A gene-by-gene mosaic of dosage compensation strategies on the human X chromosome

Dosage compensation in humans – ensuring the viability and fitness of females, with two X chromosomes, and males, with one – is thought to be achieved chromosome-wide by heterochromatinization of one X chromosome during female development. We reassessed this through quantitative gene-by-gene analyses of expression in individuals with one to four X chromosomes, tolerance for loss-of-function mutations, regulation by miRNAs, allele-specific expression, and the presence of homologous genes on the Y chromosome. We found a mosaic of dosage compensation strategies on the human X chromosome reflecting gene-by-gene differences in multiple dimensions, including sensitivity to under- or over-expression. These insights enrich our understanding of Turner, Klinefelter, and other sex chromosome aneuploidy syndromes, and of sex-chromosome-mediated effects on health and disease in euploid males and females. One-Sentence Summary The human X chromosome displays several modes of dosage compensation, tailored to the qualities of individual genes. ### Competing Interest Statement The authors have declared no competing interest.