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Immunity. 2015 Jul 21;43(1):200-9. doi: 10.1016/j.immuni.2015.06.011. Epub 2015 Jul 7.

Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice.

Author information

1
Inflammation Research Center, VIB, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium. Electronic address: tom.vandenberghe@irc.vib-ugent.be.
2
Inflammation Research Center, VIB, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
3
Department of Biomedical Engineering, University of Rochester, Rochester NY 14627, USA.
4
GNOMIXX bvba, Statistics for Genomics, 9000 Ghent, Belgium.
5
Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, Vavilov Institute for General Genetics, Moscow 119333, Russia.
6
Inflammation Research Center, VIB, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium; Methusalem Program, Ghent University, 9000 Ghent. Electronic address: peter.vandenabeele@irc.vib-ugent.be.

Abstract

Targeted mutagenesis in mice is a powerful tool for functional analysis of genes. However, genetic variation between embryonic stem cells (ESCs) used for targeting (previously almost exclusively 129-derived) and recipient strains (often C57BL/6J) typically results in congenic mice in which the targeted gene is flanked by ESC-derived passenger DNA potentially containing mutations. Comparative genomic analysis of 129 and C57BL/6J mouse strains revealed indels and single nucleotide polymorphisms resulting in alternative or aberrant amino acid sequences in 1,084 genes in the 129-strain genome. Annotating these passenger mutations to the reported genetically modified congenic mice that were generated using 129-strain ESCs revealed that nearly all these mice possess multiple passenger mutations potentially influencing the phenotypic outcome. We illustrated this phenotypic interference of 129-derived passenger mutations with several case studies and developed a Me-PaMuFind-It web tool to estimate the number and possible effect of passenger mutations in transgenic mice of interest.

PMID:
26163370
PMCID:
PMC4800811
DOI:
10.1016/j.immuni.2015.06.011
[Indexed for MEDLINE]
Free PMC Article

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