Abstract: Several studies have demonstrated that women show pre-copulatory mating preferences for human leucocyte antigen (HLA)-dissimilar men. A fascinating, yet unexplored, possibility is that the ultimate mating bias towards HLA-dissimilar partners could occur after copulation, at the gamete level. Here, we explored this possibility by investigating whether the selection towards HLA-dissimilar partners occurs in the cervical mucus. After combining sperm and cervical mucus from multiple males and females (full factorial design), we found that sperm performance (swimming velocity, hyperactivation, and viability) was strongly influenced by the male–female combination. This indicates that sperm fertilization capability may be dependent on the compatibility between cervical mucus (female) and sperm (male). We also found that sperm viability was associated with partners' HLA dissimilarity, indicating that cervical mucus may selectively facilitate later gamete fusion between immunogenetically compatible partners. Together, these results provide novel insights into the female-mediated sperm selection (cryptic female choice) in humans and indicate that processes occurring after copulation may contribute to the mating bias towards HLA-dissimilar partners. Finally, by showing that sperm performance in cervical mucus is influenced by partners' genetic compatibility, the present findings may promote a deeper understanding of infertility.
4. Discussion
Our results show that along with sperm intrinsic quality (male effect) and cervical mucus identity (female effect), sperm performance was also strongly dependent on male–female combination (interaction), explaining 8.5–32.3% of the total variation in measured sperm traits. In other words, females had a stronger effect on the sperm of some males than the others. We also observed that both the number of different HLA alleles and the Grantham pairwise amino acid distance of HLA alleles affected sperm viability: sperm had higher survival rates in HLA-dissimilar male–female combinations than in more similar combinations. Conversely, we found that HLA-allele sharing did not affect sperm motility, but the Grantham distance was negatively associated with sperm swimming velocity and hyperactivation in one of the three time points (180 min). In other words, sperm motility was higher in male–female combinations that had low HLA amino acidic divergence in comparison to more dissimilar combinations. However, the observed effect was male-dependent, indicating that the effect of the Grantham distance on sperm motility varies across males. None of the measured sperm traits was associated with male–female genome-wide similarity. Although all the male subjects were diagnosed as normozoospermic it is possible that reproductive physiology of the study subjects may partly differ from that of the average male and/or female population. Consequently, some caution should be applied to generalize our findings and future research should ideally aim to test whether the same mechanisms are widespread in the human population.
The female reproductive tract allows only a minute subset of spermatozoa to reach the site of fertilization [49,75,76], but the mechanisms and function of this stringent sperm selection have remained ambiguous. It has been suggested that the functional incompatibility between cervical mucus and sperm could play an important role in the process [62,66], but to the best of our knowledge none of the earlier studies have experimentally tested this possibility. The present results demonstrate that the chemical composition of the cervical mucus may selectively maintain sperm viability of HLA-dissimilar males, indicating that cervical mucus could mediate post-copulatory choice towards the sperm of immunologically compatible males. Furthermore, given that sperm performance in cervical mucus predicts fertilization success [62], these results raise the novel possibility that immunological compatibility between sperm and cervical mucus plays an important role in determining the reproductive success of the partners. While previous studies have reported an effect of MHC-dissimilarity on egg-sperm fusion [6,17–19,21], to our knowledge, this is the first study to show that MHC-based cryptic female choice could be mediated by fluids of the female reproductive tract in mammals.
Earlier studies have demonstrated that cervical mucus is capable of conserving sperm function [62] and it has been hypothesized that cervical crypts could serve as sperm reservoirs [77], where sperm motility is restrained to enhance longevity, such as in the sperm storage sites of the oviduct [78,79]. Besides demonstrating that cervical mucus likely preserves sperm viability of HLA-dissimilar males, we also found evidence that cervical mucus may simultaneously restrict sperm motility of these males. This could indicate that one key function of cervical mucus is to selectively store the sperm of immunologically compatible males, possibly for later use in fertilization. Alternatively, our results raise the intriguing possibility that females (via cervical mucus) may reduce the survival of sperm of (overly) HLA-similar males on the one hand and slow down the sperm of (overly) HLA-dissimilar ones on the other. Such a search for intermediate MHC dissimilarity may facilitate ‘production' of intermediately heterozygous offspring at MHC loci, which, according to the optimal MHC-heterozygosity hypothesis, may have better immunocompetence than more heterozygous individuals [80]. In fact, while highly heterozygous individuals at MHC loci are able to present more antigens to the immune system, they are likely to have smaller T-cell repertoires following thymic selection [80]. Supporting the optimal heterozygosity hypothesis, Jacob et al. [81] showed that women prefer the body odour of men with whom they share few HLA alleles over the more similar and dissimilar men [36]. However, since observed sperm motility associations were present only at one time point and were not consistent across males, further studies are required to investigate the relative importance of these alternative functions of cervical mucus. Furthermore, since performed cervical mucus dilution likely altered sperm motility patterns, we encourage future studies to confirm whether our results can be replicated in undiluted cervical mucus to fully account for its natural viscoelastic features.
The observed effects of partners' HLA dissimilarity on sperm function could potentially arise at least through two evolutionary mechanisms. First, as highlighted above, cervical mucus -mediated selection towards HLA-dissimilar males may represent an evolutionary strategy that ensures the ‘production' of offspring that have broad (or optimal) antigen recognition capability and thus better ability to fight against infections [82]. Supporting this possibility, pathogens have been widely assumed to be the strongest selective agent in human evolution (e.g. [9]). Alternatively, it is possible that HLA-associated sperm preferences represent a gamete-level inbreeding avoidance mechanism that prevents mating between close relatives [10]. In the present study, however, we found that overall (genome-wide) genetic similarity was not associated with sperm performance, indicating that observed findings are more likely to be a direct consequence of HLA-dependent sperm selection, instead of inbreeding avoidance based on HLA-independent cues. Although detailed molecular-level mechanisms behind our findings remain to be described, we envisage that sperm surface HLA molecules and/or HLA-linked olfactory receptors [83] may play an important role in the demonstrated sperm selection process.
Besides clarifying the mechanistic basis of female-induced sperm selection in humans, our findings may have novel implications for the deeper understanding of infertility and for the development of new contraceptives. Infertility affects about 15% of couples globally and currently remains unexplained in 30–40% of cases [84]. Furthermore, a reliable diagnosis of infertility is extremely challenging, and the accuracy of diagnoses is low when compared to several other areas of medicine [85,86]. According to current clinical practice, infertility problems are partitioned into male- and female-derived pathological factors and are thus thought to represent a disease of the reproductive system [87]. Our results indicate that this may represent an overly simplistic view, since it does not consider the fact that some male–female (or their gamete) combinations may be immunologically more compatible than others. Consequently, gamete-level incompatibility may reduce the probability of conception and may help to understand fertilization problems, especially in couples that are diagnosed with unexplained infertility.
In conclusion, our results show that chemical factors in the cervical mucus preferentially conserve sperm viability (and possibly constrain sperm motility) of HLA-dissimilar males. This indicates that one of the key functions of cervical mucus may be to selectively facilitate gamete fusion between immunogenetically compatible partners and this way facilitate optimization of offspring immunocompetence. Immunological mechanisms of sperm selection have remained virtually unexplored in mammals and internally fertilizing species, in general. The present results provide novel insights into MHC-based post-copulatory sperm selection in humans and may be potentially applied to many other species. Furthermore, a more pervasive integration of the demonstrated ‘gamete compatibility' concept into current infertility diagnostic guidelines may facilitate development of more personalized infertility diagnostics and increase accuracy of the diagnoses.
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