Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease
Abstract
Non-random (skewed) X chromosome inactivation (XCI) in the female brain can ameliorate X-linked phenotypes, though clinical studies typically consider 80-90% skewing favoring the healthy allele as necessary for this effect. Here we quantify for the first time whole-brain XCI at single-cell resolution and discover a preferential inactivation of paternal to maternal X at ∼60:40 ratio, which surprisingly impacts disease penetrance. In Fragile-X-syndrome mouse model, Fmr1-KO allele transmitted maternally in ∼60% brain cells causes phenotypes, but paternal transmission in ∼40% cells is unexpectedly tolerated. In the affected maternal Fmr1-KO(m)/+ mice, local XCI variability within distinct brain networks further determines sensory versus social manifestations, revealing a stochastic source of X-linked phenotypic diversity. Taken together, our data show that a modest ∼60% bias favoring the healthy allele is sufficient to ameliorate X-linked phenotypic penetrance, suggesting that conclusions of many clinical XCI studies using the 80-90% threshold should be re-evaluated. Furthermore, the paternal origin of the XCI bias points to a novel evolutionary mechanism acting to counter the higher rate of de novo mutations in male germiline. Finally, the brain capacity to tolerate a major genetic lesion in ∼40% cells is also relevant for interpreting other neurodevelopmental genetic conditions, such as brain somatic mosaicism.
Additional Information
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Version 1 - November 2, 2018; Version 2 - October 13, 2021. We would like to thank CSHL Hillside animal husbandry services for their support and efforts, members of the Osten lab for inputs on the study and Dr. Kristin Baldwin for comments on the manuscript. This work was funded by grants R01 MH096946 and U01 MH105971 to P.O and funds from The Gertrude and Louis Feil Family Trust to PO. Author Contributions: E.R.S. and P.O. conceptualized the study. E.R.S., P.O., and Y.K. designed the imaging experiments. R.P. performed genotyping and animal husbandry and assisted with experimental design. E.R.S. and K.U.V. implemented CN algorithms for automated cell detection. E.R.S. designed and D.F. performed all behavioral experiments. E.R.S. performed tissue processing and imaging experiments and most data analyses. J.K. and J.A.H. designed and performed brain network structural connectivity weight analyses. J.A.G. performed logistic regression analyses. E.R.S. and P.O. wrote the manuscript. The authors have declared no competing interest.Attached Files
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Additional details
- Alternative title
- A brain network basis of Fragile X syndrome behavioral penetrance determined by X chromosome inactivation in female mice
- Eprint ID
- 111712
- Resolver ID
- CaltechAUTHORS:20211102-195240613
- R01 MH096946
- NIH
- U01 MH105971
- NIH
- Gertrude and Louis Feil Family Trust
- Created
-
2021-11-02Created from EPrint's datestamp field
- Updated
-
2021-11-02Created from EPrint's last_modified field