• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Jun 1997; 146(2): 655–668.
PMCID: PMC1208005

Ancestral Polymorphism of Mhc Class II Genes in Mice: Implications for Balancing Selection and the Mammalian Molecular Clock

Abstract

To investigate the evolutionary dynamics at Mhc class II DR genes of mice (genus Mus), we sequenced the peptide binding regions (PBRs) of 41 DRB (=Eβ) genes and eight DRA (=Eα) genes from 15 strains representing eight species. As expected trees of these PBR sequences imply extensive maintenance of ancestral DRB alleles across species. We use a coalescent simulation model to show that the number of interspecific coalescent events (c) observed on these trees was higher than the number expected for neutral genealogies and similar sample sizes and is more consistent with balancing selection than with neutrality. Patterns of ancestral polymorphism in mouse DRB alleles were also used to examine the tempo of synonymous substitution in the PBR of mouse class II genes. Both absolute and relative rate tests on DRA and DRB genes imply increased substitution rates at two- and fourfold degnerate sites of mice and rats relative to primates, and decreased rates for the DRB genes of primates relative to ungulate and carnivore relatives. Thus rates of synonymous substitution at Mhc DR genes in mammals appear to be subject to generation time effects in ways similar to those found at other mammalian genes.

Full Text

The Full Text of this article is available as a PDF (2.4M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adachi J, Cao Y, Hasegawa M. Tempo and mode of mitochondrial DNA evolution in vertebrates at the amino acid sequence level: rapid evolution in warm-blooded vertebrates. J Mol Evol. 1993 Mar;36(3):270–281. [PubMed]
  • Albright-Fraser DG, Reid R, Gerber V, Bailey E. Polymorphism of DRA among equids. Immunogenetics. 1996;43(5):315–317. [PubMed]
  • Allard MW, McNiff BE, Miyamoto MM. Support for interordinal eutherian relationships with an emphasis on primates and their archontan relatives. Mol Phylogenet Evol. 1996 Feb;5(1):78–88. [PubMed]
  • Begovich AB, Vu TH, Jones PP. Characterization of the molecular defects in the mouse E beta f and E beta q genes. Implications for the origin of MHC polymorphism. J Immunol. 1990 Mar 1;144(5):1957–1964. [PubMed]
  • Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. [PubMed]
  • Edwards SV, Wakeland EK, Potts WK. Contrasting histories of avian and mammalian Mhc genes revealed by class II B sequences from songbirds. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12200–12204. [PMC free article] [PubMed]
  • Figueroa F, Günther E, Klein J. MHC polymorphism pre-dating speciation. Nature. 1988 Sep 15;335(6187):265–267. [PubMed]
  • Figueroa F, Tichy H, Singleton G, Franguedakis-Tsolis S, Klein J. High frequency of H-2E0 alleles among wild mice. Immunogenetics. 1989;30(3):222–225. [PubMed]
  • Figueroa F, O'hUigin C, Tichy H, Klein J. The origin of the primate Mhc-DRB genes and allelic lineages as deduced from the study of prosimians. J Immunol. 1994 May 1;152(9):4455–4465. [PubMed]
  • Fu YX, Li WH. Statistical tests of neutrality of mutations. Genetics. 1993 Mar;133(3):693–709. [PMC free article] [PubMed]
  • Graser R, O'hUigin C, Vincek V, Meyer A, Klein J. Trans-species polymorphism of class II Mhc loci in danio fishes. Immunogenetics. 1996;44(1):36–48. [PubMed]
  • 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. [PubMed]
  • Gyllensten UB, Sundvall M, Erlich HA. 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. [PMC free article] [PubMed]
  • Gyllensten UB, Lashkari D, Erlich HA. Allelic diversification at the class II DQB locus of the mammalian major histocompatibility complex. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1835–1839. [PMC free article] [PubMed]
  • Hudson RR, Kreitman M, Aguadé M. A test of neutral molecular evolution based on nucleotide data. Genetics. 1987 May;116(1):153–159. [PMC free article] [PubMed]
  • Hughes AL, Hughes MK, Howell CY, Nei M. Natural selection at the class II major histocompatibility complex loci of mammals. Philos Trans R Soc Lond B Biol Sci. 1994 Nov 29;346(1317):359–367. [PubMed]
  • Hughes AL, Nei M. Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci U S A. 1989 Feb;86(3):958–962. [PMC free article] [PubMed]
  • Hughes AL, Nei M. Evolutionary relationships of class II major-histocompatibility-complex genes in mammals. Mol Biol Evol. 1990 Nov;7(6):491–514. [PubMed]
  • Janke A, Feldmaier-Fuchs G, Thomas WK, von Haeseler A, Päbo S. The marsupial mitochondrial genome and the evolution of placental mammals. Genetics. 1994 May;137(1):243–256. [PMC free article] [PubMed]
  • Kawamura S, Tanabe H, Watanabe Y, Kurosaki K, Saitou N, Ueda S. Evolutionary rate of immunoglobulin alpha noncoding region is greater in hominoids than in Old World monkeys. Mol Biol Evol. 1991 Nov;8(6):743–752. [PubMed]
  • 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. [PubMed]
