An ancient fecundability-associated polymorphism switches a repressor into an enhancer of endometrial TAP2 expression

Abstract

Variation in female reproductive traits such as fertility, fecundity, and fecundability are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here we explore the functional significance and evolutionary history of a C/T polymorphism of SNP rs2071473, which we have previously shown is an eQTL for TAP2 and significantly associated with fecundability (time to pregnancy). We replicated the association between rs2071473 genotype and TAP2 expression using GTEx data and demonstrate that TAP2 is expressed by decidual stromal cells at the maternal-fetal interface. Next, we show that rs2071473 is located within a progesterone responsive cis-regulatory element that functions as a repressor with the T allele and an enhancer with the C allele. Remarkably, we found this polymorphism arose before the divergence of modern and archaic humans, is segregating at intermediate to high frequencies across human populations, and has genetic signatures of long-term balancing selection. This variant has also previously been identified in GWA studies of immune related disease, suggesting both alleles are maintained due to antagonistic pleiotropy.\n\nAuthor SummaryFemale reproductive traits such as fertility and the time it takes to become pregnant are heritable. Many factors, including widespread contraceptive use and environmental influences, make identifying the genetic differences between individuals that are responsible for fertility differences between women difficult. We previously identified a common single nucleotide polymorphism that affects the expression of the gene TAP2 and is significantly associated with how long it takes woman to become pregnant. Here we show that TAP2 is expressed at the maternal-fetal interface in the uterus during pregnancy. We then show that the T version of the polymorphism functions to repress TAP2 expression whereas the C form enhances TAP2 expression. Remarkably, the C variant arose before the divergence of Neanderthals and modern humans and has become common in all human populations. This derived variant has previously associated with immune related diseases, suggesting the ancestral T and derived C variants are being maintained because they affect multiple traits.