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