Despite much progress in detecting structural variation in the human genome, the variation contributed by transposable elements has been difficult to study. Four studies now demonstrate methods for mapping retrotransposons across the human genome and reveal that they are a major component of interindividual variation that might contribute to disease and complex traits.
Long interspersed element-1s (LINE-1s or L1s) are the most abundant class of retrotransposon in the human genome, and these studies focused mainly on this class in either diverse unrelated or related individuals. To map full-length L1s, Beck and colleagues used fosmid-based, paired-end DNA sequencing. Knowing the length of a complete L1, they tracked down insertions by the distance between paired-ends mapped to the human reference genome. Taking a different approach, Iskow and colleagues developed a method — termed L1–seq — that uses linker-mediated PCR to specifically amplify young L1 elements, followed by high-throughput sequencing. Ewing and Kazazian also harnessed the power of next-generation sequencing in a method that generates a library of L1-flanking DNA through amplification from an L1-specific primer. Another technique, called TiP–chip, is presented by Huang et al.; restriction enzyme-digested DNA is amplified using primers that are specific for a unique sequence in the retrotransposon and the flanking genomic sequence is identified on high-density tiling microarrays. In addition to surveying young L1 elements, these authors demonstrated the applicability of their method to other human retrotransposons.
The striking finding from these studies is that there is a great deal more recent or current retrotransposon activity than anticipated. For example, Beck and colleagues identified 68 full-length L1s as being differentially present among individuals, and they found that just over half of these were highly active in a retrotransposition assay. The studies by Iskow et al. and Ewing and Kazazian revealed 757 and 367 new L1 insertions, respectively, and the frequency of young L1 insertions calculated by Huang and colleagues — one insertion per 108 births — is twice as high as previous estimates.
These papers suggest that the presence or absence of retrotransposons is an underappreciated source of genetic variation that should be considered alongside other variation in studies to explore the genetic basis of complex traits. Novel insertions might also be novel causes of disease. For example, a unique L1 insertion found by Huang et al. might explain a case of intellectual disability. Finally, Iskow and colleagues showed several L1 insertions in lung tumour samples, so mapping transposition in somatic tissues to explore their role in cancer is likely to be another important avenue for future studies.
Nature Reviews Genetics 11, 527 (August 2010) | doi:10.1038/nrg2832
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