Divergent MHC alleles in domesticated sheep

I know, what an exciting headline!

I’ve written quite a bit about the origins of domesticated cattle and introgression among the species of wild cattle giving rise to the current pattern of genetic diversity. I’m keeping track of that area because the process of domestication and subsequent interaction of domesticates with their wild relatives provide one kind of natural model for the interaction of ancient human groups such as the Neanderthals. We used these examples in our 2006 paper two-s.

Cattle have been a convenient example because there has been a lot of genetic work on them, and they have multiple wild species that diverged early in the Pleistocene. But other domesticates are also intense targets of sequencing and genome discovery, and as we understand more about their variation, we are beginning to find interesting patterns. Going through my notes today I found an interesting paper on sheep MHC polymorphisms Ballingall:2010:

Trans-Species Polymorphism and Selection in the MHC Class II DRA Genes of Domestic Sheep
Highly polymorphic genes with central roles in lymphocyte mediated immune surveillance are grouped together in the major histocompatibility complex (MHC) in higher vertebrates. Generally, across vertebrate species the class II MHC DRA gene is highly conserved with only limited allelic variation. Here however, we provide evidence of trans-species polymorphism at the DRA locus in domestic sheep (Ovis aries). We describe variation at the Ovar-DRA locus that is far in excess of anything described in other vertebrate species. The divergent DRA allele (Ovar-DRA*0201) differs from the sheep reference sequences by 20 nucleotides, 12 of which appear non-synonymous. Furthermore, DRA*0201 is paired with an equally divergent DRB1 allele (Ovar-DRB1*0901), which is consistent with an independent evolutionary history for the DR sub-region within this MHC haplotype. No recombination was observed between the divergent DRA and B genes in a range of breeds and typical levels of MHC class II DR protein expression were detected at the surface of leukocyte populations obtained from animals homozygous for the DRA*0201, DRB1*0901 haplotype. Bayesian phylogenetic analysis groups Ovar-DRA*0201 with DRA sequences derived from species within the Oryx and Alcelaphus genera rather than clustering with other ovine and caprine DRA alleles. Tests for Darwinian selection identified 10 positively selected sites on the branch leading to Ovar-DRA*0201, three of which are predicted to be associated with the binding of peptide antigen. As the Ovis, Oryx and Alcelaphus genera have not shared a common ancestor for over 30 million years, the DRA*0201 and DRB1*0901 allelic pair is likely to be of ancient origin and present in the founding population from which all contemporary domestic sheep breeds are derived. The conservation of the integrity of this unusual DR allelic pair suggests some selective advantage which is likely to be associated with the presentation of pathogen antigen to T-cells and the induction of protective immunity.

That probably deserves more thought and explanation that I can give it right now. As the authors point out in the paper, sheep domestication was a complicated process:

The complex origin of domestic sheep is apparent from the presence of at least five distinct mitochondrial lineages [20], some of which cannot be traced to a wild ancestor [24], [25]. This diversity is likely to originate from geographically isolated subspecies of wild sheep that have hybridised as a result of human migrations over the 810 millennia since the initial domestication events in the Near East and Asia [26][28]. Frequent hybridization events are likely to have occurred between domesticated and local wild populations providing the high levels of MHC diversity evident in present day domestic populations as well as a degree of resistance to endemic disease and adaptation to local environmental conditions [29].

Their interpretation of an ancient selective balance, retained in domesticated sheep from very distant common ancestors with oryx, probably is the most likely scenario. But I think this provides a nice example of how difficult it is to tell ancient balanced polymorphisms apart from relatively recent hybridization. That’s a problem that we continue to face with interpreting human and Neandertal genetic variation.

Also the case illustrates how important is the mixture of different wild populations in the origin of domesticates. Even if a wild population makes up a very small fraction of the genetic heritage of the current domesticated species, one or more adaptive loci from that population may nevertheless be very important to the survival and success of the later species.

Genes don’t care where they came from, and their function is not irrevocably marked by their origin.