Some Humans May Have a Weird Pregnancy Quirk Inherited From Neanderthals

Human pregnancy is downright curious. Today, we still don't know why women go into labour for so long or why they face so much risk when they give birth.

Progesterone is a hormone crucial to reproduction in many mammals, but for some unknown reason, it seems to act differently in humans.

Research shows our species has unexpectedly high genetic variation for the progesterone receptor, and recently, this has been linked to serious medical conditions, such as preterm birth and ovarian cancers, among those of non-African descent.

A new paper now adds to a growing number of studies that suggest there really is something different about the human progesterone receptor. And, as strange as it seems, some of us might have Neanderthals to thank.

Analysing United Kingdom biobank data from 450,000 thousand people (244,000 of them women) of European descent, researchers have found nearly a third carry the remnants of a gene variant, which helps encode for the progesterone receptor, and which is also present in Neanderthals.

What's more, unlike what other research has found before, the new study suggests there are benefits to having this gene. For example, those who carry this variant tend to have fewer haemorrhages in early pregnancy, fewer miscarriages, and give birth to more girls - possibly because this genetic variant is linked to more progesterone receptors.

"The proportion of women who inherited this gene is about ten times greater than for most Neanderthal gene variants," says biophysicist Hugo Zeberg from Sweden's Karolinska Institutet.

"These findings suggest that the Neanderthal variant of the receptor has a favourable effect on fertility."

However, that's exactly opposite to what other studies have found before. In 2018, scientists unexpectedly discovered a high frequency of Neanderthal progesterone receptor alleles in modern human populations, and this was linked to a higher risk of preterm birth.

This is obviously not advantageous, and it's led some scientists to argue that the force of natural selection on this particular gene was so weak, it accrued many harmful mutations along the way.

Just this year, researchers found that when they replicated ancient progesterone receptors from the common ancestor of all humans, including Denisovans and Neanderthals, and compared it to the common ancestor of all humans and chimps, there was no evidence of positive selection. Quite the opposite, in fact. Even with an incredible amount of progesterone around, these receptors were less good at doing their jobs.

Still, the authors of the most recent study think their findings can fit into this bigger picture, despite the apparent contradictions.

"[W]e suggest that the Neanderthal progesterone receptor variants may help maintain pregnancies that would otherwise be terminated, and that a consequence (or physiological trade-off) of this may be the association of the same variants with pre-term live births," they explain.

After all, in some cases, orally administered progesterone has been shown to potentially reduce the rate of spontaneous miscarriages and improve fertility among women who are experiencing bleeding in early pregnancy and recurrent miscarriages. So perhaps our differing responses has something to do with our differing receptors.

Jingjing Li, who authored the initial 2018 study on preterm births at Stanford University, and who was not involved in this new research, told ScienceAlert the new findings are very exciting.

"We want to emphasise that this gene has multiple functions," he added, "and is also implicated in ovarian cancer, so being beneficial from one aspect might be detrimental from another aspect (and vice versa). So we agree with the authors there are 'trade-offs' during species evolution." 

Biologist Vincent Lynch from the University of Buffalo agrees it's a fascinating idea and he's especially surprised by the link to Neanderthals. Still, he says, the evidence supporting the functional differences between the two species' progesterone receptors is a bit weak.

"That said, it is an excellent starting point for more detailed functional studies," he notes.

At this point, it's important to acknowledge that genes alone don't determine risk, and there's probably a whole lot of other factors at play here that we aren't accounting for.

"Complex conditions such as prematurity are not likely caused completely environmentally or completely genetically," explained Gary Shaw, a paediatrician from Stanford University, back in 2018. 

"It's the confluence of genes and environment that makes the difference in risk." 

A Neanderthal gene variant may just be part of that story, if only for some of us. But if the study authors are right, it could be an important part of determining pregnancy risks.

The study was published in Molecular Biology and Evolution.