Intra-host variation and evolutionary dynamics of SARS-CoV-2 populations in COVID-19 patients

Wang, Yanqun; Wang, Daxi; Zhang, Lu; Sun, Wanying; Zhang, Zhaoyong; Chen, Weijun; Zhu, Airu; Huang, Yongbo; Xiao, Fei; Yao, Jinxiu; Gan, Mian; Li, Fang; Luo, Ling; Huang, Xiaofang; Zhang, Yanjun; Wong, Sook-san; Cheng, Xinyi; Ji, Jingkai; Ou, Zhihua; Xiao, Minfeng; Li, Min; Li, Jiandong; Ren, Peidi; Deng, Ziqing; Zhong, Huanzi; Xu, Xun; Song, Tie; Mok, Chris Ka Pun; Peiris, Malik; Zhong, Nanshan; Zhao, Jingxian; Li, Yimin; Li, Junhua; Zhao, Jincun

BACKGROUND: Since early February 2021, the causative agent of COVID-19, SARS-CoV-2, has infected over 104 million people with more than 2 million deaths according to official reports. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown. METHODS: Using high-throughput sequencing of metatranscriptomic and hybrid captured libraries, we characterized consensus genomes and intra-host single nucleotide variations (iSNVs) of serial samples collected from eight patients with COVID-19. The distribution of iSNVs along the SARS-CoV-2 genome was analyzed and co-occurring iSNVs among COVID-19 patients were identified. We also compared the evolutionary dynamics of SARS-CoV-2 population in the respiratory tract (RT) and gastrointestinal tract (GIT). RESULTS: The 32 consensus genomes revealed the co-existence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in a single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparing allele frequencies of the iSNVs revealed a clear genetic differentiation between intra-host populations from the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events during intra-host migrations. Compared to RT populations, the GIT populations showed a better maintenance and rapid development of viral genetic diversity following the suspected intra-host bottlenecks. CONCLUSIONS: Our findings here illustrate the intra-host bottlenecks and evolutionary dynamics of SARS-CoV-2 in different anatomic sites and may provide new insights to understand the virus-host interactions of coronaviruses and other RNA viruses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00847-5.