Sampling bias and incorrect rooting make phylogenetic network tracing of SARS-COV-2 infections unreliable.

Abstract

There is obvious interest in gaining insights into the epidemiology and evolution of the virus that has recently emerged in humans as the cause of the coronavirus disease 2019 (COVID-19) pandemic. The recent paper by Forster et al. (1), analyzed 160 SARS-CoV-2 full genomes available (https://www.gisaid.org/) in early March 2020. The central claim is the identification of three main SARS-CoV-2 types, named A, B, and C, circulating in different proportions among Europeans and Americans (types A and C) and East Asian (type B). According to a median-joining network analysis, variant A is proposed to be the ancestral type because it links to the sequence of a coronavirus from bats, used as an outgroup to trace the ancestral origin of the human strains. The authors further suggest that the “ancestral Wuhan B-type virus is immunologically or environmentally adapted to a large section of the East Asian population, and may need to mutate to overcome resistance outside East Asia”. There are several serious flaws with their findings and interpretation. First, and most obviously, the sequence identity between SARS-CoV-2 and the bat virus is only 96.2%, implying that these viral genomes (which are nearly 30,000 nucleotides long) differ by more than 1,000 mutations. Such a distant outgroup is unlikely to provide a reliable root for the network. Yet, strangely, the branch to the bat virus, in Figure 1 of the paper, is only 16 or 17 mutations in length. Indeed, the network seems to be mis-rooted because (see Supplementary Figure 4) a virus from Wuhan from week 0 (24th December 2019) is portrayed as a descendant of a clade of viruses collected in weeks 1-9 (presumably from many places outside China), which makes no evolutionary (2), nor epidemiological sense (3).N