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Journal of Molecular Evolution

, Volume 59, Issue 5, pp 642–656 | Cite as

Allelic Variation of HERV-K(HML-2) Endogenous Retroviral Elements in Human Populations

  • Catriona MacfarlaneEmail author
  • Peter Simmonds
Article

Abstract

Human endogenous retroviruses (HERVs) are the remnants of ancient germ cell infection by exogenous retroviruses and occupy up to 8% of the human genome. It has been suggested that HERV sequences have contributed to primate evolution by regulating the expression of cellular genes and mediating chromosome rearrangements. After integration ∼28 million years ago, members of the HERV-K (HML-2) family have continued to amplify and recombine. To investigate the utility of HML-2 polymorphisms as markers for the study of more recent human evolution, we compiled a list of the structure and integration sites of sequences that are unique to humans and screened each insertion for polymorphism within the human genome databases. Of the total of 74 HML-2 sequences, 18 corresponded to complete or near-complete proviruses, 49 were solitary long terminal repeats (LTRs), 6 were incomplete LTRs, and 1 was a SVA retrotransposon. A number of different allelic configurations were identified including the alternation of a provirus and solitary LTR. We developed polymerase chain reaction-based assays for seven HML-2 loci and screened 109 human DNA samples from Africa, Europe, Asia, and Southeast Asia. Our results indicate that the diversity of HML-2 elements is higher in African than non-African populations, with population differentiation values ranging from 0.6 to 9.8%. These findings denote a recent expansion from Africa. We compare the phylogenetic relationships of HML-2 sequences that are unique to humans and consider whether these elements have played a role in the remodeling of the hominid genome.

Keywords

Human endogenous retrovirus (HERV) HERV-K(HML-2) Retrovirus-like sequences Solitary LTR Provirus Recombination Gene conversion SVA Human genome evolution 

Notes

Acknowledgment

We would like to thank Alastair Macdonald, Rochelle Bleeker, Anna Meredith, Benjamin Searle, and Sonia Lee for their help with sample collection.

