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Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest

Praveen Anand, View ORCID ProfilePatrick J. Lenehan, Michiel Niesen, Unice Yoo, Dhruti Patwardhan, Marcelo Montorzi, AJ Venkatakrishnan, View ORCID ProfileVenky Soundararajan
doi: https://doi.org/10.1101/2021.11.23.469709
Praveen Anand
1nference Labs, Bengaluru, Karnataka 560017, India
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Patrick J. Lenehan
2nference, Cambridge, Massachusetts 02139, USA
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  • ORCID record for Patrick J. Lenehan
Michiel Niesen
2nference, Cambridge, Massachusetts 02139, USA
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Unice Yoo
2nference, Cambridge, Massachusetts 02139, USA
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Dhruti Patwardhan
1nference Labs, Bengaluru, Karnataka 560017, India
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Marcelo Montorzi
2nference, Cambridge, Massachusetts 02139, USA
3Southcoast Health, Fairhaven, Massachusetts 02719, USA
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AJ Venkatakrishnan
2nference, Cambridge, Massachusetts 02139, USA
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  • For correspondence: venky@nference.net aj@nference.net
Venky Soundararajan
1nference Labs, Bengaluru, Karnataka 560017, India
2nference, Cambridge, Massachusetts 02139, USA
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  • ORCID record for Venky Soundararajan
  • For correspondence: venky@nference.net aj@nference.net
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Abstract

Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to a MYH6 peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.

Competing Interest Statement

All authors are employees of nference and have financial interests in the company. nference is collaborating with bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 29, 2021.
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Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest
Praveen Anand, Patrick J. Lenehan, Michiel Niesen, Unice Yoo, Dhruti Patwardhan, Marcelo Montorzi, AJ Venkatakrishnan, Venky Soundararajan
bioRxiv 2021.11.23.469709; doi: https://doi.org/10.1101/2021.11.23.469709
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Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest
Praveen Anand, Patrick J. Lenehan, Michiel Niesen, Unice Yoo, Dhruti Patwardhan, Marcelo Montorzi, AJ Venkatakrishnan, Venky Soundararajan
bioRxiv 2021.11.23.469709; doi: https://doi.org/10.1101/2021.11.23.469709

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