带TRS基序突变的新型冠状病毒威胁更大

SARS-CoV-2 with transcription regulatory sequence motif mutation poses a greater threat

目的研究冠状病毒转录调控序列(TRS)基序突变,为深入研究冠状病毒的爆发、传播规律以及开发减毒活疫苗等提供理论基础。方法采用进化与分子功能联合分析法,对公开的全部套目病毒基因组数据进行分析。结果冠状病毒基因组内的前导转录调控序列(TRS-L)通常由其5’端非编码区内的前60~70个核苷酸残基组成,长度不同的基因体转录调控序列(TRS-B)位于除ORF1a和1b外的其它基因紧邻的上游,每个冠状病毒基因组的TRS-L和TRS-B共有一段特定的一致性序列,即TRS基序,TRS基序中出现的碱基变化叫做TRS基序突变。TRS基序突变如果发生在TRS-L或多个TRS-B中,会形成超级减毒株。超级减毒株的扩散,可引起无症或轻症感染者增多,潜伏时间长,以及漏检率上升等问题,对SARS-CoV-2的防控提出新的挑战。超级减毒株还会增大与人类长期共存的概率,将长期威胁人类健康。Delta突变株与此前出现的突变株有显著不同,如果不高度重视,可能引起大规模传播。带TRS基序突变的Delta突变株已经在新加坡出现并有扩散趋势,因此新加坡,甚至东南亚可能形成下一波疫情的传播中心。结论各种SARS-CoV-2突变株都将产生TRS基序突变,只有带TRS基序突变的超级减毒株,才能最终失去跨物种传播和大爆发的能力。

Objective To analyze the mutations in transcription regulatory sequences(TRSs)of coronaviruss(CoV)to provide the basis for exploring the patterns of SARS-CoV-2 transmission and outbreak.Methods A combined evolutionary and molecular functional analysis of all sets of publicly available genomic data of viruses was performed.Results A leader transcription regulatory sequence(TRS-L)usually comprises the first 60-70 nts of the 5’UTR in a CoV genome,and the body transcription regulatory sequences(TRS-Bs)are located immediately upstream of the genes other than ORF1a and 1b.In each CoV genome,the TRS-L and TRS-Bs share a specific consensus sequence,namely the TRS motif.Any changes of nucleotide residues in the TRS motifs are defined as TRS motif mutations.Mutations in the TRS-L or multiple TRS-Bs result in superattenuated variants.The spread of super-attenuated variants may cause an increase in asymptomatic or mild infections,prolonged incubation periods and a decreased detection rate of the viruses,thus posing new challenges to SARS-CoV-2prevention and control.The super-attenuated variants also increase their possibility of long-term coexistence with humans.The Delta variant is significantly different from all the previous variants and may lead to a large-scale transmission.The Delta variant(B.1.617.2)with TRS motif mutation has already appeared and shown signs of spreading in Singapore,which,and even the Southeast Asia,may become the new epicenter of the next wave of SARS-CoV-2 outbreak.Conclusion TRS motif mutation will occur in all variants of SARS-CoV-2 and may result in super-attenuated variants.Only super-attenuated variants with TRS motif mutations will eventually lose the abilities of cross-species transmission and causing outbreaks.