Mouse lemur
Mouse Lemur. “MHC polymorphism in M. murinus is maintained through pathogen-driven selection acting by frequency-dependent selection”1

Is the major histocompatibility complex so diverse because of overdominance, frequency-dependent selection, or both?

This is part of a series that started with the observation of MHC diversity , discounted as causes high mutation frequency and maternal/fetal interactions , and suggested that mate choice (sexual selection) was not enough to account for the diversity by itself. That leaves us with two strong candidates for the cause of MHC diversity: overdominance, or frequency-dependent selection, or both. The question of which is most important hasn’t yet been definitively answered, and the story is too complex to address really properly in a single post.

What’s the difference between the candidates? According to the overdominance hypothesis, individual who carry more MHC alleles (that is, the individual’s MHC region carries as many different alleles as possible) are more fit (“heterozygote advantage”). According to the frequency-dependent hypothesis, individuals who have rare MHC alleles are more fit. Both hypotheses make biological sense, mathematical models suggest that both could lead to diversity,2 both have some support from field observation (see the picture at top for an example), and both are very difficult to test directly.

There is one major difference between the hypotheses: “A crucial difference between the two types of balancing selection is that overdominance predicts a stable polymorphism, whereas a polymorphism maintained by frequency dependence will be dynamic.” 3 In other words, “in the presence of overdominant selection polymorphic alleles (allelic lineages) may persist in the population for an extremely long time,”4 whereas in contrast “a rare old allele should have no such advantage5 and should disappear from the population by selection or genetic drift.”3

This difference — that alleles should appear and then disappear over time — has been used as an argument against frequency-dependent selection, because some MHC alleles are ancient. “Comparison of human and chimpanzee alleles reveals extensive sharing of polymorphisms, confirming that diversification is a slow process, and that much of contemporary polymorphism originated in ancestral primate species before the emergence of Homo sapiens.”6

Parham 1996 But it depends on your scale: “During the timeframe of mammalian evolution, the lifetimes of a functional class I locus are short and those of individual alleles even shorter.” 7

Even on a short scale, alleles appear and disappear at a great rate. My favourite example of this is the map on the right 8 (I liked it so much I scanned it, years ago; I don’t have access to the 1996 issues of Science on line. Click on the map for a larger version). This shows what happened to MHC diversity during the peopling of the Americas. You can see new alleles popping up down the migration route — but the key point I want to make is made by the authors in a different paper: “Although many new HLA-B alleles have been produced in Latin America, their net effect has been to differentiate populations, not to increase allele diversity within a population.” 9

In other words, rare old MHC alleles are not selected, but disappear, while rare new alleles are selected. This is consistent with the predictions of frequency-dependent selection than of overdominance, I think. But there are also lots of strong arguments for overdominant selection, some of which I’ll mention next time around.

  1. Schad, J., Ganzhorn, J. U., and Sommer, S. (2005). Parasite burden and constitution of major histocompatibility complex in the Malagasy mouse lemur, Microcebus murinus. Evolution Int J Org Evolution 59, 439-450.[]
  2. But “mathematical study alone cannot distinguish between this model [frequency-dependent selection – IY] and the overdominance model.” –Takahata, N., and Nei, M. (1990). Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124, 967-978. []
  3. Slade, R. W., and McCallum, H. I. (1992). Overdominant vs. frequency-dependent selection at MHC loci. Genetics 132(3), 861-864.[][]
  4. Takahata, N., and Nei, M. (1990). Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124, 967-978. []
  5. I believe, though, this is only true with one type of frequency-dependent selection — a pure “minority advantage” model, with no pathogen adaptation, doesn’t predict this. On the other hand, without pathogen adaptation the biological argument for this model is much weaker.[]
  6. Parham, P., Lawlor, D. A., Lomen, C. E., and Ennis, P. D. (1989). Diversity and diversification of HLA-A,B,C alleles. J Immunol 142, 3937-3950.[]
  7. Parham, P. (1994). The rise and fall of great class I genes. Semin Immunol 6, 373-382[]
  8. Parham, P., and Ohta, T. (1996). Population biology of antigen presentation by MHC class I molecules. Science 272, 67-74.[]
  9. Parham, P., Arnett, K. L., Adams, E. J., Little, A. M., Tees, K., Barber, L. D., Marsh, S. G., Ohta, T., Markow, T., and Petzl-Erler, M. L. (1997). Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 50, 219-232.[]