References

  1. Akopov, SB, Nikolaev, LG, Khil, PP, Lebedev, YB, Sverdlov, ED 1998Long terminal repeats of human endogenous retrovirus K family (HERV-K) specifically bind host cell nuclear proteinsFEES Lett421229233Google Scholar
  2. Barbulescu, M, Turner, G, Seaman, MI, Deinard, AS, Kidd, KK, Lenz, J 1999Many human endogenous retrovirus K (HERV-K) proviruses are unique to humansCurr Biol9861868Google Scholar
  3. Bosch, E, Jobling, MA 2003Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertilityHum Mol Genet12341347Google Scholar
  4. Buzdin, A, Khodosevich, K, Mamedov, I, Vinogradova, T, Lebedev, Y, Hunsmann, G, Sverdlov, E 2002A technique for genome-wide identification of differences in the interspersed repeats integrations between closely related genomes and its application to detection of human-specific integrations of HERV-K LTRsGenomics79413422Google Scholar
  5. Buzdin, A, Ustyugova, S, Khodosevich, K, Mamedov, I, Lebedev, Y, Hunsmann, G, Sverdlov, E 2003Human-specific subfamilies of HERV-K (HML-2) long terminal repeats: three master genes were active simultaneously during branching of hominoid lineagesGenomics81149156Google Scholar
  6. Chen, FC, Li, WH 2001Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzeesAm J Hum Genet68444456CrossRefPubMedGoogle Scholar
  7. Costas, J 2001Evolutionary dynamics of the human endogenous retro virus family HERV-K inferred from full-length proviral genomesJ Mol Evol53237243Google Scholar
  8. Dangel, AW, Baker, BJ, Mendoza, AR, Yu, CY 1995Complement component C4 gene intron 9 as a phylogenetic marker for primates: Long terminal repeats of the endogenous retrovirus ERV-K(C4) are a molecular clock of evolutionImmunogenetics424152PubMedGoogle Scholar
  9. Deininger, PL, Batzer, MA 2002Mammalian retroelementsGenome Res1214551465Google Scholar
  10. Domansky, AN, Kopantzev, EP, Snezhkov, EV, Lebedev, YB, Leib-Mosch, C, Sverdlov, ED 2000Solitary HERV-K LTRs possess bi-directional promoter activity and contain a negative regulatory element in the U5 regionFEES Lett472191195Google Scholar
  11. Faerman, M, Filon, D, Kahila, G, Greenblatt, CL, Smith, P, Oppenheim, A 1995Sex identification of archaeological human remains based on amplification of the X and Y amelogenin allelesGene167327332Google Scholar
  12. Frazer, KA, Chen, X, Hinds, DA, Pant, PV, Patil, N, Cox, DR 2003Genomic DNA insertions and deletions occur frequently between humans and nonhuman primatesGenome Res13341346Google Scholar
  13. Goodchild, NL, Freeman, JD, Mager, DL 1995Spliced HERV-H endogenous retroviral sequences in human genomic DNA: Evidence for amplification via retrotranspositionVirology206164173Google Scholar
  14. Horton, R, Niblett, D, Milne, S, Palmer, S, Tubby, B, Trowsdale, J, Beck, S 1998Large-scale sequence comparisons reveal unusually high levels of variation in the HLA-DQB1 locus in the class II region of the human MHCJ Mol Biol2827197Google Scholar
  15. Hughes, JF, Coffin, JM 2001Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolutionNat Genet29487489Google Scholar
  16. Huh, JW, Hong, KW, Yi, JM, Kirn, TH, Takenaka, O, Lee, WH, Kim, HS 2003Molecular phylogeny and evolution of the human endogenous retrovirus HERV-W LTR family in hominoid primatesMol Cells15122126Google Scholar
  17. International Human Genome Sequencing Consortium2001Initial sequencing and analysis of the human genomeNature409860921Google Scholar
  18. Johnson, WE, Coffin, JM 1999Constructing primate phylogenies from ancient retrovirus sequencesProc Natl Acad Sci USA961025410260Google Scholar
  19. Kass, DH, Batzer, MA, Deninger, PL 1995Gene conversion as a secondary mechanism in SINE evolutionMol Cell Biol151925Google Scholar
  20. Kurdyukov, SG, Lebedev, YB, Artamonova, II, Gorodentseva, TN, Batrak, AV, Mamedov, IZ, Azhikina, TL, Legchilina, SP, Efimenko, IG, Gardiner, K, Sverdlov, ED 2001Full-sized HERV-K (HML-2) human endogenous retroviral LTR sequences on human chromosome 21: map locations and evolutionary historyGene2735161Google Scholar
  21. Lapuk, AV, Khil, PP, Lavrentieva, IV, Lebedev, YB, Sverdlov, ED 1999A human endogenous retrovirus-like (HERV) LTR formed more than 10 million years ago due to an insertion of HERV-H LTR into the 5′ LTR of HERV-K is situated on human chromosomes 10, 19 and YJ Gen Virol80835839Google Scholar
