Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
Identifieur interne : 001377 ( Main/Exploration ); précédent : 001376; suivant : 001378Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
Auteurs : Donghyun Park [Corée du Sud] ; Hee Jae Huh [Corée du Sud] ; Yeon Jeong Kim [Corée du Sud] ; Dae-Soon Son [Corée du Sud] ; Hyo-Jeong Jeon [Corée du Sud] ; Eu-Hyun Im [Corée du Sud] ; Jong-Won Kim [Corée du Sud] ; Nam Yong Lee [Corée du Sud] ; Eun-Suk Kang [Corée du Sud] ; Cheol In Kang [Corée du Sud] ; Doo Ryeon Chung [Corée du Sud] ; Jin-Hyun Ahn [Corée du Sud] ; Kyong Ran Peck [Corée du Sud] ; Sun Shim Choi [Corée du Sud] ; Yae-Jean Kim [Corée du Sud] ; Chang-Seok Ki [Corée du Sud] ; Woong-Yang Park [Corée du Sud]Source :
- Cold Spring Harbor Molecular Case Studies [ 2373-2873 ] ; 2016.
Descripteurs français
- KwdFr :
- Analyse de séquence d'ADN, Coronavirus (génétique), Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Coronavirus du syndrome respiratoire du Moyen-Orient (métabolisme), Femelle, Flambées de maladies, Glycoprotéine de spicule des coronavirus (), Glycoprotéine de spicule des coronavirus (génétique), Génome viral (génétique), Humains, Hétérogénéité génétique, Infections à coronavirus (épidémiologie), Liaison aux protéines, Mâle, Récepteurs viraux (), République de Corée (épidémiologie), Séquençage nucléotidique à haut débit.
- MESH :
- génétique : Coronavirus, Coronavirus du syndrome respiratoire du Moyen-Orient, Glycoprotéine de spicule des coronavirus, Génome viral.
- métabolisme : Coronavirus du syndrome respiratoire du Moyen-Orient.
- épidémiologie : Infections à coronavirus, République de Corée.
- Analyse de séquence d'ADN, Femelle, Flambées de maladies, Glycoprotéine de spicule des coronavirus, Humains, Hétérogénéité génétique, Liaison aux protéines, Mâle, Récepteurs viraux, Séquençage nucléotidique à haut débit.
English descriptors
- KwdEn :
- Coronavirus (genetics), Coronavirus Infections (epidemiology), Disease Outbreaks, Female, Genetic Heterogeneity, Genome, Viral (genetics), High-Throughput Nucleotide Sequencing, Humans, Male, Middle East Respiratory Syndrome Coronavirus (genetics), Middle East Respiratory Syndrome Coronavirus (metabolism), Protein Binding, Receptors, Virus (chemistry), Republic of Korea (epidemiology), Sequence Analysis, DNA, Spike Glycoprotein, Coronavirus (chemistry), Spike Glycoprotein, Coronavirus (genetics), Whole Genome Sequencing (methods).
- MESH :
- chemical , chemistry : Receptors, Virus, Spike Glycoprotein, Coronavirus.
- epidemiology : Coronavirus Infections, Republic of Korea.
- genetics : Coronavirus, Genome, Viral, Middle East Respiratory Syndrome Coronavirus, Spike Glycoprotein, Coronavirus.
- metabolism : Middle East Respiratory Syndrome Coronavirus.
- methods : Whole Genome Sequencing.
- Disease Outbreaks, Female, Genetic Heterogeneity, High-Throughput Nucleotide Sequencing, Humans, Male, Protein Binding, Sequence Analysis, DNA.
