Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003
Identifieur interne : 000A44 ( Ncbi/Merge ); précédent : 000A43; suivant : 000A45Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003
Auteurs : Vinsensius B. Vega ; Yijun Ruan ; Jianjun Liu ; Wah Heng Lee ; Chia Lin Wei ; Su Yun Se-Thoe ; Kin Fai Tang ; Tao Zhang ; Prasanna R. Kolatkar ; Eng Eong Ooi ; Ai Ee Ling ; Lawrence W. Stanton ; Philip M. Long [États-Unis] ; Edison T. LiuSource :
- BMC Infectious Diseases [ 1471-2334 ] ; 2004.
Descripteurs français
- KwdFr :
- ADN complémentaire (), ARN viral (génétique), ARN viral (isolement et purification), Alignement de séquences, Analyse de regroupements, Animaux, Cellules Vero, Génome viral, Humains, Mutation, Passage en série, Phylogénie, Polymorphisme de nucléotide simple, Probabilité, Singapour, Spectrométrie de masse, Syndrome respiratoire aigu sévère (virologie), Virus du SRAS (), Virus du SRAS (génétique), Virus du SRAS (isolement et purification).
- MESH :
- génétique : ARN viral, Virus du SRAS.
- isolement et purification : ARN viral, Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- ADN complémentaire, Alignement de séquences, Analyse de regroupements, Animaux, Cellules Vero, Génome viral, Humains, Mutation, Passage en série, Phylogénie, Polymorphisme de nucléotide simple, Probabilité, Singapour, Spectrométrie de masse, Virus du SRAS.
- Wicri :
- geographic : Singapour.
English descriptors
- KwdEn :
- Animals, Chlorocebus aethiops, Cluster Analysis, DNA, Complementary (chemistry), Genome, Viral, Humans, Mass Spectrometry, Mutation, Phylogeny, Polymorphism, Single Nucleotide, Probability, RNA, Viral (genetics), RNA, Viral (isolation & purification), SARS Virus (classification), SARS Virus (genetics), SARS Virus (isolation & purification), Sequence Alignment, Serial Passage, Severe Acute Respiratory Syndrome (virology), Singapore, Vero Cells.
- MESH :
- chemical , chemistry : DNA, Complementary.
- chemical , genetics : RNA, Viral.
- chemical , isolation & purification : RNA, Viral.
- geographic : Singapore.
- classification : SARS Virus.
- genetics : SARS Virus.
- isolation & purification : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Animals, Chlorocebus aethiops, Cluster Analysis, Genome, Viral, Humans, Mass Spectrometry, Mutation, Phylogeny, Polymorphism, Single Nucleotide, Probability, Sequence Alignment, Serial Passage, Vero Cells.
Abstract
The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations.
We sequenced complete SARS-CoV genomes taken from primary human tissues (SIN3408, SIN3725V, SIN3765V), cultured isolates (SIN848, SIN846, SIN842, SIN845, SIN847, SIN849, SIN850, SIN852, SIN3408L), and five consecutive Vero cell passages (SIN2774_P1, SIN2774_P2, SIN2774_P3, SIN2774_P4, SIN2774_P5) arising from SIN2774 isolate. These represented individual patient samples, serial in vitro passages in cell culture, and paired human and cell culture isolates. Employing a refined mutation filtering scheme and constant mutation rate model, the mutation rates were estimated and the possible date of emergence was calculated. Phylogenetic analysis was used to uncover molecular relationships between the isolates.
