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Yale Team Proposes Transposon Role in Evolution of Mammalian Pregnancy

NEW YORK (GenomeWeb News) – The introduction of certain mobile genetic elements to the genome helped spur the transition from egg production to pregnancy during mammalian evolution, according to a study appearing online yesterday in Nature Genetics.

Yale University researchers used RNA sequencing to profile the transcriptomes of human endometrial stromal cells and endometrial tissue samples from a pregnant armadillo and a short-tailed opossum. In the process, they found more than 1,500 genes that were expressed in the placental mammals but not in the opossum, a marsupial. A subset of the differentially expressed sequences fell near sequences for MER20 transposons, a type of transposable element found exclusively in eutherian mammals.

Findings from the group's follow-up experiments hinted that these MER20 transposon sequences help to switch on some genes in endometrial cells during pregnancy in response to appropriate hormone and other cell signals. If so, they explained, placental pregnancy may have evolved through a set of large rather than gradual genetic changes.

"These transposons are not genes that underwent small changes over long periods of time and eventually grew into their new role during pregnancy," lead author Vincent Lynch, a researcher at Yale's ecology and evolutionary biology department, said in a statement. "They are more like prefabricated regulatory units that install themselves into a host genome, which then recycles them to carry out entirely new functions like facilitating maternal-fetal communication."

The researchers focused their attention on endometrial cells in their effort to unravel the genetic contributors to pregnancy in placental (eutherian) mammals because the differentiation and re-programming of the endometrial tissue lining the uterus is an early and important step in pregnancy.

To investigate which genes get turned on during endometrial differentiation, the investigators did RNA sequencing of progesterone-treated human endometrial stroma cells and endometrial samples from a pregnant armadillo and a pregnant opossum using the Illumina GAII platform.

When they compared the expression of orthologs shared by all three species, the team found 1,532 genes that were expressed in human and armadillo samples but not in the sample from the marsupial opossum. On the other hand, in the opossum sample they detected expression for 199 genes not expressed in the placental mammals.

Many of the genes whose expression was bumped up in the placental mammals had functions consistent with a role in pregnancy and endometrial cell differentiation or "decidualization" based on their Gene Ontology profiles.

And when the researchers looked at the differentially expressed sequences in more detail, the team found that a subset of the genes that are more highly expressed in placental mammals — including the dramatically up-regulated PRL gene, which codes for prolactin — appear to be regulated by sequences derived from MER20 transposons.

Around 42 percent of the known MER20 sequences in the placental mammalian genome turned up near genes that are differentially regulated during pregnancy, the researchers found when they looked more closely at the sequence.

In addition, their follow-up experiments suggest that these transposons are more likely to be found by genes that respond to progesterone hormone and cyclic AMP signaling in endometrial cells during pregnancy. Moreover, they explained, the transposon sequences appear to facilitate shifts in the expression of these genes via interactions with pregnancy-related transcription factors.

"We conclude that the transposable element, MER20, contributed to the origin of a novel gene regulatory network dedicated to pregnancy in placental mammals," they wrote, "particularly by recruiting the [cyclic AMP] signaling pathway into endometrial stromal cells."

Beyond their implications for understanding placental pregnancy, the results offer new insights into the role that transposable elements can play in evolutionary processes.

"We used to believe that changes only took place through small mutations in our DNA that accumulated over time," senior author Günter Wagner, an ecology and evolutionary biology researcher at Yale, said in a statement. "But in this case we found a huge cut-and-paste operation that altered wide areas of the genome to create large-scale morphological change."

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