Dosage Compensation

The sex chromosomes evolved from a pair of autosomes that deviated over a period of time, with one chromosome losing most of its genes. In many animal groups, females have two X-chromosomes—a large chromosome with numerous genes. Males have one X and a Y chromosome, which has lost most genes except those involved in sex determination and fertility. Thus males are effectively monosomic for the X-chromosome. Monosomy being lethal for other chromosomes, organisms evolved a mechanism called ‘dosage compensation’ (DC) which quantitatively equalizes X-linked gene products between the sexes, compensating for their numerical disparity (dosage). Best studied in Drosophila, Caenorhabditis elegans, and mammals, different species adopt different mechanisms of DC. In Drosophila, genes on the male X-chromosome are twice as active as on each X-chromosome in females. In C. elegans, DC is achieved by the lowered activity of each X-chromosome in XX individuals vis-a-vis the male X. In mammals, the inactivation of an entire X-chromosome in the female results in the parity between the two sexes. Despite the difference in gross mechanisms, the molecular processes achieving DC are uniform due to chromatin modifications (histone acetylation, methylation, and DNA methylation) and synthesis of various noncoding RNAs (lncRNAs). Together, they regulate the X-chromosome activity. In mammals, a lncRNA from the inactive X—XIST (X-inactive specific transcript)—binds with the same X to initiate inactivation. X-chromosome inactivation (XCI) in humans reveals interesting mechanisms for en bloc regulation of gene function, as well as modifiers of Mendelian inheritance patterns in genetic disorders.