Mickey and Minnie Mouse Inbreeding is a bad thing, genetically, and almost all species have ways of avoiding it. One way of avoiding inbreeding is to recognize individuals who are related to you, and not mate with them. That’s not so difficult when you’re a big-brained, highly social animal like a wolf, or a human, who have lots of brain devoted to issues of who is who and where they stand in a group. It’s a little more challenging for mice, though.

How do mice distinguish individuals? How do they determine relatedness? For the past 30 years1, the answer has been MHC: Mice select mates that differ at the major histocompatibility complex.

When I talked about this last fall, in the context of MHC diversity, I was rather skeptical that mating preference was the major driver of MHC diversity, quoting Piertney and Oliver:2

A lack of repeatability of several studies, and an apparent plasticity in response across experiments, questioned the robustness of the data, and the general relevance of mate choice as a primary driver of MHC diversity.

It didn’t occur to me to question the fundamental observation that MHC is even involved in distinguishing relatedness.

MHC seemed like a logical candidate for distinguishing individuals and determining relatedness because of its great polymorphism: in an outbred population, the MHC is so variable that few individuals are identical across the region, and individuals with similar MHC are most likely related to some extent. 3 And in fact, mice clearly can distinguish differences in MHC type by smell. 4 However, that doesn’t mean that mice recognize different individuals, or determine relatedness, by the differences in MHC. A couple of papers from Jane Hurst’s group in the past year suggest that in fact they do not. 5,6

Hurst’s group tried to move away from the artificial situation of highly-inbred lab mice, using instead wild mice breeding in semi-natural conditions. They find that under these conditions, mice do (as expected) avoid breeding with close relatives. But this incest avoidance doesn’t correlate with MHC type. Instead, there was a strong correlation with MUP type.

What, you cry, is MUP? These are “major urinary proteins”, which are known to be highly polymorphic in wild mouse populations — though not in lab mice — and which are also known to be very important in scent marking. Indeed, the only known function of MUPs is in scent marking. The lack of variability of MUPs in lab mice might have led to the use of MHC as markers instead in those studies, but in Hurst’s study MHC didn’t contribute to incest avoidance:

By contrast, MUP sharing had a strong and highly significant effect on the likelihood of successful mating (Table 1: model 3, p = 0.005; Figure S1). Specifically, there was no deficit when only one MUP haplotype was shared, but there were many fewer matings between mice that shared both MUP haplotypes (complete match) than expected under random mating conditions (Table 1: model 4, p < 0.002). … Mice thus avoid mating when shared MUP type reliably indicates very close relatedness.

Rodentia:Johnson's household book of nature, containing full & interesting descriptions of the animal kingdom. (New York : Johnson, c1880) Craig, Hugh, Editor.Incidentally, this is consistent with a recent paper from Peter Overath and Hans-Georg Rammensee.7 They looked for influences on urine odor in mice (try writing to your Mom and tell her that’s what you’re doing for your living, by the way, and see how long it takes before she starts talking about your cousin the investment banker) and didn’t find any influence of MHC:

… within the limits of the ensemble of components analysed, the results do not support the notion that functional MHC class I molecules influence the urinary volatile composition.

(However, there are non-volatile as well as volatile components to urine odor, so this isn’t definitive.)

MUPs are highly polymorphic in wild domestic mice, but are non-polymorphic (actually, basically non-existent) in humans. (In fact, MUPs are non-polymorphic even in Mus macedonicus, a mouse species closely related to M. musculus domesticus, but a species that doesn’t need as careful management of increeding because individuals normally disperse more. ) That means that MUPs can’t be a universal mechanism for inbreeding avoidance, so the work on MHC-linked mate choice in other species might still be valid. However, I still think the work on MHC and mate selection in humans is mostly pretty crappy unconvincing. Since the work in humans leans heavily on the assumption that MHC is important in mate selection in mice, that work can be looked at with an even more jaundiced eye now, I think.

  1. Yamazaki, K., Boyse, E. A., Mike, V., Thaler, H. T., Mathieson, B. J., Abbott, J., Boyse, J., Zayas, Z. A., and Thomas, L. (1976). Control of mating preferences in mice by genes in the major histocompatibility complex. J Exp Med 144, 1324-1335[]
  2. Piertney, S. B., and Oliver, M. K. (2006). The evolutionary ecology of the major histocompatibility complex. Heredity 96, 7-21.[]
  3. A review is here: Adv Genet. 2007;59:129-45. Genetic basis for MHC-dependent mate choice. Yamazaki K, Beauchamp GK.[]
  4. For example, Carroll, L.S., Penn, D.J., and Potts, W.K. (2002). Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues. Proc. Natl. Acad. Sci. USA 99, 2187–2192.[]
  5. Sherborne, A., Thom, M., Paterson, S., Jury, F., Ollier, W., Stockley, P., Beynon, R., Hurst, J. (2007). The Genetic Basis of Inbreeding Avoidance in House Mice. Current Biology, 17(23), 2061-2066. DOI: 10.1016/j.cub.2007.10.041[]
  6. The Genetic Basis of Inbreeding Avoidance in House Mice
    Amy L. Sherborne, Michael D. Thom, Steve Paterson, Francine Jury, William E.R.
    Ollier, Paula Stockley, Robert J. Beynon, and Jane L. Hurst. Curr Biol. 2007 December 04; 17(23): 2061–2066. doi: 10.1016/j.cub.2007.10.041 []
  7. Röck F, Hadeler K-P, Rammensee H-G, Overath P (2007) Quantitative Analysis of Mouse Urine Volatiles: In Search of MHC-Dependent Differences. PLoS ONE 2(5): e429. doi:10.1371/journal.pone.0000429.[]