Advertisement

Immunogenetics

, Volume 59, Issue 4, pp 261–271 | Cite as

Full-length sequence analysis of the HLA-DRB1 locus suggests a recent origin of alleles

  • Jenny von Salomé
  • Ulf Gyllensten
  • Tomas F. BergströmEmail author
Original Paper

Abstract

The HLA region harbors some of the most polymorphic loci in the human genome. Among them is the class II locus HLA-DRB1, with more than 400 known alleles. The age of the polymorphism and the rate at which new alleles are generated at HLA loci has caused much controversy over the years. Previous studies have mostly been restricted to the 270 base pairs that constitute the second exon and represent the most variable part of the gene. Here, we investigate the evolutionary history of the HLA-DRB1 locus on the basis of an analysis of 15 genomic full-length alleles (10–15 kb). In addition, the variation in 49 complete coding sequences and 322 exon 2 sequences were analyzed. When excluding exon 2 from the analysis, the diversity at the synonymous sites was found to be similar to the intron diversity. The overall diversity in noncoding region was also similar to the genome average. The DRB1*03 lineage has been found in human, chimpanzee, bonobo, gorilla, and orangutan. An ancestral “proto HLA-DRB1*03 lineage” appeared to have diverged in the last 5 million years into the human-specific lineages *08, *11, *13, and *14. With exception to exon 2, both the coding- and the noncoding diversity suggests a recent origin (<1 million years ago) for most of the alleles at the HLA-DRB1 locus. Sites encoding for amino acids involved in antigen binding [antigen recognizing sites (ARS)] appear to have a more ancient origin. Taken together, the recent origin of most alleles, the high diversity between allelic lineages, and the ancient origin of sequence motifs in exon 2, is consistent with a relatively rapid generation of novel alleles by gene conversion like events.

Keywords

HLA MHC DRB1 Intron Evolution Polymorphisms 

Notes

Acknowledgements

This work was supported by grants from the Graduate Research School in Genomics and Bioinformatics, the Swedish Natural Science Research Council, the Erik Philip-Sörensen foundation, the Beijer foundation, the Marcus Borgström Foundation, and the Magnus Bergvall Foundation.

Supplementary material

251_2007_196_MOESM1_ESM.doc (36 kb)
Table S1a Sequencing primers, HLA-DRB1 fragment 1 (DOC 36 kb)
251_2007_196_MOESM2_ESM.doc (37 kb)
Table S1b Sequencing primers, HLA-DRB1 fragment 2 (DOC 37 kb)
251_2007_196_MOESM3_ESM.doc (30 kb)
Table S2 HLA-DRB1 alleles in dataset A, B, and C (DOC 31 kb)
251_2007_196_MOESM4_ESM.doc (26 kb)
Table S3 Intron diversity within lineages, dataset A (DOC 26 kb)

