bioRxiv: Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk - Controversy

[sharon sanders]

Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk


Christoph Lange, Georg Hahn, Chloe Wu, Sanghun Lee, Julian Hecker, Sharon Lutz, Sebastien Haneuse, Dandi Qiao, Michael Cho, Adrienne Randolph, Nan Laird, Scott Weiss, Edwin Silverman, Katharina Ribbeck

DOI:

10.21203/rs.3.rs-95183/v1

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This work is licensed under a CC BY 4.0 License. Read Full License

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Abstract


SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not understood. To address this issue, we used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome.

Specifically, we analyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased.

In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.

https://www.biorxiv.org/content/10.1101/2020.11.17.386714v1

[sharon sanders]

Andrew Rambaut
@arambaut
I was hesitant to bring attention to this but I suspect it will be picked up soon. I am concerned that a recently posted preprint will cause another panic about a deadly mutant which is entirely unsupported by the data.
8:29 PM ? Nov 24, 2020?Twitter Web App
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Andrew Rambaut
@arambaut

1h
Replying to
@arambaut
The preprint has identified a spike mutation V1176F and asserts that it is associated (along with another mutation in nsp7, L70F, closely linked to V1176F) with a higher mortality rate: https://doi.org/10.1101/2020.11.17.386714…
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Andrew Rambaut
@arambaut

1h
This preprint uses ‘patient status’ (i.e., alive or dead) at time of sampling as recorded in GISAID to look for mutations that have a statistical association with people who are more dead. The preprint also finds another mutation in nsp7, L70F, is closely linked to V1176F.
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Andrew Rambaut
@arambaut

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Andrew Rambaut
@arambaut

1h
There are 168 genomes with V1176F and patient status in GISAID and 160 of them are from Brazil (these are lineage B.1.1.28 or clade 1 in https://science.sciencemag.org/content/369/6508/1255.full… - this paper notes the V1176F mutation). Of these 160 cases, 131 are listed as being dead (an CFR of 81%).

Evolution and epidemic spread of SARS-CoV-2 in Brazil
Brazil has been hard-hit by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Candido et al. combined genomic and epidemiological analyses to investigate the impact of...
science.sciencemag.org
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Andrew Rambaut
@arambaut

1h
The preprint does a Fisher’s exact test and gets a vanishingly low probability that across all of Brazil this mutation could have been associated with such a high number of deaths by chance.
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Andrew Rambaut
@arambaut

1h
Of the 160 cases, 147 were sequenced by Instituto Adolfo Lutz and all 131 dead cases are in this set (CFR of 89%). IAL also sequenced 62 cases that weren’t in lineage B.1.1.28 (primarily lineage B.1.1.33 which doesn’t have V1176F) and 47 of these patients are also dead (75%).
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Andrew Rambaut
@arambaut

1h
Of the 168 cases with V1176F and with patient status, if you exclude the ones from IAL there are 20 remaining and all of them are recorded as alive. This suggests that IAL’s study has an extreme bias towards dead people (either a convenience sample or a deliberate study design).
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Andrew Rambaut
@arambaut

1h
So all of the signal for V1176F being a deadly mutation comes from genomes sequenced by IAL. But the genomes sequenced by IAL are not independent and should not be treated as such. This was a lineage or cluster that was circulating in Sao Paulo and ended up in IAL’s study.
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Andrew Rambaut
@arambaut

1h
If you remove all the IAL sequences the remaining 20 with V1176F are listed as alive. The entire signal comes from a study that is sequencing dead cases and the completely erroneous assumption that you can treat virus genomes as independent data points.
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Andrew Rambaut
@arambaut

1h
Patient status at time of sampling is an inherently flawed approach that is likely to cause spurious associations as only a few studies record it (and for these fatality may be part of the study design). And particular studies are more likely to have genetically similar viruses.
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Andrew Rambaut
@arambaut

1h
I should add that this preprint was originally posted here https://researchsquare.com/article/rs-95183/v1… about 2 weeks ago. I raised this issue with the authors then but it would seem they were comfortable enough with the results to post it to BioRxiv and hence this thread.

Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19...
SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not...
researchsquare.com
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Andrew Rambaut
@arambaut

42m
Oh and this preprint discovers the same mutation and the same cluster of Brazilian dead people: https://medrxiv.org/content/10.1101/2020.10.23.20218511v1…

[sharon sanders]

bump this