Abstract: The major histocompatibility complex (MHC) is a core part of the adaptive immune system. As in other vertebrate taxa, it may also affect human chemical communication via odour-based mate preferences, with greater attraction towards MHC-dissimilar partners. However, despite some well-known findings, the available evidence is equivocal and made complicated by varied approaches to quantifying human mate choice. To address this, we here conduct comprehensive meta-analyses focusing on studies assessing: (i) genomic mate selection, (ii) relationship satisfaction, (iii) odour preference, and (iv) all studies combined. Analysis of genomic studies reveals no association between MHC-dissimilarity and mate choice in actual couples; however, MHC effects appear to be independent of the genomic background. The effect of MHC-dissimilarity on relationship satisfaction was not significant, and we found evidence for publication bias in studies on this area. There was also no significant association between MHC-dissimilarity and odour preferences. Finally, combining effect sizes from all genomic, relationship satisfaction, odour preference and previous mate choice studies into an overall estimate showed no overall significant effect of MHC-similarity on human mate selection. Based on these findings, we make a set of recommendations for future studies, focusing both on aspects that should be implemented immediately and those that lurk on the far horizon. We need larger samples with greater geographical and cultural diversity that control for genome-wide similarity. We also need more focus on mechanisms of MHC-associated odour preferences and on MHC-associated pregnancy loss.
4. Discussion
(a) Meta-analyses
A recent meta-analysis on MHC-associated mate choice concluded that there is a consistent preference for MHC-heterozygous individuals [20]. By contrast, there was no systematic preference for MHC-dissimilarity. Here, we provide the results of further meta-analyses primarily focusing on genomic studies and relationship satisfaction, together with updated meta-analyses on odour preferences and human mate selection studies. Overall, the genomic studies show no significant association between MHC-similarity and mate choice in actual couples nor in mate preferences. However, we also found that the effect of MHC-similarity is independent of the genomic background. The overall effect of MHC-similarity on sexual satisfaction was not significant, but we found a negative association between MHC-similarity and sexual satisfaction in non-HC using women. Nevertheless, several lines of evidence for publication bias in studies investigating MHC-similarity and sexual satisfaction suggest that these results should be interpreted with caution. Furthermore, we found no significant effect of MHC-similarity on odour preferences among currently available studies. Finally, combining each of the effect sizes analysed above with previously extracted effect sizes for mate choice among couples into an overall estimate, showed no overall significant effect of MHC-similarity on human mate selection.
(b) Near horizons: issues arising from the meta-analyses
Our meta-analyses raise a number of pressing outstanding issues that should, and can be, addressed in future studies. Perhaps the strongest conclusion one can draw from the available data is that our knowledge is patchy across different populations. Even a brief inspection of figure 1 shows that most studies are based on populations of European ancestry; there is a notable absence or near-absence of data from two of the largest populations, China and India, from smaller populations in Oceania and Sub-Saharan Africa, and from small-scale societies. Why is this important? First, individual populations vary considerably in cultural norms regarding the level of consanguinity [52]. In addition, while all populations show some amount of admixture, this tends to be higher in large-scale populations such as those from Western European or Eastern Asian complex societies [53]. Owing to high MHC polymorphism, mating with almost any unrelated individual would probably lead to a sufficient level of dissimilarity. It is thus possible that humans, as in other species [54–56], tend to avoid individuals with high MHC-similarity, but show no systematic preference beyond a certain threshold (see [28] for a similar suggestion). However, large-scale populations are a relative novelty in human evolutionary history [57]; it is therefore of key importance to focus on small-scale societies with comparatively higher levels of inbreeding, which better reflect likely population structure during most of human evolution. To our knowledge, the only available study from small-scale societies comes from South Amerindian couples [58], which showed they were not significantly MHC dissimilar compared to random pairing. In that study, however, MHC typing was of relatively low sensitivity (serotyping of HLA-A and -B loci to the level of two-digit allele groups, no class II loci were recorded), sample size was too small to detect selection below a selection coefficient s = 0.45, and there is cultural promotion of cross-cousin marriages in some tribes [58].
