Evolutionary perspective suggests candidate genes for variation in Turner Syndrome phenotype

Tremendous phenotypic variation exists across people with Turner syndrome (45,X). This variation likely stems from differential dosage of genes on the X chromosome. In this study we take an evolutionary approach to rank candidate genes that may affect phenotype across people with Turner Syndrome. X-inactivation is the process whereby all X chromosomes in excess of one are silenced. However, about 15% of the genes on the silenced X chromosome escape this inactivation and are candidates for affecting phenotype in people with Turner syndrome. We analyze patterns of DNA methylation from 46,XX and 45,X individuals, to inform about X-inactivation status, comparing this with studies about X-inactivation status from cell-lines, to classify genes on the human X chromosome into those that may be more dosage sensitive. We then analyze patterns of gene expression conservation across five tissues and ten species by class of X-linked gene, to learn which may be more evolutionarily conserved, and thus more likely to affect phenotype when dosage is altered from typical levels.