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Commentary

The human genome in the LINE of fire

Richard Cordaux
PNAS December 9, 2008 105 (49) 19033-19034; https://doi.org/10.1073/pnas.0810202105
Richard Cordaux
Université de Poitiers, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6556 Ecologie, Evolution, Symbiose, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
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  • For correspondence: richard.cordaux@univ-poitiers.fr

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  • L1 recombination-associated deletions generate human genomic variation
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One of the most surprising revelations of the sequencing of the human genome was that nearly half of our DNA is derived from transposable element (TE) insertions, and this is likely to be an underestimate, because many TE-derived sequences have diverged beyond recognition (1). Remarkably, the vast majority of human TE sequences result from the activity of a single class of TEs known as LINE retrotransposons. Represented by the currently active LINE-1 or L1 elements, LINEs are autonomous TEs that propagate in the genome by making RNA copies of themselves that are subsequently reverse transcribed and integrated into the genome (2⇓–4). As a result of their ongoing activity during the past 150 million years, L1 elements account for approximately one-third of the human genome, by way of self-mobilization (≈500,000 copies) and transmobilization of nonautonomous Alu (≈1,100,000 copies) and SVA (≈3,000 copies) TEs and processed pseudogenes (≈11,000 copies) (1⇓⇓⇓–5). This high density of repetitive sequences poses a considerable threat to the stability of our genome, ranging from mutations and genomic alterations on TE insertion to large-scale genomic rearrangements triggered by recombination between nonallelic homologous TE sequences (2⇓–4, 6). The availability of multiple primate genome sequences now makes it possible to quantify the overall impact TE activity has had on human genome evolution. In this issue of PNAS, Han et al. (7) report the first comprehensive characterization of the genome-wide impact of human genomic deletions resulting from recombination between L1 elements, which occurred since the human-chimpanzee divergence approximately 6 million years ago.

Although some L1-driven rearrangements have resulted in beneficial innovations during evolution (8), the vast majority of these events are either neutral or deleterious to the genome. The deleterious nature of L1-L1 recombination events and their elimination from the population by negative selection (9) may help to understand why only 3 L1 recombination-mediated deletions causing human diseases have been reported to date (10⇓–12). However, the contribution of L1-L1 recombination in generating genomic deletions at an evolutionary timescale remained to be clarified. To address this issue, Han et al. (7) first computationally compared the human and chimpanzee genome sequences to identify candidate deletions that had accumulated in the human genome since the human-chimpanzee divergence. Of note is that the authenticity of the computational predictions was confirmed by experimental procedures, thus making the final dataset highly reliable. Han et al. identified 73 deletions associated with recombination between L1 elements that altogether removed nearly half a million base pairs of human DNA within just the past few million years of human evolution. This considerable amount of deleted DNA indicates that L1-L1 recombination substantially contributed to alter our genome during recent human evolution. Actually, some deletions occurred so recently that they are polymorphic for presence or absence among humans (7). Thus, L1-L1 recombination creates structural genomic variation among humans. Broadly known as copy number variants, this class of polymorphisms is increasingly recognized as a major source of variation among humans (13).

L1-L1 recombination is a major contributor to human genome plasticity.

The results of Han et al. (7) constitute a cornerstone that, together with other studies by the Batzer laboratory (14⇓⇓⇓–18), now allows us to quantify the genome-wide extent of deletions generated by the 2 major components of LINE retrotransposition activity in the human genome: L1 and Alu. Genomic deletions can be generated at 2 distinct stages of the retrotransposon life cycle: (i) at the time of insertion of the element at a new genomic locus via either classical endonuclease-dependent (19) or nonclassical endonuclease-independent (20) retrotransposition; and (ii) at a postinsertional stage, by recombination between nonallelic homologous elements potentially inserted in the genome for a long time. The emerging picture is that nearly 1 Mb of DNA has been deleted from the human genome by the products of LINE retrotransposition within just the past few million years of human evolution (Table 1). By extrapolation, these data suggest that during primate evolution, LINE retrotransposition may have contributed to as much as ≈50,000 deletion events removing ≈40 Mb of genomic sequences (Table 1). These remarkable figures serve to illustrate the profound implication of TEs as drivers of genome evolution.

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Table 1.

Genomic deletions associated with the products of LINE retrotransposition during human and primate evolution

The number of human-specific L1-L1 recombination deletion events identified by Han et al. (7) is relatively modest. Yet, the L1-L1 recombination process appears to be the major contributor of LINE-mediated genomic instability in terms of amounts of deleted sequences during recent human evolution (Table 1). This is because L1-L1 recombination deletions tend to be larger (>6,000 bp on average) than other types of LINE-mediated deletions (<1,000 bp on average). Because larger deletions are more likely to disrupt functional regions of the genome than shorter deletions, the lower number of L1-L1 than Alu-Alu recombination deletions detected in the human genome may reflect, at least in part, negative selection against large, deleterious L1-L1 recombination deletions (9). Consistently, only one L1-L1 recombination event reported by Han et al. (7) is involved in exon deletions. In general, L1-L1 recombination deletions tend to be preferentially distributed in genomic regions of low gene density (7) where they are less likely to be deleterious and thus negatively selected. For example, the largest deleted sequence reported by Han et al., which is also the largest TE recombination-associated deletion reported to date with ≈64,000 bp, only encompasses pseudogene and intergenic sequences. In fact, the vast majority of genomic sequences deleted by L1-L1 recombination events are L1 sequences and Han et al. suggest that this deletion process may significantly contribute to counteract the increase in genome size caused by new L1 insertions. If so, there may be an appreciable rate of L1 sequence turn over in the genome, thus further implicating LINE retrotransposition in the evolutionary dynamics of the human genome.

