Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder

Mobile DNA

Chong Chu¹  Soohyun Lee¹  Peter J. Park¹  Rebeca Borges-Monroy²  Jaejoon Choi³  Yue Gao⁴  Eunjung Alice Lee⁴  Taehwan Shin⁴  Christopher A. Walsh⁵  Caroline Dias⁶ 

[1] Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA;Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA;Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA;Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA;Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Genetics, Harvard Medical School, Boston, MA, USA;Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA;Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Pediatrics, Harvard Medical School, Boston, MA, USA;Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA;Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Pediatrics, Harvard Medical School, Boston, MA, USA;Department of Neurology, Harvard Medical School, Boston, MA, USA;Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA;Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA;Division of Developmental Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;

关键词: Transposable elements;    Retrotransposons;    Autism spectrum disorder;    de novo insertions;    Polymorphic insertions;    de novo rates;    Alu;    SVA;    LINE-1;    Neurobiology;   

DOI  :  10.1186/s13100-021-00256-w

来源: Springer

【 摘 要 】

BackgroundRetrotransposons 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

CC BY