Haldane’s rule in the developing brain: X-linked and imprinted genes contribute to male-biased transgressive expression in hybrid mice

The placenta and developing brains of eutherian mammals are intimately connected and enriched for imprinted gene (IG) expression. In hybrids, the placenta is a hotspot for genetic and epigenetic incompatibilities that preferentially affect males. Whether the hybrid brain is similarly affected is an open question. We evaluated the effects of hybridization and placental dysregulation on neural gene expression (embryonic, juvenile, adult) and behavior (juvenile, adult) in a cross between the house mouse (Mus m. domesticus) and Algerian mouse (M. spretus), in which transgressive expression of imprinted and X-linked genes is a prominent feature of undersized F1 male placentas. In hybrid hypothalamus, transgressive expression was mainly embryonic and highly male-biased. Although fewer genes were dysregulated in hybrid male embryonic hypothalamus relative to placenta, we infer a similar genetic architecture involving X-IG incompatibilities, and incompatibilities between IGs and autosomal interaction partners. Hybrids had heightened anxiety-like behaviors and reduced activity relative to parental species, with a tendency towards larger behavioral differences in adult males. As the first study to characterize the effects of interspecific hybridization on neural gene expression and behavior in a mammal, this work extends the scope of phenotypes impacted by intrinsic incompatibilities and demonstrates that the brain obeys Haldane’s rule.