Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior

Szelenyi, Eric R, Fisenne, Danielle, Knox, Joseph E, Harris, Julie A, Gornet, James A, Palaniswamy, Ramesh, Kim, Yongsoo, Venkataraju, Kannan Umadevi, Osten, Pavel (April 2024) Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior. Cell Reports, 43 (4). p. 114068. ISSN 2211-1247

[thumbnail of 10.1016.j.celrep.2024.114068.pdf] PDF
10.1016.j.celrep.2024.114068.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.
Download (6MB)

Abstract

The precise anatomical degree of brain X chromosome inactivation (XCI) that is sufficient to alter X-linked disorders in females is unclear. Here, we quantify whole-brain XCI at single-cell resolution to discover a prevalent activation ratio of maternal to paternal X at 60:40 across all divisions of the adult brain. This modest, non-random XCI influences X-linked disease penetrance: maternal transmission of the fragile X mental retardation 1 (Fmr1)-knockout (KO) allele confers 55% of total brain cells with mutant X-active, which is sufficient for behavioral penetrance, while 40% produced from paternal transmission is tolerated. Local XCI mosaicism within affected maternal Fmr1-KO mice further specifies sensorimotor versus social anxiety phenotypes depending on which distinct brain circuitry is most affected, with only a 50%-55% mutant X-active threshold determining penetrance. Thus, our results define a model of X-linked disease penetrance in females whereby distributed XCI among single cells populating brain circuitries can regulate the behavioral penetrance of an X-linked mutation.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders
organism description > animal
diseases & disorders > congenital hereditary genetic diseases > fragile X syndrome
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
organism description > animal > mammal > rodent
CSHL Authors:
Communities: CSHL labs > Osten lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 23 April 2024
Date Deposited: 16 Sep 2024 20:23
Last Modified: 16 Sep 2024 20:23
PMCID: PMC11107803
Related URLs:
URI: https://repository.cshl.edu/id/eprint/41672

Actions (login required)

Administrator's edit/view item Administrator's edit/view item