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.
