The causes of infertility are many and yet doctors sometimes can’t explain why couples have trouble conceiving. Scientists have uncovered yet another way our bodies can trip up fertilization. In a study published today (August 19) in Proceedings of the Royal Society B, researchers found that sperm function better in cervical mucus from women with less similar sequences for the genes that encode the human leukocyte antigen (HLA) system, a group of cell-surface proteins that the immune system uses to differentiate self from non-self. With more-similar genotypes, sperm were less likely to survive exposure to cervical mucus.
“Quite a lot of these type of effects have been shown in other animals . . . but obviously there’s a different importance to understanding this in humans,” says David Richardson, a biologist at the University of East Anglia in the UK who did not participate in the study.
In birds and fish, for instance, it’s clear that having dissimilar genes for the major histocompatibility complex (MHC)—the animal equivalent of the HLA system—influences choice of mate, gamete compatibility, and eventual success of fertilization. This subsequent variety of MHC alleles is thought to prepare offspring to face a wider range of pathogens and therefore increase their chances of survival.
In people, previous work has shown that men and women prefer body odor from individuals with less similar HLA sequences—a kind of pre-mating sexual selection. Researchers have also determined that HLAs may be present on the surface of sperm and that soluble HLAs are found in cervical mucus, the fluid released by glands in the cervix, raising the possibility that a well-matched egg and sperm could be a factor in humans, too.
“In many animal species, not all the male-female combinations are equally compatible at the gamete level,” says Jukka Kekäläinen, a biologist at the University of Eastern Finland. Knowledge of gamete compatibility in people is limited, he adds, and could provide insight into human infertility. There is no routine test for this kind of compatibility in medicine, he adds. “Normally, doctors just study whether the sperm quality looks okay and whether there are any problems in the females that could easily explain infertility.”
To begin to address this question, Kekäläinen and colleagues collected cervical mucus samples from nine women and sperm samples from eight men. The researchers also genotyped each subject’s HLA sequences. Then they created all possible one-to-one combinations of diluted cervical mucus and sperm and observed how the sperm fared. Sperm were more likely to survive in male-female combinations that shared fewer genetic similarities, indicating that immunological compatibility may affect fertility.
It “is very plausible that it can be advantageous to choose your mate so that your offspring is optimally set up to recognize pathogens for a highly immunocompetent immune system,” says Tobias Lenz, a biologist at the Max Planck Institute for Evolutionary Biology who was not involved in the work. As the authors write in the paper, this question of how HLA genotype can influence post-copulatory sexual selection “should now be studied in a larger context and with a larger dataset” to test whether it leads to differential levels of fertilization, he adds. “Here, they look at certain fitness traits of the sperm, which can be assumed to affect fertilization success, but would then be nice to actually show that in a study.”
Now that Kekäläinen and colleagues have identified this association between sperm viability and HLA genotype, they plan to focus on identifying the mechanism that underlies it. In another study published August 3, they uncovered a similar association between the genes for the HLA system and sperm mortality in follicular fluid, which surrounds an unfertilized human oocyte. They’re currently confirming whether or not HLAs are present on the surface of sperm cells and investigating their gene expression to determine what other genes might be involved in post-copulatory sexual selection.
Unlike in birds or fish, it’s hard to determine whether these mechanisms produce more viable or more healthy offspring in people, says Richardson. “It wouldn’t be that surprising, given what we know about other species, but it would obviously open up lots of opportunity for . . . fertility treatment.”
A. Jokiniemi et al., “Post-copulatory genetic matchmaking: HLA-dependent effects of cervical mucus on human sperm function,” Proceedings of the Royal Society B, doi:10.1098/rsbp.2020.1682, 2020.