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Published online on April 17, 2006, 10.1073/pnas.0601324103

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Genetics
Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity

( human variation | population genetics | retrotransposon )

Maria del Carmen Seleme {dagger}, Melissa R. Vetter {dagger}, Richard Cordaux {ddagger}, Laurel Bastone {sect}, Mark A. Batzer {ddagger}, and Haig H. Kazazian Jr. {dagger}

{dagger}Department of Genetics, {sect}Division of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and {ddagger}Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Multi-Scale Systems, Louisiana State University, Baton Rouge, LA 70803

Communicated by Marlene Belfort, New York State Department of Health, Albany, NY, February 22, 2006 (received for review December 3, 2005)

Despite being scarce in the human genome, active L1 retrotransposons continue to play a significant role in its evolution. Because of their recent expansion, many L1s are not fixed in humans, and, when present, their mobilization potential can vary among individuals. Previously, we showed that the great majority of retrotransposition events in humans are caused by highly active, or hot, L1s. Here, in four populations of diverse geographic origins (160 haploid genomes), we investigated the degree of sequence polymorphism of three hot L1s and the extent of individual variation in mobilization capability of their allelic variants. For each locus, we found one previously uncharacterized allele in every three to five genomes, including some with nonsense and insertion/deletion mutations. Single or multiple nucleotide substitutions drastically affected the retrotransposition efficiency of some alleles. One-third of elements were no longer hot, and these so-called cool alleles substantially increased the range of individual susceptibility to retrotransposition events. Adding the activity of the three elements in each individual resulted in a surprising degree of variation in mobilization capability, ranging from 0% to 390% of a reference L1. These data suggest that individual variation in retrotransposition potential makes an important contribution to human genetic diversity.

Author contributions: M.d.C.S. and H.H.K. designed research; M.d.C.S. and M.R.V. performed research; M.d.C.S., R.C., L.B., M.A.B., and H.H.K. analyzed data; and M.d.C.S. and H.H.K. wrote the paper.

Conflict of interest statement: No conflicts declared.

To whom correspondence should be addressed.

Haig H. Kazazian Jr., E-mail: kazazian{at}mail.med.upenn.edu

www.pnas.org/cgi/doi/10.1073/pnas.0601324103
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