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.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Fig. 1

Summary audiograms for hearing loss genes identified by individual IMPC centres. At each centre auditory thresholds (dB SPL) were assessed at five frequencies—6, 12, 18, 24 and 30 kHz. Each graph, displaying the data from a single IMPC centre, portrays a reference range (yellow shaded area) and median (dashed line) for control wild-type animals. The colour of each audiogram line relates to the classification of hearing loss as shown in Fig. 2 and listed in Table 1. Severe, magenta; mild, orange; high frequency, green; low frequency, blue. Phenotyping centres: GMC, Helmholtz Zentrum Munchen; Harwell, MRC Harwell; ICS, Institut Clinique de la Souris; JAX, Jackson Laboratories; RBRC, RIKEN Tsukuba Institute, BioResource Center; TCP, The Centre for Phenogenomics; UCD, University of California, Davis; WTSI, Wellcome Trust Sanger Institute

Fig. 2

Summary audiograms for the 67 hearing loss genes identified within the IMPC. ABR screen assessing auditory thresholds (dB SPL) at five frequencies—6, 12, 18, 24 and 30 kHz. The genes are divided into four broad categories of hearing loss—severe (magenta lines), mild (orange lines), high frequency (green lines) and low frequency (blue lines). In each category, the median of auditory thresholds for control mice for each of the contributing centres to genes in that category is shown (black lines). GMC, Helmholtz Zentrum Munchen; Harwell, MRC Harwell; ICS, Institut Clinique de la Souris; JAX, Jackson Laboratories; RBRC, RIKEN Tsukuba Institute, BioResource Center; TCP, The Centre for Phenogenomics; UCD, University of California, Davis; WTSI, Wellcome Trust Sanger Institute

Fig. 3

A network interaction map incorporating the proteins encoded by the 67 hearing loss genes identified from the IMPC ABR test. A STRING interaction map, incorporating known and predicted interactions, was generated for the known (15) and novel (52) IMPC hearing loss genes. Blue nodes are the IMPC novel candidate genes. Other nodes are previously reported genes that underlie hereditary hearing loss in humans, including DFNA (dominant hearing loss genes), DFNA/DFNAB (hearing loss genes showing both dominant and recessive inheritance), DFNB (recessive hearing loss genes), and DFNX (X-linked hearing loss genes). IMPC known genes are a subset of these genes and are highlighted by purple colour. The highly connected interaction map (shaded) consists of 65 known hearing loss genes and 11 novel candidate IMPC genes. The majority of IMPC novel candidate genes (41/52) are unconnected to the central network. Thin grey edges show interactions with a combined confidence score of ≥0.4, summated from evidence types: ‘curated databases’; ‘experimentally determined’; and, ‘automated text mining’. Bold red edges show ‘known’ interactions with a combined confidence score of ≥0.4, summated from ‘curated databases’ and ‘experimentally determined’ only

Fig. 4

Distribution of IMPC known and IMPC novel hearing loss genes on three different gene ontology-directed acyclic graphs. Over-represented gene ontology terms for a joint data set of IMPC known (K) and IMPC novel (N) hearing loss genes were identified using gProfiler (Supplementary Table 4). The number of genes associated with any given term were counted and split into known and novel groups. Manual inspection of the enriched gene ontology terms and the gene count highlighted examples, where IMPC novel candidate genes were depleted at the lower ontology level. Here we show three examples of enriched gene ontology terms mapped onto their respective directed acyclic graphs (DAGs), alongside the number of known and novel candidate genes associated with enriched terms. For instance, the first example shows 34 known genes and 10 IMPC novel genes associated with the level 1 GO term ‘Cell Projection’. From the 34 genes, 24 are annotated with ‘Stereocilium’ at level 3 while no novel candidate genes are annotated at this level