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. 2000 Oct;156(2):867–877. doi: 10.1093/genetics/156.2.867

The implications of intergenic polymorphism for major histocompatibility complex evolution.

C O'hUigin 1, Y Satta 1, A Hausmann 1, R L Dawkins 1, J Klein 1
PMCID: PMC1461294  PMID: 11014832

Abstract

A systematic survey of six intergenic regions flanking the human HLA-B locus in eight haplotypes reveals the regions to be up to 20 times more polymorphic than the reported average degree of human neutral polymorphism. Furthermore, the extent of polymorphism is directly related to the proximity to the HLA-B locus. Apparently linkage to HLA-B locus alleles, which are under balancing selection, maintains the neutral polymorphism of adjacent regions. For these linked polymorphisms to persist, recombination in the 200-kb interval from HLA-B to TNF must occur at a low frequency. The high degree of polymorphism found distal to HLA-B suggests that recombination is uncommon on both sides of the HLA-B locus. The least-squares estimate is 0.15% per megabase with an estimated range from 0.02 to 0.54%. These findings place strong restrictions on possible recombinational mechanisms for the generation of diversity at the HLA-B.

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Selected References

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  1. Abraham L. J., Leelayuwat C., Grimsley G., Degli-Esposti M. A., Mann A., Zhang W. J., Christiansen F. T., Dawkins R. L. Sequence differences between HLA-B and TNF distinguish different MHC ancestral haplotypes. Tissue Antigens. 1992 Mar;39(3):117–121. doi: 10.1111/j.1399-0039.1992.tb01920.x. [DOI] [PubMed] [Google Scholar]
  2. Andersson L., Gustafsson K., Jonsson A. K., Rask L. Concerted evolution in a segment of the first domain exon of polymorphic MHC class II beta loci. Immunogenetics. 1991;33(4):235–242. doi: 10.1007/BF00230500. [DOI] [PubMed] [Google Scholar]
  3. Andersson L., Mikko S. Generation of MHC class II diversity by intra- and intergenic recombination. Immunol Rev. 1995 Feb;143:5–12. doi: 10.1111/j.1600-065x.1995.tb00667.x. [DOI] [PubMed] [Google Scholar]
  4. Ando H., Mizuki N., Ota M., Yamazaki M., Ohno S., Goto K., Miyata Y., Wakisaka K., Bahram S., Inoko H. Allelic variants of the human MHC class I chain-related B gene (MICB). Immunogenetics. 1997;46(6):499–508. doi: 10.1007/s002510050311. [DOI] [PubMed] [Google Scholar]
  5. Bahram S., Bresnahan M., Geraghty D. E., Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6259–6263. doi: 10.1073/pnas.91.14.6259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bauer S., Groh V., Wu J., Steinle A., Phillips J. H., Lanier L. L., Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999 Jul 30;285(5428):727–729. doi: 10.1126/science.285.5428.727. [DOI] [PubMed] [Google Scholar]
  7. Cattley S. K., Longman N., Dawkins R. L., Gaudieri S., Kulski J. K., Leelayuwat C. Phylogenetic analysis of primate MIC (PERB11) sequences suggests that the representation of the gene family differs in different primates: comparison of MIC (PERB11) and C4. Eur J Immunogenet. 1999 Apr-Jun;26(2-3):233–238. doi: 10.1046/j.1365-2370.1999.00154.x. [DOI] [PubMed] [Google Scholar]
  8. Cereb N., Kong Y., Lee S., Maye P., Yang S. Y. Nucleotide sequences of MHC class I introns 1, 2, and 3 in humans and intron 2 in nonhuman primates. Tissue Antigens. 1996 Jun;47(6):498–511. doi: 10.1111/j.1399-0039.1996.tb02592.x. [DOI] [PubMed] [Google Scholar]
