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Resistance to Noise-Induced Hearing Loss in 129S6 and MOLF Mice: Identification of Independent, Overlapping, and Interacting Chromosomal Regions

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Abstract

Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 × CBACa) and (MOLF × CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17.

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Acknowledgments

This work was supported by grants from the NIH including R21DC04983 (SGK), R01DC06305 (BLT), R01DC08577 (SGK), R01DC02739 (BLT), R01DC00188 (MCL), P30DC04661 (BLT), P30DC05209 (MCL), R01GM074244 (KWB), and DoD DM102092 (BLT). Additional support provided by an NSF Graduate Research Fellowship (AM) and a Howard Hughes Medical Institute Medical Research Fellow (AJI).

Conflict of Interest

The authors have declared that no competing interests exist.

Author information

Author notes

  1. Dustin J. Shilling

    Present address: Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, USA

  2. Ayaka J. Iwata

    Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

Authors and Affiliations

  1. The V.M. Bloedel Hearing Research Center, Department of Otolaryngology–HNS, University of Washington, Seattle, WA, 98195, USA

    Valerie A. Street, Jeremy C. Kallman, Dustin J. Shilling, Ayaka J. Iwata, Linda C. Robinson, Carol A. Robbins, Jin Li & Bruce L Tempel

  2. Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA

    Bruce L Tempel

  3. The Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA

    M. Charles Liberman

  4. Department of Otology and Laryngology, Harvard Medical School, Boston, MA, 02114, USA

    Sharon G. Kujawa & M. Charles Liberman

  5. Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, 22908, USA

    Ani Manichaikul

  6. Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Karl W. Broman

  7. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Dustin J. Shilling

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  1. Valerie A. Street
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  12. Bruce L Tempel
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Corresponding author

Correspondence to Bruce L Tempel.

Additional information

Valerie A. Street and Sharon G. Kujawa contributed equally to this work.

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Street, V.A., Kujawa, S.G., Manichaikul, A. et al. Resistance to Noise-Induced Hearing Loss in 129S6 and MOLF Mice: Identification of Independent, Overlapping, and Interacting Chromosomal Regions. JARO 15, 721–738 (2014). https://doi.org/10.1007/s10162-014-0472-x

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