Periodic Reporting for period 2 - RNAVirFitness (The dark side of evolution: the deleterious mutational landscape of RNA viruses)
Período documentado: 2021-12-01 hasta 2023-05-31
Viruses evolve extremely rapidly, as exemplified amply in the ongoing SARS-Coronavirus-2 pandemic. New variants are created in viruses due to two forces: (i) erroneous copying of the genetic material of viruses, leading to the creation of mutations, and (ii) selection that drives expansion or demise of variants bearing specific mutations. Some mutations are beneficial to the virus, i.e. allow the virus to replicate better. Most mutations, however, are deleterious and generate viruses that are not able to replicate well. The aim of this project is to generate comprehensive maps of mutations across a range of different viruses and to infer how they impact virus “viability”. This is critical for managing and forecasting viral epidemics. Thus, for example, monitoring the evolution and spread of SARS-Coronavirus-2 necessitates a deep understanding of the impact of various mutations on how well the virus replicates and transmits.
The objectives of this project are to use a combination of computational and experimental approaches to investigate how mutations impact the ability of viruses to replicate. First, we aim to compare different viruses: are there basic rules that govern virus evolution? For example, are there regions of virus genomes where mutations always have a deleterious impact? This will allow us to discover the “Achilles-heel” of viruses, and this could potentially allow generating therapeutics that target this weak spot. Next, we aim to understand how combinations of mutations affect genomes of viruses. Thus, for example, one mutation may be deleterious on its own, but when two mutations occur together, they might become beneficial to the virus. It is critical to understand how this happens, since such combinations may lead to viruses that are more transmissible or more virulent. Finally, our goal is to understand if and how the effects of mutations differ in different environments. For example, a mutation may have a deleterious impact when a virus replicates in the lungs but may have a different impact when the virus replicates in upper airways. Overall, our goal is to generate comprehensive understanding of the impact of mutations across a wide range of different viruses.
The objectives of this project are to use a combination of computational and experimental approaches to investigate how mutations impact the ability of viruses to replicate. First, we aim to compare different viruses: are there basic rules that govern virus evolution? For example, are there regions of virus genomes where mutations always have a deleterious impact? This will allow us to discover the “Achilles-heel” of viruses, and this could potentially allow generating therapeutics that target this weak spot. Next, we aim to understand how combinations of mutations affect genomes of viruses. Thus, for example, one mutation may be deleterious on its own, but when two mutations occur together, they might become beneficial to the virus. It is critical to understand how this happens, since such combinations may lead to viruses that are more transmissible or more virulent. Finally, our goal is to understand if and how the effects of mutations differ in different environments. For example, a mutation may have a deleterious impact when a virus replicates in the lungs but may have a different impact when the virus replicates in upper airways. Overall, our goal is to generate comprehensive understanding of the impact of mutations across a wide range of different viruses.
One of our main achievements has been in characterizing variants of SARS-Coronavirus-2, where we performed some breakthrough studies on how this virus evolves. In particular, we were able to show that the very early variants-of-concern of this variants have very limited ability to breakthrough vaccine protection (this changed later on with the emergence of the Omicron variants). The results of this study were published in Nature Medicine, and this is one of the most highly cited papers in the field of COVID-19 research. Next, we have recently characterized how variants may emerge in chronically infected individuals, a paper that was also published in nature Medicine. Overall, these studies are shedding light on the mutations and variants and their impact on virus replication and ability to transmit under different conditions.
Beyond SARS-Coronavirus-2, which has naturally been a focus of research in the past few years, we have also made some leaps forward in our understanding of a completely different virus, called MS2. This virus attacks bacteria and is also a very fast evolving virus. We were able to infer the rate of mutation and the impact of different mutation on the viral genome. Interestingly, we were able to show that pairs of mutation behave differently from each mutation on its own. This is a first and important step in both of the first main goals of this project.
Beyond SARS-Coronavirus-2, which has naturally been a focus of research in the past few years, we have also made some leaps forward in our understanding of a completely different virus, called MS2. This virus attacks bacteria and is also a very fast evolving virus. We were able to infer the rate of mutation and the impact of different mutation on the viral genome. Interestingly, we were able to show that pairs of mutation behave differently from each mutation on its own. This is a first and important step in both of the first main goals of this project.
Our research revolving around the COVID-19 pandemic was challenging and involved multi-disciplinary collaborations that went beyond the state of the art. We succeeded in tying between specific viral variants and vaccine breakthrough, during a very narrow window of time that allowed this detection. Moreover, we have recently described what may allow the formation of dramatic SC2 variants in rare chronic infections. Our research spanned genetic sequencing, bioinformatics, in depth clinical medical understanding, combined with sophisticated statistical modeling.
We expect to continue obtaining insights into SARS-Coronavirus-2 with the aim of obtaining a better understanding of how variants are formed and how they evolve. We moreover plan to compare this to other viruses and their routes of evolution.
We expect to continue obtaining insights into SARS-Coronavirus-2 with the aim of obtaining a better understanding of how variants are formed and how they evolve. We moreover plan to compare this to other viruses and their routes of evolution.