Role of paralogs in the sex-bias transcriptional and metabolic regulation of the brain-placental axis in mice

Introduction: Duplicated genes or paralogs play important roles in the adaptive function of eukaryotic genomes. Animal studies have shown evidence for the functional role of paralogs in pregnancy, but our knowledge about the role of paralogs in the fetoplacental regulation remains limited. In particular, if fetoplacental metabolic regulation is modulated by differential expression of paralogs remains unexamined.Methods: In this study, gene expression profiles of day-15 placenta and fetal brain were compared to identify families or groups of paralogous genes expressed in the placenta and brain of male versus female fetuses in mice. A Bayesian modeling was applied to infer directional relationship of transcriptional variation of the paralogs relative to the phylogenetic variation of the genes in each family. Gas chromatography-mass spectrometry (GCMS) was used to perform untargeted metabolomics analysis of day-15 placenta and fetal brain of both sexes.Results: We identified paralog groups that were expressed in a sex and/or tissue biased manner between the placenta and fetal brain. Bayesian modeling showed evidence for directional relationship between expression and phylogeny of specific paralogs. These relationships were sex specific. GC-MS analysis identified metabolites that were expressed in a sex-bias manner between the placenta and fetal brain. By performing integrative analysis of the metabolomics and gene expression data, we showed that specific groups of metabolites and paralogous genes were expressed in a coordinated manner between the placenta and fetal brain.Discussion: The findings of this study collectively suggest that paralogs play an influential role in the regulation of the brain-placental axis in mice.