**2. What is a genetic background effect?**

First, we will explain the basic mechanisms of background effect in phenotypic modification to readers in a way that they will understand the importance of this chapter.

#### **2.1. Gene-gene interaction**

A complex disease is one that lacks a one-to-one correspondence of mutation and phenotype [19, 20], namely, the expression of phenotype is influenced by genetic modifier(s) underlying the genetic background. **Figure 1A** shows a simple model of the genetic background 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

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

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,

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

First, we will explain the basic mechanisms of background effect in phenotypic modification

A complex disease is one that lacks a one-to-one correspondence of mutation and phenotype [19, 20], namely, the expression of phenotype is influenced by genetic modifier(s) underlying the genetic background. **Figure 1A** shows a simple model of the genetic background

(ARHL) and noise-induced hearing loss (NIHL) is currently understudied.

genetic differences among individuals disturb genetic analysis.

using mouse models to study the genetic background effects of hearing loss.

to readers in a way that they will understand the importance of this chapter.

**2. What is a genetic background effect?**

**2.1. Gene-gene interaction**

4 An Excursus into Hearing Loss

**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.

evaluate whether the gene-gene, gene-protein, and protein-protein interaction are present in the regulatory pathway of the phenotype (**Figure 1B**). The nonadditive effect is called "epistasis" in technical terms of genetics, stating that there is a direct interaction between two or more genes [19, 20]. The additive effect states that phenotypic acceleration and modification occur by accumulation of mutations in genes of similar function in different molecular pathways (**Figure 1B**) [20].

waveform in strain S were significantly lower than those in strain R. This result suggests that strain R is a noise-resistant strain, whereas strain S is a noise-susceptible strain. In addition, the genetic mechanism for noise sensitivity in both strains can be explained by the presence of resistance and susceptibility alleles in addition to the risk of noise exposure, namely, a gene-environment interaction contributes to the development of NIHL (**Figure 2B**) based on a genetic background effect. Thus, the genetic background effect is important in the study of

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

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

7

There is one thing to note. Although we explained the gene-environment interaction using a model that would be easy to understand, this model is admittedly simple because it only considers the effect of one gene and one environmental factor. In the case of human diseases, the gene-environment interactions are more complicated because the interactions involve multiple genes, multiple environmental factors, genetic heterogeneity, and heterogeneity of

**3. Phenotypic variations of hearing caused by genetic backgrounds** 

Laboratory mice are one of the best experimental models to investigate the genetic background effect for ARHL as mentioned in Section 1. Moreover, the classical inbred strains have been established in large numbers and exhibit variable hearing ability and onset time of ARHL caused by genetic background [21, 22]. **Figure 3** shows the means of ABR thresholds to tone-pip stimuli at 4, 8, 16, and 32 kHz in mice from MSM/Ms, C3H/HeN, C57BL/6J, A/J, and DBA/2J at 4 months of age, as cited in our previous studies [23–25]. The hearing phenotypes of these strains can be classified into two groups: normal hearing and early onset ARHL. The MSM/Ms and C3H/HeN comprise the normal hearing group. The ABR thresholds are stable at all frequencies. The C57BL/6J mice also show normal ABR thresholds at 4, 8, and 16 kHz. However, the ABR threshold at 32 kHz of C57BL/6J mice is significantly higher than that of MSM/Ms and C3H/HeN mice, indicating that C57BL/6J developed high-frequency-specific ARHL. The A/J mice exhibit an ARHL that is more severe for high-frequency stimuli. In addition, the ABR thresholds of the A/J mice at other frequencies are clearly increased when compared with those of C57BL/6J mice. Moreover, the DBA/2J mice developed more severe hearing loss. The ABR thresholds of the DBA/2J mice exhibited levels of severe (71–90 dB SPL) and profound (<91 dB SPL) hearing loss in sound stimuli at 4/8 and 16/32 kHz, respectively, which were significantly higher than those

The difference between the normal hearing and early onset ARHL groups can be explained by a mutation of the Cadherin 23 gene (*Cdh23*). The responsible *Cdh23c.753G>A* mutation was identified at one base before the splice-donor site, leading to partial skipping of a single exon [21, 24, 26] and age-related stereocilia degeneration in cochlear hair cells [23, 24, 27]. The A/J mice have another strain-specific mutation (p.His55Asn) in the citrate synthase gene (*Cs*) [28]. By identifying *Csp.His55Asn* mutation, A/J mice were shown to have developed severe ARHL

the influence of environmental factors on complex diseases.

environmental exposure [20].

**in mouse inbred strains**

of A/J mice at 4, 8, and 16 kHz.

#### **2.2. Gene-environment interaction**

In a complex disease, the expression of phenotype is also influenced by environmental factor(s), along with the interaction between the environment and genes in genetic background. A model is shown in **Figure 2A**. Let us assume that we performed an experiment of noise exposure to mice. We performed the experiment in strains R and S and then measured ABR. The ABR responses between the two strains were different. The peaks of the ABR

**Figure 2.** Simple models for genetic background effect in the susceptibility of environmental factors. (A) Schematic representation of the genetic background effect in noise-induced hearing loss of mice. Illustrations show the differences between strain R and S of ABR waveforms by the effects of the noise exposure and susceptible allele (black stars). The locations of ABR peaks I–V are indicated with ranges (μV) of the negative wave apex and latency (ms). (B) a model for genetic background effect in the susceptibility of environmental factors.

waveform in strain S were significantly lower than those in strain R. This result suggests that strain R is a noise-resistant strain, whereas strain S is a noise-susceptible strain. In addition, the genetic mechanism for noise sensitivity in both strains can be explained by the presence of resistance and susceptibility alleles in addition to the risk of noise exposure, namely, a gene-environment interaction contributes to the development of NIHL (**Figure 2B**) based on a genetic background effect. Thus, the genetic background effect is important in the study of the influence of environmental factors on complex diseases.

evaluate whether the gene-gene, gene-protein, and protein-protein interaction are present in the regulatory pathway of the phenotype (**Figure 1B**). The nonadditive effect is called "epistasis" in technical terms of genetics, stating that there is a direct interaction between two or more genes [19, 20]. The additive effect states that phenotypic acceleration and modification occur by accumulation of mutations in genes of similar function in different molecu-

In a complex disease, the expression of phenotype is also influenced by environmental factor(s), along with the interaction between the environment and genes in genetic background. A model is shown in **Figure 2A**. Let us assume that we performed an experiment of noise exposure to mice. We performed the experiment in strains R and S and then measured ABR. The ABR responses between the two strains were different. The peaks of the ABR

**Figure 2.** Simple models for genetic background effect in the susceptibility of environmental factors. (A) Schematic representation of the genetic background effect in noise-induced hearing loss of mice. Illustrations show the differences between strain R and S of ABR waveforms by the effects of the noise exposure and susceptible allele (black stars). The locations of ABR peaks I–V are indicated with ranges (μV) of the negative wave apex and latency (ms). (B) a model for

genetic background effect in the susceptibility of environmental factors.

lar pathways (**Figure 1B**) [20].

6 An Excursus into Hearing Loss

**2.2. Gene-environment interaction**

There is one thing to note. Although we explained the gene-environment interaction using a model that would be easy to understand, this model is admittedly simple because it only considers the effect of one gene and one environmental factor. In the case of human diseases, the gene-environment interactions are more complicated because the interactions involve multiple genes, multiple environmental factors, genetic heterogeneity, and heterogeneity of environmental exposure [20].
