A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.

Homeostatic maintenance and age-related functional decline in theDrosophilaear

“…We also found that 67% (74 out of 111) of recently identified mammalian hearing loss genes 10–12 are conserved in flies - and expressed in A2 – with 32% of them also showing age-variable expression in JO (Table 2).…”

“…Over the past few decades, gene discovery studies using mouse models have identified numerous candidate genes for human deafness 3–9 . Three recent larger scale screens have brought the total number of candidate hearing loss genes for humans to 111 10–12 . Yet, the underlying mechanisms and molecular networks of ARHL, and particularly the maintenance of hearing throughout the lifespan, have remained elusive.…”

A resource of targeted mutant mouse lines for 5,061 genes

“…To date, more than 17,500 individual production attempts (microinjection or aggregation) have resulted in the germline transmission of KO alleles for 5,061 unique genes ( Figure 1A; Supplemental Table ST1). These lines have been expanded for phenotyping, providing key insights into mammalian biology and disease [10][11][12][13][14][15] ; www.mousephenotype.org). The IMPC contribution extends the total number of genes with targeted KO alleles produced by the scientific community from the 8,391 reported and curated by Mouse Genome Informatics (MGI; 16 )( Figure 1B; Supplemental Table ST2), to 11,241, or more than half of the genome.…”

Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

“…Rare mutations in five of the 50 genes have been shown previously to cause Mendelian forms of deafness or hearing loss: TRIOBP, EYA4, FTO, SOX2, and LMX1A 4, [35][36][37][38][39][40][41][42][43] . Genetic studies in mice have demonstrated hearing loss or cochlear development phenotypes for an additional seven of the 50 genes: SYNJ2, TYR, PTGDR, MMP2, RPGRIP1L, RBL2, and BAIAPL2 [44][45][46][47][48][49][50] . Notably, three of the five genes with independent support from human rare variants --FTO, SOX2 (Fig.…”