Human Genetics

, Volume 117, Issue 5, pp 411–427 | Cite as

A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease

  • Jian-Min Chen
  • Peter D. Stenson
  • David N. Cooper
  • Claude Férec
Review Article

Abstract

Diverse long interspersed element-1 (LINE-1 or L1)-dependent mutational mechanisms have been extensively studied with respect to L1 and Alu elements engineered for retrotransposition in cultured cells and/or in genome-wide analyses. To what extent the in vitro studies can be held to accurately reflect in vivo events in the human genome, however, remains to be clarified. We have attempted to address this question by means of a systematic analysis of recent L1-mediated retrotranspositional events that have caused human genetic disease, with a view to providing a more complete picture of how L1-mediated retrotransposition impacts upon the architecture of the human genome. A total of 48 such mutations were identified, including those described as L1-mediated retrotransposons, as well as insertions reported to contain a poly(A) tail: 26 were L1 trans-driven Alu insertions, 15 were direct L1 insertions, four were L1 trans-driven SVA insertions, and three were associated with simple poly(A) insertions. The systematic study of these lesions, when combined with previous in vitro and genome-wide analyses, has strengthened several important conclusions regarding L1-mediated retrotransposition in humans: (a) approximately 25% of L1 insertions are associated with the 3′ transduction of adjacent genomic sequences, (b) ~25% of the new L1 inserts are full-length, (c) poly(A) tail length correlates inversely with the age of the element, and (d) the length of target site duplication in vivo is rarely longer than 20 bp. Our analysis also suggests that some 10% of L1-mediated retrotranspositional events are associated with significant genomic deletions in humans. Finally, the identification of independent retrotranspositional events that have integrated at the same genomic locations provides new insight into the L1-mediated insertional process in humans.

Supplementary material

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Jian-Min Chen
    • 1
  • Peter D. Stenson
    • 2
  • David N. Cooper
    • 2
  • Claude Férec
    • 1
  1. 1.INSERM (Institut National de la Santé et de la Recherche Médicale) U613–Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang–BretagneUniversité de Bretagne Occidentale, Centre Hospitalier UniversitaireBrestFrance
  2. 2.Institute of Medical GeneticsCardiff UniversityCardiffUK

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