Close examination of whole genome sequence of 54 SARS-CoV isolates identified before 14th October 2003, including 22 from patients in Singapore, revealed the mutations engendered during human-to-Vero and Vero-to-human transmission as well as in multiple Vero cell passages in order to refine our analysis of human-to-human transmission. Though co-infection by different quasipecies in individual tissue samples is observed, the in vitro mutation rate of the SARS-CoV in Vero cell passage is negligible. The in vivo mutation rate, however, is consistent with estimates of other RNA viruses at approximately 5.7 × 10-6 nucleotide substitutions per site per day (0.17 mutations per genome per day), or two mutations per human passage (adjusted R-square = 0.4014). Using the immediate Hotel M contact isolates as roots, we observed that the SARS epidemic has generated four major genetic groups that are geographically associated: two Singapore isolates, one Taiwan isolate, and one North China isolate which appears most closely related to the putative SARS-CoV isolated from a palm civet. Non-synonymous mutations are centered in non-essential ORFs especially in structural and antigenic genes such as the S and M proteins, but these mutations did not distinguish the geographical groupings. However, no non-synonymous mutations were found in the 3CLpro and the polymerase genes.
Our results show that the SARS-CoV is well adapted to growth in culture and did not appear to undergo specific selection in human populations. We further assessed that the putative origin of the SARS epidemic was in late October 2002 which is consistent with a recent estimate using cases from China. The greater sequence divergence in the structural and antigenic proteins and consistent deletions in the 3' – most portion of the viral genome suggest that certain selection pressures are interacting with the functional nature of these validated and putative ORFs.
The online version of this article (doi:10.1186/1471-2334-4-32) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/1471-2334-4-32
PubMed: 15347429
PubMed Central: 517714
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PMC:517714Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003</title>
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<author><name sortKey="Ruan, Yijun" sort="Ruan, Yijun" uniqKey="Ruan Y" first="Yijun" last="Ruan">Yijun Ruan</name>
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<author><name sortKey="Lee, Wah Heng" sort="Lee, Wah Heng" uniqKey="Lee W" first="Wah Heng" last="Lee">Wah Heng Lee</name>
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<author><name sortKey="Wei, Chia Lin" sort="Wei, Chia Lin" uniqKey="Wei C" first="Chia Lin" last="Wei">Chia Lin Wei</name>
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<author><name sortKey="Se Thoe, Su Yun" sort="Se Thoe, Su Yun" uniqKey="Se Thoe S" first="Su Yun" last="Se-Thoe">Su Yun Se-Thoe</name>
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Singapore</nlm:aff>
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<author><name sortKey="Tang, Kin Fai" sort="Tang, Kin Fai" uniqKey="Tang K" first="Kin Fai" last="Tang">Kin Fai Tang</name>
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<author><name sortKey="Zhang, Tao" sort="Zhang, Tao" uniqKey="Zhang T" first="Tao" last="Zhang">Tao Zhang</name>
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<author><name sortKey="Kolatkar, Prasanna R" sort="Kolatkar, Prasanna R" uniqKey="Kolatkar P" first="Prasanna R" last="Kolatkar">Prasanna R. Kolatkar</name>
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<author><name sortKey="Ling, Ai Ee" sort="Ling, Ai Ee" uniqKey="Ling A" first="Ai Ee" last="Ling">Ai Ee Ling</name>
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<author><name sortKey="Stanton, Lawrence W" sort="Stanton, Lawrence W" uniqKey="Stanton L" first="Lawrence W" last="Stanton">Lawrence W. Stanton</name>
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<country xml:lang="fr">États-Unis</country>
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<series><title level="j">BMC Infectious Diseases</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Cluster Analysis</term>
<term>DNA, Complementary (chemistry)</term>
<term>Genome, Viral</term>
<term>Humans</term>
<term>Mass Spectrometry</term>
<term>Mutation</term>
<term>Phylogeny</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Probability</term>
