Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus

A large number of sars-related coronaviruses (sarsr-cov) have been detected in horseshoe bats since 2005 in different areas of china. however,these bat sarsr-covs show sequence differences from sars coronavirus (sars-cov) in different genes (s,orf8,orf3,etc) and are considered unlikely to represent the direct progenitor of sars-cov. herein,we report the findings of our 5-year surveillance of sarsr-covs in a cave inhabited by multiple species of horseshoe bats in yunnan province,china. the full-length genomes of 11 newly discovered sarsr-cov strains,together with our previous findings,reveals that the sarsr-covs circulating in this single location are highly diverse in the s gene,orf3 and orf8. importantly,strains with high genetic similarity to sars-cov in the hypervariable n-terminal domain (ntd) and receptor-binding domain (rbd) of the s1 gene,the orf3 and orf8 region,respectively,were all discovered in this cave. in addition,we report the first discovery of bat sarsr-covs highly similar to human sars-cov in orf3b and in the split orf8a and 8b. moreover,sarsr-cov strains from this cave were more closely related to sars-cov in the non-structural protein genes orf1a and 1b compared with those detected elsewhere. recombination analysis shows evidence of frequent recombination events within the s gene and around the orf8 between these sarsr-covs. we hypothesize that the direct progenitor of sars-cov may have originated after sequential recombination events between the precursors of these sarsr-covs. cell entry studies demonstrated that three newly identified sarsr-covs with different s protein sequences are all able to use human ace2 as the receptor,further exhibiting the close relationship between strains in this cave and sars-cov. this work provides new insights into the origin and evolution of sars-cov and highlights the necessity of preparedness for future emergence of sars-like diseases. © 2017 hu et al.