  22. Lavrentieva, I, Khil, P, Vinogradova, T, Akhmedov, A, Lapuk, A, Shakhova, O, Lebedev, Y, Monastyrskaya, G, Sverdlov, ED 1998Subfamilies and nearest-neighbour dendrogram for the LTRs of human endogenous retroviruses HERV-K mapped on human chromosome 19: Physical neighbourhood does not correlate with identity levelHum Genet102107116Google Scholar
  23. Lebedev, YB, Belonovitch, OS, Zybrova, NV, Khil, PP, Kurdyukov, SG, Vinogradova, TV, Hunsmann, G, Sverdlov, ED 2000Differences in HERV-K LTR insertions in orthologous loci of humans and great apesGene247265277Google Scholar
  24. Liao, D, Pavelitz, T, Weiner, AM 1998Characterization of a novel class of interspersed LTR elements in primate genomes: Structure, genomic distribution, and evolutionJ Mol Evol46649660Google Scholar
  25. Liu, G, Zhao, S, Bailey, JA, Sahinalp, SC, Alkan, C, Tuzun, E, Green, ED, Eichler, EE 2003Analysis of primate genomic variation reveals a repeat-driven expansion of the human genomeGenome Res13358368Google Scholar
  26. Locke, DP, Segraves, R, Carbone, L, Archidiacono, N, Albertson, DG, Pinkel, D, Eichler, EE 2003Large-scale variation among human and great ape genomes determined by array comparative genomic hybridizationGenome Res13347357Google Scholar
  27. Lower, R, Lower, J, Kurth, R 1996The viruses in all of us: Characteristics and biological significance of human endogenous retrovirus sequencesProc Natl Acad Sci USA9351775184CrossRefPubMedGoogle Scholar
  28. Mager, DL, Freeman, DJ 1995HERV-H endogenous retroviruses: Presence in the new world branch but amplification in the old world primate lineageVirology213395404Google Scholar
  29. Mager, DL, Goodchild, NL 1989Homologous recombination between the LTRs of a human retrovirus-like element causes a 5-kb deletion in two siblingsAm J Hum Genet45848854Google Scholar
  30. Mamedov, I, Batrak, A, Buzdin, A, Arzumanyan, E, Lebedev, Y, Sverdlov, ED 2002Genome-wide comparison of differences in the integration sites of interspersed repeats between closely related genomesNucleic Acids Res30e71Google Scholar
  31. Mayer, J, Meese, E, Mueller-Lantzsch, N 1997aChromosomal assignment of human endogenous retrovirus K (HERV-K) env open reading framesCytogenet Cell Genet79157161Google Scholar
  32. Mayer, J, Meese, E, Mueller-Lantzsch, N 1997bMultiple human endogenous retrovirus (HERV-K) loci with gag open reading frames in the human genomeCytogenet Cell Genet7815Google Scholar
  33. Mayer, J, Meese, E, Mueller-Lantzsch, N 1998Human endogenous retrovirus K homologous sequences and their coding capacity in Old World primatesJ Virol7218701875Google Scholar
  34. Medstrand, P, Blomberg, J 1993Characterization of novel reverse transcriptase encoding human endogenous retroviral sequences similar to type A and type B retroviruses: Differential transcription in normal human tissuesJ Virol6767786787Google Scholar
  35. Medstrand, P, Mager, DL 1998Human-specific integrations of the HERV-K endogenous retrovirus familyJ Virol7297829787Google Scholar
  36. Myers, JS, Vincent, BJ, Udall, H, Watkins, WS, Morrish, TA, Kilroy, GE, Swergold, GD, Henke, J, Henke, L, Moran, JV, Jorde, LB, Batzer, MA 2002A comprehensive analysis of recently integrated human Ta L1 elementsAm J Hum Genet71312326Google Scholar
  37. Nadezhdin, EV, Lebedev, YB, Glazkova, DV, Bornholdt, D, Arman, IP, Grzeschik, KH, Hunsmann, G, Sverdlov, ED 2001Identification of paralogous HERV-K LTRs on human chromosomes 3, 4, 7 and 11 in regions containing clusters of olfactory receptor genesMol Genet Genomics265820825Google Scholar
  38. Ono, M, Yasunaga, T, Miyata, T, Ushikubo, H 1986Nucleotide sequence of human endogenous retrovirus genome related to the mouse mammary tumor virus genomeJ Virol60589598PubMedGoogle Scholar
  39. Ostertag, EM, Goodier, JL, Zhang, Y, Kazazian, HH 2003SVA elements are nonautonomous retrotransposons that cause disease in humansAm J Hum Genet7314441451Google Scholar
  40. Patience, C, Wilkinson, DA, Weiss, RA 1997Our retroviral heritageTrends Genet13116120Google Scholar
  41. Reus, K, Mayer, J, Sauter, M, Scherer, D, Muller-Lantzsch, N, Meese, E 200laGenomic organization of the human endogenous retrovirus HERV-K(HML-2.HOM) (ERVK6) on chromosome 7Genomics72314320Google Scholar
