Genetic modification of heaving in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss

Quantitative trait locus (QTL) analysis of genetic crosses has proven to be a useful tool for identifying loci associated with specific phenotypes and for dissecting genetic components of complex traits. Inclusion of a mutati on that interacts epistatically with QTLs in genetic crosses is a unique an d potentially powerful method of revealing the function of novel genes and pathways. Although we know that a mutation within the novel tub gene leads to obesity and cochlear and retinal degeneration, the biological function o f the gene and the mechanism by which it induces its phenotypes are not kno wn. In the current study, a QTL analysis for auditory brainstem response (A BR) thresholds, which indicates hearing ability, was performed in tubby mic e from F-2 intercrosses between C57BL/6J-tub/tub and AKR/J-+/+ F-1 hybrids (AKR intercross) and between C57BL/6J-tub/tub and CAST/Ei.B6-tub/tub F-1 hy brids (CAST intercross). A major QTL, designated as modifier of tubby heari ng1 (moth1), was identified on chromosome 2 with a LOD score of 33.4 (P < 1 0(-33)) in the AKR intercross (181 mice) and of 6.0 (P < 10(-6)) in the CAS T intercross (46 mice). This QTL is responsible for 57 and 43% of ABR thres hold variance, respectively, in each strain combination. In addition, a C57 BL/6J congenic line carrying a 129/OIa segment encompassing the described Q TL region when made homozygous for tubby also exhibits normal hearing abili ty. We hypothesize that C57BL/6J carries a recessive mutation of the moth1 gene which interacts with the tub mutation to cause hearing loss in tub/tub mice, A moth1 allele from either AKR/J, CAST/Ei or 129/OIa is sufficient t o protect C57BL/6J-tub/tub mice from hearing loss.