A Cross-Species Neuroimaging Study of Sex Chromosome Dosage Effects on Human and Mouse Brain Anatomy
- Elisa Guma1,
- Antoine Beauchamp2,3,4,
- Siyuan Liu1,
- Elizabeth Levitis1,
- Liv S. Clasen1,
- Erin Torres1,
- Jonathan Blumenthal1,
- Francois Lalonde1,
- Lily R. Qiu2,3,
- Haley Hrncir6,
- Allan MacKenzie-Graham5,
- Xia Yang6,
- Arthur P. Arnold6,
- Jason P. Lerch2,3,4,7, and
- Armin Raznahan1
- 1Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, 20892, Maryland
- 2Mouse Imaging Centre, Toronto, Ontario M5T 3H7, Canada
- 3The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
- 4Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
- 5Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095
- 6Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California 90095
- 7Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, OX3 9DU, United Kingdom
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Author contributions: E.G., A.M.-G., X.Y., A.P.A., J.P.L., and A.R. designed research; E.G., S.L., E.L., L.S.C., E.T., J.B., F.L., L.R.Q., H.H., and A.R. performed research; A.P.A. and J.P.L. contributed unpublished reagents/analytic tools; E.G., A.B., S.L., E.L., and J.P.L. analyzed data; E.G. wrote the first draft of the paper; E.G., A.B., S.L., E.L., X.Y., A.P.A., J.P.L., and A.R. edited the paper; E.G. wrote the paper.
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*J.P.L. and A.R. contributed equally to this work.
Abstract
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) versus XY controls. Total brain size was substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Robust and spatially convergent effects of XXY and XYY on regional brain volume were observed in humans, but not mice, when controlling for global volume differences. 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 (cerebellar, 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.
SIGNIFICANCE STATEMENT Sex chromosome dosage (SCD) affects neuroanatomy and risk for psychopathology in humans. Performing mechanistic studies in the human brain is challenging but possible in mouse models. Here, we develop a framework for cross-species neuroimaging analysis and use this to show that an added X- or Y-chromosome significantly alters human brain anatomy but has muted effects in the mouse brain. However, we do find evidence for conserved cross-species impact of an added chromosome in the fronto-parietal cortices and cerebellum, which point to regions for future mechanistic dissection of sex chromosome dosage effects on brain development.
- comparative neuroimaging
- cross-species homology
- magnetic resonance imaging
- neuroanatomy
- sex chromosome aneuploidy
- sex chromosome trisomy
- Received September 12, 2022.
- Revision received December 12, 2022.
- Accepted December 22, 2022.
- Copyright © 2023 the authors
