Natural selection at major histocompatibility complex loci of vertebrates

The loci of the vertebrate major histocompatibility complex encode cell-sur face glycoproteins that present peptides to T cells. Certain of these loci are highly polymorphic, and the mechanisms responsible for this polymorphis m have been intensely debated. Four independent lines of evidence support t he hypothesis that MHC polymorphisms are selectively maintained: (a) The di stribution of allelic frequencies does not fit the neutral expectation. (b) The rate of nonsynonymous nucleotide substitution significantly exceeds th e rate of synonymous substitution in the codons encoding the peptide-bindin g region of the molecule. (c) Polymorphisms have been maintained for long p eriods of time ("trans-species polymorphism"). (d) Introns have been homoge nized relative to exons over evolutionary time, suggesting that balancing s election acts to maintain diversity in the latter, in contrast to the forme r.