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      Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses.

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          Abstract

          Middle East respiratory syndrome-related coronavirus (MERS-CoV) spreads to humans via zoonotic transmission from camels. MERS-CoV belongs to lineage C of betacoronaviruses (betaCoVs), which also includes viruses isolated from bats and hedgehogs. A large portion of the betaCoV genome consists of two open reading frames (ORF1a and ORF1b) that are translated into polyproteins. These are cleaved by viral proteases to generate 16 nonstructural proteins (nsp1 to nsp16) which compose the viral replication-transcription complex. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs. Results indicated widespread positive selection, acting mostly on ORF1a. The proportion of positively selected sites in ORF1a was much higher than that previously reported for the surface-exposed spike protein. Selected sites were unevenly distributed, with nsp3 representing the preferential target. Several pairs of coevolving sites were also detected, possibly indicating epistatic interactions; most of these were located in nsp3. Adaptive evolution at nsp3 is ongoing in MERS-CoV strains, and two selected sites (G720 and R911) were detected in the protease domain. While position 720 is variable in camel-derived viruses, suggesting that the selective event does not represent a specific adaptation to humans, the R911C substitution was observed only in human-derived MERS-CoV isolates, including the viral strain responsible for the recent South Korean outbreak. It will be extremely important to assess whether these changes affect host range or other viral phenotypes. More generally, data herein indicate that CoV nsp3 represents a major selection target and that nsp3 sequencing should be envisaged in monitoring programs and field surveys.

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          Author and article information

          Journal
          J. Virol.
          Journal of virology
          American Society for Microbiology
          1098-5514
          0022-538X
          Jan 20 2016
          : 90
          : 7
          Affiliations
          [1 ] Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy diego.forni@bp.lnf.it.
          [2 ] Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy.
          [3 ] Biomarker Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia.
          [4 ] Department of Physiopathology and Transplantation, University of Milan, Milan, Italy Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
          Article
          JVI.02988-15
          10.1128/JVI.02988-15
          4794664
          26792741
          26839d9a-019d-4ebd-8de9-66f3c75a7156
          History

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