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A method to find a probability that a given bias of mutations occur naturally is proposed to test whether a newly detected virus is a product of natural evolution or artificial genetic modification. The probability is calculated based on the neutral theory of molecular evolution and binominal distribution of non-synonymous (N) and synonymous (S) mutations. Though most of the conventional analyses, including dN/dS analysis, assume that any kinds of point mutations from a nucleotide to another nucleotide occurs with the same probability, the proposed model takes into account the bias in mutations, where the equilibrium of mutations is considered to estimate the probability of each mutation. The proposed method is applied to evaluate whether the Omicron variant strain of SARS-CoV-2, whose spike protein includes 29 N mutations and only one S mutation, can emerge through natural evolution. The result of binomial test based on the proposed model shows that the bias of N/S mutations in the Omicron spike can occur with a probability of 1.6 x 10^(-3)or less. Even with the conventional model where the probabilities of any kinds of mutations are all equal, the strong N/S mutation bias in the Omicron spike can occur with a probability of3.7x 10^(-3),which means that the Omicron variant is highly likely a product of artificial genetic modification.

This manuscript was submitted as a “Letter to the Editor” to Cell on October 31, 2021, to address some issues with the article "The origins of SARS-CoV-2: A critical review" published by Holmes, E.C. et al. (2021) in Cell (184, 4848-4856, DOI: https://doi.org/10.1016/j.cell.2021.08.017). Our Letter discusses logical flaws, missing information and interpretation biases of Holmes’ “Critical review”, provides complementary information and considers alternative ways of interpreting the available data. The editors refused to send it to reviewers, rejected it on Nov 5, 2021 (and confirmed on Nov 29), invoking that it “does not raise new points”, and that “the same points have, for the most part, previously been raised through other avenues”. Indeed, the points we raised have been discussed elsewhere but some of them have never been mentioned in peer-reviewed articles (but only in institutional reports, press and other media, which we cite in our “Web Resources”section). Note that the points of Holme’s “Critical Review” had also been raised earlier through other avenues. In addition, we took a critical look at some facts that were imprecisely presented in the Holmes paper. The Cell editors wrote: “you are certainly welcome to raise your points in another scientific journal”.We however think that journals like Cell should publish responses to their publications in their own columns, in order to provide their readership with a comprehensive discussion of all the scientific arguments, and should favour an open scientific debate rather than promoting a single point of view. Following Cell's refusal to publish our Letter we decided to release it via this public archive.We also posted it as a Comment onCell's web site, which was approved by Cell's editor on December 18, 2021, and assigned a direct short link (http://disq.us/p/2ley7ak). However, in May 2022 we noticed that the comment had disappeared from Cell's web site (and the short link now points towards the head of Holme's review). We reported this to Cell's editor, who answeredthat "Cell Press recently decided to discontinue the commenting function on cell.com, partly due to the lack of usage and engagement.", and suggested us to post this comment on a blog or platform like Twitter. &nbsp

Understanding the origins of the pandemic is essential to addressing our vulnerabilities and preventing future crises. Unfortunately, as outlined in previous open letters released on March 4 and April 7, structural, procedural, and analytical shortcomings of the WHO-convened joint study into COVID-19 origins have created unnecessary barriers to this understanding.

Understanding how the SARS-CoV-2 virus emerged and spread to humans is an essential foundation for prioritizing future pandemic prevention and response strategies. Yet well over a year after the initial outbreak, no robust process for examining the origins of the pandemic has been established and critical records and biological samples that could provide essential insights into pandemic origins remain inaccessible. These shortcomings pose a significant threat to everyone and future generations. As scientists, social scientists, and science communicators, including signatories of the March 4, 2021 open letter on COVID-19 origins, we believe there is a better way forward.