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Genomic Analysis of MERS Coronaviruses Reveals Complex Transmission Patterns

NEW YORK (GenomeWeb News) – Deep sequencing of the coronavirus behind a Middle East respiratory syndrome has indicated that virus has been introduced into the human population a number of times, according to a new study appearing in the Lancet yesterday.

The virus was first reported in September 2012 in Saudi Arabia, and according to the World Health Organization, there have been 132 laboratory-confirmed cases of infection with MERS-CoV and 58 deaths. Symptoms of the disease include fever, cough, and shortness of breath, and cases are typically confirmed through RT-PCR testing, as the coronavirus is an RNA virus.

The source of the virus, though, remains unknown. There have been tantalizing hints that bats, camels, or another animal may be the reservoir, but confirmation has been elusive. Additionally, whether the cases represented human-to-human transmissions or animal-to-human transmissions has also been unclear, though it remains an important factor to consider in weighing the epidemic or pandemic potential of the virus. Human-to-human transmission has been reported in hospital and home settings.

For the Lancet study, researchers at Saudi Arabia's Ministry of Health, the Wellcome Trust Sanger Center in the UK, and elsewhere analyzed genomic data from 21 viral isolates and found that there was likely a complex transmission chain. In addition, they estimated that the virus may have been circulating since the middle of 2011.

"The genome differences we discovered in some infected people were too great to be explained by replication errors occurring in the virus as it is passed from human to human during a single chain of infection," study author Paul Kellam, a professor at the Sanger Institute, said in a statement. "Instead, our findings suggest that different lineages of the virus have originated from the virus jumping across to humans from an animal source a number of times."

The team of researchers collected viral isolates from 21 RT-PCR-confirmed MERS cases from five different locations in Saudi Arabia. After RT-PCR conversion from RNA to DNA and amplification, each viral sample was sequenced using the Illumina MiSeq; 13 samples were sequenced to full coverage, four to between 85 percent and 95 percent coverage, and four to between 30 percent and 50 percent coverage.

The researchers aligned those genomes with the nine other sequenced MERS viruses, which dated back to spring 2012. As a subset, 20 sequences from the Al-Hasa outbreak in eastern Saudi Arabia were also aligned to determine the transmission chain in that hospital outbreak.

To map out the relationships between isolates, the researchers constructed a time-resolved phylogenetic tree using a Bayesian Markov Chain Monte Carlo method. Additionally, through a discrete phylogeographical diffusion model, they estimated the ancestral locations of the viruses, which suggested that Riyadh may be the center of the circulating viruses.

The virus, the researchers calculated, appears to be evolving at a rate of 6.3x10-4 substitutions per site per year, which corresponds to a July 2011 common ancestor for clade B, which includes the bulk of the viral samples. Given the time since the last common ancestor, the researchers postulated that there may be an intermediary host that the virus is passing through from the reservoir to people.

By comparing the MERS-CoV sequences to the earliest viral genome, the researchers found that a codon in the spike gene — the spike protein is involved in the binding of the virus to host cells —appeared to be under selection between the main Saudi Arabian branch and the Munich/Abu Dhabi cluster, all part of clade B.

"Because of the possible role of spike protein cleavage in potentiating membrane fusion and coronavirus entry, and previous observations on SARS coronavirus spike evolution, the phenotypic effect of this change should be established," the researchers noted.

The samples the researchers examined included a number that were isolated in Riyadh in 2012, and those viruses appeared to be phylogenetically distinct, indicating to the researchers that at least two distinct lineages were circulating there.

High local diversity of the virus in Riyadh, the researchers said, could be due to the continuous importation of the animal reservoir into the area, or due to infected people arriving there from other regions.

In contrast, the Al-Hasa viruses appeared to be highly related, and the researchers found that their close phylogenetic clustering is consistent with a human-to-human transmission.

"MERS-CoV from the Al-Hasa region is consistent with spread via human-to-human transmission, with the initial case derived from a zoonotic event," the researchers said. "In addition to the Al-Hasa cluster, multiple distinct MERS-CoV genotypes exist, possibly each from a separate zoonotic event."

The researchers noted that surveillance of possible animal reservoirs in the area is ongoing to try to determine how the virus is jumping into people.

"While our research substantially adds to the existing evidence base for how, where, and when MERS­CoV is transmitting, further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed to provide the necessary information to interrupt transmission and contain the virus," added Ziad Memish from the Saudi Arabian Ministry of Health.

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