Balanced polymorphisms in gamete-binding genes are not associated with human infertility

ABSTRACT Genes expressed in gametes that mediate sperm interaction with the mammalian egg are of considerable interest to evolutionary biologists because the evolution of such genes can account for variation in reproductive compatibility between mates and reproductive isolation between species. The human orthologs of such genes are also potential targets for both contraception and treatment of infertility. One gene system of particular interest is the sperm-binding genes of the inner egg coat or zona pellucida ( Zp2, Zp3 ) and their cognate protein in the mouse sperm acrosome ( Zp3r ). Previous population genetic analyses in humans pointed toward three balanced polymorphisms (one in each gene ZP2, ZP3 , and ZP3R ) as potential targets of some form of balancing selection in the evolution of human fertility. We tested that association using genetic analysis of couples seeking fertility assistance, but we could not reject the null hypothesis of no association between balanced polymorphisms and infertility. Our study was based on a small sample of couples, but the data were sound: the allele frequencies at those three balanced polymorphisms were not different from random expectation in that clinical sample. If an effect of those allele frequencies on infertility exists it is probably small. Our study was based in part on an old error in gene annotation that was only recently discovered (after the start of participant recruitment for this genetic analysis), and this error may account for our results, which argue against a role for balancing selection on those three genes in humans.