Zooanthroponotic transmission of SARS-CoV-2 and host-specific viral mutations revealed by genome-wide phylogenetic analysis
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Curated by eLife
eLife assessment
This important study offers compelling evidence, in the form of a rigorous and clear analysis of SARS-CoV-2 mutations observed within non-human animal hosts, of viral mutations that may provide an adaptive advantage within hosts. The authors could, however, improve the description of some elements of their methods and analysis approach, and they should cite additional relevant literature. The findings are relevant to those interested in the ecology of infectious disease, epidemiology, and specifically those who are interested in the genetic underpinnings of pandemic potential.
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Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a generalist virus, infecting and evolving in numerous mammals, including captive and companion animals, free-ranging wildlife, and humans. Transmission among non-human species poses a risk for the establishment of SARS-CoV-2 reservoirs, makes eradication difficult, and provides the virus with opportunities for new evolutionary trajectories, including the selection of adaptive mutations and the emergence of new variant lineages. Here, we use publicly available viral genome sequences and phylogenetic analysis to systematically investigate the transmission of SARS-CoV-2 between human and non-human species and to identify mutations associated with each species. We found the highest frequency of animal-to-human transmission from mink, compared with lower transmission from other sampled species (cat, dog, and deer). Although inferred transmission events could be limited by sampling biases, our results provide a useful baseline for further studies. Using genome-wide association studies, no single nucleotide variants (SNVs) were significantly associated with cats and dogs, potentially due to small sample sizes. However, we identified three SNVs statistically associated with mink and 26 with deer. Of these SNVs, ~⅔ were plausibly introduced into these animal species from local human populations, while the remaining ~⅓ were more likely derived in animal populations and are thus top candidates for experimental studies of species-specific adaptation. Together, our results highlight the importance of studying animal-associated SARS-CoV-2 mutations to assess their potential impact on human and animal health.
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eLife assessment
This important study offers compelling evidence, in the form of a rigorous and clear analysis of SARS-CoV-2 mutations observed within non-human animal hosts, of viral mutations that may provide an adaptive advantage within hosts. The authors could, however, improve the description of some elements of their methods and analysis approach, and they should cite additional relevant literature. The findings are relevant to those interested in the ecology of infectious disease, epidemiology, and specifically those who are interested in the genetic underpinnings of pandemic potential.
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Reviewer #1 (Public Review):
The authors present a clearly written manuscript detailing a phylogenomic analysis of SARS-CoV-2 isolates collected from nonhuman hosts. The methods and statistical analysis are appropriate and clearly stated. All claims are adequately justified. Despite the relatively broad host range of the virus (both predicted, https://doi.org/10.1073/pnas.201014611, and directly observed, https://www.aphis.usda.gov/aphis/dashboards/tableau/sars-dashboard), few cross-species transmission events can be confidently assessed from retrospective sequence analysis alone. It is highly likely that the majority of cross-species transmission events go undetected and that as sequencing resources become more widely distributed, more will be resolved.
Despite these limitations, the authors were able to resolve 3 mutations …
Reviewer #1 (Public Review):
The authors present a clearly written manuscript detailing a phylogenomic analysis of SARS-CoV-2 isolates collected from nonhuman hosts. The methods and statistical analysis are appropriate and clearly stated. All claims are adequately justified. Despite the relatively broad host range of the virus (both predicted, https://doi.org/10.1073/pnas.201014611, and directly observed, https://www.aphis.usda.gov/aphis/dashboards/tableau/sars-dashboard), few cross-species transmission events can be confidently assessed from retrospective sequence analysis alone. It is highly likely that the majority of cross-species transmission events go undetected and that as sequencing resources become more widely distributed, more will be resolved.
