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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

ABSTRACT

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.

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    • "Heterozygote advantage has received support from experiments in semi-natural populations of mice (Penn et al. 2002), which show increased resistance of heterozygotes to multiple-strain infection, and through the finding that among humans infected with HIV, those which are heterozygous for HLA genes have slower progression to AIDS (reviewed in Dean et al. 2002). Heterozygote advantage has also received support from substitution rate studies (Hughes and Nei 1988, 1989) as well as simulation-based studies (e.g., Takahata and Nei 1990). A second model for balancing selection at MHC genes is negative frequency dependent selection (or apostatic selection), according to which rare variants have a selective advantage over common ones, because pathogens are more likely to evade presentation by common molecules (Slade and McCallum 1992). "
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    ABSTRACT: The classical class I HLA loci of humans show an excess of nonsynonymous with respect to synonymous substitutions at codons of the antigen recognition site (ARS), a hallmark of adaptive evolution. Additionally, high polymporphism, linkage disequilibrium, and disease associations suggest that one or more balancing selection regimes have acted upon these genes. However, several questions about these selective regimes remain open. First, it is unclear if stronger evidence for selection on deep timescales is due to changes in the intensity of selection over time or to a lack of power of most methods to detect selection on recent timescales. Another question concerns the functional entities which define the selected phenotype. While most analyses focus on selection acting on individual alleles, it is also plausible that phylogenetically defined groups of alleles ("lineages") are targets of selection. To address these questions, we analyzed how [Formula: see text] ([Formula: see text]) varies with respect to divergence times between alleles and phylogenetic placement (position of branches). We find that [Formula: see text] for ARS codons of class I HLA genes increases with divergence time and is higher for inter-lineage branches. Throughout our analyses, we used non-selected codons to control for possible effects of inflation of [Formula: see text] associated to intra-specific analysis, and showed that our results are not artifactual. Our findings indicate the importance of considering the timescale effect when analysing [Formula: see text] over a wide spectrum of divergences. Finally, our results support the divergent allele advantage model, whereby heterozygotes with more divergent alleles have higher fitness than those carrying similar alleles.
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    • "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). "
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    • "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. "
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