Biology subjects

Sifrim, A.

Publications and source records attributed to Sifrim, A..

20 records · Page 2Linked to original sources

bioRxiv2018

Contribution of Retrotransposition to Developmental Disorders

Mobile genetic Elements (MEs) are segments of DNA which, through an RNA intermediate, can generate new copies of themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. As such, we have identified RT-derived events in 9,738 exome sequenced trios with DD-affected probands as part of the Deciphering Developmental Disorders (DDD) study. We have ascertained 9 de novo MEs, 4 of which are likely causative of the patients symptoms (0.04% of probands), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we have estimated genome-wide germline ME mutagenesis and constraint and demonstrated that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

genetics↗

bioRxiv2017

De novo mutations in regulatory elements cause neurodevelopmental disorders

SummaryDe novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetaLbrain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.

genetics↗