Abstract
Genome sequence analysis of Middle East respiratory syndrome coronavirus (MERS-CoV) variants from patient specimens has revealed the evolutionary dynamics and mechanisms of pathogenesis of the virus. However, most studies have analyzed the consensus sequences of MERS-CoVs, precluding an investigation of intrapatient heterogeneity. Here, we analyzed non–consensus sequences to characterize intrapatient heterogeneity in cases associated with the 2015 outbreak of MERS in South Korea. Deep-sequencing analysis of MERS-CoV genomes performed on specimens from eight patients revealed significant intrapatient variation; therefore, sequence heterogeneity was further analyzed using targeted deep sequencing. A total of 35 specimens from 24 patients (including a super-spreader) were sequenced to detect and analyze variants displaying intrapatient heterogeneity. Based on the analysis of non–consensus sequences, we demonstrated the intrapatient heterogeneity of MERS-CoVs, with the highest level in the super-spreader specimen. The heterogeneity could be transmitted in a close association with variation in the consensus sequences, suggesting the occurrence of multiple MERS-CoV infections. Analysis of intrapatient heterogeneity revealed a relationship between D510G and I529T mutations in the receptor-binding domain (RBD) of the viral spike glycoprotein. These two mutations have been reported to reduce the affinity of the RBD for human CD26. Notably, although the frequency of both D510G and I529T varied greatly among specimens, the combined frequency of the single mutants was consistently high (87.7% ± 1.9% on average). Concurrently, the frequency of occurrence of the wild type at the two positions was only 6.5% ± 1.7% on average, supporting the hypothesis that selection pressure exerted by the host immune response played a critical role in shaping genetic variants and their interaction in human MERS-CoVs during the outbreak.
Url:
DOI: 10.1101/mcs.a001214
PubMed: 27900364
PubMed Central: 5111008
Affiliations:
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National University, Chuncheon 24341, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341</wicri:regionArea><wicri:noRegion>Chuncheon 24341</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Jong Won" sort="Kim, Jong Won" uniqKey="Kim J" first="Jong-Won" last="Kim">Jong-Won Kim</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Nam Yong" sort="Lee, Nam Yong" uniqKey="Lee N" first="Nam Yong" last="Lee">Nam Yong Lee</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kang, Eun Suk" sort="Kang, Eun Suk" uniqKey="Kang E" first="Eun-Suk" last="Kang">Eun-Suk Kang</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kang, Cheol In" sort="Kang, Cheol In" uniqKey="Kang C" first="Cheol In" last="Kang">Cheol In Kang</name><affiliation wicri:level="1"><nlm:aff id="af5">Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Chung, Doo Ryeon" sort="Chung, Doo Ryeon" uniqKey="Chung D" first="Doo Ryeon" last="Chung">Doo Ryeon Chung</name><affiliation wicri:level="1"><nlm:aff id="af5">Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Ahn, Jin Hyun" sort="Ahn, Jin Hyun" uniqKey="Ahn J" first="Jin-Hyun" last="Ahn">Jin-Hyun Ahn</name><affiliation wicri:level="1"><nlm:aff id="af6">Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746</wicri:regionArea><wicri:noRegion>Suwon 440-746</wicri:noRegion></affiliation></author><author><name sortKey="Peck, Kyong Ran" sort="Peck, Kyong Ran" uniqKey="Peck K" first="Kyong Ran" last="Peck">Kyong Ran Peck</name><affiliation wicri:level="1"><nlm:aff id="af7">Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Choi, Sun Shim" sort="Choi, Sun Shim" uniqKey="Choi S" first="Sun Shim" last="Choi">Sun Shim Choi</name><affiliation