Despite these limitations, the authors were able to resolve 3 mutations overrepresented among mink (including S:N501T which has previously been suggested to confer an adaptive benefit) and 26 among deer relative to human hosts. In contrast to the present study, most prior work assessing the mutational landscape associated with zoonosis or reverse-zoonosis has focused on a single non-human species or even a single outbreak. Such a targeted analysis is more susceptible to false-positive predictions of adaptive mutations and in addition to verifying several mutations of interest, the present study serves as a generalizable framework for assessing the statistical significance of putative host-specific adaptations.
Globally, identifying characteristics of host population structure and viral molecular features which shift the balance between the emergence of generalist vs. specialist adaptations is a principal open question in viral ecology, https://doi.org/10.15252/embr.202255393. It is yet unclear whether most mutations observed to be overrepresented among non-human hosts, in this study and elsewhere, are under host-specific positive selection; subject to host-specific restriction factor activity (a possibility raised by the authors for several mutations overrepresented among deer), or represent substitutions which may be adaptive among many diverse mammalian hosts for which the probability of fixation is primarily determined by host-level dynamics (rate of contact, etc.). Additionally, while the impact of most individual mutations may be modest and, consequently, essentially host-nonspecific, slight variations among conserved host proteins (for example, the receptor ACE2, https://doi.org/10.1038/s41598-021-92388-5) may result in different epistatic landscapes. Within the receptor binding domain, however, the effect of most substitutions appears largely insensitive to context, https://doi.org/10.1128/mbio.00135-22.
The comprehensive analysis of SARS-CoV-2 mutations observed within non-human animal hosts presented in this work serves as a generalizable framework for assessing the significance of host-specific adaptations. Such analysis is essential to predicting changes in viral ecology and mitigating the risks of future zoonoses with pandemic potential.
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Reviewer #2 (Public Review):
One of the greatest challenges to the containment of the SARS-CoV-2 pandemic is the generalist nature of this virus and its ability to infect across non-human animal species, and successfully cycle within non-human species. It is, therefore, critical to understand the potential for transmission and evolution of the virus in non-human animal species and draw generalizations from both to help predict the occurrence of new viral variants and their associated risk for secondary spillover events back into human populations. This manuscript describes cross-species transmission between humans and non-human hosts, as well as non-human host-specific SNVs that have arisen presumably due to continued successful transmission cycles in non-human species. Using publicly available SARS-CoV-2 genomic sequences from four …
Reviewer #2 (Public Review):
One of the greatest challenges to the containment of the SARS-CoV-2 pandemic is the generalist nature of this virus and its ability to infect across non-human animal species, and successfully cycle within non-human species. It is, therefore, critical to understand the potential for transmission and evolution of the virus in non-human animal species and draw generalizations from both to help predict the occurrence of new viral variants and their associated risk for secondary spillover events back into human populations. This manuscript describes cross-species transmission between humans and non-human hosts, as well as non-human host-specific SNVs that have arisen presumably due to continued successful transmission cycles in non-human species. Using publicly available SARS-CoV-2 genomic sequences from four animal host species and humans, the study revealed that the highest number of animal-to-human transmission events have occurred between farmed mink populations and humans and that white-tailed deer have the highest number of single nucleotide variants specific to a non-human species from those included in the study. The authors are careful to point out the limitations of the dataset, as there are still too few publicly available SARS-CoV-2 whole genome sequences for non-human animal taxa, making non-human species inclusion impossible in some cases and creating unbalanced datasets that reflect sequencing and sampling effort. The authors could have offered a greater justification of statistical methods employed given this hurdle, both in terms of quantitative mitigation steps or qualitative justification of the methods used, but their methods provide a pipeline for addressing cross-species transmission and the emergence of non-human species-specific SNVs as scientists work to accumulate more genomic sequences from animal taxa. Their results are also largely congruent with another recently published manuscript using SARS-CoV-2 genomic data from the same source and aimed at understanding human-to-animal transmission solely. In addition to the two main goals, cross-species transmission, and species-specific SNVs, the authors have offered an evaluation and discussion of several species-specific SNVs that will aid the scientific community in the future in drawing connections between viral evolution, host biology, and epidemiological patterns related to SARS-CoV-2 across species.
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