High throughput analysis of Xenopus genes for inner ear and neuronal disorders

Vestibular and auditory disorders are prevalent sensory disabilities that can be caused by genetic and environmental (noise, trauma, chemicals) factors, often by damaging the mechanosensory hair cells of the inner ear. Because humans rely on their irreplaceable inner ears for sensory processing, model organisms that share similarities with the human inner ear are commonly used for studies of hearing and balance. This dissertation research aimed to contribute to an understanding of the genetic basis of inner ear function using the well characterized amphibian, Xenopus laevis ( X. laevis). The long term goal of this research is to determine whether there are links between inner ear dysfunction and brain disorders such as Alzheimer's. The research approach implemented high throughput technologies (microarrays and RNA-seq) in conjunction with bioinformatics to identify the expression of inner ear genes important for hearing and balance, as well as genes integral for brain function.;The first objective of this research was to identify orthologous Online Mendelian Inheritance in Man (OMIM) genes in Xenopus. Using computational methods, OMIM database was queried, resulting in the identification of 292 genes associated with deafness and 119 genes associated with vestibular disorders in humans. Bioinformatics tools were implemented resulting in the identification of orthologous genes in Xenopus by analyzing inner ear expression data captured with microarrays and RNA-seq.;These results laid the foundation and strategy for the second objective of the dissertation, to identify genes associated with hearing loss and Alzheimer's disease in order to determine whether these disorders share any genetic mechanisms. To this end, a computational approach was implemented to uncover well-characterized human genes that might be common to hearing loss and Alzheimer's disease. The OMIM database was queried resulting in a list of 282 genes associated with hearing loss and a list of 273 genes associated with Alzheimer's. Comparative analysis of the gene lists resulted in the identification of seven genes that are common to hearing loss and Alzheimer's. Furthermore, the STRING database was used to determine whether the OMIM hearing loss and Alzheimer's genes shared common signaling pathways. Using this approach several candidate genes were identified linking both diseases.;The third objective of the dissertation aimed to identify the expression of the potential candidate genes linking hearing loss and Alzheimer in Xenopus inner ear and brain transcriptomes. Using the Galaxy open source platform in combination with other open source databases, the expression of several of the candidate genes was determined including the three genes known to cause the early form of Alzheimer's disease: APP, PSEN1 and PSEN2. This result opens the possibility of using Xenopus as a model organism for studying hearing loss and Alzheimer's disease.