Genetic relatedness of the novel human group C betacoronavirus to Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5

Woo, Patrick CY; Lau, Susanna KP; Li, Kenneth SM; Tsang, Alan KL; Yuen, Kwok-Yung

After the SARS epidemic, we started to focus on CoV biodiversity, genomics and phylogeny and built up an evolutionary map of CoV evolution. Before 2003, there were less than 10 CoVs with complete genomes available, which include two human CoVs, human coronavirus 229E (HCoV-229E) and human coronavirus OC43 (HCoV-OC43). By September 2012, the number of CoVs with complete genomes sequenced had tripled. It includes two additional human CoVs, human coronavirus NL63 (HCoV-NL63) and human coronavirus HKU1 (HCoV-HKU1). 2,3 Traditionally, CoVs were classified into groups 1, 2 and 3. In 2011, the Coronavirus Study Group of the International Committee for Taxonomy of Viruses has re-classified these three groups of CoVs as three genera, Alphacoronavirus, Betacoronavirus and Gammacoronavirus; and we have discovered a fourth genus of CoV, Deltacoronavirus, which includes at least nine avian CoVs and a porcine coronavirus HKU15. 4, 5 Within the betaCoVs, they are further subclassified into group A, including HCoV-HKU1, HCoV-OC43, bovine coronavirus (BCoV), sable antelope coronavirus, giraffe coronavirus, equine coronavirus, porcine hemagglutinating encephalomyelitis virus, murine hepatitis virus, rat coronavirus and rabbit coronavirus HKU14 (RbCoV HKU14); 6 group B, including the human and civet SARS-related CoVs (SARSr-CoV) and SARS-related Rhinolophus bat coronavirus (SARSr-Rh-BatCoV); 7,8 group C, including Tylonycteris bat coronavirus HKU4 (Ty-BatCoV HKU4) and Pipistrellus bat coronavirus HKU5 (Pi-BatCoV HKU5) we discovered in 2006; 9,10 and group D, including Rousettus bat coronavirus HKU9 (Ro-BatCoV HKU9). 10, 11 In addition to Ty-BatCoV HKU4 and Pi-BatCoV HKU5, other group C bat betaCoVs should also be present, but their complete genome sequences are not available. 12, 13 Based on the CoVs discovered, we have constructed a model of CoV evolution, with evidence supporting that bat CoVs are the gene source of alphaCoVs and betaCoVs and avian CoVs are the gene source of gammaCoVs and deltaCoVs. 5 All these works have laid down an evolutionary map for rapid phylogenetic and bioinformatics analyses of HCoV-EMC. The diversity of CoVs is a result T of the infidelity of RdRp which make CoV genomes especially plastic, a high frequency of homologous RNA recombination due to their unique random template switching during RNA replication, and their large genomes. In addition to biodiversity, a number of natural recombination and possible interspecies jumping events has also been documented in betaCoVs. 6, 11, [14] [15] [16] [17] [18] For group A betaCoVs, molecular clock analysis has shown that HCoV-OC43 is a relatively recent zoonotic virus of bovine origin that emerged in around 1890 likely from bovine-to-human transmission. 17 We have also recently discovered RbCoV HKU14, closely related to other members of the species Betacoronavirus 1 including HCoV-OC43 and BCoV, with recombination events that may have played a role in interspecies transmission of these HCoV-OC43related viruses between human, cattle, rabbits, swine and horses. 6 Despite having circulated in humans for more than a century, HCoV-OC43 is also found to be continuously evolving, with the recent emergence of a novel genotype due to natural recombination. 15 For group B betaCoVs, SARSr-CoV is believed to be transmitted from civet to humans, although it is the horseshoe bat that was likely the primary host. 7, 8 Civet SARSr-CoV was also likely a recombinant virus arising from different strain