Abstract Over the past 25 years, human and mouse genetics research together has identified several hundred genes essential for mammalian hearing, leading to a greater understanding of the molecular mechanisms underlying auditory function. However, from the number of still as yet uncloned human deafness loci and the findings of large-scale mouse mutant screens, it is clear we are still far from identifying all of the genes critical for auditory function. In particular, while we have made great progress in understanding the genetic bases of congenital and early-onset hearing loss (HL), we have only just begun to elaborate upon the genetic landscape of age-related HL. With an aging population and a growing literature suggesting links between age-related HL and neuropsychiatric conditions, such as dementia and depression, understanding the genetics and subsequently the molecular mechanisms underlying this very prevalent condition is of paramount importance. Increased knowledge of genes and molecular pathways required for hearing will ultimately provide the foundation upon which novel therapeutic approaches can be built. Here we discuss the current status of deafness genetics research and the ongoing efforts being undertaken for discovery of novel genes essential for hearing. Introduction Hearing loss (HL) is a very prevalent condition that can occur as a congenital birth defect or can develop postnatally. Indeed, in developed countries it is the most common birth defect and the most prevalent sensorineural disorder (1), and globally it is the fourth leading cause of years lived with a disability (2). Congenital and early-onset HL can lead to poor educational attainment, and late-onset age-related hearing loss (ARHL) has been reported to lead to social isolation, depression, and an increased risk of dementia diagnosis (3–5). In origin, HL can be: conductive, resulting from anomalies of the external and middle ear; sensorineural, arising from defects of inner ear structures; or, central, due to dysfunction of the auditory nerve, brainstem or cortex. HL can result from environmental causes, genetic predisposition or an interaction of both. In children, the most common cause of acquired HL results from pre- or postnatal infections. Whereas in adults, acquired HL results from accumulated environmental impact, e.g. noise exposure, diet, etc. with the effect of these on a given individual likely reflecting the genetic susceptibility of that person. This is also true for drug-induced HL, for people receiving aminoglycoside antibiotics or cisplatin-based anti-cancer therapy. In around 80% of pre-lingual HL cases there is a genetic basis, with mutations giving rise to syndromic and non-syndromic forms of the condition (6). To date, there are greater than 500 genetic syndromes reported for which HL is part of the clinical presentation (7). However, in developed countries these account for <30% of genetic pre-lingual HL. In the remaining cases, genetic pre-lingual HL presents as a non-syndromic condition that can be inherited as an autosomal recessive trait (80%), autosomal dominant (19%), X-linked (<1%) or due to mitochondrial genome mutations (<1%) (8). Similar data are not available for post-lingual non-syndromic HL. However, as a general rule autosomal recessive forms of non-syndromic HL tend to be pre-lingual and severe-to-profound in nature, whereas autosomal dominant forms of non-syndromic HL tend to have a post-lingual onset and be progressive with age (6). As such, the prevalence of non-syndromic HL increases from ∼1: 1000 pre-lingual children, to nearly 3: 1000 children at 5 years of age (9). Moreover, ARHL is the most prevalent chronic sensory deficit experienced by older adults, and while it is a multifactorial disorder with several risk factors affecting its onset and progression, it is generally accepted that prevalence of ARHL doubles with every decade of life from the second, through to the seventh, decade. ARHL reflects the accumulated environmental insults on the auditory system experienced over the lifetime of an individual. However, while it is difficult to separate genetic and environmental effects, twin and family studies have shown that genetic predisposition forms a large and important risk factor for ARHL, with heritability indices of between 0.35 and 0.55 (10–12). However, to date very little is known of the genes involved in ARHL susceptibility. As of 2018, in humans more than 110 genes have reported mutations that give rise to non-syndromic HL (http://hereditaryhearingloss.org/; date last accessed April 24, 2018), and for some of these genes different alleles can also give rise to syndromic HL. Moreover, a particular gene can underlie both dominant and recessive forms of non-syndromic HL depending on the genetic lesion. Historically, identification of non-syndromic HL genes involved whole-genome linkage studies employing large kindreds to enable mapping of critical chromosomal regions, or in the case of autosomal recessive loci utilizing homozygosity mapping within consanguineous families. These mapping approaches identified large critical intervals containing many genes, which were then prioritized for Sanger sequencing. Mouse as a Model for Human Hearing Loss The similarities between human and mouse auditory structure and function, and the high level of concordance between orthologous genes critical for hearing function has seen that the mouse become the predominant model organism for