Principles of dengue virus evolvability derived from genotype-fitness maps in human and mosquito cells
- University of California, San Francisco, United States
- Stanford University, United States
- Tel Aviv University, Israel
Abstract
Dengue virus (DENV) cycles between mosquito and mammalian hosts. To examine how DENV populations adapt to these different host environments we used serial passage in human and mosquito cell lines and estimated fitness effects for all single-nucleotide variants in these populations using ultra-deep sequencing. This allowed us to determine the contributions of beneficial and deleterious mutations to the collective fitness of the population. Our analysis revealed that the continuous influx of a large burden of deleterious mutations counterbalances the effect of rare, host-specific beneficial mutations to shape the path of adaptation. Beneficial mutations preferentially map to intrinsically disordered domains in the viral proteome and cluster to defined regions in the genome. These phenotypically redundant adaptive alleles may facilitate host-specific DENV adaptation. Importantly, the evolutionary constraints described in our simple system mirror trends observed across DENV and Zika strains, indicating it recapitulates key biophysical and biological constraints shaping long-term viral evolution.
Data availability
- All data has been deposited and is available at the persistent URL: https://purl.stanford.edu/gv159td5450- All code for analysis and figure generation is deposited in GitHub: https://github.com/ptdolan/Dolan_Taguwa_Dengue_2020- Sequencing Data has been deposited as BioProject: PRJNA669406
Article and author information
Author details
Funding
National Institutes of Health (AI127447,AI36178,AI091575,F32GM113483)
- Patrick T Dolan
- Raul Andino
- Judith Frydman
Naito Foundation
- Shuhei Taguwa
Uehara Memorial Foundation
- Shuhei Taguwa
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Dolan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Principles of dengue virus evolvability derived from genotype-fitness maps in human and mosquito cells
eLife 10:e61921.
https://doi.org/10.7554/eLife.61921
Further reading
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- Evolutionary Biology
The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than 10 alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognised.
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