Recently Mobilised Transposons in the Human Genome


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?’).


An W , Han JS , Wheelan SJ , et al. (2006) Active retrotransposition by a synthetic L1 element in mice. Proceedings of the National Academy of Sciences of the United States of America 103: 18662–18667.

Baillie JK , Barnett MW , Upton KR , et al. (2011) Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479: 534–537.

Belancio VP , Roy‐Engel AM , Pochampally RR and Deininger P (2010) Somatic expression of LINE‐1 elements in human tissues. Nucleic Acids Research 38: 3909–3922.

Bennett EA , Keller H , Mills RE , et al. (2008) Active Alu retrotransposons in the human genome. Genome Research 18: 1875–1883.

Brouha B , Meischl C , Ostertag E , et al. (2002) Evidence consistent with human L1 retrotransposition in maternal meiosis I. American Journal of Human Genetics 71: 327–336.

Brouha B , Schustak J , Badge RM , et al. (2003) Hot L1s account for the bulk of retrotransposition in the human population. Proceedings of the National Academy of Sciences of the United States of America 100: 5280–5285.

Bundo M , Toyoshima M , Okada Y , et al. (2014) Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron 81: 306–313.

Cordaux R and Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nature Reviews Genetics 10: 691–703.

Coufal NG , Garcia‐Perez JL , Peng GE , et al. (2011) Ataxia telangiectasia mutated (ATM) modulates long interspersed element‐1 (L1) retrotransposition in human neural stem cells. Proceedings of the National Academy of Sciences of the United States of America 108: 20382–20387.

Coufal NG , Garcia‐Perez JL , Peng GE , et al. (2009) L1 retrotransposition in human neural progenitor cells. Nature 460: 1127–1131.

Doucet‐O'Hare TT , Rodic N , Sharma R , et al. (2015) LINE‐1 expression and retrotransposition in Barrett's esophagus and esophageal carcinoma. Proceedings of the National Academy of Sciences of the United States of America 112: E4894–E4900.

Erwin JA , Paquola AC , Singer T , et al. (2016) L1‐associated genomic regions are deleted in somatic cells of the healthy human brain. Nature Neuroscience 19: 1583–1591.

Evrony GD , Cai X , Lee E , et al. (2012) Single‐neuron sequencing analysis of l1 retrotransposition and somatic mutation in the human brain. Cell 151: 483–496.

Evrony GD , Lee E , Mehta BK , et al. (2015) Cell lineage analysis in human brain using endogenous retroelements. Neuron 85: 49–59.

Evrony GD , Lee E , Park PJ and Walsh CA (2016) Resolving rates of mutation in the brain using single‐neuron genomics. eLife 5.

Ewing AD , Gacita A , Wood LD , et al. (2015) Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Research 25: 1536–1545.

Garcia‐Perez JL , Marchetto MC , Muotri AR , et al. (2007) LINE‐1 retrotransposition in human embryonic stem cells. Human Molecular Genetics 16: 1569–1577.

Gianfrancesco O , Bubb VJ and Quinn JP (2017) SVA retrotransposons as potential modulators of neuropeptide gene expression. Neuropeptides 64: 3–7.

Hancks DC and Kazazian HH Jr (2012) Active human retrotransposons: variation and disease. Current Opinion in Genetics & Development 22: 191–203.

Hancks DC and Kazazian HH Jr (2016) Roles for retrotransposon insertions in human disease. Mobile DNA 7: 9.

Hassoun H , Coetzer TL , Vassiliadis JN , et al. (1994) A novel mobile element inserted in the alpha spectrin gene: spectrin dayton. A truncated alpha spectrin associated with hereditary elliptocytosis. The Journal of Clinical Investigation 94: 643–648.

Helman E , Lawrence MS , Stewart C , et al. (2014) Somatic retrotransposition in human cancer revealed by whole‐genome and exome sequencing. Genome Research 24: 1053–1063.

Iskow RC , McCabe MT , Mills RE , et al. (2010) Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141: 1253–1261.

Kano H , Godoy I , Courtney C , et al. (2009) L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes & Development 23: 1303–1312.

Kassiotis G and Stoye JP (2017) Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 372: 20160277.

Kazazian HH Jr , Wong C , Youssoufian H , et al. (1988) Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332: 164–166.

Klawitter S , Fuchs NV , Upton KR , et al. (2016) Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nature Communications 7: 10286.

Kuwabara T , Hsieh J , Muotri A , et al. (2009) Wnt‐mediated activation of NeuroD1 and retro‐elements during adult neurogenesis. Nature Neuroscience 12: 1097–1105.

Larsen PA , Hunnicutt KE , Larsen RJ , Yoder AD and Saunders AM (2018) Warning SINEs: Alu elements, evolution of the human brain, and the spectrum of neurological disease. Chromosome Research 26: 93–111.

Lee E , Iskow R , Yang L , et al. (2012) Landscape of somatic retrotransposition in human cancers. Science 337: 967–971.

Miki Y , Nishisho I , Horii A , et al. (1992) Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Research 52: 643–645.

Mills RE , Bennett EA , Iskow RC , et al. (2006) Recently mobilized transposons in the human and chimpanzee genomes. American Journal of Human Genetics 78: 671–679.