wicri:level="1"><nlm:aff id="af4">Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341</wicri:regionArea><wicri:noRegion>Chuncheon 24341</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Yae Jean" sort="Kim, Yae Jean" uniqKey="Kim Y" first="Yae-Jean" last="Kim">Yae-Jean Kim</name><affiliation wicri:level="1"><nlm:aff id="af8">Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Ki, Chang Seok" sort="Ki, Chang Seok" uniqKey="Ki C" first="Chang-Seok" last="Ki">Chang-Seok Ki</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Park, Woong Yang" sort="Park, Woong Yang" uniqKey="Park W" first="Woong-Yang" 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Institute, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af2">Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Huh, Hee Jae" sort="Huh, Hee Jae" uniqKey="Huh H" first="Hee Jae" last="Huh">Hee Jae Huh</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kim, Yeon Jeong" sort="Kim, Yeon Jeong" uniqKey="Kim Y" first="Yeon Jeong" last="Kim">Yeon Jeong Kim</name><affiliation wicri:level="1"><nlm:aff id="af1">Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Genome Institute, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af2">Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Son, Dae Soon" sort="Son, Dae Soon" uniqKey="Son D" first="Dae-Soon" last="Son">Dae-Soon Son</name><affiliation wicri:level="1"><nlm:aff id="af1">Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Genome Institute, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af2">Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Jeon, Hyo Jeong" sort="Jeon, Hyo Jeong" uniqKey="Jeon H" first="Hyo-Jeong" last="Jeon">Hyo-Jeong Jeon</name><affiliation wicri:level="1"><nlm:aff id="af1">Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Genome Institute, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Im, Eu Hyun" sort="Im, Eu Hyun" uniqKey="Im E" first="Eu-Hyun" last="Im">Eu-Hyun Im</name><affiliation wicri:level="1"><nlm:aff id="af4">Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341</wicri:regionArea><wicri:noRegion>Chuncheon 24341</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Jong Won" sort="Kim, Jong Won" uniqKey="Kim J" first="Jong-Won" last="Kim">Jong-Won Kim</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Nam Yong" sort="Lee, Nam Yong" uniqKey="Lee N" first="Nam Yong" last="Lee">Nam Yong Lee</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kang, Eun Suk" sort="Kang, Eun Suk" uniqKey="Kang E" first="Eun-Suk" last="Kang">Eun-Suk Kang</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kang, Cheol In" sort="Kang, Cheol In" uniqKey="Kang C" first="Cheol In" last="Kang">Cheol In Kang</name><affiliation wicri:level="1"><nlm:aff id="af5">Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Chung, Doo Ryeon" sort="Chung, Doo Ryeon" uniqKey="Chung D" first="Doo Ryeon" last="Chung">Doo Ryeon Chung</name><affiliation wicri:level="1"><nlm:aff id="af5">Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Ahn, Jin Hyun" sort="Ahn, Jin Hyun" uniqKey="Ahn J" first="Jin-Hyun" last="Ahn">Jin-Hyun Ahn</name><affiliation wicri:level="1"><nlm:aff id="af6">Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746</wicri:regionArea><wicri:noRegion>Suwon 440-746</wicri:noRegion></affiliation></author><author><name sortKey="Peck, Kyong Ran" sort="Peck, Kyong Ran" uniqKey="Peck K" first="Kyong Ran" last="Peck">Kyong Ran Peck</name><affiliation wicri:level="1"><nlm:aff id="af7">Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Choi, Sun Shim" sort="Choi, Sun Shim" uniqKey="Choi S" first="Sun Shim" last="Choi">Sun Shim Choi</name><affiliation wicri:level="1"><nlm:aff id="af4">Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341</wicri:regionArea><wicri:noRegion>Chuncheon 