2024 Articles

Phase separation as a possible mechanism for dosage sensitivity

Yang, Liang; Lyu, Jiali; Li, Xi; Guo, Gaigai; Zhou, Xueya; Chen, Taoyu; Lin, Yi; Li, Tingting

Background
Deletion of haploinsufficient genes or duplication of triplosensitive ones results in phenotypic effects in a concentration-dependent manner, and the mechanisms underlying these dosage-sensitive effects remain elusive. Phase separation drives functional compartmentalization of biomolecules in a concentration-dependent manner as well, which suggests a potential link between these two processes, and warrants further systematic investigation.

Results
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.