A major challenge in biology is determining the genetic and molecular mechanisms that underlie phenotypic differences between species . While comparative studies in a few organisms such as plants, insects, birds, fish, and rodents have identified the molecular basis for the loss (and much more rarely the gain) of some complex traits, the molecular mechanisms that underlie the divergence of morphological characters are almost entirely unknown—particularly for the origin of evolutionarily novel phenotypes (“novelties”). Among the most significant barriers to developing mechanistic explanations for the origin of evolutionary novelties is the lack of transitional forms among extant lineages and experimental systems amenable to detailed functional studies in nonmodel organisms.
Mammals are an ideal system in which to explore the molecular mechanisms that underlie the evolution of novelties because numerous genomic and experimental resources have been developed for mammals and their slow-evolving genomes facilitate tracing the origins of the novel functional DNA sequences. In addition, extant mammals span several major transitions in the origins of major morphological, developmental, and physiological novelties, including mammary glands, the cochlea, placentation, and pregnancy. Monotremes such as the platypus and echidna, for example, are oviparous and lay thin, poorly mineralized eggs that hatch about 10 days after laying, but the embryo is retained in the uterus for 10–22 days, during which time it is nourished by maternal secretions delivered through a simple yolk-sac placenta. Live birth (viviparity) evolved in the Therian mammals, the lineage that includes marsupial and Eutherian (“placental”) mammals, with the loss of the mineralized eggshell and yolk, and an elaboration of the placenta. Therian mammals, however, have dramatically different reproductive life histories. In marsupials, pregnancies are relatively short (mean 25 days), and in all but one lineage (macropods), gestation is completed within the span of a single estrous cycle. In contrast, Eutherian mammals have evolved prolonged pregnancies that can last up to 670 days (mean 131 days) and that interrupt the estrous cycle.
An essential step in the establishment and maintenance of pregnancy in many Eutherian mammals is the differentiation (decidualization) of endometrial stromal fibroblasts(ESFs) into decidual stromal cells (DSCs) in response to progesterone, the second messenger cyclic AMP (cAMP), and in some species to fetal signals. Decidualization induces large-scale gene regulatory, cellular, and physiological reprogramming in the endometrium, leading to dramatic gene expression changes, the influx of immunosuppressive immune cells, vascular remodeling, and secretory transformation of uterine glands. Decidualization evolved in the stem lineage of Eutherian mammals and underlies the suite of traits that support prolonged pregnancy in Eutherians, including direct implantation of the blastocyst and trophoblast into maternal endometrium, pronounced maternal recognition of pregnancy, maternal-fetal communication, and maternal immunotolerance of the antigenically distinct fetus.
Many of the genes that underlie the origins of maternal provisioning, viviparity, decidualization, and the collection of innovations that characterize prolonged pregnancy in Eutherian mammals likely evolved to be expressed at the fetomaternal interface coincident with the origins of pregnancy. To identify these genes we have used RNA-Seq to characterize the endometrial transcriptome from diverse Eutherian mammals, as well as marsupials, monotremes, birds, and reptiles and evolutionary methods such as ancestral state reconstruction to infer the ancestral endometrial transcriptome from early mammals. We are now using function genomics and experimental methods to reconstruct how genes were recruited into endometrial expression and to determine their functions at the maternal-fetal interface.