Sentinel Interaction Mapping (SIM) – A generic approach for the functional analysis of human disease gene variants using yeast

Autor: Young, Barry P., Post, Kathryn L., Chao, Jesse T., Meili, Fabian, Haas, Kurt, Loewen, Christopher
Rok vydání: 2020
Předmět:
human disease genes
Saccharomyces cerevisiae
Neuroscience (miscellaneous)
lcsh:Medicine
Medicine (miscellaneous)
Computational biology
yeast
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
In vivo
Gene Expression Regulation
Fungal
Databases
Genetic
lcsh:Pathology
Humans
PTEN
Genetic Predisposition to Disease
Resource Article
Gene
030304 developmental biology
variants
0303 health sciences
Functional analysis
biology
lcsh:R
PTEN Phosphohydrolase
Computational Biology
Genetic Variation
High-Throughput Nucleotide Sequencing
Reproducibility of Results
Genomics
biology.organism_classification
Yeast
Up-Regulation
Phenotype
biology.protein
Human genome
030217 neurology & neurosurgery
Function (biology)
lcsh:RB1-214
Zdroj: Disease Models & Mechanisms, Vol 13, Iss 7 (2020)
Disease Models & Mechanisms
article-version (VoR) Version of Record
ISSN: 1754-8411
1754-8403
DOI: 10.1242/dmm.044560
Popis: Advances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast Saccharomyces cerevisiae to quickly develop gene-specific in vivo assays that can be used to quantify the level of function of a genetic variant. Using synthetic dosage lethality screening, ‘sentinel’ yeast strains are identified that are sensitive to overexpression of a human disease gene. Variants of the gene can then be functionalized in a high-throughput fashion through simple growth assays using solid or liquid media. Sentinel interaction mapping (SIM) has the potential to create functional assays for the large majority of human disease genes that do not have a yeast orthologue. Using the tumour suppressor gene PTEN as an example, we show that SIM assays can provide a fast and economical means to screen a large number of genetic variants.
Summary: Sentinel interaction mapping is a technique that employs systematic genetic interaction mapping to identify yeast-human genetic interactions, which can be used to rapidly functionalize human disease genes and their variants.
Databáze: OpenAIRE
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