A new study suggests that interbreeding between Neanderthals and Homo sapiens created a genetic incompatibility that increased pregnancy failure risks in hybrid mothers, potentially contributing to Neanderthals' extinction. This mismatch involved differences in the PIEZO1 gene affecting oxygen transport in blood. The finding could explain the absence of Neanderthal mitochondrial DNA in modern humans.
Interbreeding between Homo sapiens and Neanderthals occurred between approximately 50,000 and 45,000 years ago, with Neanderthals going extinct around 41,000 years ago. Genetic studies show that 1 to 2 percent of the genome in modern humans with non-African ancestry derives from Neanderthals, but none of the mitochondrial DNA, which is inherited solely from mothers, does.
Researchers led by Patrick Eppenberger at the University of Zurich, Switzerland, analyzed DNA from modern humans and Neanderthals, focusing on the PIEZO1 gene, which is crucial for oxygen transport in red blood cells. Neanderthals carried a variant called V1, while Homo sapiens had V2. The V1 variant causes red blood cells to bind oxygen more strongly, and it is dominant.
In hybrid mothers carrying both V1 and V2, the high oxygen affinity would not harm a fetus with mixed variants. However, problems arise in the next generation: a hybrid mother with V1 and V2 carrying a fetus with two V2 copies would deliver less oxygen across the placenta, potentially impairing fetal growth and increasing pregnancy loss risks.
The team argues this led to a reproductive disadvantage for Neanderthals over millennia. “Over millennia of coexistence, even low levels of gene flow from modern humans into Neanderthal populations could have introduced a gradual reproductive disadvantage, compounding over generations,” they write in their paper.
Neanderthal populations, being smaller, were more vulnerable than the larger Homo sapiens groups, where the V1 variant would be selected against. This explains the persistence of Neanderthal nuclear DNA but not mitochondrial DNA in modern humans.
Sally Wasef at Queensland University of Technology calls it a “good insight,” noting that “even a minor hit to reproduction can push small groups below replacement, which can start a slide in numbers and, in fragile settings, an extinction spiral.” She views it as one piece of the puzzle amid other pressures.
Laurits Skov at the University of Copenhagen emphasizes multiple factors in Neanderthals' demise, including climate changes, modern human arrival, small group sizes, new diseases, and genetic issues. He questions if a single PIEZO1 mutation was decisive and calls for more research.
The study also notes similar PIEZO1 mutations today may contribute to unexplained pregnancy losses.
The research is published on bioRxiv (DOI: 10.1101/2025.09.29.679417).