  9. Charlesworth B., Morgan M. T., Charlesworth D. The effect of deleterious mutations on neutral molecular variation. Genetics. 1993 Aug;134(4):1289–1303. doi: 10.1093/genetics/134.4.1289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Felsenstein J. The evolutionary advantage of recombination. Genetics. 1974 Oct;78(2):737–756. doi: 10.1093/genetics/78.2.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fodil N., Laloux L., Wanner V., Pellet P., Hauptmann G., Mizuki N., Inoko H., Spies T., Theodorou I., Bahram S. Allelic repertoire of the human MHC class I MICA gene. Immunogenetics. 1996;44(5):351–357. doi: 10.1007/BF02602779. [DOI] [PubMed] [Google Scholar]
  12. Gaudieri S., Leelayuwat C., Tay G. K., Townend D. C., Dawkins R. L. The major histocompatability complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes. J Mol Evol. 1997 Jul;45(1):17–23. doi: 10.1007/pl00006194. [DOI] [PubMed] [Google Scholar]
  13. Geraghty D. E., Koller B. H., Hansen J. A., Orr H. T. The HLA class I gene family includes at least six genes and twelve pseudogenes and gene fragments. J Immunol. 1992 Sep 15;149(6):1934–1946. [PubMed] [Google Scholar]
  14. Guillaudeux T., Janer M., Wong G. K., Spies T., Geraghty D. E. The complete genomic sequence of 424,015 bp at the centromeric end of the HLA class I region: gene content and polymorphism. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9494–9499. doi: 10.1073/pnas.95.16.9494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gustafsson K., Andersson L. Structure and polymorphism of horse MHC class II DRB genes: convergent evolution in the antigen binding site. Immunogenetics. 1994;39(5):355–358. doi: 10.1007/BF00189233. [DOI] [PubMed] [Google Scholar]
  16. Gyllensten U. B., Sundvall M., Erlich H. A. Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3686–3690. doi: 10.1073/pnas.88.9.3686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Iris F. J., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V., Jurka J., Rodriguez-Tome P., Claverie J. M., Dausset J. Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment. Nat Genet. 1993 Feb;3(2):137–145. doi: 10.1038/ng0293-137. [DOI] [PubMed] [Google Scholar]
  18. Kaplan N. L., Hudson R. R., Langley C. H. The "hitchhiking effect" revisited. Genetics. 1989 Dec;123(4):887–899. doi: 10.1093/genetics/123.4.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kimura M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol. 1980 Dec;16(2):111–120. doi: 10.1007/BF01731581. [DOI] [PubMed] [Google Scholar]
  20. Klein J., Satta Y., O'hUigin C., Takahata N. The molecular descent of the major histocompatibility complex. Annu Rev Immunol. 1993;11:269–295. doi: 10.1146/annurev.iy.11.040193.001413. [DOI] [PubMed] [Google Scholar]
  21. Kriener K., O'hUigin C., Tichy H., Klein J. Convergent evolution of major histocompatibility complex molecules in humans and New World monkeys. Immunogenetics. 2000 Mar;51(3):169–178. doi: 10.1007/s002510050028. [DOI] [PubMed] [Google Scholar]
  22. Leelayuwat C., Abraham L. J., Pinelli M., Townend D. C., Wilks A. F., Dawkins R. L. The primate MHC contains sequences related to the fibroblast growth factor receptor gene family. Tissue Antigens. 1996 Jul;48(1):59–64. doi: 10.1111/j.1399-0039.1996.tb02607.x. [DOI] [PubMed] [Google Scholar]
  23. Leelayuwat C., Abraham L. J., Tabarias H., Christiansen F. T., Dawkins R. L. Genomic organization of a polymorphic duplicated region centromeric of HLA-B. Immunogenetics. 1992;36(4):208–212. doi: 10.1007/BF00215049. [DOI] [PubMed] [Google Scholar]
