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The development and application of mass spectrometry (MS) approaches to detect, characterize and distinguish variants of the SARS-CoV2 virus and types/subtypes of other respiratory viruses (influenza and parainfluenza viruses) are described. The benefits of MS approaches over PCR-based methods are presented together with the advantages of high mass resolution, high mass accuracy strategies and MS instrumentation. Recent and new developments, reported for the first time in this chapter, include the measured detection limits for identification of SARS-CoV2 virus variants in clinical specimens, their evolutionary trajectories using peptide mass map data and the use of numerical mass-based trees to interrogate mechanisms associated with epistasis and the role of compensatory mutations that promote antiviral resistance and restore viral fitness during virus evolution.

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