Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jun;64(6):1709–1718. doi: 10.1086/302401

Tracing the origin of HLA-DRB1 alleles by microsatellite polymorphism.

T F Bergström 1, H Engkvist 1, R Erlandsson 1, A Josefsson 1, S J Mack 1, H A Erlich 1, U Gyllensten 1
PMCID: PMC1377915  PMID: 10330359

Abstract

We analyzed the origin of allelic diversity at the class II HLA-DRB1 locus, using a complex microsatellite located in intron 2, close to the polymorphic second exon. A phylogenetic analysis of human, gorilla, and chimpanzee DRB1 sequences indicated that the structure of the microsatellite has evolved, primarily by point mutations, from a putative ancestral (GT)x(GA)y-complex-dinucleotide repeat. In all contemporary DRB1 allelic lineages, with the exception of the human *04 and the gorilla *08 lineages, the (GA)y repeat is interrupted, often by a G-->C substitution. In general, the length of the 3' (GA)y repeat correlates with the allelic lineage and thus evolves more slowly than a middle (GA)z repeat, whose length correlates with specific alleles within the lineage. Comparison of the microsatellite sequence from 30 human DRB1 alleles showed the longer 5' (GT)x to be more variable than the shorter middle (GA)z and 3' (GA)y repeats. Analysis of multiple samples with the same exon sequence, derived from different continents, showed that the 5' (GT)x repeat evolves more rapidly than the middle (GA)z and the 3' (GA)y repeats, which is consistent with findings of a higher mutation rate for longer tracts. The microsatellite-repeat-length variation was used to trace the origin of new DRB1 alleles, such as the new *08 alleles found in the Cayapa people of Ecuador and the Ticuna people of Brazil.

