Takahata N, Nei M.. Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124: 967-978

Center for Demographic and Population Genetics, University of Texas Health Science Center, Houston 77225.
Genetics (Impact Factor: 5.96). 05/1990; 124(4):967-78.
Source: PubMed


To explain the long-term persistence of polymorphic alleles (trans-specific polymorphism) at the major histocompatibility complex (MHC) loci in rodents and primates, a computer simulation study was conducted about the coalescence time of different alleles sampled under various forms of selection. At the same time, average heterozygosity, the number of alleles in a sample, and the rate of codon substitution were examined to explain the mechanism of maintenance of polymorphism at the MHC loci. The results obtained are as follows. (1) The coalescence time for neutral alleles is too short to explain the trans-specific polymorphism at the MHC loci. (2) Under overdominant selection, the coalescence time can be tens of millions of years, depending on the parameter values used. The average heterozygosity and the number of alleles observed are also high enough to explain MHC polymorphism. (3) The pathogen adaptation model proposed by Snell is incapable of explaining MHC polymorphism, since the coalescence time for this model is too short and the expected heterozygosity and the expected number of alleles are too small. (4) From the mathematical point of view, the minority advantage model of frequency-dependent selection is capable of explaining a high degree of polymorphism and trans-specific polymorphism. (5) The molecular mimicry hypothesis also gives a sufficiently long coalescence time when the mutation rate is low in the host but very high in the parasite. However, the expected heterozygosity and the expected number of alleles tend to be too small. (6) Consideration of the molecular mechanism of the function of MHC molecules and other biological observations suggest that the most important factor for the maintenance of MHC polymorphism is overdominant selection. However, some experiments are necessary to distinguish between the overdominance and frequency-dependent selection hypotheses.

Download full-text


Available from: Naoyuki Takahata,
  • Source
    • "These characteristics contrast with neutral expectations and support the hypothesis that balancing selection has maintained variation at these codons. The high levels of variation observed at the sites involved in peptide binding support a model of host-pathogen coevolution (Apanius et al. 1997), which states that the pathogenic microorganisms are the main evolutionary force shaping HLA variation (Borghans et al. 2004; Slade and McCallum 1992; Takahata and Nei 1990). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions-the B and F pockets-of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (G ST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and G ST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens.
    Immunogenetics 10/2015; 67(11). DOI:10.1007/s00251-015-0875-9 · 2.23 Impact Factor
  • Source
    • "It has been proposed that pathogen-mediated selection (PMS) is one of the main driving forces maintaining diversity at MHC loci (Doherty and Zinkernagel 1975; Apanius et al. 1997; Jeffery and Bangham 2000; Bernatchez and Landry 2003) and several hypotheses explaining PMS have been suggested as follows: heterozygote advantage (Doherty and Zinkernagel 1975), rare allele advantage (Slade and McCallum 1992), and fluctuating selection (Hill 1991). All three mechanisms, or a combination of the three, could be the driver of MHC diversity (Hughes and Nei 1988; Takahata and Nei 1990; Apanius et al. 1997). As MHC is known to respond to PMS, the factors that drive pathogen diversity in different environments could also represent important causal predictors for MHC diversity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The genes of the major histocompatibility complex (MHC) code for proteins involved in antigen recognition and activation of the adaptive immune response and are thought to be regulated by natural selection, especially due to pathogen-driven selective pressure. In this study, we investigated the spatial distribution of MHC class II DRB exon 2 gene diversity of the lesser anteater (Tamandua tetradactyla) across five Brazilian biomes using next-generation sequencing and compared the MHC pattern with that of neutral markers (microsatellites). We found a noticeable high level of diversity in DRB (60 amino acid alleles in 65 individuals) and clear signatures of historical positive selection acting on this gene. Higher allelic richness and proportion of private alleles were found in rain forest biomes, especially Amazon forest, a megadiverse biome, possibly harboring greater pathogen richness as well. Neutral markers, however, showed a similar pattern to DRB, demonstrating the strength of demography as an additional force to pathogen-driven selection in shaping MHC diversity and structure. This is the first characterization and description of diversity of a MHC gene for any member of the magna-order Xenarthra, one of the basal lineages of placental mammals.
    Ecology and Evolution 10/2015; DOI:10.1002/ece3.1656 · 2.32 Impact Factor
  • Source
    • "The parts of the molecule coding for the peptide binding regions (PBRs) are under strong diversifying or balancing selection, and MHC-genes are the most variable functional genes described in vertebrates to date (Piertney and Oliver 2006). Exactly how the selective pressure is acting on MHC alleles with different PBRs is disputed (van Oosterhout 2009): heterozygote advantage (Doherty and Zinkernagel 1975), rare-allele-advantage (Takahata and Nei 1990), host-pathogen coevolution (Borghans et al. 2004) and MHC-based mating preferences (Penn and Potts 1999; Wedekind et al. 1995) have all been proposed as "
    [Show abstract] [Hide abstract]
    ABSTRACT: We studied variation at the class II gene of the major histocompatibility complex (MHC) in Natterjack toad populations (Bufo [Epidalea] calamita) on islands off the west coast of Sweden. These isolated populations have previously been shown to exhibit low levels of neutral genetic variation. On seven investigated islands we found only two different MHC alleles, indicating that the genetic variation at this locus is also low. The two alleles were found in all populations, although in one population there was only a single heterozygous individual. The Swedish toads showed similar low levels of MHC variation as revealed by previously published data from populations in northern Europe. We did not find a correlation between MHC and neutral genetic variation (as determined by AFLP). However, our findings show that reduced genetic variation in the Swedish Natterjack toads is not restricted to neutral markers, but is likewise reflected at the MHC.
    Conservation Genetics 08/2015; 16(4):1-4. DOI:10.1007/s10592-015-0715-3 · 2.19 Impact Factor
Show more