Chemical genetics is the study of gene-product function in a cellular or organismal context using exogenous ligands. In this approach, small molecules that bind directly to proteins are used to alter protein function, enabling a kinetic analysis of the in vivo consequences of these changes. Recent advances have strongly enhanced the power of exogenous ligands such that they can resemble genetic mutations in terms of their general applicability and target specificity. The growing sophistication of this approach raises the possibility of its application to any biological process.
Key Points
Chemical genetics is the study of gene product function in a cellular or organismal context using exogenous ligands.
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The use of exogenous ligands requires three critical technologies: first, diverse chemical or peptide libraries; second, high-throughput screening; and last, protein target identification.
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To test the effects of the thousands or millions of compounds in large chemical-libraries, rapid methods are needed to conduct many assays in parallel.
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Target-based screens, which identify ligands for a specific protein of interest, are conceptually analogous to reverse-genetic methods, such as gene targeting in mice.
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Ligands to a specific protein target can be used to highlight the phenotypic consequences of inhibiting or otherwise altering the target protein.
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Phenotype-based screens test the ability of a peptide or small organic molecule to induce a specific phenotypic outcome in a cell or organism.
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DNA microarrays are useful for identifying the protein targets of small molecules.
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Acknowledgements
The author thanks J. M. Scharf and M. S. Stockwell for critical reading of the manuscript.
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Glossary
- FORWARD GENETICS
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Genetic analysis that proceeds from phenotype to genotype through positional cloning or a candidate-gene approach.
- TARGET IDENTIFICATION
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The process of finding cellular macromolecules that bind to a small molecule or peptide.
- SMALL ORGANIC MOLECULE (also called small molecule)
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Carbon-containing compounds that usually have a molecular weight of less than 2,000 g mol−1.
- STEREOCENTRE
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A carbon atom that bears four distinct functional groups.
- PEPTIDE APTAMER
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A short oligomer of amino acids, often fused to a protein scaffold.
- LIBRARY
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A large collection of peptides, small molecules or other reagents.
- SOLID-PHASE SYNTHESIS
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Chemical synthesis method using a solid support, such as a plastic bead.
- COMBINATORIAL CHEMISTRY
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The synthesis of numerous organic compounds by combining variations of each of the building blocks that comprise the compounds.
- REVERSE GENETICS
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Genetic analysis that proceeds from genotype to phenotype through gene-manipulation techniques.
- COMBINATORIAL LIBRARY
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A collection of small molecules synthesized by combinatorial chemistry.
- ALLELIC SCANNING
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The rapid detection of DNA sequence variations between two strains by analysing total genomic DNA on high-density DNA microarrays.
- EXPRESSION PROFILING
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The use of DNA microarrays to determine the expression level of thousands of genes simultaneously.
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Stockwell, B. Chemical genetics: ligand-based discovery of gene function. Nat Rev Genet 1, 116–125 (2000). https://doi.org/10.1038/35038557
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DOI: https://doi.org/10.1038/35038557
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