24341</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Yae Jean" sort="Kim, Yae Jean" uniqKey="Kim Y" first="Yae-Jean" last="Kim">Yae-Jean Kim</name><affiliation wicri:level="1"><nlm:aff id="af8">Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Ki, Chang Seok" sort="Ki, Chang Seok" uniqKey="Ki C" first="Chang-Seok" last="Ki">Chang-Seok Ki</name><affiliation wicri:level="1"><nlm:aff id="af3">Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Park, Woong Yang" sort="Park, Woong Yang" uniqKey="Park W" first="Woong-Yang" last="Park">Woong-Yang Park</name><affiliation wicri:level="1"><nlm:aff id="af1">Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Samsung Genome Institute, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af6">Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea;</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746</wicri:regionArea><wicri:noRegion>Suwon 440-746</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cold Spring Harbor Molecular Case Studies</title><idno type="eISSN">2373-2873</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Coronavirus (genetics)</term><term>Coronavirus Infections (epidemiology)</term><term>Disease Outbreaks</term><term>Female</term><term>Genetic Heterogeneity</term><term>Genome, Viral (genetics)</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>Male</term><term>Middle East Respiratory Syndrome Coronavirus (genetics)</term><term>Middle East Respiratory Syndrome Coronavirus (metabolism)</term><term>Protein Binding</term><term>Receptors, Virus (chemistry)</term><term>Republic of Korea (epidemiology)</term><term>Sequence Analysis, DNA</term><term>Spike Glycoprotein, Coronavirus (chemistry)</term><term>Spike Glycoprotein, Coronavirus (genetics)</term><term>Whole Genome Sequencing (methods)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de séquence d'ADN</term><term>Coronavirus (génétique)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (métabolisme)</term><term>Femelle</term><term>Flambées de maladies</term><term>Glycoprotéine de spicule des coronavirus ()</term><term>Glycoprotéine de spicule des coronavirus (génétique)</term><term>Génome viral (génétique)</term><term>Humains</term><term>Hétérogénéité génétique</term><term>Infections à coronavirus (épidémiologie)</term><term>Liaison aux protéines</term><term>Mâle</term><term>Récepteurs viraux ()</term><term>République de Corée (épidémiologie)</term><term>Séquençage nucléotidique à haut débit</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Receptors, Virus</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Coronavirus Infections</term><term>Republic of Korea</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Coronavirus</term><term>Genome, Viral</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Glycoprotéine de spicule des coronavirus</term><term>Génome viral</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Whole Genome Sequencing</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term></keywords><keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Infections à coronavirus</term><term>République de Corée</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Disease Outbreaks</term><term>Female</term><term>Genetic Heterogeneity</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>Male</term><term>Protein Binding</term><term>Sequence Analysis, DNA</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de séquence d'ADN</term><term>Femelle</term><term>Flambées de maladies</term><term>Glycoprotéine de spicule des coronavirus</term><term>Humains</term><term>Hétérogénéité génétique</term><term>Liaison aux protéines</term><term>Mâle</term><term>Récepteurs viraux</term><term>Séquençage nucléotidique à haut débit</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Genome