Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder.
Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder.
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DOI：
10.1186/s13100-021-00256-w
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发表时间：
2021-11-27
期刊：
影响因子：
4.9
通讯作者：
Lee EA
中科院分区：
文献类型：
--
作者：
Borges-Monroy R;Chu C;Dias C;Choi J;Lee S;Gao Y;Shin T;Park PJ;Walsh CA;Lee EA
反转录转座子被认为是孟德尔疾病的原因，但它们在自闭症谱系障碍（ASD）中的作用尚未得到系统的定义，因为它们仅在全基因组测序（WGS）数据中具有足够的灵敏度，并且最近才有足够大的队列用于这种分析。我们通过建立一个可扩展的反转录转座子插入检测的计算管道，分析了来自Simons Simplex Collection的2288个ASD家族的WGS数据。我们报告了86,154例多态性反转录转座子插入（包括> 60%以前未发现的）和158例从头反转录转座事件。ASD个体和未受影响的兄弟姐妹之间新发事件的总体负担相似，Alu、L1和SVA分别为每29、117和206例分娩1例新发插入，每21例分娩1例新发插入。然而，ASD病例显示ASD基因中的新生L1插入比预期的多。此外，我们观察到外显子插入功能丧失的不耐受基因，包括可能致病的外显子插入CSDE 1，只有在ASD的个人。这些发现表明ASD中内含子和外显子反转录转座子插入的适度但重要的影响，显示了WGS对其分析的重要性，并突出了特定生物信息学工具用于高通量检测反转录转座子插入的实用性。在线版本包含补充材料，可通过10.1186/s13100-021-00256-w获得。
Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available. We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions—including > 60% not previously reported—and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals. These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions. The online version contains supplementary material available at 10.1186/s13100-021-00256-w.
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影响因子：
7
作者：
Gardner EJ;Lam VK;Harris DN;Chuang NT;Scott EC;Pittard WS;Mills RE;1000 Genomes Project Consortium;Devine SE
通讯作者：
Devine SE
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
4.9
作者：
Hancks DC;Kazazian HH Jr
通讯作者：
Kazazian HH Jr
使用多个测序技术对转座元素插入的全面识别。
影响因子：
16.6
作者：
Chu C;Borges-Monroy R;Viswanadham VV;Lee S;Li H;Lee EA;Park PJ
通讯作者：
Park PJ
影响因子：
3.5
作者：
Carter, M. T.;Nikkel, S. M.;Scherer, S. W.
通讯作者：
Scherer, S. W.