References

  1. Arden B, Klein J (1982) Biochemical comparison of major histocompatibility complex molecules from different subspecies of Mus musculus: evidence for trans-specific evolution of alleles. Proc Natl Acad Sci USA 79:2342–2346PubMedCrossRefGoogle Scholar
  2. Ayala FJ (1995) The myth of Eve: molecular biology and human origins. Science 270:1930–1936PubMedCrossRefGoogle Scholar
  3. Ayala FJ, Escalante AA (1996) The evolution of human populations: a molecular perspective. Mol Phyl Evol 5:188–201CrossRefGoogle Scholar
  4. Ayala FJ, Escalante A, O’hUigin C, Klein J (1994) Molecular genetics of speciation and human origins. Proc Natl Acad Sci USA 91:6787–6794PubMedCrossRefGoogle Scholar
  5. Bergström TF, Josefsson A, Erlich HA, Gyllensten U (1998) Recent origin of HLA-DRB1 alleles and implications for human evolution. Nat Genet 18:237–242PubMedCrossRefGoogle Scholar
  6. Bergström TF, Erlandsson R, Engkvist H, Josefsson A, Erlich HA, Gyllensten U (1999) Phylogenetic history of hominoid DRB loci and estimation of substitution rate inferred from intron sequences. Immunol Rev Feb 351–365Google Scholar
  7. Blasczyk R, Kotsch K, Wehling J (1998) The nature of polymorphism of the HLA-DRB intron sequences is lineage specific. Tissue Antigens 52:19–26PubMedCrossRefGoogle Scholar
  8. Bontrop RE (2006) Comparative genetics of MHC polymorphisms in different primate species: duplications and deletions. Hum Immunol 67:388–397PubMedCrossRefGoogle Scholar
  9. Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364:33–39PubMedCrossRefGoogle Scholar
  10. Chen FC, Li WH (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68:444–456PubMedCrossRefGoogle Scholar
  11. Efron B, Tibshirani R (1993) An introduction to the bootstrap. Chapman and Hall, New YorkGoogle Scholar
  12. Ellis SA, Bontrop RE, Antczak DF, Ballingall K, Davies CJ, Kaufman J, Kennedy LJ, Robinson J, Smith DM, Stear MJ, Stet RJ, Waller MJ, Walter L, Marsh SG (2006) ISAG/IUIS-VIC Comparative MHC Nomenclature Committee report, 2005. Immunogenetics 57:953–958PubMedCrossRefGoogle Scholar
  13. Erlich HA, Gyllensten UB (1991) Shared epitopes among HLA class II alleles gene conversion common ancestry and balancing selection. Immunol Today 12:411–414PubMedCrossRefGoogle Scholar
  14. Erlich HA, Bergström TF, Stoneking M, Gyllensten U (1996) HLA Sequence polymorphism and the origin of humans. Science 274:1552–1554PubMedCrossRefGoogle Scholar
  15. Figueroa F, Günther E, Klein J (1988) MHC polymorphism pre-dating speciation. Nature 335:265–267PubMedCrossRefGoogle Scholar
  16. Glazko GV, Nei M (2003) Estimation of divergence times for major lineages of primate species. Mol Biol Evol 20:424–434PubMedCrossRefGoogle Scholar
  17. Gorski J, Mach B (1986) Polymorphism of human Ia antigens: gene conversion between two DRb loci results in a HLA-D/DR specificity. Nature 322:67–70PubMedCrossRefGoogle Scholar
  18. Gyllensten UB, Sundvall M, Erlich HA (1991) Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates. Proc Natl Acad Sci USA 88:3686–3690PubMedCrossRefGoogle Scholar
  19. Gyllensten U, Bergström T, Josefsson A, Sundvall M, Erlich HA (1996) Rapid allelic diversification and intensified selection at antigen recognition sites of the MHC class II DPB1 locus during hominoid evolution. Tissue Antigens 47:212–221PubMedGoogle Scholar
  20. Hohjoh H, Ohashi J, Takasu M, Nishioka T, Ishida T, Tokunaga K (2003) Recent divergence of the HLA-DRB1*04 allelic lineage from the DRB1*0701 lineage after the separation of the human and chimpanzee species. Immunogenetics 54:856–861PubMedGoogle Scholar
  21. Högstrand K, Böhme J (1994) A determination of the frequency of gene conversion in unmanipulated sperm. Proc Natl Acad Sci USA 91:9921–9925PubMedCrossRefGoogle Scholar
  22. Hughes AL (2000) Evolution of introns and exons of class II major histocompatibility complex genes of vertebrates. Immunogenetics 51:473–486PubMedCrossRefGoogle Scholar
  23. Hughes AL, Nei M (1988) Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335:167–170PubMedCrossRefGoogle Scholar
  24. Hughes AL, Nei M (1989) Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci USA 86:958–962PubMedCrossRefGoogle Scholar
  25. Jukes TH, Cantor CR (1969) Evolution of protein molecules. In: Munro HN (ed) Mammalian protein metabolism. Academic, New York, pp 21–132Google Scholar
  26. Kappes D, Strominger JL (1988) Human class II major histocompatibility complex genes and proteins. Ann Rev Biochem 57:991–1028PubMedCrossRefGoogle Scholar
