A maternal-fetal PIEZO1 incompatibility as a barrier to Neanderthal-modern human admixture

When Neanderthals and anatomically modern humans interbred, they may have faced conditional reproductive barriers. We identify a likely maternal-fetal incompatibility involving a Neanderthal PIEZO1 gene variant predicted to increase red blood cell oxygen affinity. While potentially advantageous in Neanderthals, this trait became detrimental in hybrids: heterozygous mothers carrying one Neanderthal allele could deliver insufficient oxygen to fetuses inheriting two modern alleles, reducing their survival. We tested this hypothesis using in vitro physiology, population genetic simulations, and genomic surveys. Pharmacological activation of Piezo1 in human red blood cells reproduced the high-affinity phenotype, providing a biochemical basis for impaired placental oxygen transfer. Simulations showed that maternal-fetal mismatch drives frequency-dependent selection against the Neanderthal allele, promoting demographic decline. Genomic data confirm that the variant is virtually absent in modern humans, consistent with strong purifying selection. Our findings reveal how subtle physiological mismatches plausibly restricted gene flow, contributing to Neanderthal extinction, and highlight a mechanism potentially underlying unexplained pregnancy complications today.