**Hearing Loss and Its Etiology**

**Chapter 1**

**Provisional chapter**

**Effects of Genetic Background on Susceptibility and**

**Effects of Genetic Background on Susceptibility and the** 

Acquired hearing loss, which includes age-related hearing loss and noise-induced hearing loss, is a common hearing impairment and shows phenotypic variability. One reason for phenotypic variability is influence of genetic background. The modifiers underlying genetic background are modulated and advance the hearing phenotypes through genegene interactions with other etiological genetic factors. Moreover, the modifiers play a role in the susceptibility of environmental hearing risk factors, namely, the strength and weakness of environmental susceptibility often modulate and advance hearing phenotypes via gene-environment interactions. The complicated gene-gene and geneenvironment interactions make genetic analysis of acquired hearing loss difficult. In particular, the effects of environmental factors cannot be completely excluded or controlled. Although genome-wide approaches to identify genetic modifiers have proven challenging in humans, the responsible genes and mutations are widely unknown. In this chapter, we suggest that mouse models are useful for studying genetic background effects for acquired hearing loss. The genetic analysis of mouse models identified the genetic modifiers. We review the genetic research in mouse models for acquired hearing loss to identify and confirm the modifiers by both forward and reverse genetics approaches.

**Keywords:** genetic background effects, mouse model, quantitative trait loci (QTL),

genetic modifiers, genetic interaction, epistasis, genome editing

DOI: 10.5772/intechopen.72469

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Hearing loss is the most common sensory disorder, which affects approximately 0.1–0.2% of newborns [1]. A genetic etiology of congenital hearing loss accounts for an estimate of at least 50–60% of hearing loss cases, whereas the remaining 40–50% develops from a nongenetic etiology, such as effects of risk factors for neonates and birth conditions [1–3]. To date, many

**the Acceleration of Hearing Loss in Mice**

Shumpei P. Yasuda, Yuki Miyasaka and Yoshiaki Kikkawa

**Acceleration of Hearing Loss in Mice**

Shumpei P. Yasuda, Yuki Miyasaka and

http://dx.doi.org/10.5772/intechopen.72469

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Yoshiaki Kikkawa

**Abstract**

**1. Introduction**

**Provisional chapter**

#### **Effects of Genetic Background on Susceptibility and the Acceleration of Hearing Loss in Mice Effects of Genetic Background on Susceptibility and the Acceleration of Hearing Loss in Mice**

DOI: 10.5772/intechopen.72469

Shumpei P. Yasuda, Yuki Miyasaka and Yoshiaki Kikkawa Shumpei P. Yasuda, Yuki Miyasaka and Yoshiaki Kikkawa Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72469

#### **Abstract**

Acquired hearing loss, which includes age-related hearing loss and noise-induced hearing loss, is a common hearing impairment and shows phenotypic variability. One reason for phenotypic variability is influence of genetic background. The modifiers underlying genetic background are modulated and advance the hearing phenotypes through genegene interactions with other etiological genetic factors. Moreover, the modifiers play a role in the susceptibility of environmental hearing risk factors, namely, the strength and weakness of environmental susceptibility often modulate and advance hearing phenotypes via gene-environment interactions. The complicated gene-gene and geneenvironment interactions make genetic analysis of acquired hearing loss difficult. In particular, the effects of environmental factors cannot be completely excluded or controlled. Although genome-wide approaches to identify genetic modifiers have proven challenging in humans, the responsible genes and mutations are widely unknown. In this chapter, we suggest that mouse models are useful for studying genetic background effects for acquired hearing loss. The genetic analysis of mouse models identified the genetic modifiers. We review the genetic research in mouse models for acquired hearing loss to identify and confirm the modifiers by both forward and reverse genetics approaches.

