The journal, PLOS Genetics has published the research article by Vincent Lynch and Mirna Marinić, Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage. Lynch is currently assistant professor, UB Department of Biological Sciences. About their study, the co-authors summarize, “We resurrected ancestral forms of the progesterone receptor and tested their ability to regulate a target gene. We found that the human progesterone receptor forms have changed in function, suggesting the actions regulated by progesterone may also be different in humans. Our results suggest caution in attempting to apply findings from animal models to progesterone biology of humans.” The research was funded by the March of Dimes and the Burroughs Wellcome Fund Preterm Birth Initiative. Read the news article by Charlotte Hsu.
Abstract: The steroid hormone progesterone, acting through the progesterone receptor (PR), a ligand-activated DNA-binding transcription factor, plays an essential role in regulating nearly every aspect of female reproductive biology. While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show that PGR evolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology.
Published April 24, 2020
From an evolutionary perspective, human pregnancy is quite strange, says UB biologist Vincent Lynch.
“For example, we don’t know why human women go into labor,” Lynch says. “Human pregnancy tends to last longer than pregnancy in other mammals if you adjust for factors like body size. The actual process of labor tends to last longer than in other animals. And human pregnancy and labor are also much more dangerous.”
With these oddities in mind, Lynch and colleague Mirna Marinić set out to investigate the evolution of a gene that helps women stay pregnant: the progesterone receptor gene.
But the results of the study only add to the mystery, says Lynch, assistant professor of biological sciences, College of Arts and Sciences.
Past research has shown that the progesterone receptor gene underwent rapid evolution in humans, and some scientists have suggested that these swift changes occurred because they improved the function of the gene. This is called positive selection.
But Lynch and Marinić’s study — published online on April 17 in the journal PLOS Genetics — draws a different conclusion.
Their research finds that while the progesterone receptor gene evolved rapidly in humans, there’s no evidence to support the idea that this happened because those changes were advantageous. In fact, the evolutionary force of selection was so weak that the gene accumulated many harmful mutations as it evolved in humans, Lynch says.
The results come from an analysis of the DNA of 115 mammalian species. These included a variety of primates, ranging from modern humans and extinct Neanderthals to monkeys, lemurs and lorises, along with non-primate mammalian species such as elephants, pandas, leopards, hippos, aardvarks, manatees and walruses.
The findings were a surprise, Lynch says.
“We expected something very different. It opens up this mystery that we didn’t anticipate,” he says. “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. 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. I wonder if this might predispose us to things like preterm birth, which is not that common in other animals.”
“Pregnancy is such an everyday event — none of us would be here without it — and yet, so many aspects of this process remain puzzling,” says Marinić, a postdoctoral researcher in the University of Chicago Department of Organismal Biology and Anatomy. “This study focused on an essential ingredient, progesterone signaling via progesterone receptors, and our results add another step toward deeper understanding of specificities of human pregnancy.”
The progesterone receptor gene is crucial to pregnancy because it provides cells with instructions for how to create tiny structures called progesterone receptors.
During human pregnancy, these receptors detect the presence of progesterone, an anti-inflammatory hormone that pregnant women and the placenta produce at various points in time. When progesterone is present, the receptors jump into action, triggering processes that help keep women pregnant in part by preventing the uterus from contracting, reducing uterine inflammation and suppressing the maternal immune response to the fetus, Lynch says.
In addition to exploring the evolutionary history of the progesterone receptor gene, Lynch and Marinić conducted experiments to test whether mutations in the human version of the gene altered its function. The answer is yes.
As the scientists wrote in their paper, “We resurrected ancestral forms of the progesterone receptor and tested their ability to regulate a target gene. We found that the human progesterone receptor forms have changed in function, suggesting the actions regulated by progesterone may also be different in humans. Our results suggest caution in attempting to apply findings from animal models to progesterone biology of humans.”
The research was funded by the March of Dimes and the Burroughs Wellcome Fund Preterm Birth Initiative.