The presence of sex differences in social cognition is controversial; these authors found no significant sex differences in most of social cognition tasks; conversely, women reported higher scores on empathy

Social cognition and sex: Are men and women really different? Marialaura Di Tella, Francesca Miti, Rita B. Ardito, Mauro Adenzato. Personality and Individual Differences, Volume 162, 1 August 2020, 110045. https://doi.org/10.1016/j.paid.2020.110045

Highlights
• The presence of sex differences in social cognition is controversial.
• Several social cognition measures were administrated to 210 healthy participants.
• Participants were equally divided between men and women.
• No significant sex differences were found in most of social cognition tasks.
• Conversely, women reported higher scores on empathy than men.

Abstract: Social cognition includes the ability to represent other people's intentions and beliefs, and the ability to share and recognise the emotions of others. Here, the main aim was to assess the possible presence of sex differences across four aspects of social cognition: (1) recognition of dynamic facial expressions; (2) representation of other people's mental states (both affective and cognitive Theory of Mind, ToM); (3) empathy; (4) identification and regulation of one's own emotions. Measures assessing social cognition were administrated to two hundred ten participants equally divided between men and women. Results showed no significant sex differences in affective and cognitive ToM, in the recognition of emotional facial expressions (with the exception of anger: women were more accurate than men), and in the ability to identify and regulate one's own emotions. A different result was found for empathy, with women reporting higher scores than men. No significant differences between women during follicular vs. luteal phase of menstrual cycle for all the social cognition measures were found. These results are discussed in light of the existing literature. To our knowledge, this study represents one of the few attempts to analyse in a single work sex differences across multiple areas of social cognition.

Keywords: Emotion recognitionEmotional functioningEmpathySex differencesSocial cognitionTheory of Mind

Disgust-sensitive people find little similarity between themselves and strangers; pathogen disgust predicts similarity perceptions beyond sexual and moral disgust

We're not of the same feather: Disgust sensitivity and reduced perceived similarity to unknown others. Sari Mentser, Ravit Nussinson. Personality and Individual Differences, Volume 163, 1 September 2020, 110039. https://doi.org/10.1016/j.paid.2020.110039

Highlights
• Disgust-sensitive people find little similarity between themselves and strangers
• Pathogen disgust predicts similarity perceptions beyond sexual and moral disgust
• The threat of pathogens is linked with increased perceived social distance

Abstract: Perceptions of interpersonal similarity are accompanied by attraction and bonding, often leading to physical contact. Given that physical proximity to social beings increases the odds of catching infectious diseases, we propose a reverse relationship, whereby sensitivity to the presence of pathogens results in perceiving unfamiliar others as less similar to oneself. Four studies involving 980 participants and operationalizing others in three different ways confirm that individual differences in propensity to feel disgust (i.e., react emotionally to potential sources of pathogens in the environment) are associated with perceptions of interpersonal similarity to strangers. Study 1 showed that individuals who score higher in disgust sensitivity perceive themselves as less psychologically similar to visually displayed social targets. Study 2, using vague descriptions of hypothetical figures, found that high-disgust-sensitivity participants tend to assume that others' personal preferences contrast with their own. Study 3 demonstrated that the disgust–dissimilarity association holds for prototypical members of social groups. Finally, Study 4 confirmed that this link reflects pathogen-related (above and beyond sexual or moral) disgust. In all studies, controlling for participants' gender, religiosity, and illness recency did not change the results. We discuss our findings and propose novel directions for future research.

Keywords: Disgust sensitivityPathogen threatBehavioral immune systemInterpersonal similarity

Losing stinks! The effect of competition outcome on body odour quality

Losing stinks! The effect of competition outcome on body odour quality. Jitka Fialová, Vít Třebický, Radim Kuba, David Stella, Jakub Binter and Jan Havlíček. Philosophical Transactions of the Royal Society B: Biological Sciences, Apr 20 2020. https://doi.org/10.1098/rstb.2019.0267

Abstract: Dominance hierarchy is often established via repeated agonistic encounters where consistent winners are considered dominant. Human body odour contains cues to psychological dominance and competition, but it is not known whether competition outcome (a marker of a change in dominance hierarchy) affects the hedonic quality of human axillary odour. Therefore, we investigated the effect of winning and losing on odour quality. We collected odour samples from Mixed Martial Arts fighters approximately 1 h before and immediately after a match. Raters then assessed samples for pleasantness, attractiveness, masculinity and intensity. We also obtained data on donors' affective state and cortisol and testosterone levels, since these are known to be associated with competition and body odour quality. Perceived body odour pleasantness, attractiveness and intensity significantly decreased while masculinity increased after a match irrespective of the outcome. Nonetheless, losing a match affected the pleasantness of body odour more profoundly, though bordering formal level of significance. Moreover, a path analysis revealed that match loss led to a decrease in odour attractiveness, which was mediated by participants’ negative affective states. Our study suggests that physical competition and to some extent also its outcome affect the perceived quality of human body odour in specific real-life settings, thus providing cues to dominance-related characteristics.

