The expected effect of deleterious mutations on within-host adaptation of pathogens
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Journal of Virology
American Society for Microbiology
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Fonville, J. (2015). The expected effect of deleterious mutations on within-host adaptation of pathogens. Journal of Virology, 18 9242-9251. https://doi.org/10.1128/JVI.00832-15
Adaptation is a common theme in both pathogen emergence, for example in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen’s fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediates on pathogen adaptation is smaller than their name might suggest: when two mutations are required, and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutant that is 20-fold lower than for the situation where all mutants are neutral. The negative effects of deleterious intermediates are typically substantially smaller, and outweighed, by fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when calculating the number of routes of mutation available to the pathogen, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when assessing the effect of deleterious mutations on the within-host adaptation of pathogens, for example in the context of zoonotic emergence, antigenic escape, and drug resistance.
deleterious, evolution, adaptation, epistasis, compensatory, fitness valley, fitness landscape, mutation order
This work was supported by the award of a Fellowship in Biomedical Informatics from the Medical Research Council UK (MR/K021885/1) and a Junior Research Fellowship from Homerton College Cambridge to JMF; and the award of HHSN272201400008C (NIAID Centres of Excellence for Influenza Research and Surveillance) to the Center for Pathogen Evolution.
National Institutes of Health (NIH) (via Mount Sinai School of Medicine (MSSM)) (HHSN272201400008C)
External DOI: https://doi.org/10.1128/JVI.00832-15
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248725