Full Text

The Full Text of this article is available as a PDF (286.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ayala F. J., Escalante A. A. The evolution of human populations: a molecular perspective. Mol Phylogenet Evol. 1996 Feb;5(1):188–201. doi: 10.1006/mpev.1996.0013. [DOI] [PubMed] [Google Scholar]
  2. Ayala F. J. The myth of Eve: molecular biology and human origins. Science. 1995 Dec 22;270(5244):1930–1936. doi: 10.1126/science.270.5244.1930. [DOI] [PubMed] [Google Scholar]
  3. Bergström T. F., Josefsson A., Erlich H. A., Gyllensten U. Recent origin of HLA-DRB1 alleles and implications for human evolution. Nat Genet. 1998 Mar;18(3):237–242. doi: 10.1038/ng0398-237. [DOI] [PubMed] [Google Scholar]
  4. Blanquer-Maumont A., Crouau-Roy B. Polymorphism, monomorphism, and sequences in conserved microsatellites in primate species. J Mol Evol. 1995 Oct;41(4):492–497. doi: 10.1007/BF00160321. [DOI] [PubMed] [Google Scholar]
  5. Bodmer J. G., Marsh S. G., Albert E. D., Bodmer W. F., Bontrop R. E., Charron D., Dupont B., Erlich H. A., Fauchet R., Mach B. Nomenclature for factors of the HLA system, 1996. Tissue Antigens. 1997 Mar;49(3 Pt 2):297–321. doi: 10.1111/j.1399-0039.1997.tb02759.x. [DOI] [PubMed] [Google Scholar]
  6. Crouau-Roy B., Service S., Slatkin M., Freimer N. A fine-scale comparison of the human and chimpanzee genomes: linkage, linkage disequilibrium and sequence analysis. Hum Mol Genet. 1996 Aug;5(8):1131–1137. doi: 10.1093/hmg/5.8.1131. [DOI] [PubMed] [Google Scholar]
  7. Epplen C., Santos E. J., Guerreiro J. F., van Helden P., Epplen J. T. Coding versus intron variability: extremely polymorphic HLA-DRB1 exons are flanked by specific composite microsatellites, even in distant populations. Hum Genet. 1997 Mar;99(3):399–406. doi: 10.1007/s004390050379. [DOI] [PubMed] [Google Scholar]
  8. Garza J. C., Slatkin M., Freimer N. B. Microsatellite allele frequencies in humans and chimpanzees, with implications for constraints on allele size. Mol Biol Evol. 1995 Jul;12(4):594–603. doi: 10.1093/oxfordjournals.molbev.a040239. [DOI] [PubMed] [Google Scholar]
  9. Gyllensten U., Sundvall M., Ezcurra I., Erlich H. A. Genetic diversity at class II DRB loci of the primate MHC. J Immunol. 1991 Jun 15;146(12):4368–4376. [PubMed] [Google Scholar]
  10. Jeffreys A. J., Tamaki K., MacLeod A., Monckton D. G., Neil D. L., Armour J. A. Complex gene conversion events in germline mutation at human minisatellites. Nat Genet. 1994 Feb;6(2):136–145. doi: 10.1038/ng0294-136. [DOI] [PubMed] [Google Scholar]
  11. Jin L., Macaubas C., Hallmayer J., Kimura A., Mignot E. Mutation rate varies among alleles at a microsatellite locus: phylogenetic evidence. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15285–15288. doi: 10.1073/pnas.93.26.15285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kappes D., Strominger J. L. Human class II major histocompatibility complex genes and proteins. Annu Rev Biochem. 1988;57:991–1028. doi: 10.1146/annurev.bi.57.070188.005015. [DOI] [PubMed] [Google Scholar]
  13. Klein J., Figueroa F. Evolution of the major histocompatibility complex. Crit Rev Immunol. 1986;6(4):295–386. [PubMed] [Google Scholar]
  14. Klein J. Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol. 1987 Jul;19(3):155–162. doi: 10.1016/0198-8859(87)90066-8. [DOI] [PubMed] [Google Scholar]
  15. Levinson G., Gutman G. A. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol Biol Evol. 1987 May;4(3):203–221. doi: 10.1093/oxfordjournals.molbev.a040442. [DOI] [PubMed] [Google Scholar]
  16. Li W. H., Ellsworth D. L., Krushkal J., Chang B. H., Hewett-Emmett D. Rates of nucleotide substitution in primates and rodents and the generation-time effect hypothesis. Mol Phylogenet Evol. 1996 Feb;5(1):182–187. doi: 10.1006/mpev.1996.0012. [DOI] [PubMed] [Google Scholar]
  17. Macaubas C., Jin L., Hallmayer J., Kimura A., Mignot E. The complex mutation pattern of a microsatellite. Genome Res. 1997 Jun;7(6):635–641. doi: 10.1101/gr.7.6.635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mack S. J., Erlich H. A. HLA class II polymorphism in the Ticuna of Brazil: evolutionary implications of the DRB1*0807 allele. Tissue Antigens. 1998 Jan;51(1):41–50. doi: 10.1111/j.1399-0039.1998.tb02945.x. [DOI] [PubMed] [Google Scholar]
  19. Marsh S. G. Nomenclature for factors of the HLA system, update April 1997. WHO nomenclature committee for factors of the HLA system. Tissue Antigens. 1997 Aug;50(2):207–207. doi: 10.1111/j.1399-0039.1997.tb02862.x. [DOI] [PubMed] [Google Scholar]
  20. Mayer W. E., O'hUigin C., Zaleska-Rutczynska Z., Klein J. Trans-species origin of Mhc-DRB polymorphism in the chimpanzee. Immunogenetics. 1992;37(1):12–23. doi: 10.1007/BF00223540. [DOI] [PubMed] [Google Scholar]
  21. Petes T. D., Greenwell P. W., Dominska M. Stabilization of microsatellite sequences by variant repeats in the yeast Saccharomyces cerevisiae. Genetics. 1997 Jun;146(2):491–498. doi: 10.1093/genetics/146.2.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Slierendregt B. L., Kenter M., Otting N., Anholts J., Jonker M., Bontrop R. E. Major histocompatibility complex class II haplotypes in a breeding colony of chimpanzees (Pan troglodytes). Tissue Antigens. 1993 Aug;42(2):55–61. doi: 10.1111/j.1399-0039.1993.tb02237.x. [DOI] [PubMed] [Google Scholar]
  23. Smith A. G., Nelson J. L., Regen L., Guthrie L. A., Donadi E., Mickelson E. M., Hansen J. A. Six new DR52-associated DRB1 alleles, three of DR8, two of DR11, and one of DR6, reflect a variety of mechanisms which generate polymorphism in the MHC. Tissue Antigens. 1996 Aug;48(2):118–126. doi: 10.1111/j.1399-0039.1996.tb02616.x. [DOI] [PubMed] [Google Scholar]
  24. Titus-Trachtenberg E. A., Rickards O., De Stefano G. F., Erlich H. A. 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. 1994 Jul;55(1):160–167. [PMC free article] [PubMed] [Google Scholar]
  25. Trowsdale J. "Both man & bird & beast": comparative organization of MHC genes. Immunogenetics. 1995;41(1):1–17. doi: 10.1007/BF00188427. [DOI] [PubMed] [Google Scholar]
  26. Wierdl M., Dominska M., Petes T. D. Microsatellite instability in yeast: dependence on the length of the microsatellite. Genetics. 1997 Jul;146(3):769–779. doi: 10.1093/genetics/146.3.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Williams T. M., Wu J., Foutz T., McAuley J. D., Troup G. M. A new DRB1 allele (DRB1*0811) identified in Native Americans. Immunogenetics. 1994;40(4):314–314. doi: 10.1007/BF00189984. [DOI] [PubMed] [Google Scholar]
  28. Zhang L., Leeflang E. P., Yu J., Arnheim N. Studying human mutations by sperm typing: instability of CAG trinucleotide repeats in the human androgen receptor gene. Nat Genet. 1994 Aug;7(4):531–535. doi: 10.1038/ng0894-531. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES