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A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.

SUBMITTER: Kang L

PROVIDER: S-EPMC8260498 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Among the rare colonizers of heavy-metal rich toxic soils, Arabidopsis halleri is a compelling model extremophile, physiologically distinct from its sister species A. lyrata, and A. thaliana. Naturally selected metal hypertolerance and extraordinarily high leaf metal accumulation in A. halleri both require Heavy Metal ATPase4 (HMA4) encoding a PIB-type ATPase that pumps Zn(2+) and Cd(2+) out of specific cell types. Strongly enhanced HMA4 expression results from a combination of gene copy number expansion and cis-regulatory modifications, when compared to A. thaliana. These findings were based on a single accession of A. halleri. Few studies have addressed nucleotide sequence polymorphism at loci known to govern adaptations. We thus sequenced 13 DNA segments across the HMA4 genomic region of multiple A. halleri individuals from diverse habitats. Compared to control loci flanking the three tandem HMA4 gene copies, a gradual depletion of nucleotide sequence diversity and an excess of low-frequency polymorphisms are hallmarks of positive selection in HMA4 promoter regions, culminating at HMA4-3. The accompanying hard selective sweep is segmentally eclipsed as a consequence of recurrent ectopic gene conversion among HMA4 protein-coding sequences, resulting in their concerted evolution. Thus, HMA4 coding sequences exhibit a network-like genealogy and locally enhanced nucleotide sequence diversity within each copy, accompanied by lowered sequence divergence between paralogs in any given individual. Quantitative PCR corroborated that, across A. halleri, three genomic HMA4 copies generate overall 20- to 130-fold higher transcript levels than in A. thaliana. Together, our observations constitute an unexpectedly complex profile of polymorphism resulting from natural selection for increased gene product dosage. We propose that these findings are paradigmatic of a category of multi-copy genes from a broad range of organisms. Our results emphasize that enhanced gene product dosage, in addition to neo- and sub-functionalization, can account for the genomic maintenance of gene duplicates underlying environmental adaptation.

Project description:SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and Δ H69/ Δ V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing Δ H69/ Δ V70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The Δ H69/ Δ V70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against Δ H69/ Δ V70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.

Project description:BackgroundThe current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-CoV-2, has become the most devastating public health emergency in the 21st century and one of the most influential plagues in history. Studies on the origin of SARS-CoV-2 have generally agreed that the virus probably comes from bat, closely related to a bat CoV named BCoV-RaTG13 taken from horseshoe bat (Rhinolophus affinis), with Malayan pangolin (Manis javanica) being a plausible intermediate host. However, due to the relatively low number of SARS-CoV-2-related strains available in public domain, the evolutionary history remains unclear.MethodologyNine hundred ninety-five coronavirus sequences from NCBI Genbank and GISAID were obtained and multiple sequence alignment was carried out to categorize SARS-CoV-2 related groups. Spike sequences were analyzed using similarity analysis and conservation analyses. Mutation analysis was used to identify variations within receptor-binding domain (RBD) in spike for SARS-CoV-2-related strains.ResultsWe identified a family of SARS-CoV-2-related strains, including the closest relatives, bat CoV RaTG13 and pangolin CoV strains. Sequence similarity analysis and conservation analysis on spike sequence identified that N-terminal domain, RBD and S2 subunit display different degrees of conservation with several coronavirus strains. Mutation analysis on contact sites in SARS-CoV-2 RBD reveals that human-susceptibility probably emerges in pangolin.Conclusion and implicationWe conclude that the spike sequence of SARS-CoV-2 is the result of multiple recombination events during its transmission from bat to human, and we propose a framework of evolutionary history that resolve the relationship of BCoV-RaTG13 and pangolin coronaviruses with SARS-CoV-2.Lay summaryThis study analyses whole-genome and spike sequences of coronavirus from NCBI using phylogenetic and conservation analyses to reconstruct the evolutionary history of severe acute respiratory syndrome (SARS)-CoV-2 and proposes an evolutionary history of spike in the progenitors of SARS-CoV-2 from bat to human through mammal hosts before they recombine into the current form.

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A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation.

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