Summary All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) vs. XY controls. We show that total brain size is substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Controlling for global effects reveals robust and spatially convergent effects of XXY and XYY on regional brain volume in humans, but not mice. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellum, parietal, and orbitofrontal cortex) - thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT. Highlights Parallel structural neuroimaging in humans and mice with sex chromosome trisomies Divergent X- and Y-chromosome effects on human brain size, but convergent effects on regional anatomy Muted impact of additional X or Y on mouse brain, but subtle regional effects evident Evidence for conserved cross-species impact of X and Y on fronto-parietal cortices and cerebellum

A cross-species study of sex chromosome dosage effects on mammalian brain anatomy