Abstract
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.
Highlights
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
Most polymorphic insertions are rare and novel We developed and implemented xTea [13], a scalable algorithm for detecting Transposable element insertions (TEIs) in whole-genome sequencing (WGS) data and demonstrated that the version of this tool used in our study has a high sensitivity, specificity, and comparable performance to MELT [14], the algorithm used to detect TEIs in gnomAD, as well as a better performance than Mobster [15] (Additional file 1: Fig. S1)
We found an enrichment of de novo TEIs in ASD in genes upregulated in the prefrontal cortex, this was not significant after multiple test correction (p-value = 0.0017, BenjaminiHochberg q-value = 0.07), whereas no such enrichment was detected in controls
Summary
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. About 17-50% of the overall heritability of ASD reflects common variation at a population level, rare inherited and de novo copy-number variations and single nucleotide variations confer high risk to developing ASD, and drive ASD risk when present in individual children [8]. These rare variants are enriched in simplex families, where both parents are unaffected, with de novo copy-number variations and single nucleotide variations contributing to 30% of cases in the Simons Simplex Cohort (SSC) [9]. We sought to define the role of TEIs in ASD by analyzing the largest cohort of 2288 simplex families for de novo TEIs at whole genome resolution (Fig. 1A)
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