Post-transcriptional Cross- and Auto-regulation Buffer Expression of the Human RNA Helicases and

The Y-linked gene and its X-linked homolog survived the evolution of the human sex chromosomes from ordinary autosomes. encodes a multi-functional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs, is extraordinarily dosage-sensitive. Studying cells of individuals with sex chromosome aneuploidy, we observe that when the number of Y chromosomes increases, transcript levels fall; conversely, when the number of X chromosomes increases, transcript levels fall. In 46,XY cells, CRISPRi knockdown of either or causes transcript levels of the homologous gene to rise. In 46,XX cells, chemical inhibition of DDX3X protein activity elicits an increase in transcript levels. Thus, perturbation of either or expression is buffered - by negative cross-regulation of and in 46,XY cells, and by negative auto-regulation of in 46,XX cells. - cross-regulation is mediated through mRNA destabilization - as shown by metabolic labeling of newly transcribed RNA - and buffers total levels of DDX3X and DDX3Y protein in human cells. We infer that post-transcriptional auto-regulation of the ancestral (autosomal) gene transmuted into auto- and cross-regulation of and as these sex-linked genes evolved from ordinary alleles of their autosomal precursor.