**Keywords:** genetic background effects, mouse model, quantitative trait loci (QTL), genetic modifiers, genetic interaction, epistasis, genome editing

#### **1. Introduction**

Hearing loss is the most common sensory disorder, which affects approximately 0.1–0.2% of newborns [1]. A genetic etiology of congenital hearing loss accounts for an estimate of at least 50–60% of hearing loss cases, whereas the remaining 40–50% develops from a nongenetic etiology, such as effects of risk factors for neonates and birth conditions [1–3]. To date, many

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

mutations responsible for hearing loss have been recently identified in approximately 100 human genes [3, 4]. However, most mutations are primarily associated with congenital and severe hearing loss developed at newborn and childhood stages caused by a single gene. The identification of the more common "acquired hearing loss," such as age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL) is currently understudied.

effect. In most cases, the genetic background effects are revealed by the expression of different phenotypes caused by the same genetic mutation in different genetic backgrounds. Let us assume that a gene associated with hearing loss was mutated by gene targeting in mice (strain R). We performed the hearing test of knock-out (KO) mice using measurements of ABR. The KO mouse exhibited latency peak responses for peaks I–V as well as the wild-type mouse; however, the amplitudes of all the peaks were weak and delayed. Next, we performed the gene targeting of the same gene in mice of different genetic backgrounds (strain S). The mouse had no discernable ABR waveform, indicating that the hearing loss of the mouse became more severe due to variation in the genetic background. These results suggest the presence of a genetic modifier, which affects the phenotype developed by the mutation of the causative gene, with respect to the genetic background of strain R. Moreover, it is assumed that the modifier interacts with the causative gene in the acceleration of hearing loss. The genetic interaction could be separated into nonadditive and additive effects to

Effects of Genetic Background on Susceptibility and the Acceleration of Hearing Loss in Mice

http://dx.doi.org/10.5772/intechopen.72469

5

**Figure 1.** Simple models for genetic background effect in phenotypic modification. (A) Schematic representation of the genetic background effect in hearing of mice. Illustrations show the differences of auditory brainstem response (ABR) waveforms by the effects of the susceptible allele (black stars) in the hearing loss mutant. Black circles indicate mutation associated with hearing loss. The locations of ABR peaks I–V are indicated with ranges (μV) of the negative wave apex and latency (ms). (B) Definition of additive (top) and nonadditive (bottom) interaction in phenotypic modification.

Acquired common hearing loss is a complex multifactorial disease influenced by genetic backgrounds and environments. In ARHL, an accurate estimation of the genetic etiology has not been reported. However, it is estimated that ARHL develops through the effects of genetic modifier(s) because the onset time and severity of hearing loss vary greatly among individuals [5, 6]. Moreover, there is a significant heritability of hearing phenotypes [6]. The heritability ranges from low to high [6–10], suggesting that multiple genetic modifiers and environmental factors contribute to the onset and severity of hearing loss. The documented risk factors of ARHL and acquired hearing loss are noise, smoking, alcohol consumption, diet and reduced exercise, complication of other diseases, and uses of ototoxic drugs [6, 11]. It is known that one major risk factor is exposure to loud noise, accounting for approximately 16% of the population worldwide [12]. Genetic factors from a genetic background might also play an important role in the susceptibility of NIHL [13]. However, the identification of genetic background effects in ARHL and NIHL is difficult in humans because of lower heritability of this phenotype and the influence of environmental risk factors mentioned above. In addition, genetic differences among individuals disturb genetic analysis.

To investigate genetic background effects associated with hearing loss, we propose that mouse models have several advantages to overcome weaknesses in the genetic analysis of ARHL and NIHL in humans. Mice can be controlled to avoid environmental risk factors. The techniques for evaluation of hearing, such as measurements of the auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE), have been established [14–18]. Based on the techniques, it is known that there is phenotypic heterogeneity of ARHL and NIHL caused by genetic background effects [3, 6, 11]; therefore, the genetic background effects can be analyzed using the quantitative trait loci (QTL) analysis and genome-wide association study (GWAS) of experimental populations produced by mating susceptible and resistant strains of ARHL and NIHL. This chapter applies the advantages of a genetic analysis by using mouse models to study the genetic background effects of hearing loss.
