title: Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus.
abstract: The Middle East respiratory syndrome coronavirus (MERS-CoV) was first documented in the Kingdom of Saudi Arabia (KSA) in 2012 and, to date, has been identified in 180 cases with 43% mortality. In this study, we have determined the MERS-CoV evolutionary rate, documented genetic variants of the virus and their distribution throughout the Arabian peninsula, and identified the genome positions under positive selection, important features for monitoring adaptation of MERS-CoV to human transmission and for identifying the source of infections. Respiratory samples from confirmed KSA MERS cases from May to September 2013 were subjected to whole-genome deep sequencing, and 32 complete or partial sequences (20 were ≥ 99% complete, 7 were 50 to 94% complete, and 5 were 27 to 50% complete) were obtained, bringing the total available MERS-CoV genomic sequences to 65. An evolutionary rate of 1.12 × 10(-3) substitutions per site per year (95% credible interval [95% CI], 8.76 × 10(-4); 1.37 × 10(-3)) was estimated, bringing the time to most recent common ancestor to March 2012 (95% CI, December 2011; June 2012). Only one MERS-CoV codon, spike 1020, located in a domain required for cell entry, is under strong positive selection. Four KSA MERS-CoV phylogenetic clades were found, with 3 clades apparently no longer contributing to current cases. The size of the population infected with MERS-CoV showed a gradual increase to June 2013, followed by a decline, possibly due to increased surveillance and infection control measures combined with a basic reproduction number (R0) for the virus that is less than 1.
  
  
  OBJECTIVE
  MERS-CoV adaptation toward higher rates of sustained human-to-human transmission appears not to have occurred yet. While MERS-CoV transmission currently appears weak, careful monitoring of changes in MERS-CoV genomes and of the MERS epidemic should be maintained. The observation of phylogenetically related MERS-CoV in geographically diverse locations must be taken into account in efforts to identify the animal source and transmission of the virus.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cotten
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Watson
authors.forename: Alimuddin I
authors.initials: AI
authors.lastname: Zumla
authors.forename: Hatem Q
authors.initials: HQ
authors.lastname: Makhdoom
authors.forename: Anne L
authors.initials: AL
authors.lastname: Palser
authors.forename: Swee Hoe
authors.initials: SH
authors.lastname: Ong
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: Al Rabeeah
authors.forename: Rafat F
authors.initials: RF
authors.lastname: Alhakeem
authors.forename: Abdullah
authors.initials: A
authors.lastname: Assiri
authors.forename: Jaffar A
authors.initials: JA
authors.lastname: Al-Tawfiq
authors.forename: Ali
authors.initials: A
authors.lastname: Albarrak
authors.forename: Mazin
authors.initials: M
authors.lastname: Barry
authors.forename: Atef
authors.initials: A
authors.lastname: Shibl
authors.forename: Fahad A
authors.initials: FA
authors.lastname: Alrabiah
authors.forename: Sami
authors.initials: S
authors.lastname: Hajjar
authors.forename: Hanan H
authors.initials: HH
authors.lastname: Balkhy
authors.forename: Hesham
authors.initials: H
authors.lastname: Flemban
authors.forename: Andrew
authors.initials: A
authors.lastname: Rambaut
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Memish
mesh_terms: D050936:Basic Reproduction Number; D016000:Cluster Analysis; D017934:Coronavirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification*; D018352:Coronavirus Infections / Q000453:epidemiology / Q000635:transmission / Q000821:virology*; D019143:Evolution, Molecular; D016679:Genome, Viral; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics*; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D012367:RNA, Viral