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Principal Investigator: Nash Rochman
Organization: NATIONAL LIBRARY OF MEDICINE
Fiscal Year: 2022
Award: $648,935
Funding agency: National Library of Medicine
Our work over the past year may be divided into two aims: understand the extent of the mutational repertoire accessible to Severe acute respiratory syndrome coronavirus 2 in an effort to forecast epidemiological outcomes at a molecular level, and to more broadly understand how changing social and environmental conditions will impact the evolution of endemic human viruses.
Towards the first aim, we built a computational framework to assess the epistatic effects of ensembles of mutations present within the receptor binding domain of SARS-CoV-2 on both receptor, ACE2, and neutralizing antibody affinity. We explored, through in silico mutagenesis using the Rosetta software suite, the characteristics of variants which were most likely to emerge from a background of current and prior variants of concern, Delta, Gamma, and Omicron. This was a collaborative effort involving personnel from the Broad Institute and the University of Michigan. Our work resulted in the favorable prediction that there are few avenues available for complete antibody escape of the virus (abrogating antibody binding and maintaining receptor binding); however, it was nonetheless clear that the Omicron receptor interface is more different from the antibody interface in comparison to prior variants, modestly increasing the probability that future escape-enhancing mutations will be accumulated relative to previous backgrounds.
Towards the second aim, we conducted a comprehensive phylodynamic analysis of all human non-segmented, pathogenic RNA viruses with the requisite number of complete genomes publicly available (200). We demonstrated that the linage turnover rate of these viruses is below neutral expectation indicating that almost all viral subtypes, even those which are not spatially defined (e.g. by vector range) and are immune-competing (prior infection with one protects against infection with another), occupy independent, non-competing ecological niches. However, we also showed that the genomic distribution of likely adaptive mutations is conserved at all phylogenetic depths suggesting that only the tempo, not the mode, of molecular evolution has varied since these viruses first became endemic to human hosts. Together, these findings forecast the potential for substantial changes in human virus evolution associated with demographic shifts which may disrupt these separate niches, promote inter-lineage competition, and lead to accelerated ongoing human adaptation.
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