Evolutionary model of sex chromosome dosage compensation compared to the basal compensation response of an autosome after a deletion.

<p>After the proto-Y chromosome evolved a gene with a male-determining function (green bar), it became subject to gradual gene loss on a gene-by-gene or segment-by-segment basis due to lack of recombination between the proto-sex chromosomes. If the lost region on the proto-Y chromosome contained dosage sensitive genes such as those that encode transcriptional factors (yellow bars), this would have triggered a basal dosage compensation response (yellow faucet) on the proto-X chromosome and led to a partial (1.5-fold) increase of expression (small arrows). The same basal dosage compensation process would also modify a deleted region on an autosome (A) in an abnormal cell. Dosage-insensitive genes (black bars) may escape this process. When broader regions were lost on the proto-Y chromosome, the collective imbalance effects of multiple aneuploid genes would have become highly deleterious and the increased load of aneuploidy could have stressed the basal mechanism of dosage compensation. Survival was achieved by recruiting regulatory complexes such as the MSL complex (red faucet) to aneuploid X segments (red regions), to further increase gene expression (big arrows) and rescue the X monosomy. This feed-forward sex chromosome–specific regulation would provide 1.35-fold increase in expression, which together with the basal dosage compensation (1.5-fold increase) would achieve the approximate two-fold upregulation of most genes on the present day X chromosome. In contrast, large-scale deleterious autosomal aneuploidy would be lost due to lack of a specific sex-driven compensatory mechanism.