Interestingly, some of the L1-L1 recombination events identified by Han et al. (7) may have been resolved by nonhomologous end joining, a mechanism involved in repair of DNA damage such as double-strand breaks (6, 21). Thus, L1-L1 recombination could occasionally contribute to maintain genome integrity by repairing DNA lesions, despite concomitant deletion of intervening genomic sequences in the process. Overall, the study by Han et al. demonstrates that by being responsible for the deletion of hundreds of thousands of nucleotides in the human genome during just the past few million years. More generally, the results of Han et al. add to the growing evidence showing that LINE retrotransposition has had, and continues to have, a considerable impact on primate genome evolution. By constantly challenging the integrity of our genome, the products of LINE retrotransposition create a tremendous amount of ongoing genomic fluidity and instability, thereby durably putting the human genome in the LINE of fire.

Acknowledgments

Research on mobile elements in my group is supported by a Young Investigator ATIP award from the Centre National de la Recherche Scientifique.

Footnotes

  • ↵1E-mail: richard.cordaux{at}univ-poitiers.fr
  • Author contributions: R.C. wrote the paper.

  • The author declares no conflict of interest.

  • See companion article on page 19366.

  • © 2008 by The National Academy of Sciences of the USA
View Abstract

References

  1. ↵
    1. Lander ES,
    2. et al.
    (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Han JS,
    2. Boeke JD
    (2005) LINE-1 retrotransposons: Modulators of quantity and quality of mammalian gene expression? BioEssays 27:775–784.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Babushok DV,
    2. Kazazian HH Jr.
    (2007) Progress in understanding the biology of the human mutagen LINE-1. Hum Mutat 28:527–539.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Belancio VP,
    2. Hedges DJ,
    3. Deininger P
    (2008) Mammalian non-LTR retrotransposons: For better or worse, in sickness and in health. Genome Res 18:343–358.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Karro JE,
    2. et al.
    (2007) Pseudogene.org: A comprehensive database and comparison platform for pseudogene annotation. Nucleic Acids Res 35:D55–D60.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Hedges DJ,
    2. Deininger PL
    (2007) Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity. Mutat Res 616:46–59.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Han K,
    2. et al.
    (2008) L1 recombination-associated deletions generate human genomic variation. Proc Natl Acad Sci USA 105:19366–19371.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Xing J,
    2. et al.
    (2006) Emergence of primate genes by retrotransposon-mediated sequence transduction. Proc Natl Acad Sci USA 103:17608–17613.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Song M,
    2. Boissinot S
    (2007) Selection against LINE-1 retrotransposons results principally from their ability to mediate ectopic recombination. Gene 390:206–213.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Burwinkel B,
    2. Kilimann MW
    (1998) Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease. J Mol Biol 277:513–517.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Segal Y,
    2. et al.
    (1999) LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis. Am J Hum Genet 64:62–69.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Temtamy SA,
    2. et al.
    (2008) Long interspersed nuclear element-1 (LINE1)-mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis-van Creveld syndrome with borderline intelligence. Hum Mutat 29:931–938.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Cooper GM,
    2. Nickerson DA,
    3. Eichler EE
    (2007) Mutational and selective effects on copy-number variants in the human genome. Nat Genet 39:S22–29.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Sen SK,
    2. et al.
    (2006) Human genomic deletions mediated by recombination between Alu elements. Am J Hum Genet 79:41–53.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Han K,
    2. et al.
    (2005) Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages. Nucleic Acids Res 33:4040–4052.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Callinan PA,
    2. et al.
    (2005) Alu Retrotransposition-mediated Deletion. J Mol Biol 348:791–800.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Sen SK,
    2. Huang CT,
    3. Han K,
    4. Batzer MA
    (2007) Endonuclease-independent insertion provides an alternative pathway for L1 retrotransposition in the human genome. Nucleic Acids Res 35:3741–3751.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Srikanta D,
    2. et al.
    (10 22, 2008) An alternative pathway for Alu retrotransposition suggests a role in DNA double-strand break repair. Genomics doi:10.1016/j.ygeno.2008.09.016.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Gilbert N,
    2. Lutz-Prigge S,
    3. Moran JV
    (2002) Genomic deletions created upon LINE-1 retrotransposition. Cell 110:315–325.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Morrish TA,
    2. et al.
    (2002) DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat Genet 31:159–165.
    OpenUrlCrossRefPubMed
  21. ↵
    1. van Gent DC,
    2. Hoeijmakers JH,
    3. Kanaar R
    (2001) Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2:196–206.
    OpenUrlCrossRefPubMed
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The human genome in the LINE of fire
Richard Cordaux
Proceedings of the National Academy of Sciences Dec 2008, 105 (49) 19033-19034; DOI: 10.1073/pnas.0810202105

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Richard Cordaux
Proceedings of the National Academy of Sciences Dec 2008, 105 (49) 19033-19034; DOI: 10.1073/pnas.0810202105
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