**Acknowledgements**

We thank Emiko Wakatsuki for the drawing the illustrations. This review was supported by JSPS KAKENHI (Grant Number JP15H04291).

### **Index of technical terms**

μV: microvolts

ABR: auditory brainstem response

*ahl*, *Ahl3*, *ahl4, Ahl5*, *Ahl6*, *ahl8* and *Ahl9*: loci for age-related hearing loss in mice

A/J, C3H/HeN, C57BL/6J, CAST/Ei, DBA/2J and MSM/Ms: mice inbred strains

ARHL: age-related hearing loss

AXB, BXA, BXD, BXH, CXB, LXS and SMXA: mice recombinant inbred strains

BAC: bacterial artificial chromosome

Black Swiss and NIH Swiss: mice outbred strains

C57BL/6J-Chr17MSM/Ms: a consomic (chromosome substitution) strain, which contain MSM/ Ms-derived chromosome 17 in the genetic background of the C57BL/6J strain

Cas9: CRISPR associated protein 9

*Cdh23*: cadherin 23 gene

*Cdh23c.753G>A*: a guanine-to-adenine substitution at nucleotide position 753 of cadherin 23 gene

*Chr5* QTL: QTL on chromosome 5

CRISPR: clustered regularly interspaced short palindromic repeat

*Cs*: citrate synthase gene

*Csp.His55Asn*: a histidine-to-asparagine substitution at amino acid position 55 of citrate synthase (CS) protein

CSS: consomic (chromosome substitution) strains

dB SPL: decibel sound pressure level

DPOAE: distortion product otoacoustic emission

DO: diversity outcross stock

eQTL: expression QTL

*Fscn2*: fascin 2 gene

**5. Conclusions**

16 An Excursus into Hearing Loss

**Acknowledgements**

**Index of technical terms**

ABR: auditory brainstem response

ARHL: age-related hearing loss

BAC: bacterial artificial chromosome

Cas9: CRISPR associated protein 9

*Chr5* QTL: QTL on chromosome 5

*Cdh23*: cadherin 23 gene

*Cs*: citrate synthase gene

Black Swiss and NIH Swiss: mice outbred strains

μV: microvolts

JSPS KAKENHI (Grant Number JP15H04291).

In this chapter, we attempt to highlight several issues regarding the identification of background effects in mice. To identify the modifiers underlying genetic background effects, several strains were established for QTL and GWAS. Thus, the technologies for forward genetics in mice have enabled important breakthroughs and will contribute to the identification of new loci and genes associated with hearing loss. The reverse genetics approach has also been developed based on technological innovations, that is, genome editing and will be increasingly applied. An increasing number of studies have reported that the hearing loss phenotype resulting from a single gene mutation in humans is modulated by the genetic background in which the mutation is maintained (e.g., see [67].). Using genome editing, mutations discovered in the genetic background of patients with hearing loss can be conveniently manipulated in mice, and the effects of the candidate mutation can be confirmed *in vivo* by phenotypic analyses of mice.

We thank Emiko Wakatsuki for the drawing the illustrations. This review was supported by

*ahl*, *Ahl3*, *ahl4, Ahl5*, *Ahl6*, *ahl8* and *Ahl9*: loci for age-related hearing loss in mice A/J, C3H/HeN, C57BL/6J, CAST/Ei, DBA/2J and MSM/Ms: mice inbred strains

AXB, BXA, BXD, BXH, CXB, LXS and SMXA: mice recombinant inbred strains

Ms-derived chromosome 17 in the genetic background of the C57BL/6J strain

CRISPR: clustered regularly interspaced short palindromic repeat

C57BL/6J-Chr17MSM/Ms: a consomic (chromosome substitution) strain, which contain MSM/

*Cdh23c.753G>A*: a guanine-to-adenine substitution at nucleotide position 753 of cadherin 23 gene

*Fscn2p.Arg109His*: an arginine-to-histidine substitution at amino acid position 109 amino acid of fascin 2 (FSCN2) protein

*Gipc3*: GIPC PDZ domain containing family member 3

GWAS: genome-wide association study

HDR: homology-directed repair

HFHL: high-frequency hearing loss

*Hfhl1*, *2* and *3*: loci for high-frequency hearing loss in mice

HMDP: hybrid mouse diversity panel

HS: heterogeneous stock

kHz: kilohertz

KI: knock-in

KO: knock-out

*Map1a*: microtubule-associated protein 1

*moth1*: modifier of tubby hearing

ms: milliseconds

*mt-TrArg*: mitochondrial tRNA-Arg

NIHL: noise-induced hearing loss

*Nox3*: NADPH oxidase-3

OS: outbred stock

QTL: quantitative trait loci

QTN: quantitative trait nucleotides

RIS: recombinant inbred strain

sgRNA: single guide RNA

*Snhl*: a locus for sensorineural hearing loss in mice

SNP: single nucleotide polymorphism

*Tub*: tubby bipartite transcription factor gene

*Ush1g*: USH1 protein network component sans gene

*Ush1gjs*: Jackson shaker mouse
