Abstract:
BACKGROUND: Major Histocompatibility Complex (MHC) genes are central to vertebrate immune response and are
believed to be under balancing selection by pathogens. This hypothesis has been supported by observations of
extremely high polymorphism, elevated nonsynonymous to synonymous base pair substitution rates and transspecies
polymorphisms at these loci. In equids, the organization and variability of this gene family has been
described, however the full extent of diversity and selection is unknown. As selection is not expected to act
uniformly on a functional gene, maximum likelihood codon-based models of selection that allow heterogeneity in
selection across codon positions can be valuable for examining MHC gene evolution and the molecular basis for
species adaptations.
RESULTS: We investigated the evolution of two class II MHC genes of the Equine Lymphocyte Antigen (ELA), DRA
and DQA, in the genus Equus with the addition of novel alleles identified in plains zebra (E. quagga, formerly E.
burchelli). We found that both genes exhibited a high degree of polymorphism and inter-specific sharing of allele
lineages. To our knowledge, DRA allelic diversity was discovered to be higher than has ever been observed in
vertebrates. Evidence was also found to support a duplication of the DQA locus. Selection analyses, evaluated in
terms of relative rates of nonsynonymous to synonymous mutations (dN/dS) averaged over the gene region,
indicated that the majority of codon sites were conserved and under purifying selection (dN <dS). However, the
most likely evolutionary codon models allowed for variable rates of selection across codon sites at both loci and, at
the DQA, supported the hypothesis of positive selection acting on specific sites.
CONCLUSIONS: Observations of elevated genetic diversity and trans-species polymorphisms supported the
conclusion that balancing selection may be acting on these loci. Furthermore, at the DQA, positive selection was
occurring at antigen binding sites, suggesting that a few selected residues may play a significant role in equid
immune function. Future studies in natural equid populations will be valuable for understanding the functional
significance of the uniquely diverse DRA locus and for elucidating the mechanism maintaining diversity at these
MHC loci.
