An evolutionary-driven approach to detect critical coding and non-coding regions in deafness

TRIGILA, ANABELLA; PISCIOTTANO, FRANCISCO; FRANCHINI, LUCIA FLORENCIA

Workshop; IBRO Reports Volume 6, Supplement, Page S543; 2019

IBRO

An evolutionary-driven approach to detectcritical coding and non-coding regions indeafnessAnabella Trigila, Francisco Pisciottano, LuciaFranchini ∗INGEBI - CONICET, Buenos Aires, ArgentinaGenome-wide studies identifying critical innovations in codingand non-coding DNA are continually growing, but the evidenceshowing how these genetic changes may simultaneously impactphenotype is scarce. In the inner ear, no studies have previouslyaddressed the relevance of coding and non-coding DNA for itsimpact on evolution, development or disease. Classical and recentstudies on non-syndromic hearing loss, a condition that affectsapproximately 1 in 1000 human newborns, have identified pos-sible causal genes. We hypothesize that these hearing loss genesmust play a critical role in the development and physiology ofthe mammalian inner ear and have thus been a critical targetduring evolution. Using a stringent bioinformatic pipeline, we iden-tified signatures of selection at the coding and non-coding levelfor a compiled dataset including classic non-syndromic deafnessgenes and novel hearing loss genes candidates recently identifiedby the Mouse Phenotype Consortium. Using this dual approach,we detected genes showing signatures of accelerated evolution innon-coding conserved regions and in protein-coding regions. Wefunctionally tested several of these regions in transgenic reporteressays, expanding the number of functional genomic territoriesassociated with inner ear physiology and in close association withits development. We predicted the implications of ancestral codingvariants in the functional properties of hearing loss genes. More-over, we suggest that certain deafness genes could have played animportant role in the appearance of the functional novelties thatcharacterize the mammalian inner ear.