  24. Li W. H., Sadler L. A. Low nucleotide diversity in man. Genetics. 1991 Oct;129(2):513–523. doi: 10.1093/genetics/129.2.513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McAdam S. N., Boyson J. E., Liu X., Garber T. L., Hughes A. L., Bontrop R. E., Watkins D. I. A uniquely high level of recombination at the HLA-B locus. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5893–5897. doi: 10.1073/pnas.91.13.5893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. McDevitt H. Evolution of MHC class II allelic diversity. Immunol Rev. 1995 Feb;143:113–122. doi: 10.1111/j.1600-065x.1995.tb00672.x. [DOI] [PubMed] [Google Scholar]
  27. Mizuki N., Ando H., Kimura M., Ohno S., Miyata S., Yamazaki M., Tashiro H., Watanabe K., Ono A., Taguchi S. Nucleotide sequence analysis of the HLA class I region spanning the 237-kb segment around the HLA-B and -C genes. Genomics. 1997 May 15;42(1):55–66. doi: 10.1006/geno.1997.4708. [DOI] [PubMed] [Google Scholar]
  28. Pellet P., Renaud M., Fodil N., Laloux L., Inoko H., Hauptmann G., Debré P., Bahram S., Theodorou I. Allelic repertoire of the human MICB gene. Immunogenetics. 1997;46(5):434–436. doi: 10.1007/s002510050299. [DOI] [PubMed] [Google Scholar]
  29. Prasad V. K., Yang S. Y. Allele assignment for HLA-A, -B, and -C genes to the Tenth International Histocompatibility Workshop cell lines. Tissue Antigens. 1996 Jun;47(6):538–546. doi: 10.1111/j.1399-0039.1996.tb02596.x. [DOI] [PubMed] [Google Scholar]
  30. Rozas J., Rozas R. DnaSP version 2.0: a novel software package for extensive molecular population genetics analysis. Comput Appl Biosci. 1997 Jun;13(3):307–311. [PubMed] [Google Scholar]
  31. Satta Y., O'hUigin C., Takahata N., Klein J. The synonymous substitution rate of the major histocompatibility complex loci in primates. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7480–7484. doi: 10.1073/pnas.90.16.7480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. She J. X., Boehme S. A., Wang T. W., Bonhomme F., Wakeland E. K. Amplification of major histocompatibility complex class II gene diversity by intraexonic recombination. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):453–457. doi: 10.1073/pnas.88.2.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shiina T., Tamiya G., Oka A., Yamagata T., Yamagata N., Kikkawa E., Goto K., Mizuki N., Watanabe K., Fukuzumi Y. Nucleotide sequencing analysis of the 146-kilobase segment around the IkBL and MICA genes at the centromeric end of the HLA class I region. Genomics. 1998 Feb 1;47(3):372–382. doi: 10.1006/geno.1997.5114. [DOI] [PubMed] [Google Scholar]
  34. Smith J. M., Haigh J. The hitch-hiking effect of a favourable gene. Genet Res. 1974 Feb;23(1):23–35. [PubMed] [Google Scholar]
  35. Takahata N., Satta Y. Evolution of the primate lineage leading to modern humans: phylogenetic and demographic inferences from DNA sequences. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4811–4815. doi: 10.1073/pnas.94.9.4811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Takahata N., Satta Y. Selection, convergence, and intragenic recombination in HLA diversity. Genetica. 1998;102-103(1-6):157–169. [PubMed] [Google Scholar]
  37. Visser C. J., Tilanus M. G., Schaeffer V., Tatari Z., Tamouza R., Janin A., Charron D. Sequencing-based typing reveals six novel MHC class I chain-related gene B (MICB) alleles. Tissue Antigens. 1998 Jun;51(6):649–652. doi: 10.1111/j.1399-0039.1998.tb03008.x. [DOI] [PubMed] [Google Scholar]
  38. Yao Z., Volgger A., Helmberg W., Keller E., Fan L. A., Chandanayingyong D., Albert E. D. Definition of new alleles of MIC-A using sequencing-based typing. Eur J Immunogenet. 1999 Apr-Jun;26(2-3):225–232. doi: 10.1046/j.1365-2370.1999.00094.x. [DOI] [PubMed] [Google Scholar]

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