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Contribution of retrotransposition to developmental disorders

Contribution of retrotransposition to developmental disorders
Contribution of retrotransposition to developmental disorders

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.

2041-1723
Gardner, Eugene J.
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Prigmore, Elena
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Gallone, Giuseppe
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Danecek, Petr
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Samocha, Kaitlin E.
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Handsaker, Juliet
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Gerety, Sebastian S.
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Ironfield, Holly
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Short, Patrick J.
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Sifrim, Alejandro
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Singh, Tarjinder
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Chandler, Kate E.
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Clement, Emma
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Lachlan, Katherine L.
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Prescott, Katrina
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Rosser, Elisabeth
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FitzPatrick, David R.
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Firth, Helen V.
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Hurles, Matthew E.
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Gardner, Eugene J.
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Prigmore, Elena
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Gallone, Giuseppe
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Danecek, Petr
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Samocha, Kaitlin E.
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Handsaker, Juliet
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Gerety, Sebastian S.
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Ironfield, Holly
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Short, Patrick J.
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Sifrim, Alejandro
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Singh, Tarjinder
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Chandler, Kate E.
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Clement, Emma
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Lachlan, Katherine L.
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Prescott, Katrina
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Rosser, Elisabeth
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FitzPatrick, David R.
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Firth, Helen V.
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Hurles, Matthew E.
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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. and Hurles, Matthew E. (2019) Contribution of retrotransposition to developmental disorders. Nature Communications, 10 (1), [4630]. (doi:10.1038/s41467-019-12520-y).

Record type: Article

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.

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Accepted/In Press date: 11 September 2019
e-pub ahead of print date: 11 October 2019
Published date: 1 December 2019

Identifiers

Local EPrints ID: 435412
URI: http://eprints.soton.ac.uk/id/eprint/435412
ISSN: 2041-1723
PURE UUID: b7b45d7e-5cde-4f92-b59a-d59fbfdee0b9

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Date deposited: 06 Nov 2019 17:30
Last modified: 07 Dec 2020 17:33

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Contributors

Author: Eugene J. Gardner
Author: Elena Prigmore
Author: Giuseppe Gallone
Author: Petr Danecek
Author: Kaitlin E. Samocha
Author: Juliet Handsaker
Author: Sebastian S. Gerety
Author: Holly Ironfield
Author: Patrick J. Short
Author: Alejandro Sifrim
Author: Tarjinder Singh
Author: Kate E. Chandler
Author: Emma Clement
Author: Katherine L. Lachlan
Author: Katrina Prescott
Author: Elisabeth Rosser
Author: David R. FitzPatrick
Author: Helen V. Firth
Author: Matthew E. Hurles

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