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Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novelXceallele associated with copy number changes

Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novelXceallele associated with copy number changes

Authors :
Paola Giusti-Rodríguez
Sarah A. Schoenrock
Lisa M. Tarantino
Daniel Oreper
Kathie Y. Sun
Vasyl Zhabotynsky
Fernando Pardo-Manuel de Villena
William Valdar
Rachel C. McMullan
Darla R. Miller
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176 kb candidate interval. A series of functionalXcealleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function-structure basis and location of theXce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross strains. Using published sequence data and applying a Bayesian “Pólya urn” model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20-30 cells contributing to brain. Second, NOD/ShiLtJ has a novel and unique functional allele,Xcef, that is the weakest in theXceallelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within theXce. Copy number variation is common at theXcelocus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weakXcealleles.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........6666b0553a6d91acc5a5cf507edf8c3d
Full Text :
https://doi.org/10.1101/2020.11.13.380535