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• W2043206875 abstract "Genetic differences in environmental toxicity and cancer susceptibility among individuals in a human population often reflect polymorphisms in the genes encoding drug-metabolizing enzymes (DMEs), drug transporters, and receptors that control DME levels. This field of study is called ecogenetics, and a subset of this field--concerning genetic variability in response to drugs--is termed pharmacogenetics. Although human-mouse differences might be 3- to perhaps 10-fold, human interindividual differences can be as great as 20-fold or more than 40-fold. It would be helpful, therefore, to study toxicokinetics/pharmacokinetics of particular environmental agents and drugs in mice containing these high- and low-extreme human alleles. We hope to use transgenic knock-in technology in order to insert human alleles in place of the orthologous mouse gene. However, the knock-in of each gene has normally been a separate event requiring the following: (a) construction of the targeting vector, (b) transfection into embryonic stem (ES) cells, (c) generation of a targeted mouse having germline transmission of the construct, and (d) backcross breeding of the knock-in mouse (at least 6-8 times) to produce a suitable genetically homogeneous background (i.e., to decrease experimental noise). These experiments require 1 1/2 to 2 years to complete, making this very powerful technology inefficient for routine applications. If, on the other hand, the initial knock-in targeting vector might include sequences that would allow the knocked-in gene to be exchanged (quickly and repeatedly) for one new allele after another, then testing distinctly different human polymorphic alleles in transgenic mice could be accomplished in a few months instead of several years. This gene-swapping technique will soon be done by zygotic injection of a human allele cassette into the sperm or fertilized ovum of the parental knock-in mouse inbred strain or by the cloning of whole mice from cumulus ovaricus cells or tail-snip fibroblasts containing the nucleus wherein each new human allele has already been swapped. In mouse cells in culture using heterotypic lox sites, we and others have already succeeded in gene swapping, by exchanging one gene, including its regulatory regions, with a second gene (including its regulatory regions). It is anticipated that mouse lines carrying numerous human alleles will become commonplace early in the next millennium." @default.
• W2043206875 created "2016-06-24" @default.
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• W2043206875 date "2000-09-01" @default.
• W2043206875 modified "2023-10-18" @default.
• W2043206875 title "“Gene-Swap Knock-in” Cassette in Mice to Study Allelic Differences in Human Genes" @default.
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• W2043206875 doi "https://doi.org/10.1111/j.1749-6632.2000.tb06876.x" @default.
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