Relationship of X Chromosome Dosage Compensation to Intracellular Self/Not-self Discrimination: A Resolution of Mullerʹs Paradox?

Mullerʹs paradox is that X chromosome dosage compensation seems to have evolved in spite of there being only "exceedingly minute differences" between compensated and uncompensated phenotypes. The paradox can be resolved by considering, not the specific functions of individual proteins, but the collective functions of proteins per se. One such function could be the collective pressure exerted by proteins in the crowded cytosol to drive individual protein species from simple solution (aggregation) when their concentrations exceed specific thresholds. It is proposed that over evolutionary time, individual genes, both on X chromosomes and autosomes, would have fine-tuned factors such as transcription rates and protein stabilities to this collective pressure. However, without X chromosome dosage compensation the total concentration of cytosolic proteins, and hence the collective pressure, would have fluctuated between male and female generations. Fine-tuning, a process of viral importance for intracellular self/not-self discrimination, would have been severely compromised.