Free-living human cells reconfigure their chromosomes in the evolution back to uni-cellularity

Cells of multi-cellular organisms evolve toward uni-cellularity in the form of cancer and, if humans intervene, continue to evolve in cell culture. During this process, gene dosage relationships may evolve in novel ways to cope with the new environment and may regress back to the ancestral unicellular state. In this context, the evolution of sex chromosomes vis-a-vis autosomes is of particular interest. Here, we report the chromosomal evolution in ~600 cancer cell lines. Many of them jettisoned either Y or the inactive X; thus, free-living male and female cells converge by becoming “de-sexualized”. Surprisingly, the active X often doubled, accompanied by the addition of one haploid complement of autosomes, leading to an X:A ratio of 2:3 from the extant ratio of 1:2. Theoretical modeling of the frequency distribution of X:A karyotypes suggests that the 2:3 ratio confers a higher fitness and may reflect aspects of sex chromosome evolution.