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A call for caution in the biological interpretation of viral auxiliary metabolic genes

Nature Microbiology volume 10, pages 2122–2129 (2025)Cite this article

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Abstract

Virus-encoded auxiliary metabolic genes (AMGs) are non-essential genes that increase viral fitness by maintaining or manipulating host metabolism during infection. AMGs are intriguing from an evolutionary perspective, as most viral genomes are highly compact and have limited coding capacity for accessory genes. Advances in viral (meta)genomics have expanded the detection of putative AMGs from viruses in diverse environments. However, this has also led to many instances of misannotation due to the limitations of annotation tools, resulting in misinterpretations about the roles of some viral genes. Here, we highlight studies that support claims about AMGs with more than just function predictions for guidance on best practices. We then propose the adoption of an expanded, inclusive view of all genes auxiliary to core viral functions with the term ‘auxiliary viral genes’ (AVGs), alongside an associated eco-evolutionary framework for considering the types of analyses that can better support claims made about AVGs.

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Fig. 1: Common limitations when studying viral AMGs.
Fig. 2: Limitations of semiautomated viral protein annotation.
Fig. 3: Eco-evolutionary forces driving AVG evolution.

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Acknowledgements

We thank members of the Anantharaman, Roux and Emerson laboratories for helpful discussions. C.M. was funded by a National Science Foundation Graduate Research Fellowship and by a UW-Madison SciMed Graduate Research Fellowship. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM143024 (to K.A.), by the US Department of Energy (DOE), Office of Science, Office of Biological and Environmental Research (BER), Genomic Science Program, award no. DE-SC0021198 (to J.B.E.), and by the US DOE, Office of Science, Biological and Environmental Research, Early Career Research Program awarded under UC-DOE prime contract DE-AC02-05CH11231 (to S.R.). The work conducted by the US DOE Joint Genome Institute (https://ror.org/04xm1d337), a DOE Office of Science User Facility, is supported by the Office of Science of the US DOE operated under contract no. DE-AC02-05CH11231.

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Authors and Affiliations

  1. Department of Bacteriology, University of Wisconsin–Madison, Madison, WI, USA

    Cody Martin & Karthik Anantharaman

  2. Microbiology Doctoral Training Program, University of Wisconsin–Madison, Madison, WI, USA

    Cody Martin

  3. Department of Plant Pathology, University of California, Davis, Davis, CA, USA

    Joanne B. Emerson

  4. DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Simon Roux

  5. Department of Integrative Biology, University of Wisconsin–Madison, Madison, WI, USA

    Karthik Anantharaman

  6. Department of Data Science and AI, Indian Institute of Technology Madras, Chennai, India

    Karthik Anantharaman

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  2. Joanne B. Emerson
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  3. Simon Roux
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  4. Karthik Anantharaman
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All authors conceptualized the content and direction of the manuscript. C.M. and K.A. wrote the manuscript draft. J.B.E., S.R. and K.A. provided content feedback. All authors reviewed, edited and approved the manuscript.

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Correspondence to Joanne B. Emerson, Simon Roux or Karthik Anantharaman.

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Martin, C., Emerson, J.B., Roux, S. et al. A call for caution in the biological interpretation of viral auxiliary metabolic genes. Nat Microbiol 10, 2122–2129 (2025). https://doi.org/10.1038/s41564-025-02095-4

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