Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2.

David D Pollock,Richard A Goldstein,Blair W Perry,Pleuni S Pennings,Rhys Parry,Edward C Holmes,Elizabeth J Carlton,Spyros Lytras,James L N Wood,Maciej F Boni,Todd A Castoe,David L Robertson,Sergei L Kosakovsky Pond,Kristen J Wade

doi:10.1093/molbev/msaa178

Abstract

Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia’s inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited.

Highlights

The COVID-19 pandemic began following a cross-species transmission event of the causative virus, SARS-CoV-2, sometime in late 2019 (Gorbalenya et al 2020; Li et al 2020; Lu et al 2020; Zhang and Holmes 2020; Zhou, Yang, et al 2020)
Clarifying the Uncertainty in SARS-CoV-2 Origins To date, the closest known relative of SARS-CoV-2 across its genome as a whole is the RaTG13 virus that was isolated from a horseshoe bat, the established reservoir of the earlier SARS coronaviruses that emerged in 2002–2003 (Zhou, Chen, et al 2020)
CpG depletion levels are known to be diverse among RNA viruses broadly, CpG levels are depleted in noncanine viruses closely related to SARS-CoV-2, evidence that natural selection drove the CpG depletion in SARSCoV-2 ancestors is lacking, and there are a variety of competing mechanisms for genomes to become relatively depleted in CpG over evolutionary time

Summary

Introduction

The COVID-19 pandemic began following a cross-species transmission event of the causative virus, SARS-CoV-2, sometime in late 2019 (Gorbalenya et al 2020; Li et al 2020; Lu et al 2020; Zhang and Holmes 2020; Zhou, Yang, et al 2020). CpG depletion levels are known to be diverse among RNA viruses broadly, CpG levels are depleted in noncanine viruses closely related to SARS-CoV-2, evidence that natural selection drove the CpG depletion in SARSCoV-2 ancestors is lacking, and there are a variety of competing mechanisms for genomes to become relatively depleted in CpG over evolutionary time.

Results

Conclusion