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

Infected P0 MHC q/q congenic homozygotes lost significantly more weight (p = 0.02) and had significantly higher Salmonella (p < 0.01) and TMEV (p = 0.02) titers than the infected F2 q/q homozygotes. Neither weight nor pathogen load differences were present in sham-infected controls.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.It is assumed that knockout, transgenic or other congenic strains of mice are identical at all loci or genomic regions except the one being studied. There are three principal sources of genetic variation that could cause congenic strains to diverge: 1) residual heterozygosity may remain after the construction of the strains, 2) poor animal husbandry could lead to contamination of the strains, and 3) new mutations could become fixed in the strains. There are documented cases in strains of mice of residual heterozygosity [1], genetic contamination [2] and accumulated mutations [3,4]. The relative importance of these three possible sources of genetic divergence among laboratory strains is unclear.Appreciation of the problem of genetic divergence in strains of inbred mice is not a new one. It has long been expected that independently maintained strains (substrains) might accumulate genetic differences over time [5] and there are now numerous documented cases of phenotypic divergence between substrains. For instance, different substrains of mice respond differently with respect