<term>RNA, Viral (genetics)</term>
<term>RNA, Viral (isolation & purification)</term>
<term>SARS Virus (classification)</term>
<term>SARS Virus (genetics)</term>
<term>SARS Virus (isolation & purification)</term>
<term>Sequence Alignment</term>
<term>Serial Passage</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Singapore</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ADN complémentaire ()</term>
<term>ARN viral (génétique)</term>
<term>ARN viral (isolement et purification)</term>
<term>Alignement de séquences</term>
<term>Analyse de regroupements</term>
<term>Animaux</term>
<term>Cellules Vero</term>
<term>Génome viral</term>
<term>Humains</term>
<term>Mutation</term>
<term>Passage en série</term>
<term>Phylogénie</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Probabilité</term>
<term>Singapour</term>
<term>Spectrométrie de masse</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (génétique)</term>
<term>Virus du SRAS (isolement et purification)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>DNA, Complementary</term>
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<term>Virus du SRAS</term>
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<term>Virus du SRAS</term>
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<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
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<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Cluster Analysis</term>
<term>Genome, Viral</term>
<term>Humans</term>
<term>Mass Spectrometry</term>
<term>Mutation</term>
<term>Phylogeny</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Probability</term>
<term>Sequence Alignment</term>
<term>Serial Passage</term>
<term>Vero Cells</term>
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<keywords scheme="MESH" xml:lang="fr"><term>ADN complémentaire</term>
<term>Alignement de séquences</term>
<term>Analyse de regroupements</term>
<term>Animaux</term>
<term>Cellules Vero</term>
<term>Génome viral</term>
<term>Humains</term>
<term>Mutation</term>
<term>Passage en série</term>
<term>Phylogénie</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Probabilité</term>
<term>Singapour</term>
<term>Spectrométrie de masse</term>
<term>Virus du SRAS</term>
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<keywords scheme="Wicri" type="geographic" xml:lang="fr"><term>Singapour</term>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations.</p>
</sec>
<sec><title>Methods</title>
<p>We sequenced complete SARS-CoV genomes taken from primary human tissues (SIN3408, SIN3725V, SIN3765V), cultured isolates (SIN848, SIN846, SIN842, SIN845, SIN847, SIN849, SIN850, SIN852, SIN3408L), and five consecutive Vero cell passages (SIN2774_P1, SIN2774_P2, SIN2774_P3, SIN2774_P4, SIN2774_P5) arising from SIN2774 isolate. These represented individual patient samples, serial in vitro passages in cell culture, and paired human and cell culture isolates. Employing a refined mutation filtering scheme and constant mutation rate model, the mutation rates were estimated and the possible date of emergence was calculated. Phylogenetic analysis was used to uncover molecular relationships between the isolates.</p>
</sec>
<sec><title>Results</title>
<p>Close examination of whole genome sequence of 54 SARS-CoV isolates identified before 14<sup>th</sup>
October 2003, including 22 from patients in Singapore, revealed the mutations engendered during human-to-Vero and Vero-to-human transmission as well as in multiple Vero cell passages in order to refine our analysis of human-to-human transmission. Though co-infection by different quasipecies in individual tissue samples is observed, the in vitro mutation rate of the SARS-CoV in Vero cell passage is negligible. The in vivo mutation rate, however, is consistent with estimates of other RNA viruses at approximately 5.7 × 10<sup>-6</sup>
nucleotide substitutions per site per day (0.17 mutations per genome per day), or two mutations per human passage (adjusted R-square = 0.4014). Using the immediate Hotel M contact isolates as roots, we observed that the SARS epidemic has generated four major genetic groups that are geographically associated: two Singapore isolates, one Taiwan isolate, and one North China isolate which appears most closely related to the putative SARS-CoV isolated from a palm civet. Non-synonymous mutations are centered in non-essential ORFs especially in structural and antigenic genes such as the S and M proteins, but these mutations did not distinguish the geographical groupings. However, no non-synonymous mutations were found in the 3CLpro and the polymerase genes.</p>