Munoz‐Lopez M , Garcia‐Canadas M , Macia A , Morell S and Garcia‐Perez JL (2012) Analysis of LINE‐1 expression in human pluripotent cells. Methods in Molecular Biology 873: 113–125.

Muotri AR , Chu VT , Marchetto MC , et al. (2005) Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435: 903–910.

Muotri AR , Marchetto MC , Coufal NG , et al. (2010) L1 retrotransposition in neurons is modulated by MeCP2. Nature 468: 443–446.

Newkirk SJ , Lee S , Grandi FC , et al. (2017) Intact piRNA pathway prevents L1 mobilization in male meiosis. Proceedings of the National Academy of Sciences of the United States of America 114: E5635–E5644.

Ostertag EM , Goodier JL , Zhang Y and Kazazian HH Jr (2003) SVA elements are nonautonomous retrotransposons that cause disease in humans. American Journal of Human Genetics 73: 1444–1451.

Paterson AL , Weaver JM , Eldridge MD , et al. (2015) Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired‐end sequencing analysis. BMC Genomics 16: 473.

Prak ET , Dodson AW , Farkash EA and Kazazian HH Jr (2003) Tracking an embryonic L1 retrotransposition event. Proceedings of the National Academy of Sciences of the United States of America 100: 1832–1837.

Richardson SR , Gerdes P , Gerhardt DJ , et al. (2017) Heritable L1 retrotransposition in the mouse primordial germline and early embryo. Genome Research 27: 1395–1405.

Rodic N , Steranka JP , Makohon‐Moore A , et al. (2015) Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nature Medicine 21: 1060–1064.

Rodriguez‐Martin B , Alvarez EG , Baez‐Ortega A , et al. (2018) Pan‐cancer analysis of whole genomes reveals driver rearrangements promoted by LINE‐1 retrotransposition in human tumours. Nature Genet. 20160277. DOI: 10.1098/rstb.2016.0277.

Rosser JM and An W (2012) L1 expression and regulation in humans and rodents. Frontiers in Bioscience (Elite Edition) 4: 2203–2225.

Scott EC , Gardner EJ , Masood A , et al. (2016) A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Research 26: 745–755.

Shukla R , Upton KR , Munoz‐Lopez M , et al. (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 153: 101–111.

Solyom S , Ewing AD , Rahrmann EP , et al. (2012) Extensive somatic L1 retrotransposition in colorectal tumors. Genome Research 22: 2328–2338.

Stewart C , Kural D , Stromberg MP , et al. (2011) A comprehensive map of mobile element insertion polymorphisms in humans. PLoS Genetics 7: e1002236.

Tang WW , Kobayashi T , Irie N , Dietmann S and Surani MA (2016) Specification and epigenetic programming of the human germ line. Nature Reviews Genetics 17: 585–600.

Tubio JM , Li Y , Ju YS , et al. (2014) Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345: 1251343.

Upton KR , Gerhardt DJ , Jesuadian JS , et al. (2015) Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161: 228–239.

van den Hurk JA , Meij IC , Seleme MC , et al. (2007) L1 retrotransposition can occur early in human embryonic development. Human Molecular Genetics 16: 1587–1592.

Wallace MR , Andersen LB , Saulino AM , et al. (1991) A de novo Alu insertion results in neurofibromatosis type 1. Nature 353: 864–866.

Wimmer K , Callens T , Wernstedt A and Messiaen L (2011) The NF1 gene contains hotspots for L1 endonuclease‐dependent de novo insertion. PLoS Genetics 7: e1002371.

Further Reading

Burns KH (2017) Transposable elements in cancer. Nature Reviews. Cancer 17: 415–424.

Friedli M and Trono D (2015) The developmental control of transposable elements and the evolution of higher species. Annual Review of Cell and Developmental Biology 31: 429–451.

Goodier JL (2016) Restricting retrotransposons: a review. Mobile DNA 7: 16.

Kazazian HH Jr and Moran JV (2017) Mobile DNA in health and disease. The New England Journal of Medicine 377: 361–370.

Newkirk SJ and An W (2017) L1 regulation in mouse and human germ cells. In: Cristofari G (ed.) Human Retrotransposons in Health and Disease, pp. 29–61. Cham, Switzerland: Springer International Publishing.

Percharde M , Lin CJ , Yin Y , et al. (2018) A LINE1‐nucleolin partnership regulates early development and ESC identity. Cell 174 (391‐405): e319.

Richardson SR and Faulkner GJ (2018) Heritable L1 retrotransposition events during development: understanding their origins: examination of heritable, endogenous L1 retrotransposition in mice opens up exciting new questions and research directions. Bioessays 40: e1700189.

Sedivy JM , Kreiling JA , Neretti N , et al. (2013) Death by transposition – the enemy within? Bioessays 35: 1035–1043.

Suarez NA , Macia A and Muotri AR (2018) LINE‐1 retrotransposons in healthy and diseased human brain. Developmental Neurobiology 78: 434–455.

Volkman HE and Stetson DB (2014) The enemy within: endogenous retroelements and autoimmune disease. Nature Immunology 15: 415–422.

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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. [doi: 10.1002/9780470015902.a0020837]