Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.
Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.
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DOI：
10.1186/s13059-017-1158-6
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发表时间：
2017-03-06
期刊：
影响因子：
12.3
通讯作者：
Talkowski ME
中科院分区：
文献类型：
--
作者：
Collins RL;Brand H;Redin CE;Hanscom C;Antolik C;Stone MR;Glessner JT;Mason T;Pregno G;Dorrani N;Mandrile G;Giachino D;Perrin D;Walsh C;Cipicchio M;Costello M;Stortchevoi A;An JY;Currall BB;Seabra CM;Ragavendran A;Margolin L;Martinez-Agosto JA;Lucente D;Levy B;Sanders SJ;Wapner RJ;Quintero-Rivera F;Kloosterman W;Talkowski ME
结构变异(SV)影响基因组组织并导致人类疾病。然而，在疾病相关性研究中，SV的完整突变谱并没有被常规捕捉到。我们对689名患有自闭症谱系障碍(ASD)和其他发育异常的参与者进行了测序，以构建大SV的全基因组图谱。利用105X平均物理覆盖率的长插入跳跃文库和10X基因组的连锁阅读全基因组测序，我们在~5kb的SV分辨率下记录了七个主要的SV类。我们的结果涵盖了11,735个不同的大型SV站点，其中38.1%是新的，16.8%是平衡或复杂的。我们描述了16个复杂SV(CxSV)的递归亚类，揭示了：(1)cxSV比典型SV更大和更罕见；(2)每个基因组平均含有14个大的cxSV；(3)84.4%的大cxSV涉及倒位；(4)大多数大的cxSV(93.8%)在以往的研究中没有被描述。罕见的SVS更有可能扰乱编码和调控的非编码基因座，特别是在截断受限制的和疾病相关的基因时。我们还发现了多个称为染色体重排的灾难性案例，包括体细胞染色体融合，以及涉及四条染色体多达65个断裂点和60.6个Mb的极端平衡生殖系染色质事件，进一步定义了罕见的极端cxSV类型。这些数据提供了病态人类基因组中大SV的基本图谱，并证明了cxSV先前被低估的丰度和多样性，在人类疾病的基因组研究中应予以考虑。本文的在线版本(doi：10.1186/s13059-017-1158-6)包含补充材料，授权用户可以使用。
Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease. The online version of this article (doi:10.1186/s13059-017-1158-6) contains supplementary material, which is available to authorized users.