Viral infectious diseases remain a significant threat and, as demonstrated in recent years, can be particularly disruptive and unpredictable in their impact on human lives, economies, and public health. Advances in genomic science have enabled leaps in how to manage, respond to, and mitigate viral disease, but significant gaps remain in what we know: we have a limited understanding of the pathogens that exist in our environment, how they spread, and which of them have epidemic potential, leaving us vulnerable to the emergence of future threats. Without more complete knowledge of the pathogens around us, it will be difficult or impossible to develop countermeasures with sufficient speed to stop major outbreaks in the future. Our long-term goal is to advance understanding and utility of viral genomics so that we are better able to prepare for and respond to future outbreaks: we aim to comprehensively identify circulating viruses, infer viral evolutionary signals and human transmission chains, and characterize the effect of consequential mutations on the virus, its immunogenicity, and impact on humans. The Broad Institute’s GCID has led many technical, analytical, and translational advances that have revolutionized the application of genomics to viral disease. The experience, resources, and innovative capacity of this group will all be necessary to address the gaps that remain, and new challenges that emerge, in our understanding of and our ability to respond to ongoing threats posed by viral diseases. The premise of this proposal is improved insights from viral genomic data will accelerate the design of viral diagnostics, therapeutics, and vaccines, and will inform public health strategies and policy. We plan to do this by pursuing the following three specific aims: 1) Detect emerging viral threats with robust metagenomics and diagnostic designs (this includes improving methods for metagenomic surveillance and PCR diagnostic designs). 2) Genomic epidemiology and population genetics of viral outbreaks and epidemics (this includes analytic methods for Bayesian phylogenetic inference of evolutionary signals and of human transmission chains and clusters. 3) Identify and characterize viral genetic variation with phenotypic impact (this includes identification and in vitro characterization of viral mutations). The expected outcomes of this work are a systematic understanding of circulating viral threats with epidemic potential, genomics-informed view of viral transmission during outbreaks, and a characterization of the viral genetic adaptations that affect their spread and impact on society. This proposal will have a positive impact by providing genomic data resources, insights into viral circulation, developing new analytic and interpretive frameworks for epidemiological insights to influence public health practice, and creating public data sets to enable the design of new interventions for viral disease. Our work will advance viral genomics by creating...