5. Discussion

In this study, we tested the effect of winning and losing a physical confrontation on human body odour quality and investigated factors that may mediate observed changes. We expected that winning would have a positive effect on body odour quality and losing a negative effect on it. We also predicted that winning would be associated with positive affective states, a rise in T levels and decrease in C levels, while losing would be characterized by the opposite pattern. Moreover, we hypothesized that these factors would mediate a change in body odour quality.

We found that after a match, perceived odour pleasantness, attractiveness and intensity significantly decreased, while masculinity increased in both winners and losers. Nevertheless, the decrease in pleasantness was more pronounced in losers, which suggests that losing has a more negative effect on body odour quality. We found no statistically significant differences in body odour ratings between winners and losers either before or after a match. Path analysis showed that a loss led to a decrease in odour attractiveness and this effect was mediated by participants' negative emotions.

Winning a match may entail a rise in the dominance hierarchy, while losing lowers the rank: in our case, the match score was added to a personal profile, which affects the league rank. Both losing and winning have consequences for both competitors. Nonetheless, the relatively more profound odour changes in losers suggest that losing may be perceived as having more serious consequences because it may be linked not only to lower league ranking but also to more or less serious injuries. In ring-tailed lemurs (Lemur catta), injury affects the chemical composition of secretion and injury status can be discerned by other individuals [86,87]. Similarly, it could be expected that fighters who lost suffered more injuries during a match and that might be reflected in their body odour. In our study, however, that does not seem to be the case since self-assessed pain did not significantly differ between winners and losers and it was not associated with any of the rated odour characteristics.

Our results thus indicate that competitive situations per se can have an effect on body odour, because after a match, while masculinity increased, both pleasantness and attractiveness decreased. The influence of competition on body odour has been demonstrated already by Adolph et al. [37], although they found that the tested odour samples affected exposed individuals on a subliminal level without any perceived differences between competition-linked and control odours. In our study, the perceived odour quality changed, which could be linked to increased sweating owing to the physical effort during the match. Thermoregulation involves mainly eccrine glands [88], which during exertion produce more diluted, watery, and less oily secretion consisting mostly of water and electrolytes derived from blood plasma and sodium chloride [89]. The change in odour quality we observed could thus be owing to the different quality of sweat. This finding should raise caution with respect to using sports odours as control stimuli (e.g. [90,91]), because they may have somewhat different properties than for example odours collected during sleep (e.g. [83]).

(a) Link between dominance and body odour

The results of some animal studies suggest dominant individuals may have specific intrinsic odour qualities [27] that are probably androgen-dependent [43]. In our study, however, ratings of pre-match body odour were similar for winners and losers, suggesting no prior differences in fighters’ body odour quality. Still, we obtained data on the result of only one match and have no information about the fighters' current rank position. We cannot, therefore, draw stronger conclusions about possible links between various qualities of body odour and rank in the dominance hierarchy. In other words, we do not know whether there exists any connection between dominance rank and specific odour qualities, although previous studies did find some olfactory cues to psychological dominance [31,33].

(b) Sex-related differences in rating

The absence of significant sex-linked differences in raters’ assessments in most rated characteristics suggests that these odour cues have no specific role in intra- or intersexual selection. The sole exception was masculinity ratings. Overall, losers' post-match body odour was rated as more masculine than their odour before a match. This effect was driven by male raters who evaluated losers’ body odour as more masculine after a match. Females did not perceive any difference between pre- and post-match quality. Comparison between the calculated POS values and the actual number of male raters, however, indicates a lower stability in masculinity rating by men, which is why this result should be interpreted rather cautiously. Future studies should further investigate these findings to assess their robustness.

