Human pregnancy is no easy feat. Unlike other mammals, the process is unusually long and dangerous, and that might have something to do with a key reproductive gene.
The hormone progesterone plays a crucial role in mammal biology. It helps regulate nearly every aspect of female reproduction, from menstruation, to implantation, to pregnancy, and in humans, its receptor has evolved in a mysteriously unique way.
In our species, the gene that encodes for this receptor has undergone rapid evolution, but that doesn't mean its function in human pregnancy is any more advantageous.
In fact, new research has found the force of natural selection on this particular gene has been so weak overall, that it's accrued many harmful mutations along the way.
"We expected something very different," says biologist Vincent Lynch from the University of Buffalo.
"It opens up this mystery that we didn't anticipate."
Today, there's conflicting evidence on whether the progesterone receptor gene has been positively selected for in human evolution.
While some research comparing humans, chimps, and mice suggests this gene has accumulated several benefits over time, other research comparing the genes of humans, chimps, and macaques has found no such thing.
The new study is based on a dataset of more than 100 progesterone receptor genes sourced from a broad number of mammals, ranging from dolphins to primates, including ancient humans such as Neanderthals and Denisovans.
In their analysis, the team claims to have stumbled upon an explanation for the past discrepancy: some animal models might simply not translate to humans.
In biology, the progesterone receptor mediates many of the hormone's functions in the body. When progesterone comes into contact with one of these receptors, it triggers processes that can maintain pregnancy by preventing uterine contraction or inflammation.
But in our species, the gene that instructs how these receptors are made shows marked differences.
"We found that the human progesterone receptor forms have changed in function, suggesting the actions regulated by progesterone may also be different in humans," the authors write in their paper.
"Our results suggest caution in attempting to apply findings from animal models to progesterone biology of humans."
Recent research, for instance, has found humans have unexpectedly high genetic variation in this progesterone receptor, and this has been significantly associated with medical conditions, such as preterm birth and the development of ovarian cancers.
Could it be that the progesterone receptor in humans predisposes us to more risk during pregnancy? If that's the case, then positive selection doesn't seem like the best explanation for its evolution.
By resurrecting ancestral forms of the progesterone receptor and then testing their ability to regulate a target gene already known to respond to the hormone's presence, the authors found no evidence of positive selection.
Instead, they argue "an episode of relaxed purifying selection" altered the very function of the human progesterone receptor. Furthermore, this may have impacted our reproductive biology, and not always for the better.
"I thought that the progesterone receptor gene would have evolved to respond better to progesterone, to be better at suppressing inflammation or contractions to keep us pregnant for longer," says Lynch.
"It looks like it's the reverse: In human pregnancy, there's just an incredible amount of progesterone around, and yet the gene is less good at doing its job."
The authors admit their study does not include other cell types that respond to progesterone, only the core progesterone receptor. Nevertheless, they think their results will be consistent in other cell types and contexts other than reproduction.
Still, it's hard to pin anything down to one gene, given how variable these factors can be in certain environments. Pregnancy is extremely complicated, and basic questions like why do we go into labour still remain unanswered.
"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."
The study was published in PLOS Genetics.