Contribution of retrotransposition to developmental disorders

• Published in: Nature communications Vol. 10; no. 1; pp. 4630 - 10
• Main Authors: Gardner, Eugene J., Prigmore, Elena, Gallone, Giuseppe, Danecek, Petr, Samocha, Kaitlin E., Handsaker, Juliet, Gerety, Sebastian S., Ironfield, Holly, Short, Patrick J., Sifrim, Alejandro, Singh, Tarjinder, Chandler, Kate E., Clement, Emma, Lachlan, Katherine L., Prescott, Katrina, Rosser, Elisabeth, FitzPatrick, David R., Firth, Helen V., Hurles, Matthew E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 45/77; 49; 49/23; 631/208/212/2301; 631/208/457/649/2157; 631/208/737; 692/617/375/366; Biological evolution; Deoxyribonucleic acid; Developmental disabilities; Developmental Disabilities - genetics; Diagnostic systems; Disorders; DNA; Gene sequencing; Genetic Variation; Genomes; Humanities and Social Sciences; Humans; Interrogation; multidisciplinary; Mutation; Mutation Rate; Mutation rates; Nucleotide sequence; Retroelements - genetics; Retroelements - physiology; Retrotransposition; Science; Science (multidisciplinary); Signs and symptoms
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12520-y

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. Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.