Phase separation as a possible mechanism for dosage sensitivity

Deletion of haploinsufficient genes or duplication of triplosensitive ones

Together, our study shows that phase separation is functionally linked to dosage sensitivity and provides novel insights for phase-separating protein prediction from the perspective of population genetics data.

Here we provide bioinformatic and experimental evidence to show a close link between phase separation and dosage sensitivity. We first demonstrate that haploinsufficient or triplosensitive gene products exhibit a higher tendency to undergo phase separation. Assessing the well-established dosage-sensitive genes HNRNPK, PAX6, and PQBP1 with experiments, we show that these proteins undergo phase separation. Critically, pathogenic variations in dosage-sensitive genes disturb the phase separation process either through reduced protein levels, or loss of phase-separation-prone regions. Analysis of multi-omics data further demonstrates that loss-of-function genetic perturbations on phase-separating genes cause similar dysfunction phenotypes as dosage-sensitive gene perturbations. In addition, dosage-sensitive scores derived from population genetics data predict phase-separating proteins with much better performance than available sequence-based predictors, further illustrating close ties between these two parameters. Conclusions: Together, our study shows that phase separation is functionally linked to dosage sensitivity and provides novel insights for phase-separating protein prediction from the perspective of population genetics data.