中比之前认为的更普遍。在染色体8p23上发现了一种常见的倒位多态。这项提议的主要目标是描述8p23倒位区域的特征，并开发工具用于全基因组范围内类似重排的研究。 8p23重排是一种跨越约4Mb区域的倒位多态，其两侧是相邻的序列，直到最近才在不同的触型上被发现。围绕或包括8p染色体倒位的区域已经被几项复杂表型的独立图谱研究所牵连，这些复杂表型包括精神分裂症、双相情感障碍、多发性抽动症、伤害避免和前列腺癌易感性。为了研究8P转换区在基因组进化中的作用，需要了解8P转换区的潜在结构和历史，而对这些可能的基因座的研究也需要8P转换区的分子特征。 人们对常见的倒置知之甚少。我们将对侧翼的邻近序列进行详细的分析，并调查该区域是否存在单倍型块；这将揭示这些重复片段的系统发育历史，并使我们能够重建最可能的祖先构型。将为不同的倒位单倍型建立表达谱，以检验8P倒位事件可能影响局部或更多全局基因表达的假设。我们将开发一种简单的检测方法，以筛选大量样本中8P反转的存在。此外，这种倒位和类似的倒位可能会影响统计遗传分析的结果；我们将调查这些重排对作图研究的可能影响，开发连锁和连锁不平衡作图的统计方法，以整合每条染色体的倒位信息，并重新分析先前与该区域相关的不同性状的先前基因型数据。此外，还将开发和应用工具来预测和识别具有类似变异性的其他基因组区域，进一步扩大染色体结构和复杂特征之间的可能联系。

DESCRIPTION (provided by applicant): Recent studies of the human genome have revealed large blocks of almost identical sequences in particular chromosomal regions, comprising about 5 percent of the human genomic sequence. Non-allelic homologous recombination between these paralogous sequences results in changes of genomic structure creating inversions and other types of chromosomal rearrangements. Variation in chromosomal architecture, such as submicroscopical inversions, is more widespread in the human genome than previously thought. One example of a common inversion polymorphism is identified on chromosome 8p23. The main goal of this proposal is to characterize the 8p23 inversion region and develop tools for genome-wide investigation of similar rearrangements. The 8p23 rearrangement, an inversion polymorphism spanning about a 4Mb region flanked by paralogous sequences, was only recently recognized on different haptotypes. The region surrounding or including the inversion on chromosome 8p has been implicated by several independent mapping studies of complex phenotypes including schizophrenia, bipolar disorder, Tourette syndrome, harm avoidance, and prostate cancer susceptibility. Understanding the underlying structure and history of the 8p inversion region is needed to study its role in genome evolution and investigation of these putative loci also requires molecular characterization of the 8p inversion region. Little is known about common inversions. We will conduct detailed analysis of the flanking paralogous sequences and investigate the presence of haplotypes blocks for this region; this will reveal the phylogenetic history of these duplicated segments and enable us to reconstruct the most likely ancestral configuration. Expression profiles will be established for different inversion haplotypes to test the hypothesis that 8p inversion events may affect local or more global gene expression. We will develop a simple assay in order to screen large numbers of samples for the presence of the 8p inversion. Additionally, this and similar inversions may affect the results of statistical genetic analyses; we will investigate the possible implications of these rearrangements on mapping studies, develop statistical methods for linkage and linkage disequilibrium mapping to integrate inversion information for each chromosome, and re-analyze prior genotype data for the different traits that were previously associated with this region. Furthermore, tools will be developed and applied to predict and identify additional genome regions with similar variability, further expanding the possible link between chromosomal architecture and complex traits.