The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the earlier SARS-CoV-2 variants, BA.1 has many mutations, some of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (215 = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.
Epistasis is an evolutionary phenomenon whereby the fitness effect of a mutation depends on the genetic background in which it arises. A key source of epistasis in an RNA molecule is its secondary structure, which contains functionally important topological motifs held together by hydrogen bonds between Watson–Crick (WC) base pairs. Here we study epistasis in the secondary structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by examining properties of derived alleles arising from substitution mutations at ancestral WC base-paired and unpaired (UP) sites in 15 conserved topological motifs across the genome. We uncover fewer derived alleles and lower derived allele frequencies at WC than at UP sites, supporting the hypothesis that modifications to the secondary structure are often deleterious. At WC sites, we also find lower derived allele frequencies for mutations that abolish base pairing than for those that yield G·U “wobbles,” illustrating that weak base pairing can partially preserve the integrity of the secondary structure. Last, we show that WC sites under the strongest epistatic constraint reside in a three-stemmed pseudoknot motif that plays an essential role in programmed ribosomal frameshifting, whereas those under the weakest epistatic constraint are located in 3’ UTR motifs that regulate viral replication and pathogenicity. Our findings demonstrate the importance of epistasis in the evolution of the SARS-CoV-2 secondary structure, as well as highlight putative structural and functional targets of different forms of natural selection.
more » « less- NSF-PAR ID:
- 10372561
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Journal of Molecular Evolution
- Volume:
- 90
- Issue:
- 6
- ISSN:
- 0022-2844
- Page Range / eLocation ID:
- p. 429-437
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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