Genetic Architecture of Skewed X Inactivation in the Laboratory Mouse

Abstract

X chromosome inactivation (XCI) is the mammalian mechanism of dosage compensation that balances X-linked gene expression between the sexes. Early during female development, each cell of the embryo proper independently inactivates one of its two parental X-chromosomes. In mice, the choice of which X chromosome is inactivated is affected by the genotype of a cis-acting locus, the X-chromosome controlling element (Xce). Xce has been localized to a 1.9 Mb interval within the X-inactivation center (Xic), yet its molecular identity and mechanism of action remain unknown. We combined genotype and sequence data for mouse stocks with detailed phenotyping of ten inbred strains and with the development of a statistical model that incorporates phenotyping data from multiple sources to disentangle sources of XCI phenotypic variance in natural female populations on X inactivation. We have reduced the Xce candidate 10-fold to a 176 kb region located approximately 500 kb proximal to Xist. We propose that structural variation in this interval explains the presence of multiple functional Xce alleles in the genus Mus. We have identified a new allele, Xcee present in Mus musculus and a possible sixth functional allele in Mus spicilegus. We have also confirmed a parent-of-origin effect on X inactivation choice and provide evidence that maternal inheritance magnifies the skewing associated with strong Xce alleles. Based on the phylogenetic analysis of 155 laboratory strains and wild mice we conclude that Xcea is either a derived allele that arose concurrently with the domestication of fancy mice but prior the derivation of most classical inbred strains or a rare allele in the wild. Furthermore, we have found that despite the presence of multiple haplotypes in the wild Mus musculus domesticus has only one functional Xce allele, Xceb. Lastly, we conclude that each mouse taxa examined has a different functional Xce allele.

Noncanonical Genomic Imprinting Effects in Offspring

“…As detailed in the Supplemental Information, we can gain insights into the sensitivity of our methods by taking advantage of the known Xm expression bias in somatic tissues of female mice (Calaway et al, 2013;Chadwick and Willard, 2005;Fowlis et al, 1991;Gregg et al, 2010a;Wang et al, 2010). Between 80%-90% of X-linked genes exhibit a maternal allele expression bias in each of the four tissue types (Figures S2A and S2B).…”

X-chromosome inactivation: new insights into cis and trans regulation

“…Most of the candidate regions overlap with the Xic, but tend to exclude the Tsix/Xist region and Xite. The most recent identified a 176 kb region located approximately 500 kb proximal to Xist, that notably includes a set of tandem duplications and inversions [26 ]. The Xic was defined as a minimal region of 450 kb, although it is topologically organized in two adjacent TADs that span a total of over 750 kb.…”

Developmental regulation of X-chromosome inactivation

“…Besides individual SNPs, also copy number variations of trans--acting factor binding sites through duplications and inversions could be responsible for the differences in Xce allele strength [144]. In summary, it appears that the Xce consists of multiple genes, which can affect X--inactivation choice, and this is likely controlled by a number of different trans--acting factors.…”

“…So far the following Xce alleles have been identified in order of their strength (starting with the weakest / most likely to be inactivated allele): Xce a ≤ Xce f ≤ Xce e < Xce b < Xce c < Xce d [144]. In addition to the difference in skewing depending on Xce allele strength, a parent--of origin effect has been observed, with a tendency to slightly favor the paternal X--chromosome for inactivation, which might be caused by an incomplete erasure of epigenetic memory from imprinted XCI [132,133,144--147].…”

“…In addition to the difference in skewing depending on Xce allele strength, a parent--of origin effect has been observed, with a tendency to slightly favor the paternal X--chromosome for inactivation, which might be caused by an incomplete erasure of epigenetic memory from imprinted XCI [132,133,144--147]. A number of genetic mapping studies have defined the mouse Xce to different regions sized between several megabases [145,148,149] and down to 176 kilobases [144], either overlapping and/or proximal/distal to the Xic region. The mutations and associated genes on the X--chromosome responsible for the Xce effect have not yet been identified, but it has been suggested that multiple regions within the Xce region might contribute [145].…”