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.
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.
- 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[↩]
- Piertney, S. B., and Oliver, M. K. (2006). The evolutionary ecology of the major histocompatibility complex. Heredity 96, 7-21.[↩]
- A review is here: Adv Genet. 2007;59:129-45. Genetic basis for MHC-dependent mate choice. Yamazaki K, Beauchamp GK.[↩]
- 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.[↩]
- 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[↩]
- 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 [↩] - 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.[↩]
I am glad to read this, as I have always had problems believing in MHCs playing a role in mate choice (but then, I have problems believing in a lot of things that are considered established knowledge).
This is not really my area, so I don’t have convincing scientific arguments. Nevertheless, my gut feeling says that MHCs are not very well positioned for doing this job. Polymorphic they are, but that’s about it. MUPs look much better to me, but still they can only be part of the story. The whole business of selecting mates by smell should have two components, one of them emitting the odorant, the other one detecting it. I would naively assume that the emitting component should be secreted (protein, peptide, or small molecule), while the detecting ‘receptor’ should at least have one component attached to a cell – for signaling purposes. One could imagine that the MUPs, as typical lipocalins, have an intermediate role by detecting a specific subset of small molecules and transporting or presenting them to some downstream component.
Any idea why posting a comment at your site works for me only if I do not provide a website? Otherwise, I get an empty page with a complicated URL saying something about OpenID, but the comment never appears on the blog. Even worse, when going back to the previous page, the comment is gone!
The whole business of selecting mates by smell should have two components, one of them emitting the odorant, the other one detecting it.
Well, one very intriguing observation (I mentioned it in passing way back here) is the odorant detectors that are members of the MHC class I family. I would have to go back to some of the MHC/mate detection papers to see if anyone has ever knocked out beta-2 microglobulin, found that mate detection is screwed up, and concluded that it was the odorant emission that was messed up rather than the detector. Just speculating, but it’s interesting.
Any idea why posting a comment at your site works for me only if I do not provide a website?
Probably something screwy about the OpenID plugin, which I’ve just disabled; I don’t think it’s ever done any good.
This is a fascinating topic. Can’t say I’ve looked at the paper in any detail, but seems humans can also smell MHC as well…Paternally inherited HLA alleles are associated with women’s choice of male odor
Yeah, as I said, the papers on MHC and mate selection in humans have been offered up at fairly regular intervals for years now, but they’re mostly fairly low-quality — small sample size, poor experimental, design, marginal statistical significance. The main reason they’ve been accepted at all (aside from the expected titillation value of smelly T-shirts and sex) is the apparent support from lab animals, and if that’s gone then the human papers are pretty shaky, I think.
There are a number of other species where an apparent link between MHC and mate choice has been demonstrated, especially sticklebacks — some of those studies looked rather more solid, but I am not an expert in the field.
Seems like you have disabled a little more than just the OpenID plugin…
That’s what happens when I get halfway through tweaking plugins and then my 4-year-old smashes a glass vase all over the floor.
Try it now.
One could imagine that the MUPs, as typical lipocalins, have an intermediate role by detecting a specific subset of small molecules and transporting or presenting them to some downstream component.
Oh, and I forgot to note that this is exactly true — MUPs are known to transport volatiles (pheremones) in the urine. For example, from Stopka, P., Janotova, K., and Heyrovsky, D. (2007). The advertisement role of major urinary proteins in mice. Physiol Behav 91, 667-670 (a reference that was in an earlier version of this post but that vanished somewhere along the road):
Mouse major urinary proteins (MUPs) are known to carry volatile substances and protect them during their passage from the liver, through the kidneys into the urine.
Some of the MUPs are also found in nasal tissue; because of their ability to bind pheremones they may be receptors as well, though I am not at all sure about the physiology:
Utsumi, M., Ohno, K., Kawasaki, Y., Tamura, M., Kubo, T., and Tohyama, M. (1999). Expression of major urinary protein genes in the nasal glands associated with general olfaction. J Neurobiol 39, 227-236.
Altogether the MUPs are more biologically plausible candidates for scent-based recognition than is MHC.
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