sequence analysis of Middle East respiratory syndrome coronavirus (MERS-CoV) variants from patient specimens has revealed the evolutionary dynamics and mechanisms of pathogenesis of the virus. However, most studies have analyzed the consensus sequences of MERS-CoVs, precluding an investigation of intrapatient heterogeneity. Here, we analyzed non–consensus sequences to characterize intrapatient heterogeneity in cases associated with the 2015 outbreak of MERS in South Korea. Deep-sequencing analysis of MERS-CoV genomes performed on specimens from eight patients revealed significant intrapatient variation; therefore, sequence heterogeneity was further analyzed using targeted deep sequencing. A total of 35 specimens from 24 patients (including a super-spreader) were sequenced to detect and analyze variants displaying intrapatient heterogeneity. Based on the analysis of non–consensus sequences, we demonstrated the intrapatient heterogeneity of MERS-CoVs, with the highest level in the super-spreader specimen. The heterogeneity could be transmitted in a close association with variation in the consensus sequences, suggesting the occurrence of multiple MERS-CoV infections. Analysis of intrapatient heterogeneity revealed a relationship between D510G and I529T mutations in the receptor-binding domain (RBD) of the viral spike glycoprotein. These two mutations have been reported to reduce the affinity of the RBD for human CD26. Notably, although the frequency of both D510G and I529T varied greatly among specimens, the combined frequency of the single mutants was consistently high (87.7% ± 1.9% on average). Concurrently, the frequency of occurrence of the wild type at the two positions was only 6.5% ± 1.7% on average, supporting the hypothesis that selection pressure exerted by the host immune response played a critical role in shaping genetic variants and their interaction in human MERS-CoVs during the outbreak.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Borucki, Mk" uniqKey="Borucki M">MK Borucki</name></author><author><name sortKey="Lao, V" uniqKey="Lao V">V Lao</name></author><author><name sortKey="Hwang, M" uniqKey="Hwang M">M Hwang</name></author><author><name sortKey="Gardner, S" uniqKey="Gardner S">S Gardner</name></author><author><name sortKey="Adney, D" uniqKey="Adney D">D Adney</name></author><author><name sortKey="Munster, V" uniqKey="Munster V">V Munster</name></author><author><name sortKey="Bowen, R" uniqKey="Bowen R">R Bowen</name></author><author><name sortKey="Allen, Je" uniqKey="Allen J">JE 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R" uniqKey="Shahriar R">R Shahriar</name></author><author><name sortKey="Liu, T" uniqKey="Liu T">T Liu</name></author><author><name sortKey="Wang, C" uniqKey="Wang C">C Wang</name></author><author><name sortKey="Holmes, Sp" uniqKey="Holmes S">SP Holmes</name></author><author><name sortKey="Babrzadeh, F" uniqKey="Babrzadeh F">F Babrzadeh</name></author><author><name sortKey="Gharizadeh, B" uniqKey="Gharizadeh B">B Gharizadeh</name></author><author><name sortKey="Hanczaruk, B" uniqKey="Hanczaruk B">B Hanczaruk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mckenna, A" uniqKey="Mckenna A">A McKenna</name></author><author><name sortKey="Hanna, M" uniqKey="Hanna M">M Hanna</name></author><author><name sortKey="Banks, E" uniqKey="Banks E">E Banks</name></author><author><name sortKey="Sivachenko, A" uniqKey="Sivachenko A">A Sivachenko</name></author><author><name sortKey="Cibulskis, K" uniqKey="Cibulskis K">K Cibulskis</name></author><author><name sortKey="Kernytsky, A" uniqKey="Kernytsky A">A Kernytsky</name></author><author><name sortKey="Garimella, K" uniqKey="Garimella K">K Garimella</name></author><author><name sortKey="Altshuler, D" uniqKey="Altshuler