Most previous studies have specifically targeted the MHC region, assuming that their findings are a consequence of selective processes in that region. While this is a reasonable assumption in view of MHC polymorphism and allele-specific associations with some diseases [8–11], apparent MHC-similar mate selection might be an epiphenomenon of more general population stratification (e.g. positive assortment [59]). In support of this, a recent meta-analysis found that MHC-similarity in couples was observed in ethnically heterogeneous, but not homogeneous, populations [20]. However, our new analysis of studies that control for genomic similarity shows that MHC-dissimilarity among couples is independent of genome-wide similarity (although the association is positive). In addition, the positive relationship detected between MHC effects (spouses versus permuted pairs) and the extremeness of the MHC within spouses indicates that observed MHC effects are relatively independent of socio-demographic processes that would affect spouses genome-wide. For example, if spouses were highly dissimilar at the MHC compared to randomly assigned mates, but had levels of MHC-similarity in line with the rest of the genome, we may conclude that the MHC does not play an independent role in mate choice and mate choice may be for inbreeding avoidance. But this was not what we observed.
The overall effect of MHC-associated mate selection was not significant but was restricted to some populations. In other words, we may observe MHC-associated preferences in some populations but not in others. For example, we found that Israeli individuals showed a significant preference for mates with higher levels of MHC-similarity. Dandine-Roulland et al. [29] contributed one of the three effect sizes to this result, and using principal component analysis detected genetic stratification, with clusters of samples lying between European and Middle Eastern populations. The two other effect sizes contributed by Israeli et al. [51] came from unmarried couples to determine paternity status and from married couples undergoing infertility treatment. The study did not specifically detail testing for population stratification, and it is likely that a random sample of the population would capture multiple ethnic groups, as Dandine-Roulland et al. [29] demonstrated. Thus, MHC-similarity preferences most likely reflect social homogamy in a genetically heterogeneous population. The Swiss individuals' significant preference for MHC-dissimilar odours was observed in the dataset without HC-using individual effects and included both female and male odour preferences. These MHC-dissimilar preferences might be related to relatively low levels of genetic variation and were specifically present in German-speaking cantons, perhaps as a consequence of geographical isolation in Alpine valleys [60]. By contrast, studies based on other European populations (such as in neighbouring Germany) did not report MHC-dissimilar preferences, emphasizing the need for investigations across diverse populations which differ in levels of genetic variation. For example, cultural practices vary related to body care. If body odour is a primary source of information about one's MHC profile, then practices such as armpit hair shaving and use of extrinsic fragrances or deodorants may impact perceptibility of MHC-associated odours. Although there is conjecture that fragrance selection may be linked to a wearer's own MHC [61,62], perhaps as a mechanism to complement body odour rather than cover it [63], we do not yet know how such cultural effects influence odour perceptibility and MHC-associated preference. Further, in cultures which idealize an ‘odourless human body’, it is considered inappropriate to overtly smell other people; under such circumstances, the effect of MHC-associated preferences might go unrealized. Clearly, our understanding of the interplay between cultural and biological evolution is far from complete, and MHC-associated mate choice is no exception.
Many cultures also practice various types of positive assortment such as ethnic, socio-economic, religious, and caste-based endogamy. Even within a single culture, mate choice is a multidimensional process based on a set of preferences for various traits which might not be linked to MHC, such as physical appearance, socio-economic status, personality, attitudes, age and many others [64,65]. Each of these may be prioritized over genotypic factors [66], including MHC. Furthermore, if positive assortment occurs for any trait with a genetic component, even subtle assortment on such traits might interfere with MHC-associated preferences.