</sec>
<sec><title>Conclusions</title>
<p>Our results show that the SARS-CoV is well adapted to growth in culture and did not appear to undergo specific selection in human populations. We further assessed that the putative origin of the SARS epidemic was in late October 2002 which is consistent with a recent estimate using cases from China. The greater sequence divergence in the structural and antigenic proteins and consistent deletions in the 3' – most portion of the viral genome suggest that certain selection pressures are interacting with the functional nature of these validated and putative ORFs.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/1471-2334-4-32) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Se Thoe, Su Yun" sort="Se Thoe, Su Yun" uniqKey="Se Thoe S" first="Su Yun" last="Se-Thoe">Su Yun Se-Thoe</name>
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Singapore</nlm:aff>
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<author><name sortKey="Tang, Kin Fai" sort="Tang, Kin Fai" uniqKey="Tang K" first="Kin Fai" last="Tang">Kin Fai Tang</name>
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41 Science Park Road, Singapore Science Park II, Singapore, 117610</nlm:aff>
<wicri:noCountry code="subfield">117610</wicri:noCountry>
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60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kolatkar, Prasanna R" sort="Kolatkar, Prasanna R" uniqKey="Kolatkar P" first="Prasanna R" last="Kolatkar">Prasanna R. Kolatkar</name>
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60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name>
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<institution-id institution-id-type="ISNI">0000000403924620</institution-id>
<institution>Environmental Health Institute,</institution>
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41 Science Park Road, Singapore Science Park II, Singapore, 117610</nlm:aff>
<wicri:noCountry code="subfield">117610</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ling, Ai Ee" sort="Ling, Ai Ee" uniqKey="Ling A" first="Ai Ee" last="Ling">Ai Ee Ling</name>
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<institution-id institution-id-type="ISNI">0000000094865048</institution-id>
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Singapore</nlm:aff>
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</author>
<author><name sortKey="Stanton, Lawrence W" sort="Stanton, Lawrence W" uniqKey="Stanton L" first="Lawrence W" last="Stanton">Lawrence W. Stanton</name>
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60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
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New York, NY 10027 USA</nlm:aff>
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</author>
<author><name sortKey="Liu, Edison T" sort="Liu, Edison T" uniqKey="Liu E" first="Edison T" last="Liu">Edison T. Liu</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003</title>
<author><name sortKey="Vega, Vinsensius B" sort="Vega, Vinsensius B" uniqKey="Vega V" first="Vinsensius B" last="Vega">Vinsensius B. Vega</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ruan, Yijun" sort="Ruan, Yijun" uniqKey="Ruan Y" first="Yijun" last="Ruan">Yijun Ruan</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Lee, Wah Heng" sort="Lee, Wah Heng" uniqKey="Lee W" first="Wah Heng" last="Lee">Wah Heng Lee</name>
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</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wei, Chia Lin" sort="Wei, Chia Lin" uniqKey="Wei C" first="Chia Lin" last="Wei">Chia Lin Wei</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Se Thoe, Su Yun" sort="Se Thoe, Su Yun" uniqKey="Se Thoe S" first="Su Yun" last="Se-Thoe">Su Yun Se-Thoe</name>
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<institution-id institution-id-type="ISNI">0000000094865048</institution-id>
<institution>Virology Section,</institution>
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</institution-wrap>
Singapore</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tang, Kin Fai" sort="Tang, Kin Fai" uniqKey="Tang K" first="Kin Fai" last="Tang">Kin Fai Tang</name>