D">D Altshuler</name></author><author><name sortKey="Gabriel, S" uniqKey="Gabriel S">S Gabriel</name></author><author><name sortKey="Daly, M" uniqKey="Daly M">M Daly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oh, Md" uniqKey="Oh M">MD Oh</name></author><author><name sortKey="Choe, Pg" uniqKey="Choe P">PG Choe</name></author><author><name sortKey="Oh, Hs" uniqKey="Oh H">HS Oh</name></author><author><name sortKey="Park, Wb" uniqKey="Park W">WB Park</name></author><author><name sortKey="Lee, Sm" uniqKey="Lee S">SM Lee</name></author><author><name sortKey="Park, J" uniqKey="Park J">J Park</name></author><author><name sortKey="Lee, Sk" uniqKey="Lee S">SK Lee</name></author><author><name sortKey="Song, Js" uniqKey="Song J">JS Song</name></author><author><name sortKey="Kim, Nj" uniqKey="Kim N">NJ Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pamilo, P" uniqKey="Pamilo P">P Pamilo</name></author><author><name sortKey="Bianchi, No" uniqKey="Bianchi N">NO Bianchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Wb" uniqKey="Park W">WB Park</name></author><author><name sortKey="Kwon, Nj" uniqKey="Kwon N">NJ Kwon</name></author><author><name sortKey="Choe, Pg" uniqKey="Choe P">PG Choe</name></author><author><name sortKey="Choi, Sj" uniqKey="Choi S">SJ Choi</name></author><author><name sortKey="Oh, Hs" uniqKey="Oh H">HS Oh</name></author><author><name sortKey="Lee, Sm" uniqKey="Lee S">SM Lee</name></author><author><name sortKey="Chong, H" uniqKey="Chong H">H Chong</name></author><author><name sortKey="Kim, Ji" uniqKey="Kim J">JI Kim</name></author><author><name sortKey="Song, Kh" uniqKey="Song K">KH Song</name></author><author><name sortKey="Bang, Jh" uniqKey="Bang J">JH Bang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seong, Mw" uniqKey="Seong M">MW Seong</name></author><author><name sortKey="Kim, Sy" uniqKey="Kim S">SY Kim</name></author><author><name sortKey="Corman, Vm" uniqKey="Corman V">VM Corman</name></author><author><name sortKey="Kim, Ts" uniqKey="Kim T">TS Kim</name></author><author><name sortKey="Cho, Si" uniqKey="Cho S">SI Cho</name></author><author><name sortKey="Kim, Mj" uniqKey="Kim M">MJ Kim</name></author><author><name sortKey="Lee, Sj" uniqKey="Lee S">SJ Lee</name></author><author><name sortKey="Lee, Js" uniqKey="Lee J">JS Lee</name></author><author><name sortKey="Seo, Sh" uniqKey="Seo S">SH Seo</name></author><author><name sortKey="Ahn, Js" uniqKey="Ahn J">JS Ahn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tamura, K" uniqKey="Tamura K">K Tamura</name></author><author><name sortKey="Stecher, G" uniqKey="Stecher G">G Stecher</name></author><author><name sortKey="Peterson, D" uniqKey="Peterson D">D Peterson</name></author><author><name sortKey="Filipski, A" uniqKey="Filipski A">A Filipski</name></author><author><name sortKey="Kumar, S" uniqKey="Kumar S">S Kumar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tang, Xc" uniqKey="Tang X">XC Tang</name></author><author><name sortKey="Agnihothram, Ss" uniqKey="Agnihothram S">SS Agnihothram</name></author><author><name sortKey="Jiao, Y" uniqKey="Jiao Y">Y Jiao</name></author><author><name sortKey="Stanhope, J" uniqKey="Stanhope J">J Stanhope</name></author><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author><author><name sortKey="Peterson, Ec" uniqKey="Peterson E">EC Peterson</name></author><author><name sortKey="Avnir, Y" uniqKey="Avnir Y">Y Avnir</name></author><author><name sortKey="Tallarico, As" uniqKey="Tallarico A">AS Tallarico</name></author><author><name sortKey="Sheehan, J" uniqKey="Sheehan J">J Sheehan</name></author><author><name sortKey="Zhu, Q" uniqKey="Zhu Q">Q Zhu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vignuzzi, M" uniqKey="Vignuzzi M">M Vignuzzi</name></author><author><name