  • Li WH. So, what about the molecular clock hypothesis? Curr Opin Genet Dev. 1993 Dec;3(6):896–901. [PubMed]
  • Li WH, Ellsworth DL, Krushkal J, Chang BH, 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. [PubMed]
  • Li WH, Gouy M, Sharp PM, O'hUigin C, Yang YW. Molecular phylogeny of Rodentia, Lagomorpha, Primates, Artiodactyla, and Carnivora and molecular clocks. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6703–6707. [PMC free article] [PubMed]
  • Lundberg AS, McDevitt HO. Evolution of major histocompatibility complex class II allelic diversity: direct descent in mice and humans. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6545–6549. [PMC free article] [PubMed]
  • McConnell TJ, Talbot WS, McIndoe RA, Wakeland EK. The origin of MHC class II gene polymorphism within the genus Mus. Nature. 1988 Apr 14;332(6165):651–654. [PubMed]
  • McDevitt H. Evolution of MHC class II allelic diversity. Immunol Rev. 1995 Feb;143:113–122. [PubMed]
  • McDonald JH, Kreitman M. Adaptive protein evolution at the Adh locus in Drosophila. Nature. 1991 Jun 20;351(6328):652–654. [PubMed]
  • McNicholas J, Steinmetz M, Hunkapiller T, Jones P, Hood L. DNA sequence of the gene encoding the E alpha Ia polypeptide of the BALB/c mouse. Science. 1982 Dec 17;218(4578):1229–1232. [PubMed]
  • Mnuková-Fajdelová M, Satta Y, O'hUigin C, Mayer WE, Figueroa F, Klein J. Alu elements of the primate major histocompatibility complex. Mamm Genome. 1994 Jul;5(7):405–415. [PubMed]
  • Muse SV. Estimating synonymous and nonsynonymous substitution rates. Mol Biol Evol. 1996 Jan;13(1):105–114. [PubMed]
  • Nei M, Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. [PubMed]
  • O'hUigin C. Quantifying the degree of convergence in primate Mhc-DRB genes. Immunol Rev. 1995 Feb;143:123–140. [PubMed]
  • O'hUigin C, Li WH. The molecular clock ticks regularly in muroid rodents and hamsters. J Mol Evol. 1992 Nov;35(5):377–384. [PubMed]
  • Potts WK, Wakeland EK. Evolution of MHC genetic diversity: a tale of incest, pestilence and sexual preference. Trends Genet. 1993 Dec;9(12):408–412. [PubMed]
  • Prager EM, Tichy H, Sage RD. Mitochondrial DNA sequence variation in the eastern house mouse, Mus musculus: comparison with other house mice and report of a 75-bp tandem repeat. Genetics. 1996 May;143(1):427–446. [PMC free article] [PubMed]
  • Robertson KA, McMaster WR. Complete structure of a rat RT1 E beta chain: extensive conservation of MHC class II beta chains. J Immunol. 1985 Dec;135(6):4095–4099. [PubMed]
  • Saito H, Maki RA, Clayton LK, Tonegawa S. Complete primary structures of the E beta chain and gene of the mouse major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5520–5524. [PMC free article] [PubMed]
  • Sarich VM, Wilson AC. Generation time and genomic evolution in primates. Science. 1973 Mar 16;179(4078):1144–1147. [PubMed]
  • Satta Y, Mayer WE, Klein J. Evolutionary relationship of HLA-DRB genes inferred from intron sequences. J Mol Evol. 1996 Jun;42(6):648–657. [PubMed]
  • 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. [PMC free article] [PubMed]
  • She JX, Boehme SA, Wang TW, Bonhomme F, Wakeland EK. 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. [PMC free article] [PubMed]
  • Slatkin M, Maddison WP. A cladistic measure of gene flow inferred from the phylogenies of alleles. Genetics. 1989 Nov;123(3):603–613. [PMC free article] [PubMed]
  • Takahata N. A simple genealogical structure of strongly balanced allelic lines and trans-species evolution of polymorphism. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2419–2423. [PMC free article] [PubMed]
  • Takahata N. Comments on the detection of reciprocal recombination or gene conversion. Immunogenetics. 1994;39(2):146–149. [PubMed]
  • Takezaki N, Rzhetsky A, Nei M. Phylogenetic test of the molecular clock and linearized trees. Mol Biol Evol. 1995 Sep;12(5):823–833. [PubMed]
  • Uyenoyama MK. A generalized least-squares estimate for the origin of sporophytic self-incompatibility. Genetics. 1995 Feb;139(2):975–992. [PMC free article] [PubMed]
  • Vekemans X, Slatkin M. Gene and allelic genealogies at a gametophytic self-incompatibility locus. Genetics. 1994 Aug;137(4):1157–1165. [PMC free article] [PubMed]
  • Wakeland EK, Boehme S, She JX. The generation and maintenance of MHC class II gene polymorphism in rodents. Immunol Rev. 1990 Feb;113:207–226. [PubMed]
  • Wakeland EK, Price-LaFace M, Henson V, Peck AB. Production of 35 H-2 homozygous strains from wild mice. Immunogenetics. 1987;26(1-2):115–119. [PubMed]
  • Wu CI, Li WH. Evidence for higher rates of nucleotide substitution in rodents than in man. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1741–1745. [PMC free article] [PubMed]
  • Zangenberg G, Huang MM, Arnheim N, Erlich H. New HLA-DPB1 alleles generated by interallelic gene conversion detected by analysis of sperm. Nat Genet. 1995 Aug;10(4):407–414. [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...