(c) The mediating effect of affective states and hormone levels on body odour quality

If we view winning and losing a fight as a way of change in an individual's rank in dominance hierarchy, then a change of position can be reflected in body odour and others can use it to assess the result of competition. This effect could be owing to changes in hormone levels (T and/or C) associated with victory or defeat. This effect has been repeatedly shown in previous studies (e.g. [60,62]). T stimulates the proliferation of sebocytes and affects the function of apocrine sweat glands [92]. Similarly, C has an either direct or indirect link (via adrenaline) with the activity of apocrine glands [93], which can, in turn, affect the quality of body odour. Two studies that investigated the association between T and C levels and body odour quality produced rather contradictory results. Rantala et al. [72] found no significant correlation between T levels and either intensity or attractiveness of men's body odour. Interestingly, however, they found that C concentrations were positively associated with odour attractiveness, though not its intensity. Using a larger sample and a slightly different methodology (a longer sampling period and elimination of samples from men who reported violations of instructions on the use of fragranced cosmetics), Thornhill et al. [94] observed that women in the fertile phase of their menstrual cycle preferred body odours of men with higher T levels than women in the non-fertile phase. This study did not, however, find any significant relation between odour preferences and C levels.

Our study showed no significant effect of competition outcome on T levels. C levels, however, were higher after a match, which suggests that a match is a stressful event for both winners and losers. The positive relationship between C levels and perceived odour attractiveness, shown by mediation analysis, is in line with a previous study by Rantala et al. [72]. Similarly, we found that C levels did not significantly correlate with intensity ratings (a marker of the amount of perspiration), which indicates a qualitative, not quantitative effect. Glucocorticoids possess certain immunosuppressive qualities [95,96] and it has been hypothesized that only immunocompetent individuals can maintain high C levels [97], which is why such preference would be adaptive.

Another set of variables that have previously been linked to both competition outcomes and body odour are affective states. Body odour can contain cues to affective states such as happiness [98], disgust [99], fear [100], anxiety [90], stress [91], but also aggression [38] and contexts such as competition [37]. This is why we investigated possible mediating effects of changes in hormone levels and affective states. A path analysis showed not only a direct effect of competition outcome on perceived odour attractiveness, where a loss led to decrease in odour attractiveness, but also a mediating indirect effect of negative affective state, where the more negative emotions participants experienced, the less attractive was their perceived body odour. Exploratory correlation analysis showed further relationships between some odour characteristics, affective states and hormone levels, which are in line with the evidence summarized above. These findings, however, should be interpreted with caution owing to our relatively small donor sample.

(d) Study limitations

It is a common procedure in body odour studies to ask odour donors to avoid activities that could affect body odour quality, such as eating spicy food, using soaps, deodorants, demanding physical activities, smoking etc. the day before and on the day of sampling (e.g. [83,31]). Owing to logistical reasons, we were able to contact study participants only a few hours before the match. They did not, therefore, receive any such list of restrictions and followed their habitual regime without any standardization as to diet, smoking, shaving, the use of fragranced cosmetics or dietary supplements. This may have introduced some noise to the data and obscured some effects. Nevertheless, we were still able to detect some significant changes and the use of a within-subject experimental design should diminish inter-individual differences. Such an approach has a higher ecological validity, although future studies should investigate the issue under more standardized settings as well.

We explored the possible effect of injuries on body odour quality using a single question regarding participants' self-perceived pain as a proxy for suffered injuries. Admittedly, a record of actual injuries would be a more objective measure, because participants’ answers may be biased by competitiveness and excitement induced by the competition. These data were not, however, available and we did not want to overload participants with additional tasks and screenings.

In the present study, we used hedonic ratings to assess changes in body odour quality induced by winning or losing a match. Apart from explicit subjective ratings, future studies could employ some objective psychophysiological measures such as skin conductance, heart rate, possible activation of different brain areas by fMRI or variance in time activation by EEG.

Finally, future studies should collect data from the same individual both after a victory and a loss in a competition to assess the effect of outcome on body odour directly. In our field study conditions, such balanced design could not be implemented. It therefore remains as a challenge for future research.

Major histocompatibility complex-associated odour preferences and human mate choice: near and far horizons

Major histocompatibility complex-associated odour preferences and human mate choice: near and far horizons. Jan Havlíček, Jamie Winternitz and S. Craig Roberts. Philosophical Transactions of the Royal Society B: Biological Sciences, April 20 2020. https://doi.org/10.1098/rstb.2019.0260

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.
(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.
(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.
(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).
(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.
(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).
(vii)	We need to distinguish between a threshold-based avoidance of very similar individuals and a fluid preference for the most dissimilar individuals.
(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.
(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.
(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.

