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Nat Rev Genet. 2017 Jan;18(1):24-40. doi: 10.1038/nrg.2016.118. Epub 2016 Oct 31.

Loss-of-function genetic tools for animal models: cross-species and cross-platform differences.

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Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna 1030, Austria.
Department of Biomedical Engineering and the Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA.
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 43 Ludwigstrasse, Bad Nauheim 61231, Germany.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21218, USA.
Howard Hughes Medical Institute, 725 North Wolfe Street, Baltimore, Maryland 21218, USA.
Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.


Our understanding of the genetic mechanisms that underlie biological processes has relied extensively on loss-of-function (LOF) analyses. LOF methods target DNA, RNA or protein to reduce or to ablate gene function. By analysing the phenotypes that are caused by these perturbations the wild-type function of genes can be elucidated. Although all LOF methods reduce gene activity, the choice of approach (for example, mutagenesis, CRISPR-based gene editing, RNA interference, morpholinos or pharmacological inhibition) can have a major effect on phenotypic outcomes. Interpretation of the LOF phenotype must take into account the biological process that is targeted by each method. The practicality and efficiency of LOF methods also vary considerably between model systems. We describe parameters for choosing the optimal combination of method and system, and for interpreting phenotypes within the constraints of each method.

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