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<institution-id institution-id-type="ISNI">0000000403924620</institution-id>
<institution>Environmental Health Institute,</institution>
</institution-wrap>
41 Science Park Road, Singapore Science Park II, Singapore, 117610</nlm:aff>
<wicri:noCountry code="subfield">117610</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Tao" sort="Zhang, Tao" uniqKey="Zhang T" first="Tao" last="Zhang">Tao Zhang</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kolatkar, Prasanna R" sort="Kolatkar, Prasanna R" uniqKey="Kolatkar P" first="Prasanna R" last="Kolatkar">Prasanna R. Kolatkar</name>
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<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name>
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<institution-id institution-id-type="ISNI">0000000403924620</institution-id>
<institution>Environmental Health Institute,</institution>
</institution-wrap>
41 Science Park Road, Singapore Science Park II, Singapore, 117610</nlm:aff>
<wicri:noCountry code="subfield">117610</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ling, Ai Ee" sort="Ling, Ai Ee" uniqKey="Ling A" first="Ai Ee" last="Ling">Ai Ee Ling</name>
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<institution-id institution-id-type="ISNI">0000000094865048</institution-id>
<institution>Virology Section,</institution>
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</institution-wrap>
Singapore</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stanton, Lawrence W" sort="Stanton, Lawrence W" uniqKey="Stanton L" first="Lawrence W" last="Stanton">Lawrence W. Stanton</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.418377.e</institution-id>
<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Long, Philip M" sort="Long, Philip M" uniqKey="Long P" first="Philip M" last="Long">Philip M. Long</name>
<affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.21729.3f</institution-id>
<institution-id institution-id-type="ISNI">0000000419368729</institution-id>
<institution>Center for Computational Learning Systems,</institution>
<institution>Columbia University,</institution>
</institution-wrap>
New York, NY 10027 USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>New York</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Liu, Edison T" sort="Liu, Edison T" uniqKey="Liu E" first="Edison T" last="Liu">Edison T. Liu</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.418377.e</institution-id>
<institution-id institution-id-type="ISNI">000000040620715X</institution-id>
<institution>Genome Institute of Singapore,</institution>
</institution-wrap>
60 Biopolis Street, Singapore 138672</nlm:aff>
<wicri:noCountry code="subfield">Singapore 138672</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">BMC Infectious Diseases</title>
<idno type="eISSN">1471-2334</idno>
<imprint><date when="2004">2004</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations.</p>
</sec>
<sec><title>Methods</title>
<p>We sequenced complete SARS-CoV genomes taken from primary human tissues (SIN3408, SIN3725V, SIN3765V), cultured isolates (SIN848, SIN846, SIN842, SIN845, SIN847, SIN849, SIN850, SIN852, SIN3408L), and five consecutive Vero cell passages (SIN2774_P1, SIN2774_P2, SIN2774_P3, SIN2774_P4, SIN2774_P5) arising from SIN2774 isolate. These represented individual patient samples, serial in vitro passages in cell culture, and paired human and cell culture isolates. Employing a refined mutation filtering scheme and constant mutation rate model, the mutation rates were estimated and the possible date of emergence was calculated. Phylogenetic analysis was used to uncover molecular relationships between the isolates.</p>
</sec>
<sec><title>Results</title>
<p>Close examination of whole genome sequence of 54 SARS-CoV isolates identified before 14<sup>th</sup>
October 2003, including 22 from patients in Singapore, revealed the mutations engendered during human-to-Vero and Vero-to-human transmission as well as in multiple Vero cell passages in order to refine our analysis of human-to-human transmission. Though co-infection by different quasipecies in individual tissue samples is observed, the in vitro mutation rate of the SARS-CoV in Vero cell passage is negligible. The in vivo mutation rate, however, is consistent with estimates of other RNA viruses at approximately 5.7 × 10<sup>-6</sup>
