Decoding Asymptomatic COVID-19 Infection and Transmission

Abstract

One of the major challenges in controlling the coronavirus disease 2019 (COVID-19) outbreak is its asymptomatic transmission. The pathogenicity and virulence of asymptomatic COVID-19 remain mysterious. On the basis of the genotyping of 75775 SARS-CoV-2 genome isolates, we reveal that asymptomatic infection is linked to SARS-CoV-2 11083G>T mutation (i.e., L37F at nonstructure protein 6 (NSP6)). By analyzing the distribution of 11083G>T in various countries, we unveil that 11083G>T may correlate with the hypotoxicity of SARS-CoV-2. Moreover, we show a global decaying tendency of the 11083G>T mutation ratio indicating that 11083G>T hinders the SARS-CoV-2 transmission capacity. Artificial intelligence, sequence alignment, and network analysis are applied to show that NSP6 mutation L37F may have compromised the virus's ability to undermine the innate cellular defense against viral infection via autophagy regulation. This assessment is in good agreement with our genotyping of the SARS-CoV-2 evolution and transmission across various countries and regions over the past few months.

Figure 1.

Visualization of the Benjamini−Hochberg procedure. The y axis is the p-value of the mutation, and the x axis shows the rank of its corresponding p-values. The slope of the line is α/m, where m is the total number of independent hypotheses. Here, m = 457 and α = 0.03. The blue dots represent the mutations that pass the test, and the red dots represent the mutations that do not pass the test.

Figure 2.

Time evolution of SARS-CoV-2 mutation 11083G>T-(L37F) in nine countries and two states (i.e., New York and Washington) from the United States. The bar plots show the frequency of cases with and without the 11083G>T-(L37F) mutation. Each bar width covers a 14-day period. The blue line plot illustrates the evolution of the L37F mutation ratio computed as the count of genome sequences having the L37F mutation over the total count of genome sequences in each time period. The red line plot shows the evolution of the total count of genome sequences.

Figure 3.

(a) Pie-chart plot of the distribution of genome samples with and without the 11083G>T-(L37F) mutation in the United States. The red and blue colors represent the 11083G>T-(L37F) mutation and non-11083G>T mutations, respectively. The color of the dominant mutation type decides the base color of each state. (b) Bar plot of the age and gender distributions of the ratio of the number of samples having mutation L37F over the total number of samples having age and/or gender labels. The straight lines over all age groups are the group average ratios. (The average ratio from the total data set having age labels overlaps with the average ratio from the data set having male labels.) (c) Pie-chart plot of the distribution of genome samples with and without the 11083G>T-(L37F) mutation in the world. The color of the dominant mutation decides the base color of each country.

Figure 4.

(a) Visualization of SARS-CoV-2 NSP6 proteoform. The 11083G>T mutation in the genome sequence leads to the residue 37 leucine (L) mutant to phenylalanine (F). We use a red arrow to point out the mutation detected at residue 37. According to the sequence alignment results in (c), we color the conservative SARS-CoV-2 NSP6 residues blue. (b) Three-dimensional structure of the SARS-CoV-2 NSP6 protein. Green represents the mutation residue at position 37 of NSP6. (c) Sequence alignments for the NSP6 proteins of SARS-CoV-2, SARS-CoV, bat coronavirus RaTG13, bat coronavirus CoVZC45, and bat coronavirus BM48–31. The numbering is generated according to SARS-CoV-2.