The major histocompatibility complex (MHC) is one of the most polymorphic gene families in the vertebrate genome, with natural selection actively promoting and maintaining variability. The exact mechanism/mechanisms responsible for these characteristics re-main unclear, but identifying them is fundamental to our understanding of host–pathogen dynamics. Using targeted crosses of the model Trinidadian guppy, a tractable parasite, and exposure-controlled infection trials, we show that novel MHC variants are associated with less severe infections. Uniquely, our experimental design separates novel variant advantage from other modes of selection and confounding variables, such as individual MHC variability and genomic background. We thus demonstrate a fundamental process driving evolution of the vertebrate immune system, which helps explain the unique features of MHC genes.
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