Evolutionary perspective suggests candidate genes for variation in Turner Syndrome phenotype

abstract: Tremendous phenotypic variation exists across people with Turner syndrome (45,X). This variation likely stems from differential dosage of genes on the X chromosome. 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. In this study we take an evolutionary approach to rank candidate genes that may contribute to phenotypic variation among people with Turner Syndrome. We incorporate analysis of patterns of DNA methylation from 46,XX and 45,X individuals, and estimates of variable X-inactivation status across 46,XX individuals, with patterns of gene expression conservation on the X chromosomes across five tissues and ten species. We find that genes that escape XCI are possible candidate genes for Turner syndrome phenotype, indicated by the constant levels of expression in escape genes and inactivated genes. Variation in these genes is expected to affect phenotype when dosage is altered from typical levels