auditory research (for a review see Ref. 13). In the mouse, over many decades researchers noted animals within their colonies that exhibited behavioural signs of balance disorders such as circling and head tilting, and many of these were associated with HL. These spontaneous mutants were an important resource for the identification of HL genes. With the advent of new technologies for genetic mapping in the mouse and candidate gene sequencing, in the mid-1990s deafness gene discovery accelerated (14,15). Moreover, the ease at which mice can be genetically modified has led to the generation of many mouse models that mimic human HL mutations, allowing the study of gene function. The auditory field has also greatly benefitted from utilizing phenotype-driven screens of randomly mutagenized mice, such as ENU mutagenesis screens (16–18). The ability to screen the hearing of large numbers of mice using a simple click box test has led to the identification of many HL mutants and the identification of novel genes required for auditory function, increasing our understanding of human HL. Importantly, characterization of mouse models has allowed the relationship between genetic mutations and their consequent effect on the structure and function of the auditory apparatus to be fully examined (19–24), something that is not possible in humans given the inaccessibility of the inner ear in vivo. How Do We Proceed: What Are the Next Steps? The application of these approaches in mice for the discovery of HL genes has been incredibly fruitful, with >300 mouse genes reported to cause inner ear dysfunction (13). However, more than half of these genes have yet to be associated with HL in humans. In part, this is due to the ease at which gene discovery can be undertaken in mice compared to humans. In human families and isolated cases of HL gene identification is still not trivial but continues to accelerate with improved sequencing and analysis technologies. To date, there are >40 human non-syndromic HL loci reported for which a causative genetic has not yet been identified (http://hereditaryhearingloss.org/; date last accessed April 24, 2018). The ever-decreasing cost and increasing accuracy of next-generation sequencing (NGS) approaches (exome and whole genome), now make it an affordable and effective approach for the continued investigation of these loci to identify novel human HL genes/mutations (25). Moreover, genome sequencing of volunteer participants taking part in large-scale medical research projects, such as the UK Biobank (http://www.ukbiobank.ac.uk/; date last accessed April 24, 2018), will also provide a long list of candidate causative genetic lesions across a number of disease areas including HL. However, while NGS can readily provide lots of high-quality genetic data, understanding these data and determining which alleles are deleterious and which are benign remains a very significant challenge. It is clear that mouse models will continue to play a significant role in auditory research by helping to validate human disease-causing alleles (Fig. 1). Over recent years several genome-editing approaches have been developed that allow targeting of specific DNA sequences directly in the zygote. These technologies can be utilized to generate mice carrying human-specific alleles. For example, utilizing CRISPR/Cas9-mediated homology-directed repair it is possible to change a single nucleotide within the mouse genome (26). Allying human NGS data with genome editing in the mouse will be an important facet in understanding more about the genetics of HL. In addition, the generated mouse models will also allow the pathobiology associated with these lesions to be studied. Figure 1. View largeDownload slide Cross-species validation of genes associated with HL. Genes identified from population-based GWA studies, or mutations identified via NGS, will likely require validation in a model system. The mouse provides an opportunity for this, either through the characterization of gene knockout or, as will become more commonplace, bespoke genome-edited knock-in mutants. Reciprocally, phenotype- and gene-driven studies in the mouse have the opportunity to identify novel genes required for mammalian hearing. Interrogation of the human candidate gene lists for these orthologous mouse genes may help validate lesions of unknown significance, providing evidence for a molecular diagnosis. Figure 1. View largeDownload slide Cross-species validation of genes associated with HL. Genes identified from population-based GWA studies, or mutations identified via NGS, will likely require validation in a model system. The mouse provides an opportunity for this, either through the characterization of gene knockout or, as will become more commonplace, bespoke genome-edited knock-in mutants. Reciprocally, phenotype- and gene-driven studies in the mouse have the opportunity to identify novel genes required for mammalian hearing. Interrogation of the human candidate gene lists for these orthologous mouse genes may help validate lesions of unknown significance, providing evidence for a molecular diagnosis. Large-Scale Screens in the Mouse for the Discovery of Hearing Loss Loci As discussed above, phenotype-driven ENU mutagenesis screens incorporating tests for auditory dysfunction have been very successful in uncovering novel loci for cochlear and hair cell function. The impact of ENU screens suggests that a systematic gene by gene assessment across the