nucleotide substitutions per site per day (0.17 mutations per genome per day), or two mutations per human passage (adjusted R-square = 0.4014). Using the immediate Hotel M contact isolates as roots, we observed that the SARS epidemic has generated four major genetic groups that are geographically associated: two Singapore isolates, one Taiwan isolate, and one North China isolate which appears most closely related to the putative SARS-CoV isolated from a palm civet. Non-synonymous mutations are centered in non-essential ORFs especially in structural and antigenic genes such as the S and M proteins, but these mutations did not distinguish the geographical groupings. However, no non-synonymous mutations were found in the 3CLpro and the polymerase genes.</p>
</sec>
<sec><title>Conclusions</title>
<p>Our results show that the SARS-CoV is well adapted to growth in culture and did not appear to undergo specific selection in human populations. We further assessed that the putative origin of the SARS epidemic was in late October 2002 which is consistent with a recent estimate using cases from China. The greater sequence divergence in the structural and antigenic proteins and consistent deletions in the 3' – most portion of the viral genome suggest that certain selection pressures are interacting with the functional nature of these validated and putative ORFs.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/1471-2334-4-32) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003.</title>
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<affiliation wicri:level="1"><nlm:affiliation>Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672. vegav@gis.a-star.edu.sg</nlm:affiliation>
<country wicri:rule="url">Singapour</country>
</affiliation>
</author>
<author><name sortKey="Ruan, Yijun" sort="Ruan, Yijun" uniqKey="Ruan Y" first="Yijun" last="Ruan">Yijun Ruan</name>
</author>
<author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name>
</author>
<author><name sortKey="Lee, Wah Heng" sort="Lee, Wah Heng" uniqKey="Lee W" first="Wah Heng" last="Lee">Wah Heng Lee</name>
</author>
<author><name sortKey="Wei, Chia Lin" sort="Wei, Chia Lin" uniqKey="Wei C" first="Chia Lin" last="Wei">Chia Lin Wei</name>
</author>
<author><name sortKey="Se Thoe, Su Yun" sort="Se Thoe, Su Yun" uniqKey="Se Thoe S" first="Su Yun" last="Se-Thoe">Su Yun Se-Thoe</name>
</author>
<author><name sortKey="Tang, Kin Fai" sort="Tang, Kin Fai" uniqKey="Tang K" first="Kin Fai" last="Tang">Kin Fai Tang</name>
</author>
<author><name sortKey="Zhang, Tao" sort="Zhang, Tao" uniqKey="Zhang T" first="Tao" last="Zhang">Tao Zhang</name>
</author>
<author><name sortKey="Kolatkar, Prasanna R" sort="Kolatkar, Prasanna R" uniqKey="Kolatkar P" first="Prasanna R" last="Kolatkar">Prasanna R. Kolatkar</name>
</author>
<author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name>
</author>
<author><name sortKey="Ling, Ai Ee" sort="Ling, Ai Ee" uniqKey="Ling A" first="Ai Ee" last="Ling">Ai Ee Ling</name>
</author>
<author><name sortKey="Stanton, Lawrence W" sort="Stanton, Lawrence W" uniqKey="Stanton L" first="Lawrence W" last="Stanton">Lawrence W. Stanton</name>
</author>
<author><name sortKey="Long, Philip M" sort="Long, Philip M" uniqKey="Long P" first="Philip M" last="Long">Philip M. Long</name>
</author>
<author><name sortKey="Liu, Edison T" sort="Liu, Edison T" uniqKey="Liu E" first="Edison T" last="Liu">Edison T. Liu</name>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003.</title>
<author><name sortKey="Vega, Vinsensius B" sort="Vega, Vinsensius B" uniqKey="Vega V" first="Vinsensius B" last="Vega">Vinsensius B. Vega</name>
<affiliation wicri:level="1"><nlm:affiliation>Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672. vegav@gis.a-star.edu.sg</nlm:affiliation>
<country wicri:rule="url">Singapour</country>
</affiliation>
</author>
<author><name sortKey="Ruan, Yijun" sort="Ruan, Yijun" uniqKey="Ruan Y" first="Yijun" last="Ruan">Yijun Ruan</name>
</author>
<author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name>
</author>
<author><name sortKey="Lee, Wah Heng" sort="Lee, Wah Heng" uniqKey="Lee W" first="Wah Heng" last="Lee">Wah Heng Lee</name>
</author>
<author><name sortKey="Wei, Chia Lin" sort="Wei, Chia Lin" uniqKey="Wei C" first="Chia Lin" last="Wei">Chia Lin Wei</name>
</author>
