Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Abstract

The SARS-CoV-2 pandemic has entered an alarming new phase with the emergence of the variants of concern (VOC), P.1, B.1.351, and B.1.1.7, in late 2020, and B.1.427, B.1.429, and B.1.617, in 2021. Substitutions in the spike glycoprotein (S), such as Asn501Tyr and Glu484Lys, are likely key in several VOC. However, Asn501Tyr had been circulating for months in earlier strains and Glu484Lys is not found in B.1.1.7, indicating that they do not fully explain those fast-spreading variants. Here we use a computational systems biology approach to process more than 900,000 SARS-CoV-2 genomes and map spatiotemporal relationships, revealing other critical attributes of these variants. Comparisons to earlier dominant mutations and protein structural analyses indicate that the increased transmission is promoted by the combination of functionally complementary mutations in S and in other regions of the SARS-CoV-2 proteome. We report that the VOC have in common mutations in non-S proteins involved in immune-antagonism and replication performance, such as the nonstructural proteins 6 and 13, suggesting a convergent evolution of the virus. Critically, we propose that recombination events among divergent coinfecting haplotypes greatly accelerates the emergence of VOC by bringing together cooperative mutations and explaining the remarkably high mutation load of B.1.1.7. Therefore, extensive community distribution of SARS-CoV-2 increases the probability of future recombination events, further accelerating the evolution of the virus. This study reinforces the need for a global response to stop COVID-19 and future pandemics.

Structural Dynamics and Molecular Evolution of the SARS-CoV-2 Spike Protein

“…Thus, while the Omicron Spike is less likely to occupy the open RBD states necessary for ACE2 engagement, it may compensate by binding the receptor more strongly when such an interaction occurs and by having adapted to resist innate defenses. Such changes would be consistent with the broad pattern of host adaptation suggested by the presence of additional convergent mutations that were observed in prior variants ( 59 , 103 ).…”

“…Further, although S protein stability and fusogenicity is an important axis, the S gene is not the only part of the genome that affects viral fitness ( 97 ). Mutations in the nucleocapsid gene often appear in variants of concern and can contribute to fitness ( 98 , 99 ), as can those in the putative viroporin encoded by ORF3A ( 100 ), ORF8A ( 101 ), and NSP6 ( 102 , 103 ), among other genes ( 104 ). Moreover, mutations in different genes are capable of epistatic interaction ( 59 ).…”

Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics

“…Long-ranged interactions between different sites within a given protein is critically important for protein function (Peters and Lively 1999; Bershtein et al 2006; Collins et al 2006; Ekeberg et al 2013; Levy et al 2017; Harrigan et al 2018; Otten et al 2018; Rojas Echenique et al 2019; Shimagaki and Weigt 2019; de la Paz et al 2020; Rizzato et al 2020; Yang et al 2020; Bisardi et al 2022) and for the CoV-2 S protein in particular (Zeng et al 2020; Castiglione et al 2021; Dong et al 2021; Garvin et al 2021; Nielsen et al 2022; Ramarao-Milne et al 2022; Rochman et al 2022; Rodriguez-Rivas et al 2022). By showing dynamic differences between the interactions of CAPs, which have likely played a major role in allowing the virus to infect human hosts, the binding site, and the characteristic mutations of dominant Delta and Omicron strains, we see a “fine-tuning” of protein behavior.…”

Searching for escape-resistant anti–SARS-CoV-2 neutralizing antibodies

“…Changes in S may increase viral fitness by strengthening S-ACE2 interactions, leading to enhanced infectivity and transmissibility (18, 19), or-as potential hosts gain immunity through infection and vaccination-by destroying nAb epitopes (17,18). Deleterious mutations in S may be rescued by compensating mutations at other sites within S (20) or other viral genes (epistasis) (21). Perhaps truly mutation-proof nAbs would bind epitopes so structurally and functionally constrained that immune escape would be accompanied by total loss of infectivity.…”