Projektbeschreibung
Deletäre Mutationen in der Evolution von RNA-Viren
Deletäre Mutationen wurden im Vergleich zu den günstigen Mutationen bisher zu wenig untersucht, da es technisch nicht möglich war, jede schädliche Mutation zu sequenzieren. Sequenzierungstechniken der nächsten Generation haben kürzlich gezeigt, dass ein erheblicher Anteil der genetischen Vielfalt von Viren eine Folge schädlicher Mutationen ist. Im EU-finanzierten Projekt RNAVirFitness wird die Verteilung der Fitnesseffekte auf eine Vielzahl von RNA-Viren untersucht. Dabei werden Vertreter jeder Klasse der wichtigsten menschlichen Pathogene in vivo und in vitro untersucht. Im Projekt wird untersucht, wie die Anhäufung schädlicher Mutationen zum Aussterben der Viruspopulation führen kann und wie dies als neue Strategie zur Bekämpfung von Virusepidemien genutzt werden kann. Über ihren Beitrag zur Evolutionsbiologie hinaus können die Ergebnisse für die Entwicklung neuer Impfstämme und die Entwicklung antiviraler Breitbandtherapeutika genutzt werden.
Ziel
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.
Wissenschaftliches Gebiet
- medical and health scienceshealth sciencesinfectious diseasesRNA viruses
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
69978 Tel Aviv
Israel