Contribution of retrotransposition to developmental disorders

Eugene J. Gardner, Elena Prigmore, Giuseppe Gallone, Petr Danecek, Kaitlin E. Samocha, Juliet Handsaker, Sebastian S. Gerety, Holly Ironfield, Patrick J. Short, Alejandro Sifrim, Tarjinder Singh, Kate E. Chandler, Emma Clement, Katherine L. Lachlan, Katrina Prescott, Elisabeth Rosser, David R. FitzPatrick, Helen V. Firth and Matthew E. Hurles ()
Additional contact information
Eugene J. Gardner: Wellcome Sanger Institute
Elena Prigmore: Wellcome Sanger Institute
Giuseppe Gallone: Wellcome Sanger Institute
Petr Danecek: Wellcome Sanger Institute
Kaitlin E. Samocha: Wellcome Sanger Institute
Juliet Handsaker: Wellcome Sanger Institute
Sebastian S. Gerety: Wellcome Sanger Institute
Holly Ironfield: Wellcome Sanger Institute
Patrick J. Short: Wellcome Sanger Institute
Alejandro Sifrim: KU Leuven
Tarjinder Singh: Wellcome Sanger Institute
Kate E. Chandler: Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, Greater
Emma Clement: North East Thames Regional Genetics Service
Katherine L. Lachlan: Princess Anne Hospital
Katrina Prescott: Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital
Elisabeth Rosser: North East Thames Regional Genetics Service
David R. FitzPatrick: University of Edinburgh, WGH
Helen V. Firth: Wellcome Sanger Institute
Matthew E. Hurles: Wellcome Sanger Institute

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy 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. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate 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.

Date: 2019
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DOI: 10.1038/s41467-019-12520-y

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