Genome-wide linkage analyses identify Hfhl1 and Hfhl3 with frequency-specific effects on the hearing spectrum of NIH Swiss mice

James M Keller,Konrad Noben-Trauth

doi:10.1186/1471-2156-13-32

Abstract

BackgroundThe mammalian cochlea receives and analyzes sound at specific places along the cochlea coil, commonly referred to as the tonotopic map. Although much is known about the cell-level molecular defects responsible for severe hearing loss, the genetics responsible for less severe and frequency-specific hearing loss remains unclear. We recently identified quantitative trait loci (QTLs) Hfhl1 and Hfhl2 that affect high-frequency hearing loss in NIH Swiss mice. Here we used 2f1-f2 distortion product otoacoustic emissions (DPOAE) measurements to refine the hearing loss phenotype. We crossed the high frequency hearing loss (HFHL) line of NIH Swiss mice to three different inbred strains and performed linkage analysis on the DPOAE data obtained from the second-generation populations.ResultsWe identified a QTL of moderate effect on chromosome 7 that affected 2f1-f2 emissions intensities (Hfhl1), confirming the results of our previous study that used auditory brainstem response (ABR) thresholds to identify QTLs affecting HFHL. We also identified a novel significant QTL on chromosome 9 (Hfhl3) with moderate effects on 2f1-f2 emissions intensities. By partitioning the DPOAE data into frequency subsets, we determined that Hfhl1 and Hfhl3 affect hearing primarily at frequencies above 24 kHz and 35 kHz, respectively. Furthermore, we uncovered additional QTLs with small effects on isolated portions of the DPOAE spectrum.ConclusionsThis study identifies QTLs with effects that are isolated to limited portions of the frequency map. Our results support the hypothesis that frequency-specific hearing loss results from variation in gene activity along the cochlear partition and suggest a strategy for creating a map of cochlear genes that influence differences in hearing sensitivity and/or vulnerability in restricted portions of the cochlea.

Highlights

The mammalian cochlea receives and analyzes sound at specific places along the cochlea coil, commonly referred to as the tonotopic map
The 32 kHz auditory brainstem response (ABR) threshold distributions (Figure 1B-D) vary considerably, suggesting that the genetic factors that contribute to the differences in hearing within a population vary between populations
Correlations in distortion product otoacoustic emissions (DPOAE) data To determine if correlations between emissions intensities produced by different frequencies differed depending on the strain, we evaluated the correlations between 2f1-f2 distortion product intensities independently for each strain

Summary

Introduction

The mammalian cochlea receives and analyzes sound at specific places along the cochlea coil, commonly referred to as the tonotopic map. We crossed the high frequency hearing loss (HFHL) line of NIH Swiss mice to three different inbred strains and performed linkage analysis on the DPOAE data obtained from the second-generation populations. The astounding versatility of the mammalian cochlea is possible because its physiological and biomechanical characteristics change from the base to the apex to produce a gradient of frequency-specific regions referred to as the tonotopic map [1]. Perturbations in the expression or function of a number of the genes necessary for OHC activity have been shown to impair hearing [6], but the mechanisms responsible for coordinating and differentiating expression of these genes along the mammalian organ of Corti are yet to be determined

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