J Virol. 2014 Sep 01;88(17):9529-37. doi: 10.1128/JVI.00919-14. Epub 2014 Jun 11.

Unfixed endogenous retroviral insertions in the human population.

Journal of virology

Emanuele Marchi, Alex Kanapin, Gkikas Magiorkinis, Robert Belshaw

PMID: 24920817 PMCID: PMC4136357 DOI: 10.1128/JVI.00919-14

Abstract

UNLABELLED: One lineage of human endogenous retroviruses (HERVs), HERV-K(HML2), is upregulated in many cancers, some autoimmune/inflammatory diseases, and HIV-infected cells. Despite 3 decades of research, it is not known if these viruses play a causal role in disease, and there has been recent interest in whether they can be used as immunotherapy targets. Resolution of both these questions will be helped by an ability to distinguish between the effects of different integrated copies of the virus (loci). Research so far has concentrated on the 20 or so recently integrated loci that, with one exception, are in the human reference genome sequence. However, this viral lineage has been copying in the human population within the last million years, so some loci will inevitably be present in the human population but absent from the reference sequence. We therefore performed the first detailed search for such loci by mining whole-genome sequences generated by next-generation sequencing. We found a total of 17 loci, and the frequency of their presence ranged from only 2 of the 358 individuals examined to over 95% of them. On average, each individual had six loci that are not in the human reference genome sequence. Comparing the number of loci that we found to an expectation derived from a neutral population genetic model suggests that the lineage was copying until at least ∼250,000 years ago.

IMPORTANCE: About 5% of the human genome sequence is composed of the remains of retroviruses that over millions of years have integrated into the chromosomes of egg and/or sperm precursor cells. There are indications that protein expression of these viruses is higher in some diseases, and we need to know (i) whether these viruses have a role in causing disease and (ii) whether they can be used as immunotherapy targets in some of them. Answering both questions requires a better understanding of how individuals differ in the viruses that they carry. We carried out the first careful search for new viruses in some of the many human genome sequences that are now available thanks to advances in sequencing technology. We also compared the number that we found to a theoretical expectation to see if it is likely that these viruses are still replicating in the human population today.

Copyright © 2014 Marchi et al.

References

1. Philos Trans R Soc Lond B Biol Sci. 2013 Aug 12;368(1626):20120504 - PubMed
2. Bioinformatics. 2013 Feb 1;29(3):389-90 - PubMed
3. Microbiol Mol Biol Rev. 2008 Mar;72(1):157-96, table of contents - PubMed
4. Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15716-21 - PubMed
5. Curr Biol. 2012 Jun 5;22(11):R437-8 - PubMed
6. J Natl Cancer Inst. 2012 Feb 8;104(3):189-210 - PubMed
7. Retrovirology. 2011 Nov 08;8:90 - PubMed
8. Bioinformatics. 2002 Feb;18(2):337-8 - PubMed
9. Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4894-9 - PubMed
10. Genome Biol Evol. 2013;5(2):307-28 - PubMed
11. PLoS One. 2011;6(5):e20234 - PubMed
12. Genome Res. 2006 Dec;16(12):1548-56 - PubMed
13. Carcinogenesis. 2013 Nov;34(11):2531-8 - PubMed
14. PLoS One. 2013 Oct 18;8(10):e76472 - PubMed
15. J Virol. 2005 Oct;79(19):12507-14 - PubMed
16. Annu Rev Genet. 2008;42:709-32 - PubMed
17. BMC Genomics. 2008 Jul 29;9:354 - PubMed
18. Nat Med. 2010 May;16(5):571-9, 1p following 579 - PubMed
19. Placenta. 2012 Sep;33(9):663-71 - PubMed
20. PLoS One. 2013 Aug 30;8(8):e72756 - PubMed
21. Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21128-33 - PubMed
22. Nature. 2012 Nov 29;491(7426):774-8 - PubMed
23. Am J Hum Genet. 2003 Dec;73(6):1444-51 - PubMed
24. Genomics. 2004 Sep;84(3):596-9 - PubMed
25. J Clin Invest. 2008 Mar;118(3):1099-109 - PubMed
26. J Virol. 2008 Oct;82(20):10008-16 - PubMed
27. J Immunol. 2012 Aug 1;189(3):1467-79 - PubMed
28. Retrovirology. 2012 Jan 16;9:6 - PubMed
29. Curr Biol. 2013 Nov 18;23(22):R994-R995 - PubMed
30. Oncotarget. 2012 Oct;3(10):1204-19 - PubMed
31. Genome Res. 2013 Sep;23(9):1505-13 - PubMed
32. Nat Neurosci. 2004 Oct;7(10):1088-95 - PubMed
33. Genome Res. 2002 Apr;12(4):656-64 - PubMed
34. PLoS Pathog. 2007 Jan;3(1):e10 - PubMed
35. Bioessays. 2013 Sep;35(9):794-803 - PubMed
36. J Virol. 2012 Jan;86(1):262-76 - PubMed
37. Cell Mol Life Sci. 2008 Nov;65(21):3366-82 - PubMed
38. Genome Res. 2003 May;13(5):838-44 - PubMed
39. Trends Genet. 2007 Jul;23(7):326-33 - PubMed
40. Front Oncol. 2013 Sep 17;3:243 - PubMed
41. Curr Opin Virol. 2013 Dec;3(6):646-56 - PubMed
42. Curr Biol. 2001 Oct 2;11(19):1531-5 - PubMed
43. Mob DNA. 2011 May 04;2(1):7 - PubMed
44. Cell. 2010 Jun 25;141(7):1253-61 - PubMed
45. Brief Bioinform. 2013 Mar;14(2):178-92 - PubMed
46. J Mol Biol. 1990 Oct 5;215(3):403-10 - PubMed
47. Science. 2012 Aug 24;337(6097):967-71 - PubMed

Substances

• DNA

MeSH terms

• Computational Biology
• DNA / chemistry
• DNA / genetics
• Endogenous Retroviruses / genetics
• Genetic Loci*
• Genetic Variation*
• Genome, Human*
• High-Throughput Nucleotide Sequencing
• Humans

Publication Types

• Journal Article
• Research Support, Non-U.S. Gov't

Grant support

• Wellcome Trust/United Kingdom
• MR/K010565/1/Medical Research Council/United Kingdom