Genotype-phenotype correlation identified a novel SARS-CoV-2 variant possibly linked to severe disease

Abstract

The geographic location and heterogeneous multi-ethnic population of Dubai (United Arab Emirates; UAE) provide a unique setting to explore the global molecular epidemiology of SARS-CoV-2 and relationship between different viral strains and disease severity. We systematically selected (i.e. every 100th individual in the central Dubai COVID-19 database) 256 patients by age, sex, disease severity and month to provide a representative sample of laboratory-confirmed COVID-19 patients (nasopharyngeal swab PCR positive) during the first wave of the UAE outbreak (January to June 2020). Sociodemographic and clinical data were extracted from medical records and full SARS-CoV-2 genome sequences extracted from nasopharyngeal swabs were analysed. Older age was significantly associated with COVID-19-associated hospital admission and mortality. Overweight/obese or diabetic patients were 3-4 times more likely to be admitted to hospital and intensive care unit (ICU). Sequencing data showed multiple independent viral introductions into the UAE from Europe, Iran and Asia (29 January-18 March), and these early strains seeded significant clustering consistent with almost exclusive community-based transmission between April and June 2020. Majority of sequenced strains (N = 60, 52%) were from the European cluster consistent with the higher infectivity rates associated with the D614G mutation carried by most strains in this cluster. A total of 986 mutations were identified in 115 genomes, 272 were unique (majority were missense, n = 134) and 20/272 mutations were novel. A missense (Q271R) and synonymous (R41R) mutation in the S and N proteins, respectively, were identified in 2/27 patients with severe COVID-19 but not in patients with mild or moderate disease (0/86; p = .05, Fisher's Exact Test). Both patients were women (51-64 years) with no significant underlying health conditions. The same two mutations were identified in a healthy 37-year-old Indian man who was hospitalized in India due to COVID-19. Our findings provide evidence for continued community-based transmission of the European strains in the Dubai population and highlight new mutations that might be associated with severe disease in otherwise healthy adults.

Keywords: COVID-19; Q271R; SARS-CoV-2; molecular phylogeny; mutation; whole genome sequencing.

FIGURE 1

Distribution of UAE strains with a given variant (a) and the average sequencing coverage (b) across the SARS‐CoV‐2 genome sequence (NC_045512) (c). E = Envelope protein, M = Membrane, N = Nucleocapsid protein, ORF = open reading frame, S = Spike protein

FIGURE 2

Distribution of the unique SARS‐CoV‐2 variants (N = 272) identified in 115 SARS‐CoV‐2 genomes in the UAE by type (a), and location (b)

FIGURE 3

Maximum likelihood phylogenetic tree of SARS‐CoV‐2 sequences isolated from UAE (n = 115) was constructed using BEAST v.1.10.4 with strict clock mode, the Hasegawa–Kishino–Yano substitution model was used with 4 rate categories drawn from a gamma distribution (GTR4G). The two Wuhan genomes (Wuhan‐Hu‐1/2019, GISAID ID: EPI_ISL_402125 and Wuhan/WH01/2019, GISAID ID: EPI_ISL_406798) were used as reference genomes (branch colour = black). UAE SARS‐CoV‐2 isolates are indicated in blue (Europe, n = 60), green (Asia, n = 34) and red (Iran, n = 60). The dashed vertical line represents the date when Dubai International Airport closed to passengers

FIGURE 4

Association of SARS‐CoV‐2 sequence variants with COVID‐19 clinical severity. X‐axis indicates SARS‐CoV2 genomic locus/mutation and Y‐axis indicates the percentage of patients with severe (red circles) and mild/moderate (blue circles) disease at each mutation. Two mutations, Q271R and R41R in the S and N genes, respectively, were found in severely sick patients only (p = .055, two tailed t‐test)