Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations
Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations
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对 487,409 个英国样本的血统身份检测揭示了精细的种群结构、进化历史和性状关联
DOI：
10.1101/2020.04.20.029819
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
P. Palamara
中科院分区：
文献类型：
--
作者：
Juba Nait Saada;Georgios Kalantzis;D. Shyr;M. Robinson;A. Gusev;P. Palamara
同源（IBD）片段的检测提供了遗传相关性的基本衡量标准，并在广泛的基因组分析中起着关键作用。我们开发了一种名为FastSMC的新方法，可以准确检测由过去数百代共同祖先传播的IBD片段。FastSMC将IBD片段的快速启发式搜索与准确的基于聚结的可能性计算相结合，并能够估计传播IBD区域的共同祖先的年龄。我们将FastSMC应用于来自英国生物库的487，409个阶段性样本，并检测到在过去1，500年内由共同祖先传播的2，140亿IBD片段的存在。我们量化了120个邮政编码内和跨邮政编码的时间依赖性共同祖先，获得了英国过去两千年内遗传相关性的精细图像。共同祖先的共享与地理距离密切相关，从而能够从基因组数据中定位样本的出生坐标。我们通过鉴定近千年来具有异常强的共同祖先的基因座来寻找最近正选择的证据，我们检测到12个全基因组显著信号，包括7个新基因座。我们发现IBD共享高度预测来自英国生物库的外显子组测序样本中超罕见变异的共享。针对使用外显子组测序发现的功能丧失变异，我们设计了一种基于IBD的关联测试，并检测到29种与7种血液相关性状的关联，其中20种在外显子组测序研究中未检测到。这些结果强调了远缘关系建模的重要性，以揭示微妙的种群结构，最近的进化史和罕见的致病性变异。
Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key role in a wide range of genomic analyses. We developed a new method, called FastSMC, that enables accurate biobank-scale detection of IBD segments transmitted by common ancestors living up to several hundreds of generations in the past. FastSMC combines a fast heuristic search for IBD segments with accurate coalescent-based likelihood calculations and enables estimating the age of common ancestors transmitting IBD regions. We applied FastSMC to 487,409 phased samples from the UK Biobank and detected the presence of ∼214 billion IBD segments transmitted by shared ancestors within the past 1,500 years. We quantified time-dependent shared ancestry within and across 120 postcodes, obtaining a fine-grained picture of genetic relatedness within the past two millennia in the UK. Sharing of common ancestors strongly correlates with geographic distance, enabling the localization of a sample’s birth coordinates from genomic data. We sought evidence of recent positive selection by identifying loci with unusually strong shared ancestry within recent millennia and we detected 12 genome-wide significant signals, including 7 novel loci. We found IBD sharing to be highly predictive of the sharing of ultra-rare variants in exome sequencing samples from the UK Biobank. Focusing on loss-of-function variation discovered using exome sequencing, we devised an IBD-based association test and detected 29 associations with 7 blood-related traits, 20 of which were not detected in the exome sequencing study. These results underscore the importance of modelling distant relatedness to reveal subtle population structure, recent evolutionary history, and rare pathogenic variation.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Browning, Sharon R.;Browning, Brian L.
通讯作者：
Browning, Brian L.
影响因子：
9.8
作者：
Tian, Xiaowen;Browning, Brian L.;Browning, Sharon R.
通讯作者：
Browning, Sharon R.
影响因子：
9.8
作者：
Lines, Matthew A.;Huang, Lijia;Boycott, Kym M.
通讯作者：
Boycott, Kym M.
影响因子：
10.7
作者：
Gusev, Alexander;Palamara, Pier Francesco;Pe'er, Itsik
通讯作者：
Pe'er, Itsik