Rolf Degen summarizing: In the Far East, ongoing evolution has been wiping out the genetic foundation of people's ability to produce body odors

The specific biochemistry of human axilla odour formation viewed in an evolutionary context
Andreas Natsch and Roger Emter. Philosophical Transactions of the Royal Society B: Biological Sciences, April 20 2020. https://doi.org/10.1098/rstb.2019.0269

Abstract: Human body odour is dominated by the scent of specific odourants emanating from specialized glands in the axillary region. These specific odourants are produced by an intricate interplay between biochemical pathways in the host and odour-releasing enzymes present in commensal microorganisms of the axillary microbiome. Key biochemical steps for the release of highly odouriferous carboxylic acids and sulfur compounds have been elucidated over the past 15 years. Based on the profound molecular understanding and specific analytical methods developed, evolutionary questions could be asked for the first time with small population studies: (i) a genetic basis for body odour could be shown with a twin study, (ii) no effect of genes in the human leukocyte antigen complex on the pattern of odourant carboxylic acid was found, and (iii) loss of odour precursor secretion by a mutation in the ABCC11 gene could explain why a large fraction of the population in the Far East lack body odour formation. This review summarizes what is currently known at the molecular level on the biochemistry of the formation of key odourants in the human axilla. At the same time, we present for the first time the crystal structure of the Nα-acyl-aminoacylase, a key human odour-releasing enzyme, thus describing at the molecular level how bacteria on the skin surface have adapted their enzyme to the specific substrates secreted by the human host.

12. In the light of evolution—axilla odour as an evolutionary puzzle

In this review, we tried to give a comprehensive review on what is known of the biochemistry of human axilla odour formation and detection. We have already alluded to the potential evolutionary implications of these findings in the different sections above and will now summarize the key findings in the evolutionary context.

We highlighted the different specific odourants that are released as specific precursors by specialized glands. Combined with the fact that these precursors seem to be produced locally, axillary glands indeed appear to be a specialized metabolic organ producing these compounds for local secretion.

Multiple enzymes and transport proteins of the host are involved in scent release—some of these have already been characterized biochemically with in vitro experiments (ABCC11 and GGT1), while others can only be inferred based on what is known on the biosynthesis of related conjugates investigated especially in the toxicological field.

On the receiver side, the high sensitivity of the human nose (and hence the corresponding olfactory receptors) for axillary odourants also indicates a specific adaptation of our olfactory receptor repertoire to these human odourants, although further work is required on this aspect truly to explain the high sensitivity at the receptor level.

Taken together, the above observations on a specific and complex biochemistry for odour formation and detection in the human body suggest that axilla odours must have had an adaptive function in human evolutionary history. We contrasted this observation to other general ‘malodours’ such as foot, faecal or breath odours that can largely be explained by common bacterial catabolism of excess proteins, and no specific evolutionary adaptation is required to lead to such odours as simple by-products of the catabolism of residual proteins by opportunistic bacteria. The fact that our sense of smell is particularly tuned to those odours, too, as warning signals of decay also has evolutionary implications, but that's another story.

Turning from the human host to the commensal bacteria, an interesting case for coevolution could be described. The bacteria have highly specialized enzymes and transport proteins for precursor uptake and odour release. The analysis of the spectrum of odourant precursors released and the substrate specificity of the bacterial enzyme N-AGA reveals a close match of the substrate spectrum offered by the host and the substrate specificity of the bacterial enzyme. This could be further corroborated by the data on the crystal structure of the enzyme described herein for the first time: the Gln residue conserved in all acid precursors is tightly bound by an intricate network of hydrogen bonds in the active site explaining the high substrate specificity for Gln conjugates, while there is ample space for the binding of different hydrophobic residues found in the different substrates offered in this ecological niche by the human host.

We had found that the individual-specific odourtype is stable and genetically determined. This indicates that axilla odours can reveal individual-specific information and could, in principle, contribute to kin recognition. To what extent body odours were indeed a contributing factor in social communication in prehistoric societies may be difficult to assess, yet the stable, genetically determined pattern at least indicates that body odours could have had such a function based on the underlying (bio)chemistry.

While the observations summarized above all support the case for an adaptive function of axillary odours in an evolutionary context, the ABCC11 mutation, which confers an almost odourless phenotype and that has rapidly spread in human populations in the Far East, is telling an opposing story. The rapid spread of the haplotype containing this mutation points to a strong selection pressure and may indicate that axilla odours had already become an unwanted trait in early agrarian societies living in closer proximity. The reduced sensory capacity to smell the conspecific as revealed by high anosmia rates for body odours points in a similar direction: a loss of importance of chemical communication through axilla odours in recent evolutionary history, which now is also reflected in a widespread use of deodourants in contemporary societies. In Japan, where the frequency of the mutated ABCC11 haplotype is high, but has not reached 100%, individuals with a functional ABCC11 allele frequently undergo surgery [63,64] to remove axillary glands. Surgery is even covered by social security as axilla odours owing to a functional ABCC11 allele are perceived as a disease. Thus, axillary odours appear as a fascinating trace of our evolutionary past having largely lost their role in the contemporary context.