Engineered bipaternal mice reveal the consequences of life without a maternal genomic contribution

Successful mammalian development normally requires contributions from both maternal and paternal genomes, yet how these parental components jointly shape organismal development remains incompletely understood. Using engineered bipaternal mice generated from androgenetic embryonic stem cells carrying extensive imprinting-region modifications and produced through tetraploid complementation, we examined developmental and physiological consequences of development supported exclusively by paternal genomes. Placental analyses revealed partial normalization of placental growth but persistent differences among conceptuses. Transcriptomic profiling across embryos and postnatal tissues similarly showed broad alterations in gene expression states involving both imprinted and non-imprinted genes. Despite these differences during development, adult physiology showed a more coherent endpoint: integrated transcriptomic and metabolomic analyses revealed that adult livers converge toward an altered metabolic configuration characterized by coordinated perturbations of the tricarboxylic acid cycle and associated lipid metabolism, accompanied by hepatic lipid accumulation and increased systemic fat mass. These findings indicate that paternal-only mammalian development can proceed across multiple stages but follows altered developmental trajectories that culminate in distinct physiological states, providing insight into how maternal and paternal genomic contributions interact to shape mammalian development and physiology.