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Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus

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 investigatio...

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Autores principales: Park, Donghyun, Huh, Hee Jae, Kim, Yeon Jeong, Son, Dae-Soon, Jeon, Hyo-Jeong, Im, Eu-Hyun, Kim, Jong-Won, Lee, Nam Yong, Kang, Eun-Suk, Kang, Cheol In, Chung, Doo Ryeon, Ahn, Jin-Hyun, Peck, Kyong Ran, Choi, Sun Shim, Kim, Yae-Jean, Ki, Chang-Seok, Park, Woong-Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111008/
https://www.ncbi.nlm.nih.gov/pubmed/27900364
http://dx.doi.org/10.1101/mcs.a001214
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author Park, Donghyun
Huh, Hee Jae
Kim, Yeon Jeong
Son, Dae-Soon
Jeon, Hyo-Jeong
Im, Eu-Hyun
Kim, Jong-Won
Lee, Nam Yong
Kang, Eun-Suk
Kang, Cheol In
Chung, Doo Ryeon
Ahn, Jin-Hyun
Peck, Kyong Ran
Choi, Sun Shim
Kim, Yae-Jean
Ki, Chang-Seok
Park, Woong-Yang
author_facet Park, Donghyun
Huh, Hee Jae
Kim, Yeon Jeong
Son, Dae-Soon
Jeon, Hyo-Jeong
Im, Eu-Hyun
Kim, Jong-Won
Lee, Nam Yong
Kang, Eun-Suk
Kang, Cheol In
Chung, Doo Ryeon
Ahn, Jin-Hyun
Peck, Kyong Ran
Choi, Sun Shim
Kim, Yae-Jean
Ki, Chang-Seok
Park, Woong-Yang
author_sort Park, Donghyun
collection PubMed
description 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.
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spelling pubmed-51110082016-11-29 Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus Park, Donghyun Huh, Hee Jae Kim, Yeon Jeong Son, Dae-Soon Jeon, Hyo-Jeong Im, Eu-Hyun Kim, Jong-Won Lee, Nam Yong Kang, Eun-Suk Kang, Cheol In Chung, Doo Ryeon Ahn, Jin-Hyun Peck, Kyong Ran Choi, Sun Shim Kim, Yae-Jean Ki, Chang-Seok Park, Woong-Yang Cold Spring Harb Mol Case Stud Research Report 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. Cold Spring Harbor Laboratory Press 2016-11 /pmc/articles/PMC5111008/ /pubmed/27900364 http://dx.doi.org/10.1101/mcs.a001214 Text en © 2016 Park et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Park, Donghyun
Huh, Hee Jae
Kim, Yeon Jeong
Son, Dae-Soon
Jeon, Hyo-Jeong
Im, Eu-Hyun
Kim, Jong-Won
Lee, Nam Yong
Kang, Eun-Suk
Kang, Cheol In
Chung, Doo Ryeon
Ahn, Jin-Hyun
Peck, Kyong Ran
Choi, Sun Shim
Kim, Yae-Jean
Ki, Chang-Seok
Park, Woong-Yang
Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
title Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
title_full Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
title_fullStr Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
title_full_unstemmed Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
title_short Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus
title_sort analysis of intrapatient heterogeneity uncovers the microevolution of middle east respiratory syndrome coronavirus
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111008/
https://www.ncbi.nlm.nih.gov/pubmed/27900364
http://dx.doi.org/10.1101/mcs.a001214
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