Comparative analyses of somatic retrotransposon insertions in brain exomes of individuals with autism spectrum disorder

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder defined by deficits in social interaction and communication, as well as repetitive and restrictive behaviors. Despite much evidence supporting a substantial genetic contribution to ASD , the causes of most cases remain unknown. Understanding the molecular mechanisms underlying ASD is essential for enabling accurate diagnostics and developing targeted treatment options. Toward that goal we examined the role of somatic retrotransposition in the brains of individuals with ASD. Retrotransposons are DNA elements that copy and paste themselves within a genome, recently shown to be active in the developing human brain. It has been suggested that retrotransposition-mediated neuronal diversity is essential for brain complexity and plasticity, and thereby for optimal function. Here we performed a comprehensive comparative analysis of exomic retrotransposition in ASD. We first developed a meta transposable element (TE) insertion detection tool based on the integration of four state-of-the-art detection methods. We then applied it to deeply sequenced exomes of 20 postmortem prefrontal cortex and cerebellum tissue samples from individuals with ASD and 18 neurotypical controls. We found that retrotransposition events are significantly more common in brains of individuals with ASD as compared to neurotypical controls [1308±192 vs 153±54 insertions, P-value=2.29x10^-6], where they interrupt more genes [633±238 vs 77±21 genes, P-value=1.08x10^-5]. Among individuals with ASD, somatic retrotransposition was a lot more common in the cerebellum than in the prefrontal cortex [838± 93 vs 158± 33, P-value= 3.9x10^-3]. Taken together, this work suggests that neurodevelopmental retrotransposition might be dysregulated in ASD.