Structural impact of a new spike Y170W mutation detected in early emerging SARS-CoV-2 Omicron variants in France

Abstract

To assess the genetic characteristics of the early emerging SARS-CoV-2 Omicron variant strains, we retrospectively analyzed a collection of 150 nasopharyngeal samples taken from a series of outpatient cases tested positive by a referenced qRT-PCR assay during the reported period of Omicron variant emergence in December 2021, in northeastern region of France. Next Generation Sequencing (NGS) analysis of SARS-CoV-2 spike sequences revealed that only 3 (2 %) of these detected strains were Omicron variants, while 147 (98 %) were identified as previously described delta variants. Our phylogenetic analyzes of SARS-CoV-2 RNA genomes showed that these French early emerging Omicron variants may have originated from South Africa or India. In addition, whole viral genome sequences NGS comparison analyzes allowed us to identify an original and uncharacterized Y170W spike mutation that was weakly and transiently detected during the period of SARS-CoV-2 Omicron variant emergence in human populations. Molecular modeling and docking experiments indicated that this original mutated residue Y170W was neither directly involved in binding to the SARS-CoV-2 receptor ACE2 nor in interacting with known neutralizing antibody sites. However, this new mutation may be responsible for preventing the transition from the closed to the open Spike conformation, thus promoting the early emergence of the Omicron variant. Overall, these results underscore the epidemiological utility of a routine whole-genome viral NGS strategy that enables genotypic characterization of emerging or mutant SARS-CoV-2 variants, which could have significant implications for public health policy.

Keywords: COVID-19; Epidemiology; NGS; Omicron variant; SARS-CoV-2; Spike gene.

Fig. 1

Dynamic of apparition of Y170W spike mutation into SARS-CoV-2 delta and omicron variants genome between January 2021 and December 2022. Representation of the number of SARS-CoV-2 whole genome detected by NGS worldwide (bars) from January 2021 to December 2022. The identification frequency of SARS-CoV-2 Y170W spike mutation for delta and omicron variants (red line) from January 2021 to December 2022. The SARS-CoV-2 delta variant circulation period is delimited by a grey zone whereas the SARS-CoV-2 omicron variant circulation period is delimited by a blue zone. T: Trimestre, Y: Tyrosine (Tyr), W: Tryptophane (Trp).

Fig. 2

Phylogenetic tree of full-length RNA genome sequences of Delta and Omicron variants detected with Y170W spike mutation. The phylogenic tree of 1 SARS-CoV-2 Delta variant and 15 SARS-CoV-2 Omicron variant subdivided into sub-lineage (various colors) in comparison to first reference genome of SARS-CoV-2 Delta variant. Scale lengths represent the genetic distance. The reference SARS-CoV-2 Delta variant from India is marked with an empty triangle (GISAID number: EPI_ISL_3473613) and the study patient is marked with a black star. The Delta case with Y170W mutation is marked with a black triangle (GISAID number: EPI_ISL_15003336) and the Omicron cases with Y170W mutation is marked with a black circle (GISAID numbers: EPI_ISL_15388688; EPI_ISL_7855060; EPI_ISL_9246158; EPI_ISL_16282412; EPI_ISL_16216131; EPI_ISL_9835825; EPI_ISL_9835840; EPI_ISL_9087735; EPI_ISL_10053705; EPI_ISL_9750628; EPI_ISL_9679240; EPI_ISL_16216217; EPI_ISL_9446579; EPI_ISL_10758391; EPI_ISL_12223836).

Fig. 3

Impact of the Y170W mutation. The position of residue Y170 on each chain is highlighted on the structure of the spike protein forming a complex with ACE2 molecule (A) or with the NTD-directed neutralizing antibody (B). The red Van der Waals representation is used to represent the tyrosine residues. The ACE2 molecule is depicted using green surface (A) and the neutralizing antibody is depicted using yellow surface (B). Zoom representation of the close vicinity of residues Y170 or W170 in an open (C) or closed (D) conformation. Y170 and W170 residues are shown using the CPK mode and blue licorice mode is used to represent residues making contact with residue 170 both in the native and the mutated structure. Light green licorice mode is used to highlight residues making contact with residue 170 only in the mutated structure. Spike/ACE2 complexes obtained from docking experiments between ACE2 and the native open protein (E) or the mutated open protein (F). Y170 or W170 residues are depicted using red Van der Waals mode and the ACE2 molecule is depicted using green surface (E) or orange surface (F). In all panels, New Cartoon color coded chain texture is assigned to the spike protein. The complex with ACE2 molecule (A) corresponds to the open form of the spike protein and is processed from the PDB ID 7DF4 and the complex with the neutralizing antibody (B) corresponds to the closed form of the spike protein and is processed from the PBD ID 7L2D. Docking experiments (E and F) are set-up using the spike structure extracted from PDB ID 7DF4. Attention is drawn to the fact that the spike protein structures shown in panels A, B, E and F are oriented in the same way.