Multi-allelic forms of human genome structural variation

摘要/摘要 数十万个人类基因组正在被测序，这得益于大大降低了 测序。这些数据为确定人类基因组如何变化以及如何变化提供了前所未有的机会。 这种变异塑造了人类生物学。而精细的序列变化今天很容易被成熟的 分析方法，更大规模的基因组变异形式--特别是那些具有许多结构上不同的等位基因的 -识别、分析和纳入关联分析具有挑战性。我们试图理解如何 人类基因组在这些尺度上有所不同，以及这种变异是如何影响人类表型的。 我们相信，在基因组序列数据中确定比可见的更多的遗传变异是可能的 今天的分析方法。在大型收集的统计模式中有大量未充分利用的信息 序列读数的形式跨越个人、家庭和群体，并进一步利用单倍型 多等位基因变异与SNPs和其他变异一起形成。我们在这项工作中的重点将是两个大的， 我们试图将其纳入常规基因组分析的有趣的基因组变异类别。一节课 涉及多等位基因CNV，其中存在一个基因组片段(大小从1到几百个千碱基) 每个二倍体人类基因组的大范围的拷贝数(如2-10个)，通常在精细的序列中变化 以及复印号。另一类涉及更高拷贝数的可变串联重复数(VNTR) 多态，在更大的范围内存在较短的基因组序列(数十到数千个碱基对) 每个二倍体基因组的拷贝数(高达数十个甚至数百个拷贝)。我们将推进分析 这些方法可以测量这些基因座的序列变异，识别结构等位基因 并分析这种变异与人类表型的关系。我们将创造 并分发研究软件和数据资源，例如参考单倍型，使人类能够 遗传学家将这些基因座纳入关联和精细作图分析。我们亦会评估 这些变异对在大群体中收集的数量表型的贡献 一群人。 我们希望这项工作有助于更多地发现疾病的遗传和生物学基础。

SUMMARY/ABSTRACT Hundreds of thousands of human genomes are being sequenced, enabled by profound reduction in the costs of sequencing. These data offer unprecedented opportunities to ascertain how the human genome varies and how this variation shapes human biology. While fine-scale sequence variation is today readily recognized by mature analysis methods, larger-scale forms of genome variation – especially those with many structurally distinct alleles – are challenging to recognize, analyze, and incorporate into association analyses. We seek to understand how human genomes vary at these scales and how this variation contributes to human phenotypes. We believe that it is possible to ascertain far more genetic variation in genome sequence data than is visible with analysis methods today. There is vast under-utilized information in the statistical patterns that large collections of sequence reads form across individuals, families and populations, and in further utilizing the haplotypes that multi-allelic variants form together with SNPs and other variants. Our focus in this work will be on two large, intriguing classes of genome variation that we seek to incorporate into routine genome analysis. One class involves multi-allelic CNVs, in which a genomic segment (from one to several hundred kilobases size) exists in a wide range of copy numbers (such as 2–10) per diploid human genome, often varying in fine-scale sequence as well as copy number. Another class involves higher-copy-number variable-number-of-tandem-repeat (VNTR) polymorphisms, in which a shorter genomic sequence (tens to thousands of base pairs) exists in a wider range of copy numbers (up to scores or even hundreds of copies) per diploid genome. We will advance analysis methods that make it possible to measure sequence variation at these loci, identify the structural alleles from which this variation arises, and analyze the relationships of such variation to human phenotypes. We will create and distribute research software and data resources, such as reference haplotypes, that enable human geneticists to incorporate such loci into association and fine-mapping analyses. We will also assess the contribution of these kinds of variation to quantitative phenotypes that are being collected in large population cohorts. We hope that this work contributes to many discoveries about the genetic and biological basis of disease.