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Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease

Szelenyi, Eric R. and Fisenne, Danielle and Knox, Joseph E. and Harris, Julie A. and Gornet, James A. and Palaniswamy, Ramesh and Kim, Yongsoo and Venkataraju, Kannan Umadevi and Osten, Pavel (2018) Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20211102-195240613

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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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/458992DOIDiscussion Paper
https://github.com/AllenInstitute/chromosome-network-modelingRelated ItemData/Code
ORCID:
AuthorORCID
Szelenyi, Eric R.0000-0003-2636-0912
Kim, Yongsoo0000-0002-4277-0279
Alternate Title:A brain network basis of Fragile X syndrome behavioral penetrance determined by X chromosome inactivation in female mice
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.
Funders:
Funding AgencyGrant Number
NIHR01 MH096946
NIHU01 MH105971
Gertrude and Louis Feil Family TrustUNSPECIFIED
DOI:10.1101/458992
Record Number:CaltechAUTHORS:20211102-195240613
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211102-195240613
Official Citation:Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease. Eric R Szelenyi, Danielle Fisenne, Joseph E Knox, Julie A Harris, James A Gornet, Ramesh Palaniswamy, Yongsoo Kim, Kannan Umadevi Venkataraju, Pavel Osten. bioRxiv 458992; doi: https://doi.org/10.1101/458992
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111712
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Nov 2021 21:16
Last Modified:02 Nov 2021 21:16

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