Large-Scale Population Study of Human Cell Lines Indicates that Dosage Compensation Is Virtually Complete

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Abstract
X chromosome inactivation in female mammals results in dosage compensation of X-linked gene products between the sexes. In humans there is evidence that a substantial proportion of genes escape from silencing. We have carried out a large-scale analysis of gene expression in lymphoblastoid cell lines from four human populations to determine the extent to which escape from X chromosome inactivation disrupts dosage compensation. We conclude that dosage compensation is virtually complete. Overall expression from the X chromosome is only slightly higher in females and can largely be accounted for by elevated female expression of approximately 5% of X-linked genes. We suggest that the potential contribution of escape from X chromosome inactivation to phenotypic differences between the sexes is more limited than previously believed. The males and females of many species are distinguished by their inheritance of different sets of sex chromosomes. This creates a significant imbalance in gene number between the sexes. Dosage compensation is the correction for this imbalance and is achieved by regulating gene activity across entire sex chromosomes. For example, human females have two X chromosomes and males have only one. Dosage compensation in humans involves X chromosome inactivation, which is the silencing of one X chromosome in female cells. Some genes are known to escape the silencing process and so are expressed at higher levels in females than males. We have investigated the extent to which such genes disrupt dosage compensation by comparing the activity of X chromosome genes in a large number of human male and female cell lines. We have shown that gene expression from the X chromosome pair in female cell lines is only slightly higher than from the single X in males. The small difference can be accounted for by increased female expression of approximately 5% of X chromosome genes. We conclude therefore that dosage compensation in these human cell lines is virtually complete, and we suggest that differences in X chromosome gene expression between males and females may be less extensive than previously thought.