Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses

ABSTRACT The ultimate outcome of the coronavirus disease 2019 (COVID-19) pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility, and population immunity. In the current study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated fo...

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Autor principal:	P. Simmonds
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	COVID-19 RNA secondary structure SARS-CoV-2 persistence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/33e64cc6285e46478907360865d1b424
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spelling	oai:doaj.org-article:33e64cc6285e46478907360865d1b4242021-11-15T15:55:43ZPervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses10.1128/mBio.01661-202150-7511https://doaj.org/article/33e64cc6285e46478907360865d1b4242020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01661-20https://doaj.org/toc/2150-7511ABSTRACT The ultimate outcome of the coronavirus disease 2019 (COVID-19) pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility, and population immunity. In the current study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated for the presence of large-scale internal RNA base pairing in its genome. This property, termed genome-scale ordered RNA structure (GORS) has been previously associated with host persistence in other positive-strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as hepatitis C virus (HCV) (MFED of 7 to 9%). High MFED values were shared with all coronavirus genomes analyzed and created by several hundred consecutive energetically favored stem-loops throughout the genome. In contrast to replication-associated RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses—even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base paired in SARS-CoV-2 showed less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus that is potentially restrictive to its longer evolution. Although functionally uncharacterized, GORS in SARS-CoV-2 and other coronaviruses represents important elements in their cellular interactions that may contribute to their persistence and transmissibility. IMPORTANCE The detection and characterization of large-scale RNA secondary structure in the genome of SARS-CoV-2 indicate an extraordinary and unsuspected degree of genome structural organization; this could be effectively visualized through a newly developed contour plotting method that displays positions, structural features, and conservation of RNA secondary structure between related viruses. Such RNA structure imposes a substantial evolutionary cost; paired sites showed greater restriction in diversity and represent a substantial additional constraint in reconstructing its molecular epidemiology. Its biological relevance arises from previously documented associations between possession of structured genomes and persistence, as documented for HCV and several other RNA viruses infecting humans and mammals. Shared properties potentially conferred by large-scale structure in SARS-CoV-2 include increasing evidence for prolonged infections and induced immune dysfunction that prevents development of protective immunity. The findings provide an additional element to cellular interactions that potentially influences the natural history of SARS-CoV-2, its pathogenicity, and its transmission.P. SimmondsAmerican Society for MicrobiologyarticleCOVID-19RNA secondary structureSARS-CoV-2persistenceMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 RNA secondary structure SARS-CoV-2 persistence Microbiology QR1-502
spellingShingle	COVID-19 RNA secondary structure SARS-CoV-2 persistence Microbiology QR1-502 P. Simmonds Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses
description	ABSTRACT The ultimate outcome of the coronavirus disease 2019 (COVID-19) pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility, and population immunity. In the current study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated for the presence of large-scale internal RNA base pairing in its genome. This property, termed genome-scale ordered RNA structure (GORS) has been previously associated with host persistence in other positive-strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as hepatitis C virus (HCV) (MFED of 7 to 9%). High MFED values were shared with all coronavirus genomes analyzed and created by several hundred consecutive energetically favored stem-loops throughout the genome. In contrast to replication-associated RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses—even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base paired in SARS-CoV-2 showed less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus that is potentially restrictive to its longer evolution. Although functionally uncharacterized, GORS in SARS-CoV-2 and other coronaviruses represents important elements in their cellular interactions that may contribute to their persistence and transmissibility. IMPORTANCE The detection and characterization of large-scale RNA secondary structure in the genome of SARS-CoV-2 indicate an extraordinary and unsuspected degree of genome structural organization; this could be effectively visualized through a newly developed contour plotting method that displays positions, structural features, and conservation of RNA secondary structure between related viruses. Such RNA structure imposes a substantial evolutionary cost; paired sites showed greater restriction in diversity and represent a substantial additional constraint in reconstructing its molecular epidemiology. Its biological relevance arises from previously documented associations between possession of structured genomes and persistence, as documented for HCV and several other RNA viruses infecting humans and mammals. Shared properties potentially conferred by large-scale structure in SARS-CoV-2 include increasing evidence for prolonged infections and induced immune dysfunction that prevents development of protective immunity. The findings provide an additional element to cellular interactions that potentially influences the natural history of SARS-CoV-2, its pathogenicity, and its transmission.
format	article
author	P. Simmonds
author_facet	P. Simmonds
author_sort	P. Simmonds
title	Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses
title_short	Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses
title_full	Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses
title_fullStr	Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses
title_full_unstemmed	Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses
title_sort	pervasive rna secondary structure in the genomes of sars-cov-2 and other coronaviruses
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/33e64cc6285e46478907360865d1b424
work_keys_str_mv	AT psimmonds pervasivernasecondarystructureinthegenomesofsarscov2andothercoronaviruses
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Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses

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