  42. Reus, K, Mayer, J, Sauter, M, Zischler, H, Muller-Lantzsch, N, Meese, E 2001bHERV-K (OLD): Ancestor sequences of the human endogenous retrovirus family HERV-K (HML-2)J Virol7589178926Google Scholar
  43. Roy-Engel, AM, Carroll, ML, El-Sawy, M, Salem, A, Garger, RK, Nguyen, SV, Deininger, PL, Batzer, MA 2002Non-traditional Alu evolution and primate genomic diversityJ Mol Biol31610331040Google Scholar
  44. Seifarth, W, Baust, C, Murr, A, Skladny, H, Krieg-Schneider, F, Blusch, J, Werner, T, Hehlmann, R, Leib-Mosch, C 1998Proviral structure, chromosomal location, and expression of HERV-K- T47D, a novel human endogenous retrovirus derived from T47D particlesJ Virol7283848391Google Scholar
  45. Shen, L, Wu, LC, Sanlioglu, S, Chen, R, Mendoza, AR, Dangel, AW, Carroll, MC, Zipf, WB, Yu, CY 1994Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and C4B genes in the HLA class III region: Molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplicationJ Biol Chem26984668476Google Scholar
  46. Shih, A, Coutavas, EE, Rush, MG 1991Evolutionary implications of primate endogenous retrovirusesVirology185495502Google Scholar
  47. Simmonds, P, Smith, DB 1999Structural constraints on RNA virus evolutionJ Virol7357875794Google Scholar
  48. Simpson, GR, Patience, C, Lower, R, Tonjes, RR, Moore, HD, Weiss, RA, Boyd, MT 1996Endogenous D-type (HERV-K) related sequences are packaged into retroviral particles in the placenta and possess open reading frames for reverse transcriptaseVirology222451456Google Scholar
  49. Stankiewicz, P, Lupski, JR 2002Molecular-evolutionary mechanisms for genomic disordersCurr Opin Genet Dev12312319Google Scholar
  50. Stringer, C 2002Modern human origins: progress and prospectsPhilos Trans R Soc Lond B Biol Sci357563579Google Scholar
  51. Sugimoto, J, Matsuura, N, Kinjo, Y, Takasu, N, Oda, T, Jinno, Y 2001Transcriptionally active HERV-K genes: Identification, isolation, and chromosomal mappingGenomics72137144Google Scholar
  52. Sun, C, Skaletsky, H, Rozen, S, Gromoll, J, Nieschlag, E, Oates, R, Page, DC 2000Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 provirusesHum Mol Genet922912296Google Scholar
  53. Sverdlov, ED 2000Retroviruses and primate evolutionBioessays22161171CrossRefPubMedGoogle Scholar
  54. Tonjes, RR, Czauderna, F, Kurth, R 1999Genome-wide screening, cloning, chromosomal assignment, and expression of full-length human endogenous retrovirus type KJ Virol7391879195Google Scholar
  55. Towler, EM, Gulnik, SV, Bhat, TN, Xie, D, Gustschina, E, Sumpter, TR, Robertson, N, Jones, C, Sauter, M, Mueller-Lantzsch, N, Debouck, C, Erickson, JW 1998Functional characterization of the protease of human endogenous retrovirus, K10: Can it complement HIV-1 protease? Biochemistry371713717144Google Scholar
  56. Tristem, M 2000Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the human genome mapping project databaseJ Virol7437153730Google Scholar
  57. Turner, G, Barbulescu, M, Su, M, Jensen-Seaman, MI, Kidd, KK, Lenz, J 2001Insertional polymorphisms of full-length endogenous retroviruses in humansCurr Biol1115311535Google Scholar
  58. Urnovitz, HB, Murphy, WH 1996Human endogenous retroviruses: nature, occurrence, and clinical implications in human diseaseClin Microbiol Rev97299PubMedGoogle Scholar
  59. Vinogradova, TV, Leppik, LP, Nikolaev, LG, Akopov, SB, Kleiman, AM, Senyuta, NB, Sverdlov, ED 2001Solitary human endogenous retroviruses-K LTRs retain transcriptional activity in vivo, the mode of which is different in different cell typesVirology2908390Google Scholar
  60. Zhu, ZB, Jian, B, Volanakis, JE 1994Ancestry of SINE-R.C2 a human-specific retroposonHum Genet93545551Google Scholar
  61. Zsiros, J, Jebbink, MF, Lukashov, VV, Voute, PA, Berkhout, B 1998Evolutionary relationships within a subgroup of HERV-K-related human endogenous retrovirusesJ Gen Virol796170Google Scholar
  62. Zsiros, J, Jebbink, MF, Lukashov, VV, Voute, PA, Berkhout, B 1999Biased nucleotide composition of the genome of HERV-K related endogenous retroviruses and its evolutionary implicationsJ Mol Evol48102111Google Scholar

Copyright information

© Springer Science + Business Media Inc. 2004

Authors and Affiliations

  1. 1.Center for Infectious DiseasesUniversity of EdinburghSummerhall, EdinburghUK

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