Adaptive history of single copy genes highly expressed in the term human placenta

Abstract

The chorioallantoic placenta is a shared derived feature of "placental" mammals essential for the success of eutherian reproduction. Identifying the genes involved in the emergence of the placenta may provide clues for understanding the biology of this organ. Here we identify among 4960 single copy genes in mammals, 222 that show high expression levels in human placentas at term. Further, we present evidence that 94 of these 222 genes evolved adaptively during human evolutionary history since the time of the last common ancestor of eutherian mammals. Remarkably, the majority of positive selection occurred on the eutherian stem lineage suggesting that ancient adaptations have been retained in the human placenta. Of these positively selected genes, 28 have been shown to play a role in human pregnancy and placental biology, and at least 26 have important pregnancy-related phenotypes in mice. Adaptations in genes highly expressed in human placenta are attractive candidates for functional and clinical studies.

Fig. 1. Phylogenetic relationships among study species

The phylogenetic relationships and divergence time estimates among eutherian mammals are from the literature [13, 14]. Branch lengths outside Theria are not drawn to scale. Stem lineages that were tested for positive selection among the set of placentally highly expressed protein coding genes during human descent from the LCA of therian mammals are indicated and abbreviated as follows: Eutheria (EUT), Boreoeutheria (BOR), Euarchontoglires (EUA), primates (PRI), Homo-Pan group (HC), and human (H). Superordinal clades discussed in the text are also indicated.

Fig. 2. Workflow for this study

This workflow includes the relationship among the single copy gene inference, MGI database searching, literature searching, gene expression and evolutionary analyses.

Fig. 3. Relationship among orthologs, expression data, positively selected genes (PSGs), and human and mouse pregnancy-related phenotypes

SO = single copy ortholog; HE = highly expressed gene in placenta; MOU_PHE = PSG with pregnancy-related mouse gene phenotypes; HUM_REP = PSGs with human pregnancy-related phenotypes. NMH: PSGs that have neither (N) mouse (M) nor known human pregnancy-related phenotypes (H) by literature searching.