The Blood Divide: How a Gene May Have Quietly Ended the Neanderthals

A quiet incompatibility

Roughly 50,000 years ago, in the frozen landscapes of Ice Age Eurasia, Homo sapiens and Neanderthals did something profoundly human: they had children together. Their encounters left a genetic legacy that endures in the DNA of nearly every person of non-African ancestry today. Yet the story of that interbreeding was never one of seamless fusion. Something—biological, environmental, or social—kept the two species from blending fully.

A new study may have identified one of those hidden barriers. Researchers from the University of Zurich, led by Patrick Eppenberger, suggest that an incompatibility in a single gene, PIEZO1, disrupted the balance between Neanderthal mothers and their hybrid offspring. The mismatch, they argue, could have increased the risk of pregnancy loss in women with mixed ancestry, subtly but persistently reducing Neanderthal fertility over generations.

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.

Their hypothesis, posted on bioRxiv in September 2025 (Makhro et al., 2025),¹ offers a rare biological lens on why modern humans inherited so little from Neanderthal mothers—and none of their mitochondrial DNA at all.

“When gene flow occurs between distinct species, incompatibilities often manifest not in the first generation but in the next,” says Dr. Helena Moretti, an evolutionary geneticist at the Max Planck Institute for Evolutionary Anthropology. “It’s a delayed echo of hybridization, and its effects can be devastatingly subtle.”