Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models

Abstract

Background A mechanistic understanding of the spread of SARS-CoV-2 and diligent tracking of ongoing mutagenesis are of key importance to plan robust strategies for confining its transmission. Large numbers of available sequences and their dates of transmission provide an unprecedented opportunity to analyze evolutionary adaptation in novel ways. Addition of high-resolution structural information can reveal the functional basis of these processes at the molecular level. Integrated systems biology-directed analyses of these data layers afford valuable insights to build a global understanding of the COVID-19 pandemic. Results Here we identify globally distributed haplotypes from 15,789 SARS-CoV-2 genomes and model their success based on their duration, dispersal, and frequency in the host population. Our models identify mutations that are likely compensatory adaptive changes that allowed for rapid expansion of the virus. Functional predictions from structural analyses indicate that, contrary to previous reports, the Asp614Gly mutation in the spike glycoprotein (S) likely reduced transmission and the subsequent Pro323Leu mutation in the RNA-dependent RNA polymerase led to the precipitous spread of the virus. Our model also suggests that two mutations in the nsp13 helicase allowed for the adaptation of the virus to the Pacific Northwest of the USA. Finally, our explainable artificial intelligence algorithm identified a mutational hotspot in the sequence of S that also displays a signature of positive selection and may have implications for tissue or cell-specific expression of the virus. Conclusions These results provide valuable insights for the development of drugs and surveillance strategies to combat the current and future pandemics.

Introduction of ORF3a-Q57H SARS-CoV-2 Variant Causing Fourth Epidemic Wave of COVID-19, Hong Kong, China

“…Our full genome analysis revealed that the wave 4 virus has several nonsilent mutations associated with host adaptation ( 4 – 6 ; B. Zhou et al, unpub. data, https://doi.org/10.1101/2020.10.27.357558 ), including mutations in the RNA-dependent RNA polymerase (RdRp[L323P]), Spike(D614G), open reading frame 3a (ORF3a[Q57H]), ORF3b(E14*), and nucleocapsid (N[S194L]) proteins.…”

Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hotspots, Functional Crosstalk and Regulatory Interactions in SARS-CoV-2

“…Nsp13 contains a helicase domain, allowing efficient strand separation of extended regions of double-stranded RNA and DNA (48). Dual mutations in Nsp13 were reported with profound effect on its activity specifically in Pacific northwest of USA (49). P409L, mutation leads to increased affinity of helicase RNA interaction, whereas Y446C is a destabilizing mutation increasing the molecular flexibility and leading to decreased affinity of helicase binding with RNA (50).…”

Genetic Diversity of SARS-CoV-2 over a One-Year Period of the COVID-19 Pandemic: A Global Perspective

“…The coexistence of D614G (spike), P323L (NSP12), and C241U (5′-UTR) may contribute to increased transmission fitness [ 61 ]. The P323L variant might alter the secondary and tertiary structures of NSP12 to interact with NSP8, thereby affecting viral replication [ 62 , 63 ]. Additionally, other variants like S25L in NSP7, S194L, R203K, G204R, and T205I in nucleocapsid, T85I and I120F in NSP2, S477N in spike, and Q57H in ORF3a have also been confirmed by previous studies [ 62 , 64 ].…”

“…The P323L variant might alter the secondary and tertiary structures of NSP12 to interact with NSP8, thereby affecting viral replication [ 62 , 63 ]. Additionally, other variants like S25L in NSP7, S194L, R203K, G204R, and T205I in nucleocapsid, T85I and I120F in NSP2, S477N in spike, and Q57H in ORF3a have also been confirmed by previous studies [ 62 , 64 ]. Although many SARS-CoV-2 variants have been observed, their associations with viral loads and infectivity need more investigation.…”