Infection-dependent phenotypes in MHC-congenic mice are not due to MHC: can we trust congenic animals?

摘要

Background Congenic strains of mice are assumed to differ only at a single gene or region of the genome. These mice have great importance in evaluating the function of genes. However, their utility depends on the maintenance of this true congenic nature. Although, accumulating evidence suggests that congenic strains suffer genetic divergence that could compromise interpretation of experimental results, this problem is usually ignored. During coinfection studies with Salmonella typhimurium and Theiler's murine encephalomyelitis virus (TMEV) in major histocompatibility complex (MHC)-congenic mice, we conducted the proper F₂ controls and discovered significant differences between these F₂ animals and MHC-genotype-matched P₀ and F₁ animals in weight gain and pathogen load. To systematically evaluate the apparent non-MHC differences in these mice, we infected all three generations (P₀, F₁ and F₂) for 5 MHC genotypes (b/b, b/q and q/q as well as d/d, d/q, and q/q) with Salmonella and TMEV. Results Infected P₀ MHC q/q congenic homozygotes lost significantly more weight (p = 0.02) and had significantly higher Salmonella (p 2 q/q homozygotes. Neither weight nor pathogen load differences were present in sham-infected controls. Conclusions These data suggest that these strains differ for genes other than those in the MHC congenic region. The most likely explanation is that deleterious recessive mutations affecting response to infection have accumulated in the more than 40 years that this B10.Q-H-2q MHC-congenic strain has been separated from its B10-H-2b parental strain. During typical experiments with congenic strains, the phenotypes of these accumulated mutations will be falsely ascribed to the congenic gene(s). This problem likely affects any strains separated for appreciable time and while usually ignored, can be avoided with the use of F₂ segregants.