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. TeaserMaternal-fetal oxygen affinity mismatches resulting from a Neanderthal PIEZO1 gene variant may have hastened their extinction. O_FIG O_LINKSMALLFIG WIDTH=142 HEIGHT=200 SRC="FIGDIR/small/679417v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1132476org.highwire.dtl.DTLVardef@1bec6b5org.highwire.dtl.DTLVardef@1e7ae96org.highwire.dtl.DTLVardef@1772d17_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Conceptual model of maternal-fetal oxygen affinity mismatch caused by PIEZO1 gain-of-function (GOF) variants. Upper panel: In uncomplicated pregnancies, maternal RBCs exhibit lower hemoglobin-oxygen affinity (higher P50) than fetal RBCs, creating a gradient that facilitates placental oxygen transfer. PIEZO1 GOF variants increase maternal oxygen affinity (lower P50), narrowing this gradient and reducing fetal oxygen supply. Lower panel: Genetic inheritance scenarios illustrate how this physiological effect translates into a hybrid incompatibility. While heterozygous mothers (WT/GOF) can be healthy, pregnancies with wild-type fetuses (WT/WT) are at risk of impaired oxygen transfer, leading to growth restriction, hydrops, or fetal loss. Other maternal-fetal genotype combinations are not affected. Together, these data support a model in which PIEZO1-driven maternal-fetal mismatch acts as a non-immune reproductive barrier with relevance for both evolutionary admixture and modern pregnancy complications. C_FIG