Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2
ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in 92 million cases in a span of 1 year. The study focuses on understanding population-specific variations attributing its high rate of infections in specific geographical regions particularly in the Unit...
Guardado en:
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
American Society for Microbiology
2021
|
Materias: | |
Acceso en línea: | https://doaj.org/article/61af3254473544cfb7ec2c0410f45ae3 |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:61af3254473544cfb7ec2c0410f45ae3 |
---|---|
record_format |
dspace |
spelling |
oai:doaj.org-article:61af3254473544cfb7ec2c0410f45ae32021-12-02T19:36:37ZComparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-210.1128/mSystems.00030-212379-5077https://doaj.org/article/61af3254473544cfb7ec2c0410f45ae32021-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00030-21https://doaj.org/toc/2379-5077ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in 92 million cases in a span of 1 year. The study focuses on understanding population-specific variations attributing its high rate of infections in specific geographical regions particularly in the United States. Rigorous phylogenomic network analysis of complete SARS-CoV-2 genomes (245) inferred five central clades named a (ancestral), b, c, d, and e (subtypes e1 and e2). Clade d and subclade e2 were found exclusively comprised of U.S. strains. Clades were distinguished by 10 co-mutational combinations in Nsp3, ORF8, Nsp13, S, Nsp12, Nsp2, and Nsp6. Our analysis revealed that only 67.46% of single nucleotide polymorphism (SNP) mutations were at the amino acid level. T1103P mutation in Nsp3 was predicted to increase protein stability in 238 strains except for 6 strains which were marked as ancestral type, whereas co-mutation (P409L and Y446C) in Nsp13 were found in 64 genomes from the United States highlighting its 100% co-occurrence. Docking highlighted mutation (D614G) caused reduction in binding of spike proteins with angiotensin-converting enzyme 2 (ACE2), but it also showed better interaction with the TMPRSS2 receptor contributing to high transmissibility among U.S. strains. We also found host proteins, MYO5A, MYO5B, and MYO5C, that had maximum interaction with viral proteins (nucleocapsid [N], spike [S], and membrane [M] proteins). Thus, blocking the internalization pathway by inhibiting MYO5 proteins which could be an effective target for coronavirus disease 2019 (COVID-19) treatment. The functional annotations of the host-pathogen interaction (HPI) network were found to be closely associated with hypoxia and thrombotic conditions, confirming the vulnerability and severity of infection. We also screened CpG islands in Nsp1 and N conferring the ability of SARS-CoV-2 to enter and trigger zinc antiviral protein (ZAP) activity inside the host cell. IMPORTANCE In the current study, we presented a global view of mutational pattern observed in SARS-CoV-2 virus transmission. This provided a who-infect-whom geographical model since the early pandemic. This is hitherto the most comprehensive comparative genomics analysis of full-length genomes for co-mutations at different geographical regions especially in U.S. strains. Compositional structural biology results suggested that mutations have a balance of opposing forces affecting pathogenicity suggesting that only a few mutations are effective at the translation level. Novel HPI analysis and CpG predictions elucidate the proof of concept of hypoxia and thrombotic conditions in several patients. Thus, the current study focuses the understanding of population-specific variations attributing a high rate of SARS-CoV-2 infections in specific geographical regions which may eventually be vital for the most severely affected countries and regions for sharp development of custom-made vindication strategies.Vipin GuptaShazia HaiderMansi VermaNirjara SinghviKalaisaran PonnusamyMd. Zubbair MalikHelianthous VermaRoshan KumarUtkarsh SoodPrincy HiraShiva SatijaYogendra SinghRup LalAmerican Society for Microbiologyarticlecomparative genomicsphylogenomicsphylogenySARS-CoV-2mutational studiesstructural biologyMicrobiologyQR1-502ENmSystems, Vol 6, Iss 1 (2021) |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
comparative genomics phylogenomics phylogeny SARS-CoV-2 mutational studies structural biology Microbiology QR1-502 |
spellingShingle |
comparative genomics phylogenomics phylogeny SARS-CoV-2 mutational studies structural biology Microbiology QR1-502 Vipin Gupta Shazia Haider Mansi Verma Nirjara Singhvi Kalaisaran Ponnusamy Md. Zubbair Malik Helianthous Verma Roshan Kumar Utkarsh Sood Princy Hira Shiva Satija Yogendra Singh Rup Lal Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2 |
description |
ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in 92 million cases in a span of 1 year. The study focuses on understanding population-specific variations attributing its high rate of infections in specific geographical regions particularly in the United States. Rigorous phylogenomic network analysis of complete SARS-CoV-2 genomes (245) inferred five central clades named a (ancestral), b, c, d, and e (subtypes e1 and e2). Clade d and subclade e2 were found exclusively comprised of U.S. strains. Clades were distinguished by 10 co-mutational combinations in Nsp3, ORF8, Nsp13, S, Nsp12, Nsp2, and Nsp6. Our analysis revealed that only 67.46% of single nucleotide polymorphism (SNP) mutations were at the amino acid level. T1103P mutation in Nsp3 was predicted to increase protein stability in 238 strains except for 6 strains which were marked as ancestral type, whereas co-mutation (P409L and Y446C) in Nsp13 were found in 64 genomes from the United States highlighting its 100% co-occurrence. Docking highlighted mutation (D614G) caused reduction in binding of spike proteins with angiotensin-converting enzyme 2 (ACE2), but it also showed better interaction with the TMPRSS2 receptor contributing to high transmissibility among U.S. strains. We also found host proteins, MYO5A, MYO5B, and MYO5C, that had maximum interaction with viral proteins (nucleocapsid [N], spike [S], and membrane [M] proteins). Thus, blocking the internalization pathway by inhibiting MYO5 proteins which could be an effective target for coronavirus disease 2019 (COVID-19) treatment. The functional annotations of the host-pathogen interaction (HPI) network were found to be closely associated with hypoxia and thrombotic conditions, confirming the vulnerability and severity of infection. We also screened CpG islands in Nsp1 and N conferring the ability of SARS-CoV-2 to enter and trigger zinc antiviral protein (ZAP) activity inside the host cell. IMPORTANCE In the current study, we presented a global view of mutational pattern observed in SARS-CoV-2 virus transmission. This provided a who-infect-whom geographical model since the early pandemic. This is hitherto the most comprehensive comparative genomics analysis of full-length genomes for co-mutations at different geographical regions especially in U.S. strains. Compositional structural biology results suggested that mutations have a balance of opposing forces affecting pathogenicity suggesting that only a few mutations are effective at the translation level. Novel HPI analysis and CpG predictions elucidate the proof of concept of hypoxia and thrombotic conditions in several patients. Thus, the current study focuses the understanding of population-specific variations attributing a high rate of SARS-CoV-2 infections in specific geographical regions which may eventually be vital for the most severely affected countries and regions for sharp development of custom-made vindication strategies. |
format |
article |
author |
Vipin Gupta Shazia Haider Mansi Verma Nirjara Singhvi Kalaisaran Ponnusamy Md. Zubbair Malik Helianthous Verma Roshan Kumar Utkarsh Sood Princy Hira Shiva Satija Yogendra Singh Rup Lal |
author_facet |
Vipin Gupta Shazia Haider Mansi Verma Nirjara Singhvi Kalaisaran Ponnusamy Md. Zubbair Malik Helianthous Verma Roshan Kumar Utkarsh Sood Princy Hira Shiva Satija Yogendra Singh Rup Lal |
author_sort |
Vipin Gupta |
title |
Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2 |
title_short |
Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2 |
title_full |
Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2 |
title_fullStr |
Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2 |
title_full_unstemmed |
Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2 |
title_sort |
comparative genomics and integrated network approach unveiled undirected phylogeny patterns, co-mutational hot spots, functional cross talk, and regulatory interactions in sars-cov-2 |
publisher |
American Society for Microbiology |
publishDate |
2021 |
url |
https://doaj.org/article/61af3254473544cfb7ec2c0410f45ae3 |
work_keys_str_mv |
AT vipingupta comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT shaziahaider comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT mansiverma comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT nirjarasinghvi comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT kalaisaranponnusamy comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT mdzubbairmalik comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT helianthousverma comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT roshankumar comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT utkarshsood comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT princyhira comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT shivasatija comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT yogendrasingh comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 AT ruplal comparativegenomicsandintegratednetworkapproachunveiledundirectedphylogenypatternscomutationalhotspotsfunctionalcrosstalkandregulatoryinteractionsinsarscov2 |
_version_ |
1718376384057835520 |