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The value of large-scale coordinated sequencing activities to understand a pandemic in real-time

Evaluating D614G Spike mutation on transmissibility and pathogenicity

What are the drivers of fast-growing SARS-CoV-2 lineages? 

Is SARS-CoV-2 becoming more dangerous? Don’t panic.

All viruses evolve by mutation and natural selection, and the novel SARS Coronavirus 2 (SARS-CoV-2) is no exception. When a new mutation is observed and starts to spread, should we be alarmed? One of the missions of the COVID-19 Genomics UK (COG-UK) Consortium is to track new genetic variants as they spread and investigate if these genetic changes lead to detectable changes in the behaviour of the virus or the severity of COVID-19 infections.

Most mutations that arise and spread have no detectable effect on the biology of the virus. But a few have the potential to change both the biological behaviour of the virus and persist if they confer an advantage to the virus. Yet by itself, the emergence of a widespread mutation is not necessarily of significance. The increased frequency of a particular mutation might be driven by many factors. If a particular strain of a virus becomes more dominant, that does not necessarily mean it is better at spreading. It may simply be more “lucky”.

A particular mutation that has captured the attention of scientists is an amino acid change from aspartate (D) to glycine (G) in the amino acid at position 614 in the sequence of the SARS-CoV-2 Spike protein, which is known to bind the ACE2 receptor on host cells and play a crucial role for viral entry into the host cell. When the novel variant 614G arose in the Spring and spread simultaneously to many countries around the globe, many scientists wondered if the virus had become more transmissible (Ref 1). Laboratory experiments later showed differences in the virus carrying the 614G mutation which infected cells at a higher rate (Ref 2). But does that mean this virus is more transmissible between people? Although experiments have suggested that this mutation enhances virus ability to infect human host cells because of structural changes to the Spike protein, it is crucial to understand what consequences this mutation has in a human population.

 

How can we understand a pandemic in real-time?

In recent work from COG-UK consortium investigators, published in the journal Cell, Erik Volz and colleagues investigated the D614G mutation in the population by using more than 25,000 viral genomes that have been sequenced in the UK over a period between February and June 2020 in order to understand the pandemic in real-time (Ref 3). Several statistical models were used to describe the faster growth of the 614G variant in comparison to its ancestral unmutated variant, but not all of them showed a conclusive signal of higher transmissibility. Importantly, the difference in the rate of growth of the 614G variant is consistent with about a 20% difference in transmission between people, far less than the difference in cell-infectivity measured in lab experiments. Genomic sequences from across the UK were also associated with data about the age, sex and severity of the desease of patients (i.e no respiratory support, supplemental oxygen, invasive or non-invasive ventilation or highflow nasal cannulae, death). This unprecedented dataset available in the consortium allowed Volz and colleagues to investigate the effect of D614G on the severity of the disease and look for correlations with different groups of individuals grouped into age categories. In the large comparison of patients considered in this study, no increased disease severity or mortality was observed. However, 614G has been found to be associated with higher viral load and younger age of patients. Scientists are also now looking at different clusters of mutations combined to D614G which showed different numbers of infections. It will be important to continue assessing whether viruses carrying D614G and other mutations have the potential to confer changes in the virus.

 

Figure 1. Summary outcomes 

 

References

  1. Korber, B., et al. (2020). “Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus.” Cell 182(4): 812-827 e819.
  2. Yurkovetskiy, L., et al. (2020). “Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant.” Cell 183(3): 739-751 e738.
  3. Volz, E., et al. (2020). “Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity.” Cell.

 

COVID-19 Genomics UK (COG-UK)

The current COVID-19 pandemic, caused by the SARS-CoV-2 virus, represents a major threat to health. The COVID-19 Genomics UK (COG-UK) consortium has been created to deliver large-scale and rapid whole-genome virus sequencing to local NHS centres and the UK government.

Led by Professor Sharon Peacock of the University of Cambridge, COG-UK is made up of an innovative partnership of NHS organisations, the four Public Health Agencies of the UK, the Wellcome Sanger Institute and twelve academic partners providing sequencing and analysis capacity. A full list of collaborators can be found here: https://www.cogconsortium.uk/about/

COG-UK was established in March 2020 supported by £20 million funding from the UK Department of Health and Social Care (DHSC), UK Research and Innovation (UKRI) and the Wellcome Sanger Institute, administered by UK Research and Innovation. For more information, visit: https://www.cogconsortium.uk