Mutational signatures and heterogeneous host response revealed via large-scale characterization of SARS-CoV-2 genomic diversity

Abstract

<jats:title>A<jats:sc>bstract</jats:sc></jats:title><jats:p>To dissect the mechanisms underlying the observed inflation of variants in SARS-CoV-2 genome, we present the largest up-to-date analysis of intra-host genomic diversity, which reveals that the majority of samples present a complex sublineage architecture, due to the interplay between host-related mutational processes and transmission dynamics.</jats:p><jats:p>Strikingly, the deconvolution of the entire set of intra-host variants reveals the existence of mutually exclusive viral mutational signatures, which prove that distinct hosts differently respond to SARS-CoV-2 infections. In particular, two signatures are likely ruled by APOBEC and Reactive Oxygen Species (ROS), which induce hypermutation in a significant number of samples, and appear to be affected by severe purifying selection.</jats:p><jats:p>Conversely, several mutations linked to low-rate mutational processes appear to transit to clonality in the population, eventually leading to the definition of new viral genotypes and to an increase of overall genomic diversity. Finally, we demonstrate that a high number of variants are observed in samples associated to independent lineages, likely due to signature-related mutational hotspots or to positive selection.</jats:p>

Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck

“…Here we use a cat transmission model to show that SARS-CoV-2 genetic diversity is largely shaped by genetic drift and purifying selection. This finding is in broad agreement with recent analyses of evolutionary forces acting on SARS-CoV-2 in humans 25,[27][28][29][30][31][32] . Our results further suggest that human SARS-CoV-2 isolates are relatively well-adapted to feline hosts, and that cat models recapitulate key aspects of SARS-CoV-2 evolution in humans.…”

“…We find genetic drift and purifying selection shape SARS-CoV-2 genetic diversity within feline hosts, and a stringent bottleneck defines viral transmission. This latter finding is at odds with some recent studies in humans, which have estimated wide and variable SARS-CoV-2 transmission bottlenecks [25][26][27][28] . Our data, however, is in line with other narrow estimates 25 .…”

“…Our data, however, is in line with other narrow estimates 25 . These discordant estimates are likely due to a combination of factors including uncertain sources of infection, difficulty collecting samples which closely bookend the transmission event, and inaccurate variant calls [25][26][27][28] . These studies have commonly identified transmission pairs using intrahousehold infections diagnosed within a defined timeframe.…”

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes

“…Besides the APOBEC and ADAR1 editing changes, we also observed substantial abundance of G-to-T and C-to-A substitutions in some samples. These might be due to Reactive Oxygen Species (ROS), as hypothesized in a recent study ( 36 ). ROS activity oxidizes guanine to 7,8-dihydro-8-oxo-2'-deoxyguanosine (oxoguanine) that base pairs with adenine, leading to G-to-T transversions.…”

Within-patient genetic diversity of SARS-CoV-2

“…Previous studies highlight that intra-host genetic diversity in clinical samples is indeed prevalent, and some genomic regions that are susceptible to alterations in the SARS-CoV-2 virus have been identified [37, 38]. Accounting for intra-host diversity can also improve the resolution of phylogenomic analyses of SARS-CoV-2 [39] and our ability to detect selection pressure [40].…”