Statistical challenges for inferring multiple SARS-CoV-2 spillovers with early outbreak phylodynamics

Understanding how SARS-CoV-2 entered the human population, thereby causing the COVID-19 pandemic, is one of the most urgent questions in science today. Two hypotheses are widely acknowledged as being most likely to explain the pandemics origin in late 2019: (i) the "natural origin" hypothesis that one or more cross-species transmissions from animals into humans occurred, most likely at the Huanan Seafood Market in Wuhan, China; (ii) the "laboratory origin" hypothesis, that scientific research activities led to the unintentional leak of SARS-CoV-2 from a laboratory into the general population. A recent analysis of SARS-CoV-2 genomes by Pekar et al. [Science 377:960-966 (2022)] claims to establish at least two separate spillover events from animals into humans, thus claiming to provide strong evidence for the natural origin hypothesis. However, here we use outbreak simulations to show that the findings of Pekar et al. are heavily impacted by two methodological artifacts: the dubious exclusion of informative SARS-CoV-2 genomes, and their reliance on unrealistic phylodynamic models of SARS-CoV-2. Absent models that incorporate these effects, one cannot conclude multiple SARS-CoV-2 spillovers into humans. Our results cast doubt on a primary point of evidence in favor of the natural origin hypothesis. Lay SummaryIt is not known if SARS-CoV-2 spilled over from animals into humans at the Huanan Seafood Market, or arose as a result of research activities studying bat coronaviruses. Two recent papers had claimed to answer this question, but here we show those papers are both inconclusive as they fail to account for biases in how medical managers became alerted to SARS-CoV-2 and how public health authorities sampled early cases. Additionally, key data points conflicting with the authors conclusions were improperly excluded from the analysis. The papers methods do not justify their conclusions, and the origin of SARS-CoV-2 remains an urgent, open question for science.