Recently Mobilised Transposons in the Human Genome

Abstract

Transposable elements make up approximately half of the human genome. Apart from an evolutionary role in altering the genomic landscape and gene expression, recent discoveries have brought into focus the scale and impact of active movement by non‐LTR retrotransposons, both in the germline and in somatic niches. Heritable insertions that originate from either early embryonic or germ cell development have contributed to over 100 cases of human genetic diseases. Alu, L1 and SVA contribute to 60%, 25% and 10% of disease‐causing germline insertions, respectively. In contrast, L1 retrotransposition is responsible for the majority of nonheritable (or somatic) insertions found in the brain and many types of cancers. A multidisciplinary effort is required to fully understand the role of active retrotransposition in human physiology and pathophysiology.

Key Concepts

  • Recently mobilised transposons in the human genome are confined to three types of non‐LTR retrotransposons: L1, Alu and SVA.
  • Ongoing retrotransposition in the germline has contributed to over 100 cases of tumour and nontumour human genetic diseases, including 21 cases of neurofibromatosis type 1 (NF1).
  • Early embryonic development is a critical window for retrotransposition and may harbour excessive insertional activities.
  • Elevated L1 retrotransposition in germ cells is expected in individuals with partially compromised piRNA pathway.
  • Human brain is a hub for somatic retrotransposition during neuronal development. Its implication on neuronal function or dysfunction (friend or foe) remains to be elucidated.
  • Human cancers can be categorised into very‐high, high, medium, low and very‐low insertional activity groups. Some insertions are cancer drivers but the majority are likely passenger events.

Keywords: Alu; brain; cancer; embryonic; disease; germline; LINE‐1; somatic; SVA ; retrotransposition

Figure 1. Active retrotransposition in human somatic and germ cell lineages. (a) Retrotransposition has been observed in both somatic and germ cell lineages during human development. Nonheritable retrotransposition occurs in somatic cells. The brain has the highest insertional activities on a per cell basis across the entire body even in a physiologically normal individual (section titled 'Somatic Retrotransposition in Human Brain: Friend or Foe?'). On a pathological level, there are irrefutable evidence for rampant somatic retrotransposition in many types of cancers (section titled 'Somatic Retrotransposition in Human Cancer: Driver or Passenger?'). Heritable retrotransposition occurs in the germline genome, either in developing germ cells (section titled ‘Heritable Retrotransposition in the Human Germline: Insight from Case Studies’) or during early embryogenesis before PGC specification (section titled 'Retrotransposition during Early Embryogenesis: A Critical Window of Opportunity'), both of which are supported by specific case reports. However, the precise developmental timing remains undetermined for the majority of the known disease‐causing insertions. (b) Contribution of different TE families to 103 cases of sporadic human genetic diseases that are caused by germline insertions. For this calculation, we included 72 nontumour cases as well as 31 tumour cases for which the mutation of a single gene has been known to predispose an individual to these tumours (section titled ‘Heritable Retrotransposition in the Human Germline: Insight from Case Studies’). (c) Contribution of different TE families to >20 000 somatic retrotransposition events that have been identified in 37 human cancer subtypes (section titled ‘Somatic Retrotransposition in Human Cancer: Driver or Passenger?’).
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Saha, Partha S, and An, Wenfeng(Jan 2019) Recently Mobilised Transposons in the Human Genome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020837]