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

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.

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…2; Shao et al 2010;Yazbek et al 2011;DeSantis et al 2013;Kato et al 2014;Winawer et al 2014;Zhu and Matin 2014). The CSSs and congenic strains derived from CSSs have been used to map QTLs and identify causal genetic variants for traits such as body weight, glucose homeostasis, anxiety, hearing loss, bone morphology, blood clotting, liver fibrosis, energy expenditure, seizure susceptibility, among others (Singer et al 2004;Singer 2005;Winawer et al 2007;Gregorová et al 2008;Sa et al 2008;Shao et al 2008;Boell et al 2011;DeSantis et al 2013;Spiezio et al 2014;Street et al 2014). …”

“…For example, a double CSS, which combined substituted Chromosomes 2 and 6, synergistically increased airway hyperresponsiveness (Ackerman et al 2005). Another example involves noise-induced hearing loss in CSSs and congenic strains derived from 129S6/SvEvTac and CBA/CaJ (Street et al 2014). Although QTLs were mapped to Chromosomes 4 and 17 with CSSs, subsequent studies with congenic strains and CSS crosses revealed both inter-and intrachromosomal epistatic interactions that regulated hearing loss.…”

A Chromosome 17 Locus Engenders Frequency-Specific Non-Progressive Hearing Loss that Contributes to Age-Related Hearing Loss in Mice

“…The phl1 locus on proximal Chr 17 and the ahl3 locus on distal Chr 17 are in the same regions that were shown on 129S6 mouse to have nr1 and nr6 loci, respectively (Street et al 2014). In light of this evidence, we speculated whether the AHL phenotype in 129S6 mice is genetically linked to the NR loci of Chr 17.…”

“…The strongest statistical association with NR was found on Chr 17, indicating that genes in these regions are most likely to contribute to the NR phenotype. Chr 17 was linked to two loci, nr1 on proximal Chr 17 (between markers D17Mit143-D17Mit100) and nr6 on distal Chr 17 (between markers D17Mit119-D17Mit1) (Street et al 2014). Independently, other research has shown that these genomic regions were also associated to other AHL genes (Mashimo et al 2006;Nemoto et al 2004).…”

“…Inbred mice strains with age-related hearing loss (AHL) are commonly used to understand the genetic basis of presbycusis. The 129S6 inbred mouse is a unique model of presbycusis in that it has early-onset AHL starting by 1 month of age, as well as having a remarkable resistance to noise-induced hearing loss (NIHL) (Yoshida et al 2000;Rosowski et al 2003;Ohlemiller and Gagnon 2004;Street et al 2014). Other known mice with AHL have a predisposition for NIHL, suggesting these traits are associated (Erway et al 1996;Davis et al 2001;Vázquez et al 2004).…”