Hotspots of disruption in placental regulatory gene networks reflect a common genetic architecture underlying hybrid placental dysplasia in rodents
Authors: Emily Moore 1; Fernando Rodriguez-Caro 1; Kathryn Wilsterman 2; Quynh McKelvey-Pham 3; Jeffrey Good 1
Affiliations: 1) University of Montana, Missoula, MT; 2) Colorado State University, Fort Collins, CO; 3) Hellgate High School, Missoula, MT
Keywords: Speciation & hybridization
Mammalian hybrids often show abnormal, parent-of-origin specific placental growth, suggesting that disruption of this critical developmental tissue plays an important role in the early stages of speciation. The placenta is among the most rapidly evolving mammalian organ and is enriched for genes that show parent-of-origin bias in expression due to epigenetic imprints, making divergence in imprinted placental gene pathways a prime candidate for the rapid evolution of hybrid inviability. To gain insight into the genomic bases of hybrid placental disruption, we compared placenta size, tissue composition, pregnancy failure, and gene co-expression network structure for house mouse (Mus) hybrids at increasing levels of evolutionary divergence. Using reciprocal crosses between wild-derived inbred strains of M. musculus musculus, M. musculus domesticus, and M. spretus, we tracked parent-of-origin gene expression within each lineage as well as in F1 hybrids between subspecies and species. To evaluate co-expressed and imprinted genes, we used transcriptomes and methylomes from whole placenta, augmented by transcriptomes from functionally distinct placental layers. We identified previously cryptic placental and pregnancy phenotypes between house mouse subspecies, revealing parent-of-origin incompatibilities between these closely related lineages. Placental growth abnormalities and patterns of regulatory disruption scaled with lineage divergence, with co-expressed sets of genes showing transgressive expression in hybrid placentas. Comparison between F1 experiments revealed a core set of disrupted genes shared between subspecific and specific Mus crosses and enriched for fetally expressed genes at junction of the fetal-maternal interface. Using a backcross between M. musculus musculus and M. spretus, we then showed that extreme placental overgrowth and disrupted placental pathways were primarily caused by genetic incompatibilities on the maternal X chromosome. Comparison of these data with results from dwarf hamster (Phodopus) hybrids revealed a parallel X-linked genetic architecture of placental incompatibilities mapping to a homologous region of the X chromosome and resulting in disrupted expression of a common imprinted autosomal gene network. These findings demonstrate that the placenta is a hotspot for evolutionary divergence contributing to rodent speciation, and that recurrent patterns of hybrid inviability may reflect common genetic and regulatory bases.