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Transduction-Specific ATLAS Reveals a Cohort of Highly Active L1 Retrotransposons in Human Populations

Authors


  • Contract grant sponsors: Wellcome Trust Project Grant (Grant Number 075163/Z/04/Z); National Institutes of Health Training Grants (Grant Numbers T32GM7544, T32000040); Wellcome Trust VIP Award; BBSRC Doctoral Training Grant (Grant Number BB/F016727/1); National Institutes of Health Grant (Grant Number GM060518); The University of Michigan Cancer Center Support Grant (Grant Number 5P30CA4659); Investigator of the Howard Hughes Medical Institute.

  • Communicated by Claude Férec

ABSTRACT

Long INterspersed Element-1 (LINE-1 or L1) retrotransposons are the only autonomously active transposable elements in the human genome. The average human genome contains ∼80–100 active L1s, but only a subset of these L1s are highly active or ‘hot’. Human L1s are closely related in sequence, making it difficult to decipher progenitor/offspring relationships using traditional phylogenetic methods. However, L1 mRNAs can sometimes bypass their own polyadenylation signal and instead utilize fortuitous polyadenylation signals in 3′ flanking genomic DNA. Retrotransposition of the resultant mRNAs then results in lineage specific sequence “tags” (i.e., 3′ transductions) that mark the descendants of active L1 progenitors. Here, we developed a method (Transduction-Specific Amplification Typing of L1 Active Subfamilies or TS-ATLAS) that exploits L1 3′ transductions to identify active L1 lineages in a genome-wide context. TS-ATLAS enabled the characterization of a putative active progenitor of one L1 lineage that includes the disease causing L1 insertion L1RP, and the identification of new retrotransposition events within two other “hot” L1 lineages. Intriguingly, the analysis of the newly discovered transduction lineage members suggests that L1 polyadenylation, even within a lineage, is highly stochastic. Thus, TS-ATLAS provides a new tool to explore the dynamics of L1 lineage evolution and retrotransposon biology.

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