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Contribution of retrotransposition to developmental disorders

Author

Listed:
  • 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
    University of Southampton)

  • 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
    Cambridge University Hospitals NHS Foundation Trust)

  • Matthew E. Hurles

    (Wellcome Sanger Institute)

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.

Suggested Citation

  • 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 S, 2019. "Contribution of retrotransposition to developmental disorders," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12520-y
    DOI: 10.1038/s41467-019-12520-y
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    Cited by:

    1. Zhengyi Li & Haiyan Xu & Jiaqun Li & Xiao Xu & Junjiao Wang & Danya Wu & Jiateng Zhang & Juan Liu & Ziwei Xue & Guankai Zhan & Bobby Cheng Peow Tan & Di Chen & Yun-Shen Chan & Huck Hui Ng & Wanlu Liu , 2023. "Selective binding of retrotransposons by ZFP352 facilitates the timely dissolution of totipotency network," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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