X-inactivation profile reveals extensive variability in X-linked gene expression in females

The human X chromosome The detailed sequence of the human X chromosome is published this week, together with a survey of inactivated X genes in females. Females have two Xs and males have one X and a Y; to make the gene dosage equivalent, females inactivate almost an entire chromosome. The X inactivation profile has important clinical implications, as the unique nature of sex chromosomes means that it contains a disproportionate number of disease-causing genes. With both the X and Y chromosomes sequenced, their evolution from a pair of ‘normal’ chromosomes can be studied in detail. The cover, by Alfred Pasieka (Science Photo Library), depicts the inactivation signal starting at the middle of the chromosome (where it is reddest) and moving out through the arms. In female mammals, most genes on one X chromosome are silenced as a result of X-chromosome inactivation 1 , 2 . However, some genes escape X-inactivation and are expressed from both the active and inactive X chromosome. Such genes are potential contributors to sexually dimorphic traits, to phenotypic variability among females heterozygous for X-linked conditions, and to clinical abnormalities in patients with abnormal X chromosomes 3 . Here, we present a comprehensive X-inactivation profile of the human X chromosome, representing an estimated 95% of assayable genes in fibroblast-based test systems 4 , 5 . In total, about 15% of X-linked genes escape inactivation to some degree, and the proportion of genes escaping inactivation differs dramatically between different regions of the X chromosome, reflecting the evolutionary history of the sex chromosomes. An additional 10% of X-linked genes show variable patterns of inactivation and are expressed to different extents from some inactive X chromosomes. This suggests a remarkable and previously unsuspected degree of expression heterogeneity among females.