Molecular and Epigenetic Mechanisms of Hereditary Hearing Loss

National Institute On Deafness And Other Communication Disorders

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Abstract

We conducted IsoSeq of whole cochlea, flow-sorted cochlear hair cells, and isolated single cells from the inner ear. In total we have generated 573,989 unique isoforms from 20,253 known genes and 16,619 novel genes, for an average 15 isoforms per gene. Of the transcripts, 446,038 (77%) are novel when compared to the GENCODE vM23 reference annotation. The vast majority of unique isoforms differ in 5 and 3 UTR exon usage when compared to the reference, and may harbor important regulatory motifs specific to the inner ear. Our data set also includes 21,103 protein coding exons (CDS) that have no overlap with any CDS in the reference transcriptome. Most interestingly, 268 of these inner ear specific CDS exons are in genes known to cause hearing loss in humans (DFNA/B loci). We inspected the homologous regions of some of these CDS exons in human samples from families segregating DFNA or DFNB, but in whom no causative mutation had been found in the known CDS exons. No additional mutations were found in the homologous CDS exons in any of the families.