Department of Environmental Science, Policy and Management, University of California Berkeley, USA.
BMC Evol Biol. 2011 May 18;11:128. doi: 10.1186/1471-2148-11-128.
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 trans-species 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.
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.
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.
主要组织相容性复合体（MHC）基因是脊椎动物免疫反应的核心，据信它们受到病原体的平衡选择。这一假设得到了以下观察结果的支持：这些基因座的高度多态性、非同义与同义碱基对替换率升高以及跨物种多态性。在马科动物中，该基因家族的组织和变异性已被描述，但多样性和选择的全部程度尚不清楚。由于选择不应均匀作用于功能基因，因此允许密码子位置异质性的最大似然基于密码子的选择模型对于研究 MHC 基因进化和物种适应的分子基础非常有价值。
我们通过在平原斑马（E. quagga，前身为 E. burchelli）中鉴定出的新等位基因，研究了马属动物的两个 II 类 MHC 基因——DRA 和 DQA 的进化。我们发现这两个基因都表现出高度的多态性和种间等位基因谱系的共享。据我们所知，DRA 等位基因多样性的发现高于以往在脊椎动物中观察到的水平。还发现了支持 DQA 基因座重复的证据。选择分析，根据基因区域内非同义与同义突变的相对速率（dN/dS）进行评估，表明大多数密码子位点是保守的，并受到纯化选择（dN <dS）的作用。然而，最有可能的进化密码子模型允许两个基因座的密码子位置的选择率存在差异，并在 DQA 上支持特定位点存在正选择的假设。
观察到遗传多样性升高和跨物种多态性支持了这些基因座可能受到平衡选择的结论。此外，在 DQA 上，抗原结合位点发生了正选择，这表明少数选择的残基可能在马科动物的免疫功能中发挥重要作用。在自然马科动物种群中进行的未来研究将有助于理解独特多样的 DRA 基因座的功能意义，并阐明维持这些 MHC 基因座多样性的机制。
