Abstract
BackgroundGenesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. De novo generation of novel cis-regulatory elements (CREs) is much rarer than genomic events that alter existing CREs such as transposition, promoter switching or co-option. Only one case of de novo generation has been reported to date, in fish and without involvement of phenotype alteration. Yet, this event likely occurs in other animals and helps drive genetic/phenotypic variation.ResultsUsing a porcine model of spontaneous hearing loss not previously characterized we performed gene mapping and mutation screening to determine the genetic foundation of the phenotype. We identified a mutation in the non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor (MITF) gene that generated a novel silencer. The consequent elimination of expression of the MITF-M isoform led to early degeneration of the intermediate cells of the cochlear stria vascularis and profound hearing loss, as well as depigmentation, all of which resemble the typical phenotype of Waardenburg syndrome in humans. The mutation exclusively affected MITF-M and no other isoforms. The essential function of Mitf-m in hearing development was further validated using a knock-out mouse model.ConclusionsElimination of the MITF-M isoform alone is sufficient to cause deafness and depigmentation. To our knowledge, this study provides the first evidence of a de novo CRE in mammals that produces a systemic functional effect.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0273-2) contains supplementary material, which is available to authorized users.
Highlights
Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution
We performed whole-genome mapping and detected a short insertion in the distal melanocyte-specific regulatory region of microphthalmia-associated transcription factor (MITF). We showed that this insertion creates a de novo silencer that completely eliminated the expression of the transcripts for the MITF-M isoform both in vivo and in vitro
Results from auditory brainstem response (ABR) tests show that the albino pigs produced no recognizable waveforms up to 100 dB sound pressure level (SPL) stimuli in the range from 4–32 kHz, whereas normal pigs produced ABR thresholds at 5–10 dB SPL (Fig. 1b)
Summary
Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. Due to the sequence-specific nature of transcription factors’ binding to DNA, introduction of a singlenucleotide polymorphism (SNP) or a small-sized insertion or deletion (indel) in the target regulatory sequence can incapacitate or inhibit binding [1, 2] These relatively small mutations can be sufficient to generate a novel cis-regulatory element (CRE). One case has been reported to date, that of an enhancer generated by whole-genome duplication in sequences in fish that were demonstrated as formerly lacking cis-regulatory activity [10] No such cases have been reported for mammals, and there are no reports of minor changes driving either de novo genesis of regulatory elements or systemic functional alterations
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