sortKey="Stone, Jk" uniqKey="Stone J">JK Stone</name></author><author><name sortKey="Arnold, Jj" uniqKey="Arnold J">JJ Arnold</name></author><author><name sortKey="Cameron, Ce" uniqKey="Cameron C">CE Cameron</name></author><author><name sortKey="Andino, R" uniqKey="Andino R">R Andino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author><author><name sortKey="Liu, D" uniqKey="Liu D">D Liu</name></author><author><name sortKey="Shi, W" uniqKey="Shi W">W Shi</name></author><author><name sortKey="Lu, R" uniqKey="Lu R">R Lu</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W Wang</name></author><author><name sortKey="Zhao, Y" uniqKey="Zhao Y">Y Zhao</name></author><author><name sortKey="Deng, Y" uniqKey="Deng Y">Y Deng</name></author><author><name sortKey="Zhou, W" uniqKey="Zhou W">W Zhou</name></author><author><name sortKey="Ren, H" uniqKey="Ren H">H Ren</name></author><author><name sortKey="Wu, J" uniqKey="Wu J">J Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Corée du Sud</li></country><region><li>Région capitale de Séoul</li></region><settlement><li>Séoul</li></settlement></list><tree><country name="Corée du Sud"><region name="Région capitale de Séoul"><name sortKey="Park, Donghyun" sort="Park, Donghyun" uniqKey="Park D" first="Donghyun" last="Park">Donghyun Park</name></region><name sortKey="Ahn, Jin Hyun" sort="Ahn, Jin Hyun" uniqKey="Ahn J" first="Jin-Hyun" last="Ahn">Jin-Hyun Ahn</name><name sortKey="Choi, Sun Shim" sort="Choi, Sun Shim" uniqKey="Choi S" first="Sun Shim" last="Choi">Sun Shim Choi</name><name sortKey="Chung, Doo Ryeon" sort="Chung, Doo Ryeon" uniqKey="Chung D" first="Doo Ryeon" last="Chung">Doo Ryeon Chung</name><name sortKey="Huh, Hee Jae" sort="Huh, Hee Jae" uniqKey="Huh H" first="Hee Jae" last="Huh">Hee Jae Huh</name><name sortKey="Im, Eu Hyun" sort="Im, Eu Hyun" uniqKey="Im E" first="Eu-Hyun" last="Im">Eu-Hyun Im</name><name sortKey="Jeon, Hyo Jeong" sort="Jeon, Hyo Jeong" uniqKey="Jeon H" first="Hyo-Jeong" last="Jeon">Hyo-Jeong Jeon</name><name sortKey="Kang, Cheol In" sort="Kang, Cheol In" uniqKey="Kang C" first="Cheol In" last="Kang">Cheol In Kang</name><name sortKey="Kang, Eun Suk" sort="Kang, Eun Suk" uniqKey="Kang E" first="Eun-Suk" last="Kang">Eun-Suk Kang</name><name sortKey="Ki, Chang Seok" sort="Ki, Chang Seok" uniqKey="Ki C" first="Chang-Seok" last="Ki">Chang-Seok Ki</name><name sortKey="Kim, Jong Won" sort="Kim, Jong Won" uniqKey="Kim J" first="Jong-Won" last="Kim">Jong-Won Kim</name><name sortKey="Kim, Yae Jean" sort="Kim, Yae Jean" uniqKey="Kim Y" first="Yae-Jean" last="Kim">Yae-Jean Kim</name><name sortKey="Kim, Yeon Jeong" sort="Kim, Yeon Jeong" uniqKey="Kim Y" first="Yeon Jeong" last="Kim">Yeon Jeong Kim</name><name sortKey="Kim, Yeon Jeong" sort="Kim, Yeon Jeong" uniqKey="Kim Y" first="Yeon Jeong" last="Kim">Yeon Jeong Kim</name><name sortKey="Lee, Nam Yong" sort="Lee, Nam Yong" uniqKey="Lee N" first="Nam Yong" last="Lee">Nam Yong Lee</name><name sortKey="Park, Donghyun" sort="Park, Donghyun" uniqKey="Park D" first="Donghyun" last="Park">Donghyun Park</name><name sortKey="Park, Woong Yang" sort="Park, Woong Yang" uniqKey="Park W" first="Woong-Yang" last="Park">Woong-Yang Park</name><name sortKey="Park, Woong Yang" sort="Park, Woong Yang" uniqKey="Park W" first="Woong-Yang" last="Park">Woong-Yang Park</name><name sortKey="Peck, Kyong Ran" sort="Peck, Kyong Ran" uniqKey="Peck K" first="Kyong Ran" last="Peck">Kyong Ran Peck</name><name sortKey="Son, Dae Soon" sort="Son, Dae Soon" uniqKey="Son D" first="Dae-Soon" last="Son">Dae-Soon Son</name><name sortKey="Son, Dae Soon" sort="Son, Dae Soon" uniqKey="Son D" first="Dae-Soon" last="Son">Dae-Soon Son</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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