Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Abstract

In February 2020 a substitution at the interface between SARS-CoV-2 Spike protein subunits, Spike D614G, was observed in public databases. The Spike 614G variant subsequently increased in frequency in many locations throughout the world. Global patterns of dispersal of Spike 614G are suggestive of a selective advantage of this variant, however the origin of Spike 614G is associated with early colonization events in Europe and subsequent radiations to the rest of the world. Increasing frequency of 614G may therefore be due to a random founder effect. We investigate the hypothesis for positive selection of Spike 614G at the level of an individual country, the United Kingdom, using more than 25,000 whole genome SARS-CoV-2 sequences collected by COVID-19 Genomics UK Consortium. Using phylogenetic analysis, we identify Spike 614G and 614D clades with unique origins in the UK and from these we extrapolate and compare growth rates of co-circulating transmission clusters. We find that Spike 614G clusters are introduced in the UK later on average than 614D clusters and grow to larger size after adjusting for time of introduction. Phylodynamic analysis does not show a significant increase in growth rates for clusters with the 614G variant, but population genetic modelling indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We also investigate the potential influence of Spike 614D versus G on virulence by matching a subset of records to clinical data on patient outcomes. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality, but younger patients have slightly increased odds of 614G carriage. Despite the availability of a very large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of higher transmission rate for 614G, but significant differences in growth, size, and composition of these lineages indicate a need for continued study.

No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2

“…2 and 3 and Supplementary Data 4). Given the importance of monitoring potential changes in virus transmissibility, several other studies have investigated whether particular sets of mutations in SARS-CoV-2 are associated with changes in transmission and virulence 15,21,39 . We strongly caution that efforts to determine whether any specific mutation contributes to a change in viral phenotype, using solely genomic approaches, rely on the ability to distinguish between changes in allele frequency due to demographic or epidemiological processes, compared to those driven by selection 22 .…”

“…A recent study on a sample of 25,000 whole-genome sequences exclusively from the UK used different approaches to investigate D614G. Not all analyses found a conclusive signal for D614G, and effects on transmission, when detected, appeared relatively moderate 39 .…”

Jumping back and forth: anthropozoonotic and zoonotic transmission of SARS-CoV-2 on mink farms

“…Recently, a specific mutation in the spike protein (D614G) was shown to result in an increased virulence in vitro (55), while it was not associated an increased growth rate for cluster nor an increased mortality (56). This mutation was present in farm clusters A, C and E, but no obvious differences in clinical presentation, disease severity, or rate of transmission to humans was observed.…”

Genomic Diversity of SARS-CoV-2 During Early Introduction into the United States National Capital Region

“…We found no clear correlation, but were limited by sample size. It will be important to continue to analyze genomic data alongside clinical metadata as the number of available viral 11 genomes increases to look for potentially subtle associations between the viral genome and patient characteristics 33 .…”