Mouse Knockout Screen Leads To Discovery
Novel Hearing-Related Genes Identified by Mouse Knockout Screen
Detailed analysis of 3006 lines of knockout mice has identified 67 genes related to hearing, including 52 genes not previously associated with that process. This result was made possible by the work of the International Mouse Phenotyping Consortium (IMPC), a group with the goal of testing the function of 20,000 genes in mouse knockout models. Each gene is tested by making an individual knockout line, then measuring a wide variety of properties such as heart function, muscle development, vision and hearing. For this study the results of hearing tests were analyzed to find which genes are necessary for that process. The analysis was able to distinguish between mutations that cause mild and severe hearing loss, or selective loss of response to only low- or high-frequency sound.
Multiple Phenotypes Identified
The identified genes span a wide range of cellular functions, from transcription factors to structural proteins. Such variety is due to the unbiased nature of the IMPC screen – all genes are tested for all phenotypes to uncover unexpected gene functions. This strategy produced another important result: multiple phenotypes were identified in addition to hearing defects for the vast majority of hearing-associated genes. This matches the observation that in humans a mutation that affects hearing will also often affect other physiological processes. Identified genes may be required at any step in the process of hearing, including proper formation of the ear during embryonic development, functioning of the ear during the test, or transmission of signals to the brain. Therefore follow-up work on each gene will be required to identify its specific function in the hearing pathway.
The Power of Large-Scale Unbiased Screens
This result demonstrates the power of large-scale unbiased screens for mapping genes to complex phenotypes. More than 400 genetic syndromes are known to affect hearing in humans but less than a third of those have been mapped to a specific gene. Comprehensive analysis of screens with mouse knockout models such as this, combined with rigorous statistical analysis, can identify non-obvious hearing-related genes. Understanding the entire network of genes that control hearing will greatly advance our understanding of this process and inform research into treatments for hearing loss.
- Bowl MR, Simon MM, Ingham NJ, Greenaway S, Santos L, Cater H, Taylor S, Mason J, Kurbatova N, Pearson S, Bower LR, Clary DA, Meziane H, Reilly P6, Minowa O, Kelsey L, et al. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. Nat Commun 8(1):886.