Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus.
Identifieur interne : 000E68 ( PubMed/Corpus ); précédent : 000E67; suivant : 000E69Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus.
Auteurs : Donghyun Park ; Hee Jae Huh ; Yeon Jeong Kim ; Dae-Soon Son ; Hyo-Jeong Jeon ; Eu-Hyun Im ; Jong-Won Kim ; Nam Yong Lee ; Eun-Suk Kang ; Cheol In Kang ; Doo Ryeon Chung ; Jin-Hyun Ahn ; Kyong Ran Peck ; Sun Shim Choi ; Yae-Jean Kim ; Chang-Seok Ki ; Woong-Yang ParkSource :
- Cold Spring Harbor molecular case studies [ 2373-2873 ] ; 2016.
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.
DOI: 10.1101/mcs.a001214
PubMed: 27900364
Links to Exploration step
pubmed:27900364Le document en format XML
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Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27900364</idno><idno type="pmid">27900364</idno><idno type="doi">10.1101/mcs.a001214</idno><idno type="wicri:Area/PubMed/Corpus">000E68</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000E68</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus.</title><author><name sortKey="Park, Donghyun" sort="Park, Donghyun" uniqKey="Park D" first="Donghyun" last="Park">Donghyun Park</name><affiliation><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</nlm:affiliation></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><nlm:affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Cold Spring Harbor molecular case studies</title><idno type="ISSN">2373-2873</idno><imprint><date when="2016" type="published">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="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="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" 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></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27900364</PMID><DateCompleted><Year>2017</Year><Month>11</Month><Day>17</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">2373-2873</ISSN><JournalIssue CitedMedium="Print"><Volume>2</Volume><Issue>6</Issue><PubDate><Year>2016</Year><Month>11</Month></PubDate></JournalIssue><Title>Cold Spring Harbor molecular case studies</Title><ISOAbbreviation>Cold Spring Harb Mol Case Stud</ISOAbbreviation></Journal><ArticleTitle>Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus.</ArticleTitle><Pagination><MedlinePgn>a001214</MedlinePgn></Pagination><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Park</LastName><ForeName>Donghyun</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huh</LastName><ForeName>Hee Jae</ForeName><Initials>HJ</Initials><Identifier Source="ORCID">0000-0001-8999-7561</Identifier><AffiliationInfo><Affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Yeon Jeong</ForeName><Initials>YJ</Initials><Identifier Source="ORCID">0000-0003-2292-1372</Identifier><AffiliationInfo><Affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Son</LastName><ForeName>Dae-Soon</ForeName><Initials>DS</Initials><AffiliationInfo><Affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jeon</LastName><ForeName>Hyo-Jeong</ForeName><Initials>HJ</Initials><AffiliationInfo><Affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Im</LastName><ForeName>Eu-Hyun</ForeName><Initials>EH</Initials><AffiliationInfo><Affiliation>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Jong-Won</ForeName><Initials>JW</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Nam Yong</ForeName><Initials>NY</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kang</LastName><ForeName>Eun-Suk</ForeName><Initials>ES</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kang</LastName><ForeName>Cheol In</ForeName><Initials>CI</Initials><AffiliationInfo><Affiliation>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chung</LastName><ForeName>Doo Ryeon</ForeName><Initials>DR</Initials><AffiliationInfo><Affiliation>Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ahn</LastName><ForeName>Jin-Hyun</ForeName><Initials>JH</Initials><AffiliationInfo><Affiliation>Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peck</LastName><ForeName>Kyong Ran</ForeName><Initials>KR</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Choi</LastName><ForeName>Sun Shim</ForeName><Initials>SS</Initials><AffiliationInfo><Affiliation>Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Yae-Jean</ForeName><Initials>YJ</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ki</LastName><ForeName>Chang-Seok</ForeName><Initials>CS</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Park</LastName><ForeName>Woong-Yang</ForeName><Initials>WY</Initials><AffiliationInfo><Affiliation>Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South 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