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Comparative studies of X inactivation within Eutheria

University of British Columbia

X chromosome inactivation has not been well studied in mammals other than humans and mice. In both species, the inactive X expresses the XIST/Xist (X-inactivation specific transcript) non-coding R N A that is crucial for dosage compensation in females. Although both species belong to the same mammalian subclass, Eutheria, they show significant differences in imprinting patterns, negative regulation of XIST/Xist, and extent of silencing on the inactive X chromosome. Furthermore, the mechanism by which the Xist transcript coats and silences the X in cis is unknown. This study focuses on X-inactivation in other eutherians, first to unravel domains within XIST/Xist of biological significance, and second to investigate whether incomplete silencing in humans is unique within the mammalian subclass. Comparative analysis to predict conserved secondary structures between seven eutherian orthologs revealed common stems in the sequence before the Xist A repeat, the A repeat, F repeat, and exon 4. Several complex secondary structures were also similar between rodents but were not conserved in other species. These included the D repeat; structures between the B and D, as well as A and F repeats; and the unique rodent exon 5. The significance of these conserved domains in the context of potential biological functions, and how the structural differences might account for some species-specific differences, is discussed in this thesis. To investigate the species variability in the extent of silencing, methylation analysis was performed on Zfic, JaridlC, Crsp2, Utx, Ubel, Ar, and Fmrl in the cow and coast mole, in addition to human and mouse. Results from this study suggest that mouse is distinct in its more complete inactivation at several loci - Zjx, Crsp2 - on the evolutionary newer part of the X , and Ubel on an evolutionary older part of the chromosome. In addition to evolutionary age, factors such as the position o f the centromere, distance from the X inactivation centre (XIC), and presence of Y homologs failed to consistently explain or predict whether the genes on the X chromosome would escape or be subject to inactivation. Further epigenetic analysis is necessary to understand the distinct mechanisms leading to escape versus inactivation amongst different mammals.

Text

2009-12-18

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http://hdl.handle.net/2429/16914

Medical Genetics

University of British Columbia

UBCV

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