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