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

Abstract

Retrotransposons 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 158 de novo retrotransposition 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 of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed more de novo L1 insertions than expected in ASD genes, and we also found de novo intronic 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 in CSDE1, only in ASD individuals. Although de novo retrotransposition 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.

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

“…The 15q13.3 microdeletion is a recurrent CNV associated with neuropsychiatric and neurodevelopmental disorders for which the pathogenic molecular mechanism(s) are unknown. Our study expands on previous work identifying OTUD7A as a novel driver gene in the 15q13.3 microdeletion 30 , which has since emerged as a novel and independent NDD risk gene [39][40][41] . However, the mechanism through which OTUD7A regulates disease-associated phenotypes is unknown 30,36 .…”

“…Our study focused on OTUD7A, given emerging evidence that it is an independent NDD risk gene [39][40][41] , and our previous work showing evidence of its role as a driver gene in the 15q13.3 microdeletion 30 .…”

“…Case reports revealed that homozygous loss of function mutations in OTUD7A are associated with severe epilepsy, dystonia and intellectual disability 37,38 . Additionally, emerging genetic sequencing studies have provided new evidence that supports OTUD7A as an independent NDD risk gene [39][40][41] . This is consistent with OTUD7A having the highest intolerance score (pLI) for loss-of-function alleles within the 15q13.3 locus 30 , indicating that mutations could provide clues to the function of OTUD7A.…”

Integrating Genetic Structural Variations and Whole-Genome Sequencing Into Clinical Neurology

“…In addition, another recent WGS analysis also detected different types of de novo retrotransposon insertions in people with ASD, including the L1 and SINE-R/VNTR/Alu elements. 23 Given the emerging links between transposable elements and these diseases, it is important to investigate how these mutational events contribute to disease pathophysiology.…”

Genomic approaches to trace the history of human brain evolution with an emerging opportunity for transposon profiling of ancient humans

“…Among retrotransposons, there are long terminal repeat (LTR) retrotransposon families, including endogenous retrovirus (ERVs), and non-LTR retrotransposon families. We mainly focus on the latter, specifically LINE-1s (L1s), Alus, and SVAs (SINE-VNTR-Alus) that generate de novo copies at the rate of ~ 1/104 births, ~ 1/29 births, and ~ 1/192 births in human germlines, respectively [13]. We focus on these active human retrotransposons due to their potential relevance to recent human evolution after human-NHP divergence, such as during the Neolithic period.…”