>>Generation of a Lethal Infectios SARS Coronavirus
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Niman [CB- probably Dr. Henry Niman]
I used the following rationale to order and identify the 7 Metropole Hotel mutations.
The key to ordering and designating that genomic variations is GZ01 and its importance stems largely from the 29 nt insert. Of the 17 SARS coronavirus sequences at GeneBank, it is the only one with the 29 nt insert. Biologically, the insert seems to be the wild type version of the virus, based on finding the same insert in civets in game markets in Shenzhen and possibly other species and locations.
From a structure / function viewpoint, the insert also makes sense. With the insert, there is an ORF capable of producing a 122 aa protein with a well defined transmembrane anchor and an external domain with determinants related to spike proteins found in other coronaviruses such as the human OC43 as well as BCoV and MHV. There is also minor homology with the E1 product of hepatitis C.
The 29 nt deletion decapitates this protein and produces one ORF (ORF 10) that has the anchor, but little additional protein to anchor. A second ORF (ORF 11) is created, but in the deletion mutant, the portion with limited homology to the spike protein of E1 product of hepatitis C is no longer anchored into the membrane.
The GZ01 insert also seems to be the "natural" form based on the epidemiology of SARS. The first reported cases were in Guangdong Province and most cases were in Guangzhou. GZ01 was isolated from a patient in Guangzhou and the initial animal isolates were also from animals in Guangdong Province.
Thus, it seems probable that GZ01 represents the wild type for some SNPs. Polymorphisms in 7 loci are widely found in the various SARS isolates. The changes are identical in 11 of the 17 isolates and the vast majority of these 11 isolates are tightly linked to the Metropole Hotel. I designated the variations found in the isolates the 7 Metropole Hotel mutations.
Two isolates not linked to the Metropole Hotel have only 2 of the mutations. One, BJ04, has C9404T and A21721G. BJ04 was isolated from a patient in Beijing (the other 3 Beijing isolates have with wild type sequence at all 7 loci). The other isolate with only two Metropole Hotel mutations is CUHK-W1. It has C9404T and A21721G. CUHK-W1 was isolated from a Hong Kong Prince of Wales patient who had travel to Shenzhen shortly before developing SARS symptoms.
Thus it seems very possible that the 7 Metropole Hotel mutations were generated recently and can be used to trace the etiology of the disease. Spread of virus with these changes also creates of reservoir of variants which could emerge as a significant problem in the fall. These variants may be significantly more potent than the version found in the wild or even early variants found in mainland China.
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