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The heptad repeat region is a major selection target in MERS-CoV and related coronaviruses.

Diego Forni1 Giulia Filippi2 Rachele Cagliani1 Luca De Gioia2 Uberto Pozzoli1 Nasser Al-Daghri3,4 Mario Clerici5,6 Manuela Sironi1
Affiliations 6 institutions
  1. Scientific Institute IRCCS E. MEDEA, Bioinformatics, 23842 Bosisio Parini, Italy.
  2. Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy.
  3. Biomarkers research program, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Kingdom of Saudi Arabia (KSA).
  4. Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of science, King Saud University, Riyadh, KSA.
  5. Department of Physiopathology and Transplantation, University of Milan, 20090 Milan, Italy.
  6. Don C. Gnocchi Foundation ONLUS, IRCCS, 20148 Milan, Italy.
PMID 26404138 2015 Sci Rep eng epublish
PubMed DOI Browse context

Article

Publication summary

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.

Evolution, Molecular Selection, Genetic Amino Acid Sequence Animals Coronavirus Genes, Viral Genetic Variation Genotype Humans Middle East Respiratory Syndrome Coronavirus Molecular Sequence Data Phylogeny Recombination, Genetic Repetitive Sequences, Nucleic Acid Sequence Alignment

Structured evidence records

Evidence records

5 total
Genomic Evolution 2 records
Genomic Evolution Extraction confidence 0.90
Key finding

Phylogenetic and molecular evolutionary analysis of the spike gene revealed positively selected sites within the heptad repeat region of MERS-CoV and related betacoronaviruses, indicating adaptive mutations linked to host range expansion.

Virus
MERS-CoV
Host
Camelus
Location
Not specified
Supporting text

We analyzed the evolution of the spike (S) gene in betacoronaviruses (betaCoVs) isolated from different mammals ... 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.

Genes or proteins
spike; HR1; HR2
Analysis methods
phylogenetic analysis; molecular evolution analysis; positive selection analysis
Genomic Evolution Extraction confidence 0.90
Key finding

Adaptive mutations in the HR1 region of the MERS-CoV spike protein emerged in camels or a previous host and disseminated to humans, showing molecular evidence of cross-species evolution.

Virus
MERS-CoV
Location
Not specified
Supporting text

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.

Genes or proteins
spike; HR1
Analysis methods
evolutionary analysis; sequence analysis
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 0.95
Key finding

Adaptive mutations Q/R/H1020 and T1015N in the spike HR1 region of MERS-CoV enhanced structural stability and infection efficiency, indicating molecular adaptation during cross-species transmission from camels or another host to humans.

Virus
MERS-CoV
Host
Not specified
Location
Not specified
Supporting text

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. A similar effect on stability was observed for a nearby mutation (T1015N) that increases MERS-CoV infection efficiency in vitro.

Genes or proteins
spike; HR1
Mutations
Q1020; R1020; H1020; T1015N
Mechanism types
fusion_stability; infection_efficiency; cross_species_adaptation
Molecular Adaptation Extraction confidence 0.90
Key finding

Positively selected residues R652 and V1060 in betacoronaviruses were linked to expanded host range, indicating molecular adaptation in the heptad repeat region.

Host
Not specified
Location
Not specified
Supporting text

Two sites (R652 and V1060) were positively selected in the betaCoVs phylogeny and correspond to mutations associated with expanded host range in other coronaviruses.

Genes or proteins
spike; heptad repeat region
Mutations
R652; V1060
Mechanism types
host_range_expansion; adaptive_evolution
Spillover Event 1 records
Spillover Event Extraction confidence 0.85
Key finding

MERS-CoV was transmitted to humans through zoonotic transmission from camels, following its origin in bats.

Virus
MERS-CoV
Location
Not specified
Supporting text

Middle East respiratory syndrome coronavirus (MERS-CoV) originated in bats and spread to humans via zoonotic transmission from camels.

Transmission direction
animal-to-human