CheetahThe major histocompatibility complex is by far the most diverse region of vertebrate genomes; except when it isn’t. Since on the one hand it’s generally accepted that MHC genes are diverse in order to protect against pathogens, and on the other hand the precise mechanism driving diversity is controversial,1 it’s interesting to look at the species in which MHC is not particularly diverse. Are they particularly susceptible to pathogens? And is there an explanation for the lack of diversity?

I’ve mentioned a number of cases previously. Tasmanian Devils apparently have quite limited MHC diversity ,2 as do a number of other species including giant pandas,3 European beavers,4 Spanish ibex,5 and, perhaps most famously, cheetahs.

Most of these species are, as you can see, endangered. There are likely two important reasons for that: (1) Population bottlenecks lead to reduced genetic diversity, so endangered species (which have presumably been through a bottleneck relatively recently) are likely to have limited diversity; and (2) It’s easier to get funding to sequence the MHC from charismatic endangered species than from dirt-common starlings or what-not.

However, bottlenecks don’t entirely address the issue. I’ve previously mentioned the San Nicolas Island fox (Urocyon littoralis dickeyi), which has rather impressive MHC diversity despite undergoing drastic population bottlenecks within the past few hundred years.6

Although I believe the diversity at the MHC of these fox populations is still relatively low, it’s probably greater than some of the other populations I’ve mentioned here, such as the Tasmanian Devil, which have larger populations now and historically had more distant and less severe bottlenecks.

Cheetahs are the most famous example of an inbred population following a drastic population bottleneck; many people know that putatively-unrelated cheetahs can mutually tolerate skin grafts (a function of MHC similarity, of course),7 and lots of people also know that cheetahs are more susceptible to disease because of this limited diversity.

The problem with the latter “knowledge” is that as far I can find it’s not true — or at least, not demonstrated. It seems to be one of those circular things where the conclusion seems so obvious that it’s accepted with ridiculously inadequate evidence — whenever a cheetah gets sick, people nod wisely and point to the MHC, while when canine distemper wipes out half the lions in the Serengeti (leaving the cheetahs untouched)8 no one takes that as evidence for lion immunodeficiency. 9

Cottontop tamarinIn fact there’s ample evidence that populations with limited MHC diversity can do just fine out there. North American and European moose, 10 cotton-top tamarins, 11 and marmosets 12 have been claimed to have little MHC diversity. These species, like the cheetah, may indeed reflect limited populations a long time ago — moose apparently underwent a bottleneck around 10,000 years ago, about the same time as cheetahs; I don’t know about the other species — but the point is that no one is pointing to every sick moose and claiming that’s because of limited MHC diversity. What’s more, as the San Nicolas Island fox demonstrates, it’s possible to regenerate MHC diversity very fast — in hundreds rather than thousands of years; why didn’t cheetahs and moose do so? Probably because they didn’t need to, rather than couldn’t.

Limited MHC diversity is not an absolute barrier to species success. This should be pretty obvious, thinking about introduced species. There are over 100 million starlings in North America now, which arose from the 160 birds released just over 100 years ago in New York — how much MHC diversity could they possibly have? 13 Yet it was North American crows, not starlings, that were devastated by West Nile virus . Similarly, Australian rabbits, and rats around the world, have had huge populations arise from tiny numbers of founders, yet are not notorious for epidemics (except for artificially-introduced epidemics, in the case of Australian rabbits, and these are as remarkable for the rabbits’ resistance more than for their susceptibility).

So what’s the explanation? If pathogen pressure drives MHC diversity in almost all vertebrates, why do these vertebrates seem to do just fine with their limited diversity? Are these the exceptions that prove the rule, with hundreds of other introduced species disappearing because they didn’t have the right diversity? Are these species just the lucky ones, or just temporarily lucky and awaiting the right virus? I don’t know the answer, but if anyone has any ideas, let me know.

  1. Frequency-dependent selection or overdominant selection being the major two contenders; see here and links therein for more[]
  2. Siddle, H. V., Kreiss, A., Eldridge, M. D., Noonan, E., Clarke, C. J., Pyecroft, S. et al. (2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proc Natl Acad Sci U S A. []
  3. Zhu, L., Ruan, X. D., Ge, Y. F., Wan, Q. H., & Fang, S. G. (2007). Low major histocompatibility complex class II DQA diversity in the Giant Panda (Ailuropoda melanoleuca). BMC Genet, 8, 29.[]
  4. Babik, W., Durka, W., & Radwan, J. (2005). Sequence diversity of the MHC DRB gene in the Eurasian beaver (Castor fiber). Mol Ecol, 14(14), 4249-4257.[]
  5. Amills, M., Jimenez, N., Jordana, J., Riccardi, A., Fernandez-Arias, A., Guiral, J. et al. (2004). Low diversity in the major histocompatibility complex class II DRB1 gene of the Spanish ibex, Capra pyrenaica. Heredity, 93(3), 266-272.[]
  6. Aguilar, A., Roemer, G., Debenham, S., Binns, M., Garcelon, D., and Wayne, R. K. (2004). High MHC diversity maintained by balancing selection in an otherwise genetically monomorphic mammal. Proc Natl Acad Sci U S A 101, 3490-3494. []
  7. O’Brien, S. J., Roelke, M. E., Marker, L., Newman, A., Winkler, C. A., Meltzer, D. et al. (1985). Genetic basis for species vulnerability in the cheetah. Science, 227(4693), 1428-1434.[]
  8. Guiserix, Micheline, Narges Bahi-Jaber, David Fouchet, Frank Sauvage, and Dominique Pontier. 2007. The canine distemper epidemic in Serengeti: are lions victims of a new highly virulent canine distemper virus strain, or is pathogen circulation stochasticity to blame? Journal of the Royal Society 4, no. 17 (December 22): 1127-34.[]
  9. I should say that I’m not saying wild-animal veterinarians or zoo vets do this — these are relatively lay people who I have talked with over the years. However, I’ve also seen papers that blithely talk about cheetahs being “unusually susceptible” — and what does “unusually susceptible” mean, anyway? Compared to some other species? What would be “usual”? — to diseases, citing single cases in zoo cheetahs as evidence — which is utterly ridiculous. E.g. Munson, Linda, Laurie Marker, Edward Dubovi, Jennifer A. Spencer, James F. Evermann, Stephen J. O’Brien, et al. 2004. SEROSURVEY OF VIRAL INFECTIONS IN FREE-RANGING NAMIBIAN CHEETAHS (ACINONYX JUBATUS). J Wildl Dis 40, no. 1 (January 1): 23-31. []
  10. Mikko, S. & Andersson, L. (1995). Low major histocompatibility complex class II diversity in European and North American moose. Proc Natl Acad Sci U S A, 92(10), 4259-4263.[]
  11. Gyllensten, U., Bergstrom, T., Josefsson, A., Sundvall, M., Savage, A., Blumer, E. S. et al. (1994). The cotton-top tamarin revisited: Mhc class I polymorphism of wild tamarins, and polymorphism and allelic diversity of the class II DQA1, DQB1, and DRB loci. Immunogenetics, 40(3), 167-176.[]
  12. Antunes, S. G., de Groot, N. G., Brok, H., Doxiadis, G., Menezes, A. A., Otting, N. et al. (1998). The common marmoset: a new world primate species with limited Mhc class II variability. Proc Natl Acad Sci U S A, 95(20), 11745-11750.[]
  13. No one seems to have looked, actually, and it would be interesting to have some numbers on this.[]