Chemical genetics is the investigation of the function of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s and

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

pathways in cells by the

screening Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), a ...

chemical libraries A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., wi ...

small molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...

s. Chemical genetics is analogous to classical

genetic screen A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens c ...

where random mutations are introduced in organisms, the

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

of these mutants is observed, and finally the specific gene mutation (

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds.

Phenotypic screening In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

of chemical libraries is used to identify drug targets (

forward genetics Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a partic ...

chemoproteomics Chemoproteomics entails a broad array of techniques used to identify and interrogate protein- small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of allev ...

) or to validate those targets in experimental models of disease (

reverse genetics Reverse genetics is a method in molecular genetics that is used to help understand the function(s) of a gene by analysing the phenotypic effects caused by genetically engineering specific nucleic acid sequences within the gene. The process proce ...

). Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments. Chemical genetics can serve as a unifying study between chemistry and biology. The approach was first proposed by

Tim Mitchison Timothy John Mitchison is a cell biologist and systems biologist and Hasib Sabbagh Professor of Systems Biology at Harvard Medical School in the United States. He is known for his discovery, with Marc Kirschner, of dynamic instability in microt ...

in 1994 in an opinion piece in the journal ''Chemistry & Biology'' entitled "Towards a pharmacological genetics".

Method

Chemical genetic screens are performed using libraries of

s that have known activities or simply diverse chemical structures. These screens can be done in a high-throughput mode, using 96 well-plates, where each well contains cells treated with a unique compound. In addition to cells, ''

Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-known ...

'' or

zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...

embryos can also be screened in 96 well format where compounds are dissolved in the media in which embryos grow. Embryos are developed until the stage of interest and then the phenotype can be analyzed. Several concentrations can be tested in order to determine the toxic and the optimal concentrations.

Applications

Adding compounds to developing embryos allow comprehension of mechanism of action of drugs, their toxicity and developmental processes involving their targets. Chemical screens have been mostly performed on either wild type or transgenic ''

'' and

organisms as they produce a large amount of synchronized, fast-to-develop and transparent eggs easy to visually score. The use of chemicals in developmental biology offers two main advantages. Firstly, it is easy to perform high-throughput screen using wide spectrum or specific target compounds and reveal important genes or pathways involved in developmental processes. Secondly, it allows narrowing the time of action of a particular gene. It can also be used as a tool in drug development to test toxicity in whole organism. Procedures such as FETAX (Frog Embryo Teratogenesis Assay – Xenopus) are being developed to implement chemical screenings to test toxicity. Zebrafish and ''Xenopus'' embryos have also been used to identify new drugs targeting a particular gene of interest.

References

{{Reflist, 33em Genetics

Method

Applications

See also

References