Beyond actual mate choice, it remains possible that MHC-associated preferences exert effects on the quality of resulting relationships. Indeed, in a study of 48 couples, Garver-Apgar et al. [22] found that more MHC-similar couples report relatively lower sexual satisfaction. Subsequent investigations have recorded considerably larger sample sets [67,68]. Here, we quantitatively assessed these studies for a possible link between MHC-similarity and sexual satisfaction. The overall effect was not significant. However, in the subset of women not using HC, there was a negative association between MHC-similarity and sexual satisfaction: couples sharing fewer HLA alleles experienced greater sexual satisfaction. This pattern of results is consistent with the studies by Wedekind et al. [18] who found odour preferences for MHC-dissimilarity only in women not using HC, and by Roberts et al. [69,70] who report higher sexual satisfaction in women who did not use HC when they met their current partner. Nevertheless, the robustness of the HC-associated preferences was neither confirmed by a previous meta-analysis [20] nor in our updated analysis. There is another reason why the link between MHC-similarity and sexual satisfaction should be interpreted with extreme caution. The meta-analysis on relationship satisfaction found three different types of evidence for publication bias. First, there was a significant asymmetry in a funnel plot suggesting missing studies with a negative outcome, particularly those with small effect sizes. Second, there was a temporal effect suggesting the unequal distribution of the effect sizes over time; specifically, the initial study [22] found a considerably stronger effect than subsequent studies. Finally, studies with larger samples (i.e. having a higher power to detect possible effects) show significantly smaller effect sizes.
(c) Far horizons on major histocompatibility complex-associated mate choice
Beyond those issues raised above, we believe there are two further matters that require significant attention in the longer-term. The first of these concerns the generation of MHC-associated odours. Understanding this may be of fundamental interest in itself, but a clearer picture of the underlying mechanisms may also clarify how some cultural and contextual factors (e.g. fragrance use) affect odour variability. Several hypotheses have been proposed relating to interactions between MHC molecules and skin microflora, which produces volatile compounds that can subsequently be perceived. However, most evidence supports an idea that body odour is affected by antigen peptides bound by specific MHC molecules. It was first shown in mice that these peptides can be perceived by the vomeronasal organ [71]; however, subsequent research shows that the main olfactory system can perceive MHC peptide ligands via the olfactory epithelium [72]. MHC peptide ligands can be detected in mouse urine, although at very low concentration [73]. Evidence extends beyond mice, as sticklebacks prefer water enriched with MHC-dissimilar peptides [74]. So far, only one study addressed this mechanism in humans [75]. Two commercially available peptides were added to body odour samples, and neurophysiological responses were recorded using functional magnetic resonance imaging while participants attempted to recognize their own odour. The results showed a higher preference for odour samples enriched with peptides corresponding to the MHC of the smeller and activity in brain areas related to self-recognition. However, it is not clear whether the self-recognition paradigm can be simply generalized to mate preferences. More importantly, the study was criticized for not providing an explanation for the transduction mechanism, as peptide molecules are involatile and considerably larger than molecules usually perceived by smell [73,76,77]. Furthermore, it is also not clear whether the MHC-associated peptides are commonly present in human axillae or more generally on human skin.
A second area which requires more attention is the nature of potential selective benefits arising from MHC-associated mate choice. While it is usually assumed that MHC-preferences are a consequence of infection-driven selection, it might be alternatively (or additionally) driven by the probability of successful pregnancy. A foetus expresses paternal alloantigens which must be tolerated by the maternal immune system. It has been proposed that MHC allele-sharing between father and mother may lead to insufficient stimulation of the maternal immune system by paternal antigens—a factor that was expected to be important for maternal tolerance and inflammatory immune response—and thus decrease the chance of successful implantation [78]. Several studies suggest that MHC allele-sharing is associated with recurrent pregnancy loss (RPL) [79,80], with a recent meta-analysis indicating that HLA-B and -DR are especially important [81]. However, these results should be viewed with caution because many studies used serological genotyping resolving only to allele groups, which may miss related alleles that are functionally different [82]. More critically, classical MHC class I and II proteins (except for HLA-C) are not expressed on the trophoblast, a part of conceptus which subsequently develops into the embryonic part of the placenta and is in direct contact with the maternal immune system. Researchers have, therefore, recently focused on classical HLA-C and non-classical MHC class Ib, which are expressed on the trophoblast. In contrast to previous studies, it was reported that a mismatch, i.e. not sharing, at HLA-C*07 between mother and father was related to a higher risk of RPL [83]. These authors also observed a higher incidence of HLA-C antibodies in RPL patients than in the controls. There is a growing body of evidence showing that HLA-E, -G, and to some extent also HLA-F, all play a key role in immunotolerance of the foetus by the maternal immune system in general and uterine NK cells in particular (for a review, see [3]). Some studies report higher RPL in women with the HLA-E*101 allele [84], although others find no difference in HLA-E polymorphism between controls and couples with RPL [85,86]. Most studies on non-classical MHC Ib polymorphism and its role in pregnancy disorders focused on HLA-G polymorphism. For example, it was reported that a 14 bp insertion HLA-G allele is associated with a smaller placenta and higher probability of RPL [87], although this may be restricted to cases with three and more abortions [88]. In summary, there appears to be some evidence that couples sharing alleles at HLA-B and -DR loci are at higher risk of reproductive failure. Although these genes are not expressed on the trophoblast, this might arise through linkage disequilibrium with other functionally important MHC genes. Moreover, there is inconsistency across studies in both the association between HLA-G and -E polymorphism and reproductive failures, perhaps partly owing to factors such as variation in the diagnosis of the RPL. More importantly, most existing studies on MHC polymorphism and reproductive problems focused solely on RPL, but MHC polymorphism might affect pregnancy success much earlier as HLA-C and -G expression can be detected even before implantation [89,90]. Because a vast majority of unsuccessful early pregnancies are not detected, this may, in turn, bias the results of studies that rely solely on RPL (i.e. recognizable spontaneous miscarriage).
