Genomic characterization and comparative analysis of the Xce candidate region

<p>Mechanisms of sex chromosome dosage compensation vary widely between different vertebrate species. All eutherians, including humans, other primates, and rodents, undergo random X chromosome inactivation in early female embryos, a process by which the majority of the genes on one X chromosome in the female are silenced (inactive X, Xi) to create a transcription level matching that of the single X chromosome in males. Random inactivation of the placental embryo is initiated from a region on the X chromosome called the X-inactivation center (XIC in humans and Xic in mice), thus implicating this region as the key chromosomal element in distinguishing random from imprinted X inactivation during mammalian evolution. This invites a comparative genomic approach to explore the organization and evolution of this region throughout mammalian lineages</p><p>Patterns of X inactivation are genetically determined, as indicated by non-random patterns of inactivation in mice heterozygous for the X-linked X controlling element (Xce) locus, the molecular and genomic basis of which is unknown. Using QTL mapping in Xce heterozygous mice, we previously identified a 1.85Mb candidate region for Xce. This candidate region contains the X inactivation center (Xic), including the critical X inactivation genes Xist and Tsix. To explore the genomic organization of this region in C57BL/6J (B6), we identified extensive large (>5Kb) inverted and non-inverted segmental duplications lying greater than 350Kb proximal to Xist. Investigating these segmental duplications further, we then compared copy number and sequence variant differences among strains carrying different Xce alleles to identify candidate variants in a subportion of the interval that correlate with specific Xce alleles. </p><p>The Xce candidate region was then compared to the corresponding region of the X chromosome from several other species. Notably, the segmental duplications within the mouse Xce region are maintained positionally through the other species over at least 105 MYA, although they do not share the same DNA in the copy variant. </p><p>These and future experiments should provide detailed characterization of the Xce candidate region and an opportunity to address the role that these sequence signatures may play in the earliest stages of X inactivation when the two X chromosomes are distinguished from one another.</p>Dissertatio