title: The heptad repeat region is a major selection target in MERS-CoV and related coronaviruses.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) originated in bats and spread to humans via zoonotic transmission from camels. We analyzed the evolution of the spike (S) gene in betacoronaviruses (betaCoVs) isolated from different mammals, in bat coronavirus populations, as well as in MERS-CoV strains from the current outbreak. Results indicated several positively selected sites located in the region comprising the two heptad repeats (HR1 and HR2) and their linker. Two sites (R652 and V1060) were positively selected in the betaCoVs phylogeny and correspond to mutations associated with expanded host range in other coronaviruses. During the most recent evolution of MERS-CoV, adaptive mutations in the HR1 (Q/R/H1020) arose in camels or in a previous host and spread to humans. We determined that different residues at position 1020 establish distinct inter- and intra-helical interactions and affect the stability of the six-helix bundle formed by the HRs. A similar effect on stability was observed for a nearby mutation (T1015N) that increases MERS-CoV infection efficiency in vitro. Data herein indicate that the heptad repeat region was a major target of adaptive evolution in MERS-CoV-related viruses; these results are relevant for the design of fusion inhibitor peptides with antiviral function.
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, 23842 Bosisio Parini, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Filippi
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, 23842 Bosisio Parini, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, 23842 Bosisio Parini, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Biomarkers research program, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Kingdom of Saudi Arabia (KSA).|Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of science, King Saud University, Riyadh, KSA.
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Daghri
authors.affiliation: Department of Physiopathology and Transplantation, University of Milan, 20090 Milan, Italy.|Don C. Gnocchi Foundation ONLUS, IRCCS, 20148 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, 23842 Bosisio Parini, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017934:Coronavirus / Q000235:genetics*; D019143:Evolution, Molecular; D005814:Genes, Viral; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics*; D008969:Molecular Sequence Data; D010802:Phylogeny; D011995:Recombination, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D012641:Selection, Genetic; D016415:Sequence Alignment