Skewed X inactivation in genetically diverse mice is associated with recurrent copy number changes at the Xce locus
Sun, K. Y.; Oreper, D. G.; Schoenrock, S. A.; McMullan, R.; Giusti-Rodriguez, P.; Zhabotynsky, V.; Miller, D. R.; Tarantino, L. M.; Pardo-Manuel de Villena, F.; Valdar, W.
Show 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 functional Xce alleles 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 the Xce, 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 "Polya 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 the Xce allelic 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 the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.
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