Description du projet
Des mutations délétères dans l’évolution des virus à ARN
Les mutations délétères ont été sous-étudiées par rapport aux mutations bénéfiques car il était techniquement impossible de séquencer chaque mutation délétère. Les techniques de séquençage de nouvelle génération ont récemment montré qu’une proportion importante de la diversité génétique virale est la conséquence de mutations délétères. Le projet RNAVirFitness, financé par l’UE, étudie la distribution des effets sur la forme physique à travers un large éventail de virus à ARN, couvrant des représentants de chaque classe d’agents pathogènes humains majeurs, in vivo et in vitro. Le projet examinera comment l’accumulation de mutations délétères peut conduire à l’extinction de la population virale, et comment cela peut être utilisé comme une nouvelle stratégie pour lutter contre les épidémies virales. Au-delà de leur contribution à la biologie évolutive, les résultats peuvent être exploités pour la conception de nouvelles souches vaccinales et le développement de thérapies antivirales à large spectre.
Objectif
Mutations are fundamental drivers of evolution. Characterizing how mutations affect fitness is critical across diverse fields: from pathogen biology, to human genetic diseases, and models of population extinction. RNA viruses, notorious for their high mutation rates and rapid generation times, are ideal models for studying the effects of mutations. To date, deleterious mutations (i.e. mutations with a fitness cost) have been understudied as compared to beneficial mutations, mainly since it has been technically unfeasible to sequence each single rare deleterious mutation. Using novel next generation sequencing (NGS) techniques, we and others have recently overcome this gap, and shown that an appreciable proportion of viral genetic diversity is a consequence of a multitude of rare deleterious mutations. Here, we suggest investigating the distribution of fitness effects (DFE) across a diverse array of RNA viruses, spanning representatives of each class of major human pathogens, both in vivo (in patients) and in vitro (in cell culture). Next, we will focus on genetic linkage and context-dependent fitness effects of mutations. We postulate that over- and under-represented sequence contexts may represent signatures of host anti-viral activity. Finally, we will investigate how the DFE changes following an environmental perturbation (physical and metabolic changes, tissue type, and sex of the host). We will explore how the accumulation of deleterious mutations following rapid perturbations may lead to the extinction of the viral population, and how this can be used as a novel strategy to tackle viral epidemics. To this end we will integrate state-of-the-art NGS, population genetics modelling, and reverse genetics validation. Beyond their contribution to evolutionary biology, we anticipate that our results may be harnessed for the design of safe and effective attenuated vaccine strains, and the development of broad-spectrum antiviral therapeutic strategies.
Champ scientifique
- medical and health scienceshealth sciencesinfectious diseasesRNA viruses
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
69978 Tel Aviv
Israël