entire genome would bring significant rewards in revealing many hitherto undiscovered loci. The advent of the International Mouse Phenotyping Consortium (IMPC) is now providing the resource for such an endeavour—a complete genome wide assessment for loci involved in auditory dysfunction. The IMPC’s aim is to build a complete functional catalogue of a mammalian genome (27,28). The worldwide consortium is generating a null mutation for every gene in the mouse genome and undertaking a comprehensive phenotype characterization of every mutant (29). To date, over 7000 genotype confirmed null mutants have been generated, around a third of the genome, and over 5000 of these mutants have been phenotyped through the IMPC core phenotyping pipeline. Mutants are isogenic on a C57BL/6N background, allowing straightforward comparison with matched cohorts of C57BL/6N control mice. Homozygous viable mutants enter an extensive adult phenotyping pipeline from 8 to 16 weeks. Homozygous lethal mutants are characterized embryonically (30) and for these mutants, heterozygotes enter the adult phenotyping pipeline. Cohorts of 7 males and 7 females enter the adult phenotyping pipeline, which incorporates tests across diverse systems—neurological and behaviour, metabolism (31), musculoskeletal, cardiovascular, pulmonary, immune and sensory. As part of the sensory platform, IMPC undertakes an auditory brainstem response (ABR) test to assess hearing thresholds, a test that is carried out at 14 weeks. For the ABR test, the numbers of mice analysed were relaxed, with four males and four females analysed for each line. This resource for the first time allows an unbiased and systematic assessment of the number and diversity of HL loci across thousands of genes. While the screen is clearly gene driven, as with ENU phenotype-driven screens, it makes no a priori assumptions about the underlying genes or pathways involved in HL. Rather, the aim is to assess every gene in the genome for its contribution to auditory function, regardless of any prior knowledge about gene function. Ultimately, the aim of the IMPC is to undertake an auditory assessment for every gene in the mouse genome. IMPC has performed a first assessment of the genome landscape of auditory function by the analysis of 3006 knockout lines from IMPC (32). The ABR data from IMPC was analysed by a reference range approach, and for each locus mutant and matched wild-type data were used to generated P-values. From the 3006 lines, 328 loci with significant P-values were identified, which provides a first indicator of loci involved in HL. IMPC subsequently undertook a further manual curation to assess the phenotype data for each of these 328 loci and to generate a robust data set of HL loci with a low false discovery rate. This included eliminating loci showing discordant data between animals, as well as removing loci that exhibited raised thresholds at a single mid-range frequency and were unlikely thus to represent true HL. Following manual curation, a set of 67 loci was generated that IMPC deemed to show robust HL. The majority of these candidate HL genes were identified from the analysis of mutant homozygotes, but 8 of the 67 loci were identified by the analysis of heterozygous mutants from homozygous lethal lines. In addition, two lines showed sexual dimorphism with HL identified in one sex only. Of the 67 candidate HL genes identified, an extraordinary 52 genes were novel and had not been associated with deafness in either mouse or human (see Fig. 2). IMPC assigned all of the 67 genes to four classes of HL: severe HL (25 genes); mild HL (19 genes); high-frequency HL (13 genes) and low-frequency HL (10 genes). The novel HL genes were found in all four categories. Protein network analysis was utilized to investigate the interactions between the 52 novel genes and known human hereditary HL dominant, recessive and X-linked genes. The interaction map demonstrated a densely connected hub of known HL genes that incorporated a few (11) of the novel genes. However, the majority of the novel genes (41/52) were unconnected nodes, emphasizing the unexplored and diverse functionality of this class of loci. Figure 2. View largeDownload slide Summary of known and novel candidate HL genes identified in the IMPC HL screen. From 3006 knockout lines, 67 were identified as having elevated hearing thresholds, only 15 of which are known deafness genes. The 52 novel candidate HL genes are categorized into four broad types of HL: severe (all frequencies); mild (all frequencies); high-frequency; and, low frequency. A cartoon depicting a representative audiogram for each HL type is shown—the dashed lines represent normal hearing thresholds of wild-type mice, and the solid lines represent the elevated hearing threshold profiles encountered for the knockout mutant mice. Figure 2. View largeDownload slide Summary of known and novel candidate HL genes identified in the IMPC HL screen. From 3006 knockout lines, 67 were identified as having elevated hearing thresholds, only 15 of which are known deafness genes. The 52 novel candidate HL genes are categorized into four broad types of HL: severe (all frequencies); mild (all frequencies); high-frequency; and, low frequency. A cartoon depicting a representative audiogram for each HL type is shown—the dashed lines represent normal hearing thresholds of wild-type mice, and the solid lines represent the elevated hearing threshold profiles encountered for the