Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Caspases / genetics
  • Chromosome Mapping
  • Comparative Genomic Hybridization
  • Connexins / genetics
  • Genetic Variation / genetics*
  • Genome / genetics*
  • Genotype
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 8 / genetics
  • Mice
  • Mice, Congenic / genetics
  • Mice, Inbred C57BL / genetics*
  • Mice, Knockout
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide

Substances

  • Connexins
  • Nerve Tissue Proteins
  • Panx1 protein, mouse
  • Casp4 protein, mouse
  • Caspases
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • MMP8 protein, mouse
  • Matrix Metalloproteinase 8