Novel approaches for detecting and analyzing stuctural variants in personal genomes

检测和分析个人基因组结构变异的新方法

• 批准号: 167077255
• 负责人: Dr. Jan Korbel
• 金额: --
• 依托单位: Europäisches Laboratorium für Molekularbiologie (EMBL)
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/167077255?language=en
• 关键词: Novel; approaches; detecting; analyzing; stuctural

Genomic structural variants (SVs), such as copy-number variants or large balanced inversions, represent a major form of genetic variation with an impact on the human genome that is similar to single nucleotide polymorphisms (SNPs). However, compared to SNPs, our understanding of SVs is limited. The resolution of published surveys has thus far been insufficient for mapping the start- and end-points (i.e., breakpoints) of SVs, hampering detailed analyses of SVs. Here we propose to study SVs in unprecedented detail: we will [1] develop computational approaches to identify SVs and analyze their extent in the genome; [2] mine published datasets to unravel SV de novo formation processes; and [3] apply approaches to measure SV de novo formation rates and to infer the influence of natural selection. Specifically, first we will systematically collect information on SVs with known breakpoints and standardize their description in a library. Scanning short DNA sequencing reads against the library will enable accurate SV-detection and thus add significant value to “personal genomes” that presently lack detailed SV analyses. Second, we will develop a framework for untangling SV formation by devising computational approaches for inferring the likely ancestral state (by comparison with primate genomes) and the likely causal mutational mechanism (by breakpoint analysis) at each SV locus. Third, we will estimate SV formation rates experimentally and SVoccurrence frequencies computationally to assess the factors contributing to the abundance and distribution of SVs in the genome.

基因组结构变异（SV），如拷贝数变异或大的平衡倒位，代表了一种主要形式的遗传变异，对人类基因组的影响类似于单核苷酸多态性（SNP）。然而，与SNPs相比，我们对SV的理解是有限的。迄今为止，公布的调查的分辨率不足以绘制起点和终点（即，断点），妨碍了对SV的详细分析。在这里，我们建议以前所未有的细节来研究SV：我们将[1]开发计算方法来识别SV并分析它们在基因组中的程度; [2]挖掘已发表的数据集来解开SV从头形成过程;[3]应用方法来测量SV从头形成率并推断自然选择的影响。具体来说，首先，我们将系统地收集已知断点的SV信息，并在库中标准化其描述。针对文库扫描短DNA测序读段将能够实现准确的SV检测，从而为目前缺乏详细SV分析的“个人基因组”增加重要价值。第二，我们将开发一个框架解开SV的形成，通过设计计算方法推断可能的祖先状态（通过与灵长类动物基因组比较）和可能的因果突变机制（通过断点分析）在每个SV位点。第三，我们将估计SV形成率实验和SV发生频率计算评估的因素，有助于丰富和分布的SV基因组。

项目成果

Primate genome architecture influences structural variation mechanisms and functional consequences

• DOI: 10.1073/pnas.1305904110
• 发表时间: 2013-09-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Gokcumen, Omer;Tischler, Verena;Korbel, Jan O.
• 通讯作者: Korbel, Jan O.