Editors' ChoiceInfectious Disease

Passenger mutations: Backseat drivers in failed translation

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Science Translational Medicine  26 Aug 2015:
Vol. 7, Issue 302, pp. 302ec148
DOI: 10.1126/scitranslmed.aad1826

Animal models are essential to the discovery, development, and preclinical testing of new drug candidates. Despite the existence of many animal models that faithfully represent features of human diseases, more than 80% of experimental therapies that look successful in the laboratory fail in human studies. This low rate of translation cannot be attributed to any single flaw in the development pipeline, but poorly defined genetics of many animal models clearly lies at the root of some of the discrepancy. In particular, Vanden Berghe et al. highlight the frequency of confounding mutations in a specific type of genetically modified mice.

The authors focused on the thousands of existing genetically modified mouse strains that were made by transfer of modified embryonic stem cells from the 129 mouse strain to another, C57BL/6J. This method, although standard, carries significant potential for confounding experimental results because the targeted gene remains flanked by DNA from the 129 strain, while the remaining genome is C57BL/6J. To counter this, the genetically modified mice were repeatedly backcrossed with C57BL/6J mice, but Vanden Berghe and colleagues show that nearly all 129-derived strains still carry multiple unintended “passenger” mutations in their DNA. When these strains are compared with wild-type C57BL/6J mice, phenotypic differences may be attributed to the targeted gene without consideration for confounding mutations, leading to erroneous interpretation of results. To avoid this pitfall altogether, scientists can use isogenic mouse strains, which are generated on pure genetic backgrounds. Due to the prevalence of 129-derived modified mouse strains, the authors introduced a Web-based tool, called Passenger Mutations Finder (http://me-pamufind-it.org), which may be useful for estimating the effect of passenger mutations on mouse phenotype. Thus, this study highlights a potential source for failed translation of preclinical studies and emphasizes the importance of attention to the genetic background of mouse models.

T. Vanden Berghe et al., Passenger mutations confound interpretation of all genetically modified congenic mice immunity. Cell 43, 200–209 (2015).[Abstract]

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