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

View ORCID ProfileEric R Szelenyi, Danielle Fisenne, Joseph E Knox, Julie A Harris, James A Gornet, Ramesh Palaniswamy, View ORCID ProfileYongsoo Kim, Kannan Umadevi Venkataraju, Pavel Osten
doi: https://doi.org/10.1101/458992
Eric R Szelenyi
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
2Program in Neuroscience, Stony Brook University, Neurobiology and Behavior, Stony Brook, NY 11794.
3University of Washington, Department of Biological Structure, Seattle, WA 98195
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  • ORCID record for Eric R Szelenyi
Danielle Fisenne
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
4Hofstra University, Hempstead, NY 11549.
5Certerra Inc., Farmingdale, NY 11735
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Joseph E Knox
6Allen Institute for Brain Science, Seattle, WA 98109
7Facebook, Seattle, WA 98109
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Julie A Harris
6Allen Institute for Brain Science, Seattle, WA 98109
8Cajal Neuroscience Inc, Seattle, WA 98102
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James A Gornet
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
9Columbia University, New York, NY 10027
10California Institute of Technology, Pasadena, CA 91125
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Ramesh Palaniswamy
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
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Yongsoo Kim
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
11College of Medicine, Penn State University, Hershey, PA 17033
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Kannan Umadevi Venkataraju
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
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Pavel Osten
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
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  • For correspondence: osten@cshl.edu
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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 effect1–10. 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 germiline11–16. 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This version of the manuscript includes a thorough revision of main text and figures throughout.

  • https://github.com/AllenInstitute/chromosome-network-modeling

Copyright 
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.
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Posted October 13, 2021.
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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
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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

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