Neanderthals and us

I suspect I am not alone in my obsession with our close relatives, the Neanderthals. After all, being of European decent I carry some of their genes. But what were they like? We often depict Neanderthals as primitive, brutish, lacking any form of sophistication. Yet, as my DNA shows, our ancestors had more than fleeting encounters with our relatives. Hidden within our genetic make-up we can find bits of DNA that can be traced back to Neanderthals. In other words, despite their reputation as uncouth, we mated with them and made babies. Not once, but multiple times in areas in which our species came across our close relatives. That is the conclusion Limling Li and colleagues drew from their study published in 2024 in the journal Science. Such mixing has left its mark in the genomes of our species but also in that of the Neanderthals. What remains peculiar is that the pattern of gene flow seems to indicate that the father was always a Neanderthal and the mother one of us.

Let me explain.

All our cells contain two different genomes. The nuclear genome, which contains two copies of each gene, one from our father, the other from our mother. The second genome is that of the mitochondria, the so-called powerhouses of the cell where all the energy production takes place. The mitochondrial genome is tiny but essential and is only inherited from the mother. So, I carry the same mitochondrial genome as my mother did, and my maternal grandmother, and maternal great-grandmother, ad infinitum. Of course, men also have mitochondria, and thus a mitochondrial genome, but they will never pass it on because mitochondria are actively excluded from sperm. Men too share their mitochondrial genome with their mother, maternal grandmother, maternal great-grandmother and so on. Researchers have never found Neanderthal mitochondria in modern humans, which seems to suggest that Neanderthal females never produced viable babies with males of our species. Could that mean that Neanderthals were indeed the brutes we take them to be, taking advantage of the smaller and weaker females of our species? Such unflattering view of our close relatives is probably unwarranted. Instead, it seems that natural selection was the real culprit.

Neanderthals were well-adapted to cold climates, think ice-age conditions, and often lived in environments low in food. A particular version of one gene probably had a lot to do with their ability to deal with their harsh environment. That gene, called PIEZO1, affects how tightly oxygen is bound to haemoglobin inside red blood cells. The Neanderthal version of PIEZO1 binds strongly to oxygen, which was a good thing for Neanderthals as it allowed them to dial down their metabolism under stress. Trouble started when our species expanded into areas occupied by Neanderthals and the two mated. Our species, Homo sapiens, does not contain the Neanderthal version of PIEZO1 but a different version. Initially it seemed that there were no impediments to interbreeding, as crosses between a full-blood Neanderthal and Homo sapiens probably did quite well. There doesn’t seem to be a reason why having one gene copy of PIEZO1 from Neanderthals and one from our species would cause any problems. But according to a 2025 study by Asya Makhro and colleagues available on BioRxiv, that all changed when hybrid females became pregnant. In particular hybrid females who became pregnant with a foetus that carried two of the Homo sapiens versions of PIEZO1.

A foetus depends on its mother for oxygen and nutrients. Exchange of both takes place in the placenta, which starts forming as early as four weeks into the pregnancy. To provide her foetus with oxygen, the mother’s haemoglobin needs to release the oxygen molecules bounded to it when blood from the mother and foetus mix in the placenta. This transfer is passive¾ the mother’s oxygen-rich blood surrounds tiny foetal capillaries and oxygen moves from a high-oxygen environment (mother’s blood) to a low-oxygen environment (the foetus’ blood). Makhro and colleagues suspect that when the mother and the foetus differ in their blood’s affinity to bind oxygen, the foetus is at risk of dying from lack of oxygen. Haemoglobin from mothers that carry the strong-binding Neanderthal version of PIEZO1 would hold on so tight to the oxygen molecules that only a foetus that also carried the strong-binding version would be able to bind sufficient oxygen. All others would die. And that, the authors argue, was the fate of a Neanderthal-Sapiens female carrying a foetus with the Homo sapiens version of PIEZO1.

If true, and I think Makhro and colleagues make a strong case, then the severely reduced fertility of hybrid Neanderthal-Sapiens females would explain why we do not find Neanderthal mitochondrial genomes in our species. It also helps us understand why Neanderthals ultimately went extinct roughly 10,000 years after encountering Homo sapiens. By that time Neanderthal populations were already dwindling with many living in small, isolated populations under harsh conditions. Our species, in contrast, was expanding its population. Because of the difference in population size between the two species, Neanderthals were more susceptible to any force that would negatively affect their fertility. Mating with Homo sapiens could well have been the last nail in the Neanderthals’ coffin. We, on the other hand, kept some of the Neanderthal genes that turned out to be useful while their original bearers slowly went extinct. Unfair? Sure, but evolution doesn’t care.