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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.
Afiliação
  • Yang L; Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • Lyu J; IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • Li X; IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • Guo G; Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • Zhou X; Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
  • Chen T; Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • Lin Y; IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Centre for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. linyi@mail.tsinghua.edu.cn.
  • Li T; Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. litt@hsc.pku.edu.cn.
Genome Biol ; 25(1): 17, 2024 01 15.
Article em En | MEDLINE | ID: mdl-38225666
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.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Genética Populacional / Separação de Fases Tipo de estudo: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Genome Biol Assunto da revista: BIOLOGIA MOLECULAR / GENETICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Genética Populacional / Separação de Fases Tipo de estudo: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Genome Biol Assunto da revista: BIOLOGIA MOLECULAR / GENETICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China