Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Stawiski, Eric; Diwanji, Devan; Suryamohan, Kushal; Gupta, Ravi; Fellouse, Frédéric A.; Sathirapongsasuti, Fah; Liu, Jiang; Jiang, Ying-Ping; Ratan, Aakrosh; Mis, Monika; Santhosh, Devi; Somasekar, Sneha; Mohan, Sangeetha; Phalke, Sameer; Kuriakose, Boney; Antony, Aju; Junutula, Jagath R.; Schuster, Stephan C.; Jura, Natalia; Seshagiri, Somasekar

doi:10.1101/2020.04.07.024752

Cited by 147 publications

(184 citation statements)

References 50 publications

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“…S19P) have uncertain effects. Further studies are needed to confirm and correctly address recent discoveries (18,27,28) and the data presented here, investigating the possible effect of these rare variants in specific populations.…”

Section: Discussionmentioning

confidence: 61%

“…Structural analysis of variation in human ACE2 . We applied the same approach used to compare species, sequence identity and protein structural analysis, to examine the variation in ACE binding residues within humans, some of which have been proposed to alter binding affinity (18,(27)(28)(29)(30) . We integrated data from six different sources: dbSNP (31) , 1KGP (32) , Topmed (33) , UK10K (34) and CHINAMAP (28) , and identified a total of 11 variants in ten of the 25 ACE2 binding residues (Dataset S2).…”

Section: Resultsmentioning

confidence: 99%

“…Sequence variation in ACE2 affects the protein's functions. ACE2 is polymorphic in humans, with many synonymous and nonsynonymous mutations identified, although most are rare at the population level (17) and few are believed to affect cellular susceptibility to human coronavirus infections (18) .…”

Section: Introductionmentioning

confidence: 99%

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Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Damas¹,

Hughes

Keough³

et al. 2020

Preprint

155

241

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The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low . Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

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Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Damas¹,

Hughes

Keough³

et al. 2020

Preprint

155

241

View full text Add to dashboard Cite

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“…For other viruses, we know that some individuals have a natural immunity whereby even when exposed to the virus, they do not develop infection. For example, the well-known CCR5-delta32 allele has a variation that protects individuals who have been exposed to the Human Immunodeficiency Virus (HIV); they are protected from developing AIDS (Acquired Immunodeficiency Syndrome) [10]. Because of this, researchers are gearing up to study the genomes of COVID-19 positive patients in comparison to controls (COVID-19-negative patients).…”

Section: Geneticsmentioning

confidence: 99%

Ideas for how informaticians can get involved with COVID-19 research

et al. 2020

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The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on population health and wellbeing. Biomedical informatics is central to COVID-19 research efforts and for the delivery of healthcare for COVID-19 patients. Critical to this effort is the participation of informaticians who typically work on other basic science or clinical problems. The goal of this editorial is to highlight some examples of COVID-19 research areas that could benefit from informatics expertise. Each research idea summarizes the COVID-19 application area, followed by an informatics methodology, approach, or technology that could make a contribution. It is our hope that this piece will motivate and make it easy for some informaticians to adopt COVID-19 research projects.

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“…Efforts are being made worldwide to understand it better and it becomes complex with reports that BCG vaccination reduces morbidity and mortality for COVID19 in human population [10]. Due to extensive research going on in parallel, evidences in favour [11] as well as against [12] existence of SARS-CoV-2 S-protein binding-resistant ACE2 natural variants, in different populations, have been generated recently. In addition, studies highlighting role of eQTLs in ACE2 expression and resulting in potential differential COVID19 fatality [12,13] are pouring in.…”

Section: Introductionmentioning

confidence: 99%

ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

Sharma

Singh

Haider

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S protein priming by host cell serine protease TMPRSS2. Recently COVID19 has been declared pandemic by World Health Organization yet high differences in disease outcomes across countries have been seen. We provide evidences based on analyses of existing public datasets and by using various insilico approaches to explain some of these as factors that may explain population level differences. One of the key factors might be entry of virus in host cells due to differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that higher expression of ACE2 facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs) and with different frequencies in different populations, results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2 and becomes more difficult in presence of broad neutral amino acid transporter, B0AT1 (coded by SLC6A19), that usually does not express in Lungs. We also propose that the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of Virus in host cells. In addition, we suggest some other potential key host genes like ADAM17, RPS6, HNRNPA1, SUMO1, NACA,

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Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Cited by 147 publications

References 50 publications

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Ideas for how informaticians can get involved with COVID-19 research

ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

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