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Early studies in Caenorhabditis elegans [1] and Drosophila melanogaster [2] [3] saw large-scale, systematic loss of function (LOF) screens performed through saturation mutagenesis, demonstrating the potential of this approach to characterise genetic pathways and identify genes with unique and essential functions.
A suppressor screen is used to identify suppressor mutations that alleviate or revert the phenotype of the original mutation, in a process defined as synthetic viability. [13] Suppressor mutations can be described as second mutations at a site on the chromosome distinct from the mutation under study, which suppress the phenotype of the original ...
A large-scale screen for somatic mutations in breast and colorectal tumors showed that many low-frequency mutations each make small contribution to cell survival. [33] If cell survival is determined by many mutations of small effect, it is unlikely that genome sequencing will uncover a single "Achilles heel" target for anti-cancer drugs.
Currently, off-target effects of CRISPRi are minimal, and show a reduced response and sensitivity to single-base mismatches. [44] Importantly, when non-specific effects do inevitably occur they are reversible, time-dependent, and less damaging than DNA editing, making them effective alternatives that can limit the off-target burden when possible.
Germline mutations in drug targets can also influence response to medications, though this is an emerging subfield within pharmacogenomics. One well-established gene-drug interaction involving a germline mutation to a drug target is warfarin (Coumadin) and VKORC1 , which codes for vitamin K epoxide reductase (VKOR) .
Site directed mutagenesis allows the effect of specific mutation to be investigated. There are numerous uses; for example, it has been used to determine how susceptible certain species were to chemicals that are often used In labs. The experiment used site directed mutagenesis to mimic the expected mutations of the specific chemical.
More recently, large-scale phenotypic screens have also been used in animals, e.g. to study lesser understood phenotypes such as behavior. In one screen, the role of mutations in mice were studied in areas such as learning and memory, circadian rhythmicity, vision, responses to stress and response to psychostimulants.
Afterwards, these compounds are tested in animals to see if they have the desired effect. This approach is known as " reverse pharmacology " or "target based drug discovery" (TDD). [ 5 ] However recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic ...