Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic
- Academia Sinica, Taiwan
- Technical University of Munich, Germany
- University of Wisconsin-Madison, United States
- American Museum of Natural History, United States
- University of California, Berkeley, United States
Abstract
Understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics, but are still widely overlooked. We identify and characterize ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples). ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. Our results liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.
Data availability
All data generated or analyzed during this study are included in the manuscript and supplement. Scripts and source data for all analyses and figures are provided on GitHub at https://github.com/chasewnelson/SARS-CoV-2-ORF3d and Zenodo at https://zenodo.org/record/4052729.
-
Proteome and Translatome of SARS-CoV-2 infected cellsPRIDE database, PXD017710.
-
Vero cells infected with SARS CoV 2 no quantitation slices 1-10 of 20; vero cells infected with SARS CoV2 slices 11-20 of 20 slicesZenodo, 10.5281/zenodo.3722590, 10.5281/zenodo.3722596.
-
Proteomics of SARS-CoV and SARS-CoV-2 infected cellsPRIDE database, PXD018581.
-
Decoding SARS-CoV-2 coding capacityGEO database, sample IDs: SRR11713366, SRR11713367, SRR11713368, SRR11713369 from GSE149973.
-
Assays and Merits of Proteomics for SARS-CoV-2 Research and TestingPRIDE database, PXD019645.
Article and author information
Author details
Sergios-Orestis Kolokotronis
Funding
Academia Sinica (Postdoctoral Research Fellowship)
- Chase W Nelson
National Philanthropic Trust (Grant)
- Zachary Ardern
University of Wisconsin-Madison (John D. MacArthur Professorship Chair)
- Tony L Goldberg
National Science Foundation (IOS grants #1755370 and #1758800)
- Sergios-Orestis Kolokotronis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Nelson 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.
Metrics
-
- 17,125
- views
-
- 1,566
- downloads
-
- 77
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic
eLife 9:e59633.
https://doi.org/10.7554/eLife.59633
Further reading
-
- Evolutionary Biology
Gene duplication drives evolution by providing raw material for proteins with novel functions. An influential hypothesis by Ohno (1970) posits that gene duplication helps genes tolerate new mutations and thus facilitates the evolution of new phenotypes. Competing hypotheses argue that deleterious mutations will usually inactivate gene duplicates too rapidly for Ohno’s hypothesis to work. We experimentally tested Ohno’s hypothesis by evolving one or exactly two copies of a gene encoding a fluorescent protein in Escherichia coli through several rounds of mutation and selection. We analyzed the genotypic and phenotypic evolutionary dynamics of the evolving populations through high-throughput DNA sequencing, biochemical assays, and engineering of selected variants. In support of Ohno’s hypothesis, populations carrying two gene copies displayed higher mutational robustness than those carrying a single gene copy. Consequently, the double-copy populations experienced relaxed purifying selection, evolved higher phenotypic and genetic diversity, carried more mutations and accumulated combinations of key beneficial mutations earlier. However, their phenotypic evolution was not accelerated, possibly because one gene copy rapidly became inactivated by deleterious mutations. Our work provides an experimental platform to test models of evolution by gene duplication, and it supports alternatives to Ohno’s hypothesis that point to the importance of gene dosage.
-
- Evolutionary Biology
Life-history theory, central to our understanding of diversity in morphology, behaviour, and senescence, describes how traits evolve through the optimisation of trade-offs in investment. Despite considerable study, there is only minimal support for trade-offs within species between the two traits most closely linked to fitness – reproductive effort and survival – questioning the theory’s general validity. We used a meta-analysis to separate the effects of individual quality (positive survival/reproduction correlation) from the costs of reproduction (negative survival/reproduction correlation) using studies of reproductive effort and parental survival in birds. Experimental enlargement of brood size caused reduced parental survival. However, the effect size of brood size manipulation was small and opposite to the effect of phenotypic quality, as we found that individuals that naturally produced larger clutches also survived better. The opposite effects on parental survival in experimental and observational studies of reproductive effort provide the first meta-analytic evidence for theory suggesting that quality differences mask trade-offs. Fitness projections using the overall effect size revealed that reproduction presented negligible costs, except when reproductive effort was forced beyond the maximum level observed within species, to that seen between species. We conclude that there is little support for the most fundamental life-history trade-off, between reproductive effort and survival, operating within a population. We suggest that within species the fitness landscape of the reproduction–survival trade-off is flat until it reaches the boundaries of the between-species fast–slow life-history continuum. Our results provide a quantitative explanation as to why the costs of reproduction are not apparent and why variation in reproductive effort persists within species.
