Whole-genome analysis ofde novoand polymorphic retrotransposon insertions in Autism Spectrum Disorder

Abstract

AbstractRetrotransposons are dynamic forces in evolutionary genomics and have been implicated as causes of Mendelian disease and hereditary cancer, but their role in Autism Spectrum Disorder (ASD) has never been systematically defined. Here, we report 86,154 polymorphic retrotransposon insertions including >60% not previously reported and 158de novoretrotransposition events identified in whole genome sequencing (WGS) data of 2,288 families with ASD from the Simons Simplex Collection (SSC). As expected, the overall burden ofde novoevents was similar between ASD individuals and unaffected siblings, with 1de novoinsertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1de novoinsertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed morede novoL1 insertions than expected in ASD genes, and we also foundde novointronic retrotransposition events in known syndromic ASD genes in affected individuals but not in controls. Additionally, we observed exonic insertions in genes with a high probability of being loss-of-function intolerant, including a likely causative exonic insertion inCSDE1, only in ASD individuals. Althoughde novoretrotransposition occurs less frequently than single nucleotide and copy number variants, these findings suggest a modest, but important, impact of intronic and exonic retrotransposition mutations in ASD and highlight the utility of developing specific bioinformatic tools for high-throughput detection of transposable element insertions.