<author><name sortKey="Se Thoe, Su Yun" sort="Se Thoe, Su Yun" uniqKey="Se Thoe S" first="Su Yun" last="Se-Thoe">Su Yun Se-Thoe</name>
</author>
<author><name sortKey="Tang, Kin Fai" sort="Tang, Kin Fai" uniqKey="Tang K" first="Kin Fai" last="Tang">Kin Fai Tang</name>
</author>
<author><name sortKey="Zhang, Tao" sort="Zhang, Tao" uniqKey="Zhang T" first="Tao" last="Zhang">Tao Zhang</name>
</author>
<author><name sortKey="Kolatkar, Prasanna R" sort="Kolatkar, Prasanna R" uniqKey="Kolatkar P" first="Prasanna R" last="Kolatkar">Prasanna R. Kolatkar</name>
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<author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name>
</author>
<author><name sortKey="Ling, Ai Ee" sort="Ling, Ai Ee" uniqKey="Ling A" first="Ai Ee" last="Ling">Ai Ee Ling</name>
</author>
<author><name sortKey="Stanton, Lawrence W" sort="Stanton, Lawrence W" uniqKey="Stanton L" first="Lawrence W" last="Stanton">Lawrence W. Stanton</name>
</author>
<author><name sortKey="Long, Philip M" sort="Long, Philip M" uniqKey="Long P" first="Philip M" last="Long">Philip M. Long</name>
</author>
<author><name sortKey="Liu, Edison T" sort="Liu, Edison T" uniqKey="Liu E" first="Edison T" last="Liu">Edison T. Liu</name>
</author>
</analytic>
<series><title level="j">BMC infectious diseases</title>
<idno type="eISSN">1471-2334</idno>
<imprint><date when="2004" type="published">2004</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Cluster Analysis</term>
<term>DNA, Complementary (chemistry)</term>
<term>Genome, Viral</term>
<term>Humans</term>
<term>Mass Spectrometry</term>
<term>Mutation</term>
<term>Phylogeny</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Probability</term>
<term>RNA, Viral (genetics)</term>
<term>RNA, Viral (isolation & purification)</term>
<term>SARS Virus (classification)</term>
<term>SARS Virus (genetics)</term>
<term>SARS Virus (isolation & purification)</term>
<term>Sequence Alignment</term>
<term>Serial Passage</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Singapore</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ADN complémentaire ()</term>
<term>ARN viral (génétique)</term>
<term>ARN viral (isolement et purification)</term>
<term>Alignement de séquences</term>
<term>Analyse de regroupements</term>
<term>Animaux</term>
<term>Cellules Vero</term>
<term>Génome viral</term>
<term>Humains</term>
<term>Mutation</term>
<term>Passage en série</term>
<term>Phylogénie</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Probabilité</term>
<term>Singapour</term>
<term>Spectrométrie de masse</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (génétique)</term>
<term>Virus du SRAS (isolement et purification)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>DNA, Complementary</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>RNA, Viral</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>RNA, Viral</term>
</keywords>
<keywords scheme="MESH" type="geographic" xml:lang="en"><term>Singapore</term>
</keywords>
<keywords scheme="MESH" qualifier="classification" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN viral</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="isolation & purification" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr"><term>ARN viral</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Cluster Analysis</term>
<term>Genome, Viral</term>
<term>Humans</term>
<term>Mass Spectrometry</term>
<term>Mutation</term>
<term>Phylogeny</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Probability</term>
<term>Sequence Alignment</term>
<term>Serial Passage</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>ADN complémentaire</term>
<term>Alignement de séquences</term>
<term>Analyse de regroupements</term>
<term>Animaux</term>
<term>Cellules Vero</term>
<term>Génome viral</term>
<term>Humains</term>
<term>Mutation</term>
<term>Passage en série</term>
<term>Phylogénie</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Probabilité</term>
<term>Singapour</term>
<term>Spectrométrie de masse</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="Wicri" type="geographic" xml:lang="fr"><term>Singapour</term>
</keywords>
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</teiHeader>
<front><div type="abstract" xml:lang="en">The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations.</div>
</front>
</TEI>
</pubmed>
</double>
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