Researchers Trace Ancient Gene Signature in Placental Mammals
New research maps how placental mammals evolved complex pregnancy traits through single-cell transcriptomics.
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A new study published in Nature Ecology & Evolution reveals how the complex interaction between maternal and fetal tissues evolved in placental mammals. Researchers from the University of Vienna, Yale University and several collaborating institutions analyzed cell types at the interface between mother and fetus across six mammalian species. Their work provides insight into how long pregnancies and complex placental structures emerged through evolutionary time.
Cell types at the maternal–fetal boundary
The fetal–maternal interface is a site of close interaction between two genetically distinct organisms. It must allow exchange of nutrients and signaling molecules, while preventing rejection of the fetus by the maternal immune system. To explore how this system evolved, the team used single-cell transcriptomics to map gene activity in individual cells from the interface in mice, guinea pigs, macaques, humans, tenrecs and opossums.
Single-cell transcriptomics
A technique that measures gene expression in individual cells.Placental mammals
A group of mammals characterized by a complex placenta that supports the fetus during a prolonged pregnancy. They include species such as humans, mice and whales, and differ from marsupials and monotremes.These species represent diverse lineages in the mammalian evolutionary tree. Opossums, as marsupials, diverged from placental mammals before the evolution of complex placentas. The tenrec represents an early branch of placental mammals, while mice, guinea pigs, macaques and humans provide examples of more derived lineages.
A shared signature of placental invasion
Two types of cells were the focus of this investigation: fetal placenta cells that invade the uterus, and maternal stromal cells that respond to this invasion. The researchers found that invasive behavior in placenta cells, once thought to be unique to humans, is in fact marked by a gene expression signature conserved for over 100 million years in placental mammals.
In parallel, maternal cells in placental mammals were found to have developed specialized mechanisms for hormone production. These changes were not observed in the marsupial sample, suggesting a key evolutionary step in the extension of pregnancy duration and the development of gestational complexity.
"These findings suggest that evolution may have favored more coordination between mother and fetus than previously assumed."
Dr. Daniel J. Stadtmauer.
Testing evolutionary models of maternal–fetal interaction
The study explored two hypotheses about how maternal–fetal signaling may have evolved. The first, known as the disambiguation hypothesis, suggests that hormone production became functionally partitioned between maternal and fetal tissues over time. Evidence supported this idea, showing that specific signaling molecules such as WNT proteins and steroid hormones could be traced to one source.
WNT proteins
A family of signaling proteins involved in regulating cell-to-cell communication during development.IGF2
Insulin-like growth factor 2 is a hormone that promotes fetal growth.The second model, the escalation hypothesis, proposes a form of evolutionary competition between maternal and fetal genes. Evidence for this was more limited, although certain genes like IGF2, which promotes growth, did show patterns consistent with this model. Overall, the results suggest that cooperative signaling has been more dominant than conflict in the evolution of pregnancy.
Linking cellular data to evolutionary history
The researchers combined single-cell transcriptomics with evolutionary modeling to track how different cell types and their functions might have looked in ancestral species. This allowed them to reconstruct how maternal–fetal communication may have developed, providing a framework to study other complex traits across species.
The study was carried out by teams led by Mihaela Pavličev at the University of Vienna and Günter Wagner at Yale University. It was supported by funding from the John Templeton Foundation and the Austrian Science Fund.
Reference: Stadtmauer DJ, Basanta S, Maziarz JD, et al. Cell type and cell signalling innovations underlying mammalian pregnancy. Nat Ecol Evol. 2025. doi: 10.1038/s41559-025-02748-x
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