Balancing Selection atHLA-GModulates Fetal Survival, Preeclampsia and Human Birth Sex Ratio

The population sex ratio is thought to be maintained through balancing selection on rare phenotypes. However, empirical evidence for genetic influence has thus far proven elusive. We combined 1000 Genomes data and large cohorts to study human sex ratios. We found underrepresentation of male offspring in preeclampsia, a serious pregnancy disorder with uncertain pathogenesis. Genetic variation of fetal human leukocyte antigen G ( HLA-G ), regulating maternal anti-fetal immune responses, was found to be under balancing selection. Sex-linked downregulation of HLA-G and upregulation of interferon alpha-1 ( IFNA1 ) expression contribute to loss of fetal immunotolerance in preeclampsia and suggest hydroxychloroquine as a treatment option. Our findings indicate that an evolutionary trade-off between fetal immunotolerance and protection against infections promotes genetic diversity in HLA-G , thereby maintaining human sex ratios. One Sentence Summary Fetal HLA-G modulates human sex ratio.