knockout mutant mice. In terms of elaborating the function of all 67 HL genes, their wider pleiotropic impacts and the potential relationship to human syndromic loci, IMPC analysed the additional phenotypes uncovered for each gene from the extensive phenotyping undertaken in the adult pipeline. A total of 60 mutants display additional phenotypes, but there were no obvious pattern or commonalities to the co-morbidities detected. Pleiotropy is pervasive across the genome, and these data indicated that as with many other genetic disease systems, extensive pleiotropy is also manifest for deafness loci which may in some cases display as syndromic HL. Finally, the data from IMPC impinge on our understanding of the extent of the mammalian genetic landscape involved in auditory function. From an exploration of around 15% of the mouse genome, 67 HL genes were identified. This would indicate that at a minimum there are at least 450 loci genome-wide that are involved with auditory function, underlining the very extensive and unexplored genetic landscape of auditory function that remains to be investigated. Future Challenges in Elucidating the Genetic Landscape of Hearing Loss The estimate of the number of genes involved in HL that was arrived at by the IMPC must be considered an absolute minimum. There are a number of reasons as to why the number of loci involved with auditory function is likely to be much higher. First, IMPC was not able to assess the auditory function of genes that were homozygous lethal and which, on a different genetic background, might be viable and manifest pleiotropic effects on hearing. Second, it is likely that loci with modest effects on HL were not detected using the small cohort sizes employed by IMPC. Moreover, IMPC did not carry out a more detailed analysis of the waveforms of the ABRs that may have revealed more subtle effects on auditory function. Most importantly, the ABR analysis carried out at 14 weeks would not have detected loci involved with ARHL. In any case, the IMPC mutant lines are generated on a C57BL/6N background, a strain which itself is susceptible to ARHL and would confound any late adult analysis of auditory function. Assessing the genetic landscape of ARHL remains an enormous challenge both for human and mouse auditory genetics (33). Despite considerable efforts to assess human populations for loci involved in ARHL, both through GWAS and exome sequencing of families, developments have been modest. Several GWA studies have been performed, and to date the best replicated association is with the gene GRM7 (34–38). Moreover, a GWAS utilizing the British 1958 Birth Cohort provided the basis for the identification of ESRRG as a candidate novel hearing gene in humans, which was subsequently characterized in a knockout mouse model (37). While the lack of genome-wide significant hits in these studies is disappointing, they do provide a valuable candidate gene list that warrants further investigation. In addition, GWA studies into adult hearing function employing much larger cohorts (e.g. UK Biobank) may prove more successful. In the mouse, utilizing the diversity of genetic resources available from the inbred strains there have been a number of efforts to identify loci that underlie ARHL in several of the inbred strains, e.g. the hypomorphic Cdh23ahl present in C57BL/6 and several other strains (13,39–42). However, it was not until recently that efforts have been made to undertake ABR screens of aged ENU-mutagenized mice, to directly assess in an unbiased way the loci that might be involved in presbycusis (43). At MRC Harwell, large recessive pedigrees were bred and subject to a phenotyping pipeline comprising recurrent assessment up to 18 months of age across a wide range of disease areas, including recurrent click box and ABR phenotyping (44). From 157 pedigrees tested, 26 exhibited a HL phenotype, 8 of which were deemed late-onset (onset >3-months of age). Five of the eight harbour mutations in novel HL genes, and while these numbers are small, this suggests the genetic landscape of ARHL may be substantially different to that of congenital/early-onset HL. Expanding upon this type of screen would undoubtedly uncover additional ARHL models, but due to the high costs in terms of animal numbers, cage weeks and phenotyping hours, these screens are very expensive. However, such mouse screens would deliver a broader understanding of the genetic bases for progressive HL providing the foundation necessary for the development of new therapeutic modalities to slow, or stop, the age-related decline in auditory function. Outlook Integrated human and mouse approaches will continue to elaborate upon our understanding of the genetic mechanisms underlying mammalian hearing. We can expect to see a rising number of loci identified from studies of HL in the human population. At the same time, the mouse provides a key tool for functional validation of these loci and investigation of the underlying mechanisms of HL. However, ongoing comprehensive screens for auditory function across the whole of the mouse genome will continue to be transformative in revealing large numbers of new loci involved with HL and providing a more profound understanding of the genomic landscape and pathways involved with auditory function. 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Human Molecular Genetics – Oxford University Press
Published: May 2, 2018
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