Extensive Individual Variation in L1 Retrotransposition Capability Contributes to Human Genetic Diversity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Apr 19

PMID 16618923

Citations 57

Authors

Maria del Carmen Seleme

Melissa R Vetter

Richard Cordaux

Laurel Bastone

Mark A Batzer

Haig H Kazazian Jr

Affiliations

Soon will be listed here.

Abstract

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.

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References

Wang H, Xing J, Grover D, Hedges D, Han K, Walker J . SVA elements: a hominid-specific retroposon family. J Mol Biol. 2005; 354(4):994-1007. DOI: 10.1016/j.jmb.2005.09.085. View

Badge R, Alisch R, Moran J . ATLAS: a system to selectively identify human-specific L1 insertions. Am J Hum Genet. 2003; 72(4):823-38. PMC: 1180347. DOI: 10.1086/373939. View

Bandelt H, Forster P, Rohl A . Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol. 1999; 16(1):37-48. DOI: 10.1093/oxfordjournals.molbev.a026036. View

Moran J, Holmes S, Naas T, DeBerardinis R, Boeke J, Kazazian Jr H . High frequency retrotransposition in cultured mammalian cells. Cell. 1996; 87(5):917-27. DOI: 10.1016/s0092-8674(00)81998-4. View

Fanning T, Singer M . The LINE-1 DNA sequences in four mammalian orders predict proteins that conserve homologies to retrovirus proteins. Nucleic Acids Res. 1987; 15(5):2251-60. PMC: 340631. DOI: 10.1093/nar/15.5.2251. View

Boissinot S, Entezam A, Young L, Munson P, Furano A . The insertional history of an active family of L1 retrotransposons in humans. Genome Res. 2004; 14(7):1221-31. PMC: 442137. DOI: 10.1101/gr.2326704. View

Myers J, Vincent B, Udall H, Watkins W, Morrish T, Kilroy G . A comprehensive analysis of recently integrated human Ta L1 elements. Am J Hum Genet. 2002; 71(2):312-26. PMC: 379164. DOI: 10.1086/341718. View

Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P . Large-scale copy number polymorphism in the human genome. Science. 2004; 305(5683):525-8. DOI: 10.1126/science.1098918. View

Martin S, Bushman F . Nucleic acid chaperone activity of the ORF1 protein from the mouse LINE-1 retrotransposon. Mol Cell Biol. 2001; 21(2):467-75. PMC: 86601. DOI: 10.1128/MCB.21.2.467-475.2001. View

10.

Lander E, Linton L, Birren B, Nusbaum C, Zody M, Baldwin J . Initial sequencing and analysis of the human genome. Nature. 2001; 409(6822):860-921. DOI: 10.1038/35057062. View

11.

Vincent B, Myers J, Ho H, Kilroy G, Walker J, Watkins W . Following the LINEs: an analysis of primate genomic variation at human-specific LINE-1 insertion sites. Mol Biol Evol. 2003; 20(8):1338-48. DOI: 10.1093/molbev/msg146. View

12.

Bamshad M, Wooding S . Signatures of natural selection in the human genome. Nat Rev Genet. 2003; 4(2):99-111. DOI: 10.1038/nrg999. View

13.

Lavie L, Maldener E, Brouha B, Meese E, Mayer J . The human L1 promoter: variable transcription initiation sites and a major impact of upstream flanking sequence on promoter activity. Genome Res. 2004; 14(11):2253-60. PMC: 525683. DOI: 10.1101/gr.2745804. View

14.

Hohjoh H, Singer M . Sequence-specific single-strand RNA binding protein encoded by the human LINE-1 retrotransposon. EMBO J. 1997; 16(19):6034-43. PMC: 1170233. DOI: 10.1093/emboj/16.19.6034. View

15.

Lutz S, Vincent B, Kazazian Jr H, Batzer M, Moran J . Allelic heterogeneity in LINE-1 retrotransposition activity. Am J Hum Genet. 2003; 73(6):1431-7. PMC: 1180405. DOI: 10.1086/379744. View

16.

Luan D, Korman M, Jakubczak J, Eickbush T . Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell. 1993; 72(4):595-605. DOI: 10.1016/0092-8674(93)90078-5. View

17.

Ostertag E, Prak E, DeBerardinis R, Moran J, Kazazian Jr H . Determination of L1 retrotransposition kinetics in cultured cells. Nucleic Acids Res. 2000; 28(6):1418-23. PMC: 111040. DOI: 10.1093/nar/28.6.1418. View

18.

Feng Q, Moran J, Kazazian Jr H, Boeke J . Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell. 1996; 87(5):905-16. DOI: 10.1016/s0092-8674(00)81997-2. View

19.

Gilbert N, Lutz S, Morrish T, Moran J . Multiple fates of L1 retrotransposition intermediates in cultured human cells. Mol Cell Biol. 2005; 25(17):7780-95. PMC: 1190285. DOI: 10.1128/MCB.25.17.7780-7795.2005. View

20.

Furano A . The biological properties and evolutionary dynamics of mammalian LINE-1 retrotransposons. Prog Nucleic Acid Res Mol Biol. 2000; 64:255-94. DOI: 10.1016/s0079-6603(00)64007-2. View