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

Abstract

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.

Increase of SARS-CoV-2 RNA load in faecal samples prompts for rethinking of SARS-CoV-2 biology and COVID-19 epidemiology

“…22 Recent studies highlighted the significant amount of intra-host genomic diversity in SARS-CoV-2 samples. 23,24 In a 'bacteriophage-like' mode of action, as bacteria were grown for 30 days, it can't be excluded that the observed amino acid changes represent viral quasispecies emerged through replication events in bacterial hosts. In relation to this, recent studies [25][26][27] evidenced hypermutations occurrences in SARS-CoV-2 genomes and suggested APOBEC and ADAR deaminases as the possible responsible of these phenomena.…”

Increase of SARS-CoV-2 RNA load in faecal samples prompts for rethinking of SARS-CoV-2 biology and COVID-19 epidemiology

“…22 Recent studies highlighted the significant amount of intra-host genomic diversity in SARS-CoV-2 samples. 23,24 In a 'bacteriophage-like' mode of action, as bacteria were grown for 30 days, it can't be excluded that the observed amino acid changes represent viral quasispecies emerged through replication events in bacterial hosts. In relation to this, recent studies [25][26][27] evidenced hypermutations occurrences in SARS-CoV-2 genomes and suggested APOBEC and ADAR deaminases as the possible responsible of these phenomena.…”

Heterogeneity of SARS-CoV-2 virus produced in cell culture revealed by shotgun proteomics and supported by genome sequencing

“…Indeed, SARS-CoV-2 viruses inhabit the host as a population of variants (the so-called quasispecies) and this diversity changes over time. Based on metatranscriptomics, a recent study revealed the co-existence of different genotypes within the same patient [ 27 ]. Finally, recent works have shown that in some cells mutations on the spike protein could lead to loss of furin cleavage and become dominant, while wild-type SARS-CoV-2 sequence is maintained at a low percentage [ 28 ].…”