Common Chromosomal Inversions and Genomic Variability

常见的染色体倒位和基因组变异

• 批准号: 6672865
• 负责人: Roel A Ophoff
• 金额: $ 33.55万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-05 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672865
• 关键词: alleles; animal genetic material tag; animal tissue; bioassay; chromosome inversion; fluorescent in situ hybridization; gene expression; gene rearrangement; genetic polymorphism; genetic screening; genotype; human genetic material tag; human tissue; linkage disequilibriums; linkage mapping; microarray technology; phenotype; pulsed field gel electrophoresis; single nucleotide polymorphism; technology /technique development

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.

描述（由申请人提供）： 最近对人类基因组的研究揭示了特定染色体区域中几乎相同序列的大块，约占人类基因组序列的 5%。这些旁系同源序列之间的非等位基因同源重组导致基因组结构的变化，产生倒位和其他类型的染色体重排。染色体结构的变异，例如亚显微倒位，在人类基因组中比以前想象的更为普遍。常见倒位多态性的一个例子是在染色体 8p23 上发现的。该提案的主要目标是表征 8p23 倒位区域并开发用于类似重排的全基因组研究的工具。 8p23 重排是一种倒位多态性，横跨约 4Mb 区域，两侧是旁系同源序列，直到最近才在不同的触觉型上被识别。围绕或包括 8p 染色体倒位的区域已被多项复杂表型的独立绘图研究所涉及，这些表型包括精神分裂症、双相情感障碍、抽动秽语综合症、避免伤害和前列腺癌易感性。需要了解 8p 倒置区域的基本结构和历史来研究其在基因组进化中的作用，并且对这些假定基因座的研究还需要 8p 倒置区域的分子表征。 人们对常见的倒转知之甚少。我们将对侧翼旁系同源序列进行详细分析，并研究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配置。将为不同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全局基因表达的假设。我们将开发一种简单的检测方法来筛选大量样品中是否存在 8p 倒位。此外，这种倒置和类似的倒置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，以整合每个染色体的倒位信息，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，还将开发并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性状之间的可能联系。