Alleles that modulate late life hearing in genetically heterogeneous mice

Abstract

A genetically heterogeneous population of mice was tested for hearing at 8, 18 and 22 months by auditory brainstem response (ABR), and genotyped at 128 markers to identify loci that modulate late life hearing loss. Half of the test mice were exposed to noise for 2 hr at age 20 months. Polymorphisms affecting hearing at 18 months were noted on chromosomes 2, 3, 7, 10, and 15. Most of these loci had effects only on responses to 48 kHz stimuli, but a subset also influenced the ABR at lower frequencies. Loci on chromosomes 4, 10, 12, and 14 had significant effects on hearing at 22 months in noise-exposed mice, and loci on chromosomes 10 and 11 had effects on mice not exposed to noise. Outer hair cell loss was modulated by polymorphisms on chromosomes 10, 11, 12, 17, and 19. Resistance to age-related hearing loss is thus modulated by a set of genetic effects, some age-specific, some frequency specific, some dependent on prior exposure to noise, and some of which compromise survival of cochlear hair cells.

Age-related changes in auditory nerve–inner hair cell connections, hair cell numbers, auditory brain stem response and gap detection in UM-HET4 mice

“…Generation of the UM-HET4 mice has been described previously (Schacht et al, 2012). UM-HET4 mice represent a genetically heterogeneous mouse population that offers two advantages over the inbred stocks more often used for studies of ARHL: genetic heterogeneity, and postponement of hearing loss to the second half of the lifespan.…”

“…Cochlear expression of three major neurotrophic factor genes, Ntf3, Bdnf and Gdnf , was examined to test for any association between changes in their expression and loss of IHC-AN connections for which they could serve as maintenance factors. The work was conducted using UM-HET4 mice (Schacht et al, 2012), bred through a 4-way cross of grand-parental strains, each of which lacks the sensitive allele at the Ahl locus that predisposes to an early onset ARHL (Johnson et al 1997; Johnson et al 2000; Noben-Trauth et al 2003). UM-HET4 mice comprise a diverse but replicable population in which hearing loss occurs in the last half of the lifespan, resembling in this way the typical age course of hearing loss in humans (Schacht et al, 2012).…”

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

“…In contrast, for 129S6, there appears to be no critical level, as the slope of the PTS growth versus exposure level function is extremely low (G2 dB PTS growth/dB increase in exposure SPL) compared to that seen in CBACa (~8 dB PTS/dB SPL) (Yoshida et al 2000;Kujawa et al 2007). Another genome-wide analysis of NR has been conducted using a four-way cross with 20-month old mice exposed to white noise (2-22 kHz) for 2 h at 110 dB SPL (Schacht et al 2012). Loci associated with NR detected in the four-way cross do not map to the same chromosomal regions as the QTL described in our study.…”

Genes and Hearing Loss: Relationship to Oxidative Stress and Free Radical Formation

“…These types of strains have greatly assisted in identifi cation of novel genetic variants associated with ARHL (Nemoto et al 2004 ;Johnson et al 2012 ). Similar approaches should prove useful to characterize the genetic basis of known strain differences in auditory function, including differences in responses to noise stress , protection from conditioning stresses (Barden et al 2012 ), and aging (Noben-Trauth and Johnson 2009 ;NobenTrauth et al 2010 ;Schacht et al 2012 ).…”

“…Through collective study by many laboratories, these strains provide the opportunity to investigate the genetic basis of phenotypic variation in a host of developmental and physiological processes across lifespan as well as to test for potential common genetic control points among these processes (Aylor et al 2011 ). Finally, analysis of progeny from a cross involving four inbred strains of mice has recently been used to localize several novel ARHL loci (Schacht et al 2012 ). These "four-way" progenies exhibit several features that are useful as model systems for analysis of complex genetic traits in mice, including their heterozygous nature across the genome that may better approximate the characteristics of human genomes ).…”