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.
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Proteome and Translatome of SARS-CoV-2 infected cellsPRIDE database, PXD017710.
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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.
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Proteomics of SARS-CoV and SARS-CoV-2 infected cellsPRIDE database, PXD018581.
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Decoding SARS-CoV-2 coding capacityGEO database, sample IDs: SRR11713366, SRR11713367, SRR11713368, SRR11713369 from GSE149973.
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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.
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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
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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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Understanding the origins of novel, complex phenotypes is a major goal in evolutionary biology. Poison frogs of the family Dendrobatidae have evolved the novel ability to acquire alkaloids from their diet for chemical defense at least three times. However, taxon sampling for alkaloids has been biased towards colorful species, without similar attention paid to inconspicuous ones that are often assumed to be undefended. As a result, our understanding of how chemical defense evolved in this group is incomplete. Here, we provide new data showing that, in contrast to previous studies, species from each undefended poison frog clade have measurable yet low amounts of alkaloids. We confirm that undefended dendrobatids regularly consume mites and ants, which are known sources of alkaloids. Thus, our data suggest that diet is insufficient to explain the defended phenotype. Our data support the existence of a phenotypic intermediate between toxin consumption and sequestration — passive accumulation — that differs from sequestration in that it involves no derived forms of transport and storage mechanisms yet results in low levels of toxin accumulation. We discuss the concept of passive accumulation and its potential role in the origin of chemical defenses in poison frogs and other toxin-sequestering organisms. In light of ideas from pharmacokinetics, we incorporate new and old data from poison frogs into an evolutionary model that could help explain the origins of acquired chemical defenses in animals and provide insight into the molecular processes that govern the fate of ingested toxins.
