In early mammals, mobile genetic elements called jumping genes bounded through the genome, inserting regulatory elements that ultimately influenced thousands of protein-coding genes, causing them to respond to progesterone. As these progesterone-binding regulatory elements proliferated, more and more genes that would have been silent in endometrial tissue acquired the ability to become activated in response to hormonal changes. And so, with the evolution of a progesterone-responsive uterus, mammals shifted from egg laying to live birth.

This explanation for the evolution of pregnancy was developed by scientists at the University of Chicago, including Vincent Lynch, Ph.D., an assistant professor of human genetics. The scientists indicated that their explanation may apply not only to pregnancy, but to the evolution of many other biological structures and functions.

“For the first time, we have a good understanding of how something completely novel evolves in nature, of how this new way of reproducing came to be,” said Dr. Lynch. “Most remarkably, we found the genetic changes that likely underlie the evolution of pregnancy are linked to domesticated transposable elements that invaded the genome in early mammals. So I guess we owe the evolution of pregnancy to what are effectively genomic parasites.”

“It's easy to imagine how evolution can modify an existing thing, but how new things like pregnancy evolve has been much harder to understand,” Lynch continued. “We now have a new mechanistic explanation of this process that we've never had before.”

Dr. Lynch and his colleagues published their findings January 29 in Cell Reports, in an article entitled, “Ancient Transposable Elements Transformed the Uterine Regulatory Landscape and Transcriptome during the Evolution of Mammalian Pregnancy.”

“To determine the molecular bases of this transition, we characterized the pregnant/gravid uterine transcriptome from tetrapods to trace the evolutionary history of uterine gene expression,” wrote the authors. “We show that thousands of genes evolved endometrial expression during the origins of mammalian pregnancy, including genes that mediate maternal-fetal communication and immunotolerance.”

To study genetic changes during the evolution of pregnancy in mammals, Lynch and his colleagues used high-throughput sequencing to catalog genes expressed in the uterus of several types of living animals—placental mammals (a human, monkey, mouse, dog, cow, pig, horse, and armadillo), a marsupial (opossum), an egg-laying mammal (platypus), a bird, a reptile, and a frog. Then they used computational and evolutionary methods to reconstruct which genes were expressed in ancestral mammals.

The researchers found that as the first mammals evolved—and resources for fetal development began to come more from the mother and less from a yolk—hundreds of genes that are important for cellular signaling, metabolism, and uterine development started to be expressed in the uterus. As the eggshell was lost and live-birth evolved in the common ancestor to marsupials and placental mammals, more than 1,000 genes were turned on, many of which were strongly linked to the establishment of maternal-fetal communication. As prolonged pregnancy evolved in placental mammals, hundreds of genes began to be expressed that greatly strengthened and elaborated maternal-fetal communication, as well as locally suppressing the maternal immune system in the uterus—thus protecting the developing fetus.

The team also identified hundreds of genes that were turned off as these lineages evolved, many of which had been involved in egg shell formation.

“We found lots of genes important for maintaining hormone signaling and mediating maternal-fetal communication, which are essential for pregnancy, evolved to be expressed in the uterus in early mammals,” noted Dr. Lynch. “But immune suppression genes stand out. The fetus is genetically distinct from the mother. If these immune genes weren't expressed in the uterus, the fetus would be recognized by the mother's immune system as foreign and attacked like any other parasite.”

In addition to function, Dr. Lynch and his colleagues investigated the origin of these genes. They found most already had roles in other organ and tissue systems such as the brain, digestive, and circulatory systems. But during the evolution of pregnancy, these genes were recruited to be expressed in the uterus for new purposes. They evolved regulatory elements that allowed them to be activated by progesterone.

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