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Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection

Abstract

The major histocompatibility complex (MHC) loci are known to be highly polymorphic in humans, mice and certain other mammals, with heterozygosity as high as 80–90% (ref. 1). Four different hypotheses have been proposed to explain this high degree of polymorphism: (1) a high mutation rate2, (2) gene conversion or interlocus genetic exchange3–5, (3) over dominant selection6,7 and (4) frequency-dependent selection8,9. In an attempt to establish which of these hypotheses is correct, we examined the pattern of nucleotide substitution between polymorphic alleles in the region of the antigen recognition site (ARS)10,11 and other regions of human and mouse class I MHC genes. The results indicate that in ARS the rate of nonsynonymous (amino acid altering) substitution is significantly higher than that of synonymous substitution in both humans and mice, whereas in other regions the reverse is true. This observation, together with a theoretical study12 and other considerations, supports the hypothesis of overdominant selection (heterozygote advantage).

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Hughes, A., Nei, M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335, 167–170 (1988). https://doi.org/10.1038/335167a0

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