Searching for heroic MHC genes in the fight against fungal takeover

Frogs have been disappearing all around the world in the past few decades. The reasons for these declines have been complex, but one of the biggest players is a nasty disease with an even nastier-sounding name: chytridiomycosis.

I don’t know much about fungus, but I’m pretty sure this is typical chytrid morphology. Artwork via Ethan Kocak, author of The Black Mudpuppy

Batrachochytrium dendrobatidis (Bd) is the particular fungus responsible for chytrid in frogs, and while hundreds of amphibian populations (and species!) have already been lost to this pathogen, there are many other populations that are doing just fine*.

So chytrid is a big problem, but predicting susceptibility to chytrid in natural populations is tricky business. A major focus of this effort is understanding how immunity is conferred to amphibians populations, and this process starts with the heroic genes that are most responsible for fighting chytrid: those of the major histocompatibility complex (MHC).

Conservation biologists hope that immunity to Bd is being selected for quickly, but the evolution of host resistance has only been recently addressed. Most recently, Anna Savage and Kelly Zamudio took a big step by taking measurements of positive selection for immunity out of the laboratory and into the field by analyzing MHC genes in wild populations of frogs with ongoing chytrid infections.

The authors collected tissue from recently-deceased and live Lowland Leopard Frogs  (L. yavapaiensis) across Arizona and assembled three types of genetic data: 14 microsatellite loci, class II MHC alleles, and collapsed “supertypes” constructed of MHC alleles with known immune functions.

One supertype (ST1) was highly associated with mortality and three times more likely to be present in deceased animals. Most other supertypes were not associated with survival, and curiously neither were heterozygotes (which has been previously indicated in the lab studies).

However, one supertype (ST4) stood out from the rest by being highly associated with survival, but this recently-derived clade is still new on the scene and isolated to a single population.

Figure 3 from Savage and Zamudio (2016)

Figure 3 from Savage and Zamudio (2016). MHC supertypes and associated alleles frequencies across eight populations of Lowland Leopard Frog

Measures of positive selection (dN/dS ratios) indicated that 35% of the MHC codons fit a model of positive selection, but these signals of positive selection could certainly be related to changes in population demography. However, the authors go on to rule this out using the microsatellite data, which shows a discordance between MHC and neutral genetic differentiation.

The ST4 supertype? You guessed right: it showed some of the strongest signal for positive selection.

Together, these results paint a picture of selection on standing variation in MHC genes of Lowland Leopard Frogs. Those populations with MHC alleles associated with chytrid susceptibility were quickly decimated by the pathogen, while more resistant populations show indications of selection on recently-derived MHC supertypes.

One of the most important implications of this work is not necessarily good news for the amphibian fight against chytrid. The MHC dynamics among populations are highly contextual, with some populations harboring alleles associated with disease susceptibility surviving and others with resistance-associated alleles disappearing quickly (see figure 3 above).

Recent positive selection on MHC codons and strong MHC allelic associations with Bd survival may therefore be modest drivers of overall population genetic change compared with forces such as drift and population bottlenecks in a species facing ongoing habitat loss and competition from invasive species

At least in these frogs, there is no MHC superhero saving the day quite yet. But Savage and Zamudio might be documenting an origin story in the making.


*This type of “fine”. As in, only stressed out by habitat loss, invasive species, and over-exploitation.

Savage, A. E., & Zamudio, K. R. 2016. Adaptive tolerance to a pathogenic fungus drives major histocompatibility complex evolution in natural amphibian populations. Proc. R. Soc. B, 283: 20153115


About Rob Denton

I'm a Postdoctoral Fellow in the Department of Molecular and Cell Biology at UConn. I'm most interested in understanding the evolutionary/ecological consequences of strange reproduction in salamanders (unisexual Ambystoma). Topics I'm likely to write about: population and landscape genetics, mitonuclear interactions, polyploidy, and reptiles/amphibians.
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