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Paradigm Shift Intervention Monitoring
UAE/KSA Seqs Signal Human Transmission Evolution
Prior to the release of these five full sequences, similar sequences were available for four prior cases (the earliest case confirmed by PCR - 40F from ICU outbreak in Zarka – Jordan-N3/2012, the first confirmed case – 60M from Bisha – EMC/2012, the second confirmed case – 49M from Qatar ex-KSA – England1/2012, the index case for first confirmed onward transmission – 60M from England ex-KSA – England2/2012).
These four sequences were closely related to each other (>99.5% identity with consensus) and clear fell into two sub-clades due to clustered changes in the ORF-1ab gene. The two earlier sequences (Jordan-N3/EMC) formed one sub-clade, while the two more recent sequences (England1 and England2) formed a second sub-clade. The clustering of the majority of the defining polymorphisms signaled evolution via homologous recombination.
In addition to the four full sequences, partial sequences were published from four cases (first case confirmed in Riyadh -45M – Riyadh sequence, Qatari treated in Germany– 45M – Essen sequence, French tourist ex-UAE -73M - French index sequence, French hospital roommate – 51M – French contact sequence. These partial sequences (2 regions for each patient) matched the full sequences (Riyadh was identical to consensus, Essen had one polymorphisms in common with England1, French sequences matched each other and England2.
Thus, the sequences from the eight prior cases fully supported MERS-CoV evolution in humans.
Human evolution was strongly supported by the five recently released full sequences.
The sequence from UAE, MUNICH/AbuDhabi/2013, is in the England1/2 sub-clade. England1 and England2 formed separate branches within this sub-clade and AbuDabi was clearly on the England1 branch. Earlier analysis had noted the importance of position 1060 in the spike protein. A Q was at position 1020 in both sequences in the Jordan/EMC sub-clade, but England1 had Q1020H while England2 had Q1020R. AbuDabi had G24515C, which encoded Q1020H and had 6 additional polymorphisms which were specific for England1. Four of these polymorphisms (G19075A, C20848A, C22790T, T24299C) clustered with G24515C in the S gene or the 3’ end of the adjacent upstream ORF 1ab gene. The other two polymorphisms (C11492T and C11534T) clustered with each. Similarly, and additional polymorphism, C24740G was also in the S gene and was shared with England1 as well as Jordan-N3, which is in the other sub-clade. The clustering of these polymorphisms as well as sharing with a different sub-clade are associated with recombination and the presence of these shared polymorphisms in human isolates supports evolution during human transmission.
Human transmission was also supported by the four sequences from Al Hasa. All four sequences were greater than 30,000 BP yet only had a single difference at most with the consensus sequence for these isolates. This level of identity signal clonal expansion and nosocomial transmission in the hospital in Al Hofuf. This cluster is similar to the ICU cluster in Jordan last year, but the Al Hasa outbreak was more lethal and more similar to SARS-CoV outbreaks in 2003.
The four Al Hasa sequences were closely related to England2 (and all had Q1020R), signaling further evolution in humans. These sequences will be described in detail in an upcoming commentary.