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Revealing variants in SARS-CoV-2 interaction domain of ACE2 and loss of function intolerance through analysis of >200,000 exomes

View ORCID ProfileElizabeth T. Cirulli, View ORCID ProfileStephen Riffle, View ORCID ProfileAlexandre Bolze, View ORCID ProfileNicole L. Washington
doi: https://doi.org/10.1101/2020.04.07.030544
Elizabeth T. Cirulli
1Helix, 101 S Ellsworth Ave Suite 350, San Mateo, California 94401
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  • For correspondence: liz.cirulli@helix.com
Stephen Riffle
1Helix, 101 S Ellsworth Ave Suite 350, San Mateo, California 94401
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Alexandre Bolze
1Helix, 101 S Ellsworth Ave Suite 350, San Mateo, California 94401
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Nicole L. Washington
1Helix, 101 S Ellsworth Ave Suite 350, San Mateo, California 94401
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  • ORCID record for Nicole L. Washington
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Lay summary

Our researchers took a look at a sequence of DNA known as the ACE2 gene. This gene is most well known for its role in regulating blood pressure. But in recent times, it’s drawn a lot of attention from the scientific community because it may also serve as a doorway of sorts, enabling viruses like SARS-CoV-2 to infect cells. Our researchers looked at the ACE2 gene in more than 200,000 people, comparing their exact DNA sequences to see where there are differences among people. Variation in the DNA sequence of a gene is common and is sometimes meaningless. But other times, small changes in the DNA sequence can alter the protein that is made from that gene. In this case the ACE2 gene makes the ACE2 protein, which is what the SARS-CoV-2 virus interacts with. We found a lot of variation between individuals and checked to see if that variation coincided with any traits (i.e., people with variant X tend to have high blood pressure more often than people without variant X). All of the traits we looked at were non-COVID-19-related traits, meaning we haven’t asked these people anything about COVID-19 yet (this is because these DNA sequences were collected before the pandemic).

We found that there are a number of variations observed among people in a specific part of the ACE2 gene. These variations are expected to alter the shape or functionality of a specific part of the ACE2 protein: The part that interacts with the SARS-CoV-2 virus. We don’t yet know what the real-life significance of this variation is, but it’s possible that these variants decrease the protein’s ability to interact with the SARS-CoV-2 virus, thus decreasing the person’s likelihood of being infected. We can speculate that there will be a spectrum of vulnerability to COVID-19 among people, where some people are more vulnerable than others, and that variants in this part of the ACE2 gene may be one of the reasons. The research we presented here shines a light on this part of the ACE2 gene and may give future researchers a direction to go in as they try to figure out what makes people vulnerable to COVID-19 and similar viruses.

Competing Interest Statement

All authors are employees of Helix.

Footnotes

  • Figure 4 revised, allele frequency corrected

  • https://s3.amazonaws.com/helix-research-public/data_releases/ace2_variants_helix_db.txt

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted May 04, 2020.
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Revealing variants in SARS-CoV-2 interaction domain of ACE2 and loss of function intolerance through analysis of >200,000 exomes
Elizabeth T. Cirulli, Stephen Riffle, Alexandre Bolze, Nicole L. Washington
bioRxiv 2020.04.07.030544; doi: https://doi.org/10.1101/2020.04.07.030544
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Revealing variants in SARS-CoV-2 interaction domain of ACE2 and loss of function intolerance through analysis of >200,000 exomes
Elizabeth T. Cirulli, Stephen Riffle, Alexandre Bolze, Nicole L. Washington
bioRxiv 2020.04.07.030544; doi: https://doi.org/10.1101/2020.04.07.030544

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