Dataset Information

Phase separation as a possible mechanism for dosage sensitivity.

ABSTRACT:

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.

SUBMITTER: Yang L

PROVIDER: S-EPMC10789095 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Phase separation as a possible mechanism for dosage sensitivity.

Yang Liang L Lyu Jiali J Li Xi X Guo Gaigai G Zhou Xueya X Chen Taoyu T Lin Yi Y Li Tingting T

Genome biology 20240115 1

<h4>Background</h4>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.<h4>Results</h4>Here we provide bioinf ...[more]

PMID: 38225666

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Dataset Information

Phase separation as a possible mechanism for dosage sensitivity.

Background

Results

Conclusions

Publications

Phase separation as a possible mechanism for dosage sensitivity.

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