Frame shift mutation-induced ATI influence on the microbiome
Note : this project is inactive as of October 2019.
This project is part of the Université Laval / Université Côte-d'Azur research partnership.
Principal investigators
Arnaud Droit, Guillaume Sandoz
Abstract
LThe aim of this project is to pinpoint genetic variants found in nordic population that could influence the gut micriobiota composition and to develop a fish experimental model in which we can control factors that modulate host-microbiota functional interactions and measure their impacts. We previously identified a new molecular mechanism (frameshift mutation-induced alternative translation initiation, fsATI) which induces human disease (Royal et al, 2018, under review in Nature Communications). We found that frameshift mutations downstream of the first start codon can lead to alternative translation initiation to produce a second protein which can carry the pathophysiological function. This mechanism was shown to be relevant in multimeric channels where a fsATI mutation in TRESK was linked to migraine. We postulate that this mechanism could be widespread in nature.
It was also shown that ion channels can impact the microbiome (Fuante and Christianson, 2016). Thus we plan to test the impact of putative fsATI variants of ion channels on the composition of a model organism microbiote, the Zebrafish. To do so, we will first analyze exome sequencing datasets produced with nordic populations (Moltke et al., 2014 and Manousaki et al., 2016) to target fsATI variants with potential impacts on the microbiome. Then, we will apply a scoring approach to target the mutations that are the most likely to be biologically relevant. These mutants will be then tested on the Zebrafish model using an optogenetic approach as described in SN project 3.7. Considering that the intestinal microorganisms have been shown to play an important role in physical and mental health, we believe this project will be an important contribution to the understanding of these complex interactions.