Strain background effects and genetic modifiers of hearing in mice

Abstract

Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positional-candidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23(753A/G)). This variant also was shown to modify hearing loss associated with the Atp2b2(dfw-2J) and Mass1(frings) mutations. The hearing modifier (Moth1) of tubby (Tub(tub)) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans.

Fig. 1

Bimodal frequency distribution of backcross mice with different hearing thresholds. Frequency distributions of 16 kHz ABR thresholds are shown for the parental strains (NOD, CAST), the F1 hybrids, and the N2 generation progeny from a (NOD/LtJ × CAST/Ei) × NOD/LtJ backcross. The recessive nature of AHL is shown by the similar thresholds of CAST and F1 hybrid mice as contrasted with the thresholds of NOD mice. The frequency distribution of thresholds in the N2 mice is strongly bimodal, indicating the segregation of one or a few loci with large effects. The progressive nature of the hearing loss can be seen by comparing the threshold distributions of N2 mice tested at 3 and 6 months of age.

Fig. 2

Hearing loss progression and Cdh23 alleles among six different 129-related inbred strains. The average ABR thresholds for a 16 kHz pure tone stimulus and their standard error bars are shown for each strain and age when tested. The full strain names for the six abbreviations shown in the figure are as follows: 129P1/ReJ (129P1), 129P3/J (129P3), 129X1/SvJ (129X1), 129S1/SvImJ (129S1), 129S6/SvEv-Mos^tm1Ev/J (129S6), 129T2/SvEmsJ (129T2). 753A and 753G are allelic variants of the Cdh23 gene.