Diversity in fish: From Wellcome Images
Diversity in fish

Last week when I brought up the subject of MHC selection, I listed a number of possible explanations for the enormous polymorphism within the population. Let’s quickly brush aside the least likely candidates, so we can concentrate on the potential winners.

Quick review: The major histocompatibility complex region of the genome expresses proteins that are important for protection against parasites, and these proteins are sequence-specific — each allele offers the chance of protecting against a large, but not infinite, number of parasite proteins. The MHC region is also incredibly diverse in almost all vertebrate populations;1 for example, the human MHC region contains thousands of different alleles.

The question is: What kind of evolutionary forces drive this extraordinary diversity?

The list of possibilities includes two leading candidates: overdominant selection and frequency-dependent selection. Three other explanations that have been put forward are increased mutation rate at the MHC (most recently put forward by JoAnne, in the comments section here); maternal-fetal interactions; and sexual selection. I’ll treat sexual selection separately, even though it’s a distant third in the plausibility races. That leaves maternal-fetal interactions, and increased mutation rates to be eliminated here.

The idea behind the maternal-fetal interaction theory was that somehow, having an MHC that doesn’t match your mother’s improves fetal survival. Although there are a number of papers arguing both sides of this, the simple answer is that birds, amphibians, and fish — which don’t have fetal-maternal interactions at all — also show extreme diversity at the MHC region. For example, 43 MHC class II alleles were identifed among just 74 Lake Trout.2 It would take really special pleading to have this explanation work.

What about increased mutation rate? Raw mutation rates can be estimated by looking at the frequency of synonymous vs. non-synonymous changes in a coding region (dS vs. dN):

One early hypothesis … was the hypothesis that MHC loci have an unusually high mutation rate. DNA sequence data have made it possible to test this hypothesis rigorously. Because dS is expected to reflect the mutation rate, dS values for MHC genes can be compared with those of other genes to assess the comparative magnitude of the mutation rate at MHC loci. Such comparisons have shown that the mutation rates at MHC loci are below average for mammalian genes.3 [My emphasis: IY]

Similarly, what about some special form of mutation at the MHC?

A more recent version of essentially the same hypothesis held that MHC polymorphism was enhanced by interlocus recombination (gene conversion). … However, gene conversion is expected to be an essentially random process; thus it cannot explain the very specific pattern of dN > dS in the PBR4 codons that characterizes MHC loci. 5

In other words, the DNA sequence strongly argues that there’s no increased mutation at the MHC. Rather, some of those mutations that do arise are strongly positively selected.

We’re left with two major hypotheses, plus sexual selection, as to the source of that selection.

  1. And since only vertebrates have an MHC region, that’s not a very limiting qualifier[]
  2. Dorschner, M. O., Duris, T., Bronte, C. R., Burnham Curtis, M. K., and Phillips, R. B. (2000). High levels of MHC class II allelic diversity in lake trout from Lake Superior. J Hered 91, 359-363.[]
  3. Hughes, A. L., and Yeager, M. (1998). Natural selection at major histocompatibility complex loci of vertebrates. Annu Rev Genet 32, 415-435. []
  4. “PBR”: Peptide-binding regions — regions in the MHC proteins that are functionally critical, and that are much more likely to be varies than other regions.[]
  5. Hughes and Yeager again.[]