RESUMO
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 have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage and that the G/A polymorphism arose before the divergence of modern and archaic humans and segregates at intermediate to high frequencies across human populations. Remarkably, the derived A allele is has also been identified in a GWAS as a risk allele for multiple sclerosis. These data suggest that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution.
Assuntos
Elementos Facilitadores Genéticos/genética , Fator de Transcrição GATA2/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Sítios de Ligação , Endométrio/fisiologia , Feminino , Pleiotropia Genética/genética , Genótipo , Humanos , Ciclo Menstrual/genética , Esclerose Múltipla/genética , Progesterona/genética , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética , Reprodução/genética , Células Estromais/fisiologia , Regulação para Cima/genéticaRESUMO
Variation in female reproductive traits, such as fertility, fecundity, and fecundability, is 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 T/C 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 the rs2071473 genotype and TAP2 expression by using GTEx data and demonstrated that TAP2 is expressed by decidual stromal cells at the maternal-fetal interface. Next, we showed 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 that this polymorphism arose before the divergence of modern and archaic humans, segregates 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 genome-wide association studies of immune-related disease, suggesting that both alleles are maintained as a result of antagonistic pleiotropy.