(d) Suggestions for future studies
Above, we have discussed in detail the current state of knowledge on MHC-associated mate choice in light of results from our meta-analysis, that should inform approaches in the immediate future. We also commented on two important wider and relatively unexplored perspectives that lurk on the far horizon of this area of inquiry. In light of these, we here outline some recommendations for future work that we hope will help to ultimately clarify the extent to which MHC influences human mating. The suggestions (i–iii) highlight methodological issues, (iv–vi) focus on population- and culture-related questions, and (vii–x) stress several associated issues such as developmental and mechanistic questions.
| (i) |
Researchers should always perform a priori power analysis to obtain a sufficient sample size (see also [91]). Power analysis is becoming a standard procedure in other fields of behavioural research, but it is particularly needed here owing to both extreme variability in MHC genes and what appear to be, at best, small effect sizes.
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| (ii) |
To provide more complex insights, future studies should control for genome-wide similarity. The same applies to studies on MHC-heterozygosity. Genomic studies further allow assessment of the overall level of inbreeding in the given population. This is an important issue as MHC-associated mate choice might play a role only in relatively inbred populations.
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| (iii) |
Researchers should test for specificity of the MHC region. As was discussed above, without controlling for genome-wide level of similarity/heterozygosity, we cannot decide whether the observed effects are specific to the MHC region or whether we are dealing with more general phenomena.
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| (iv) |
We urgently need more studies on populations of non-European descent, and particularly those with a relatively high level of inbreeding (e.g. from small-scale societies).
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| (v) |
We need more cross-cultural comparisons assessing how shared cultural practices affect MHC-associated preferences. These include marriage practices such as various forms of endogamy.
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| (vi) |
In any study, researchers should obtain and clearly document detailed information about interindividual differences in cultural practices of the studied population, as some practices may interfere with MHC-associated effects. These include HC use and personal hygiene practices such as fragrance use (see also [92] for a similar proposal).
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| (vii) |
We need to distinguish between a threshold-based avoidance of very similar individuals and a fluid preference for the most dissimilar individuals.
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| (viii) |
Currently, there is not, to our knowledge, a single study focusing on the development of MHC-associated preferences. Therefore, we do not know when in ontogeny preferences might form and how family structure affects the development of these preferences. Rodent studies show that cross-fostering tends to reverse MHC-associated preferences [93], thus similar phenomena might be expected in humans. For instance, studies with adoptive families might be particularly informative.
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| (ix) |
We need studies testing possible mechanisms of MHC-associated preferences. These include bioassay studies testing the presence and abundance of the MHC peptide ligands. Similarly, studies testing effect of the MHC peptide ligands in the context of mate choice are of primary importance.
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| (x) |
Finally, we should link research on MHC-associated mate choice and research on MHC-associated pregnancy loss. The two areas have to date been studied separately; however, they may jointly provide key insights into this complex area of human reproduction. Such research may also examine links between pregnancy loss and infertility with the prevalence of cultural practices (e.g. fragrance use) that may have disrupted MHC-associated mate preferences at the beginning of the relationship.
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