  27. Kimura M (1977) Preponderance of synonymous changes as evidence for the neutral theory of molecular evolution. Nature 267:275–276PubMedCrossRefGoogle Scholar
  28. Klein J (1987) Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol 19:155–162PubMedCrossRefGoogle Scholar
  29. Klein J, Figueroa F (1986) Evolution of the major histocompatibility complex. CRC Crit Rev Immunol 6:295–386Google Scholar
  30. Klein J, O’hUigin C, Kasahara M, Vincek V, Klein D, Figueroa F (1991) Frozen Haplotypes in Mhc Evolution. In: Klein J, Klein D (eds) Molecular Evolution of the Major Histocompatibility Complex. Springer, Berlin, Heidelberg, New York, pp 261–286Google Scholar
  31. Kotsch K, Blasczyk R (2000) The noncoding regions of HLA-DRB uncover interlineage recombinations as a mechanism of HLA diversification. J Immunol 165:5664–5670PubMedGoogle Scholar
  32. Kumar S, Tamura K, Nei M (2004) MEGA3: Integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief Bioinform 5:150–163PubMedCrossRefGoogle Scholar
  33. Marsh SG (2005) Nomenclature for factors of the HLA system, update June 2005. Tissue Antigens 66:338–340PubMedCrossRefGoogle Scholar
  34. Mathews LM, Chi SY, Greenberg N, Ovchinnikov I, Swergold GD (2003) Large differences between LINE-1 amplification rates in the human and chimpanzee lineages. Am J Hum Genet 72:739–748PubMedCrossRefGoogle Scholar
  35. Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3:418–426PubMedGoogle Scholar
  36. Nei M, Kumar S (2000) Molecular evolution and phylogenetics. Oxford University Press, Oxford; New YorkGoogle Scholar
  37. Ohta T (1995) Gene conversion vs point mutation in generating variability at the antigen recognition site of major histocompatibility complex loci. J Mol Evol 41:115–119PubMedGoogle Scholar
  38. Raymond CK, Kas A, Paddock M, Qiu R, Zhou Y, Subramanian S, Chang J, Palmieri A, Haugen E, Kaul R, Olson MV (2005) Ancient haplotypes of the HLA Class II region. Genome Res 15:1250–1257PubMedCrossRefGoogle Scholar
  39. Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SG (2003) IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 31:311–314PubMedCrossRefGoogle Scholar
  40. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z, Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston RH, McPherson JD, Gilman B, Schaffner S, Van Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander ES, Altshuler D (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409:928–933PubMedCrossRefGoogle Scholar
  41. Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425PubMedGoogle Scholar
  42. Satta Y, Mayer WE, Klein J (1996a) Evolutionary relationship of HLA-DRB genes inferred from intron sequences. J Mol Evol 42:648–657PubMedCrossRefGoogle Scholar
  43. Satta Y, Mayer WE, Klein J (1996b) HLA-DRB intron 1 sequences: implications for the evolution of HLA-DRB genes and haplotypes. Hum Immunol 51:1–12PubMedCrossRefGoogle Scholar
  44. Stephens R, Horton R, Humphray S, Rowen L, Trowsdale J, Beck S (1999) Gene organisation, sequence variation and isochore structure at the centromeric boundary of the human MHC. J Mol Biol 291:789–799PubMedCrossRefGoogle Scholar
  45. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedCrossRefGoogle Scholar
  46. Titus-Trachtenberg EA, Rickards O, De Stefano GF, Erlich HA (1994) Analysis of HLA class II haplotypes in the Cayapa Indians of Ecuador: a novel DRB1 allele reveals evidence for convergent evolution and balancing selection at position 86. Am J Hum Genet 55:160–167PubMedGoogle Scholar
  47. Trowsdale J (1995) “Both man and bird and beast”: comparative organization of MHC genes. Immunogenetics 41:1–17PubMedCrossRefGoogle Scholar
  48. Wetterbom A, Sevov M, Cavelier L, Bergström TF (2006) Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution. J Mol Evol 63:682–690PubMedCrossRefGoogle Scholar
  49. Zangenberg G, Huang MM, Arnheim N, Erlich H (1995) New HLA-DPB1 alleles generated by interallelic gene conversion detected by analysis of sperm. Nat Genet 10:407–414PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Jenny von Salomé
    • 1
  • Ulf Gyllensten
    • 1
  • Tomas F. Bergström
    • 1
    • 2
    Email author
  1. 1.Department of Genetics and Pathology, Rudbeck LaboratoryUppsala UniversityUppsalaSweden
  2. 2.Linnaeus Center for BioinformaticsUppsala UniversityUppsalaSweden

Personalised recommendations