Abstract
BACKGROUND: X chromosome inactivation (XCI) refers to silencing of genes on one copy of the X chromosome in XX females, resulting in dosage compensation between XX females and XY males. Genes can escape this silencing, potentially leading to sex-based differences in disease. RESULTS: Across three primary tissue types, we determined XCI status by integrating whole-genome sequencing with bulk RNA-Seq data to assess allele-specific expression (ASE) at heterozygous SNPs. Across all genes and tissues, the average percentage of individuals showing escape was 4.7%. We show that models of full dosage compensation and no dosage compensation are strongly correlated over most parameter space. For G6PD deficiency, we illustrate that in G6PD*B/G6PD*A- heterozygotes, even if silencing is complete and escape is not associated with disease risk, the allele that is expressed can affect mRNA abundance. CONCLUSIONS: With respect to studies of the genetic architecture of complex traits, our results suggest that a model of full dosage compensation, although not strictly correct for much of chromosome X, is more appropriate than a model of no dosage compensation. We conclude that uncertainty about the model of dosage compensation should not be an impediment to analysis of chromosome X in genetic epidemiology studies.