Global variation in the SARS-CoV-2 proteome reveals the mutational hotspots in the drug and vaccine candidates

Abstract

To accelerate the drug and vaccine development against the severe acute respiratory syndrome virus 2 (SARS-CoV-2), a comparative analysis of SARS-CoV-2 proteome has been performed in two phases by considering manually curated 31389 whole genome sequences from 84 countries. Among the 9 mutations that occur at a high significance (T85I-NPS2, L37F-NSP6, P323L-NSP12, D614G-spike, Q57H-ORF3a, G251V-ORF3a, L84S-ORF8, R203K-nucleocapsid and G204R-nucleocapsid), R203K-nucleocapsid and G204R-nucleocapsid are co-occurring mutations and P323L-NSP12 and D614G-spike often appear simultaneously. Other notable variations that appear with a moderate to low significance are, M85-NSP1 deletion, D268-NSP2 deletion, 112 amino acids deletion in ORF8, a phenylalanine insertion amidst F34-F36 (NSP6) and several co-existing substitution/deletion (I559V & P585S in NSP2, P504L & Y541C in NSP13, G82 & H83 deletions in NSP1 and K141, S142 & F143 deletions in NSP2) mutations. P323L-NSP12, D614G-spike, L37F-NSP6, L84S-ORF8 and the sequences deficient of the high significant mutations has led to 4 major SARS-CoV-2 clades. The top 5 countries bearing all the high significant and majority of the moderate significant mutations are: USA, England, Wales, Australia and Scotland. Further, the majority of the significant mutations has evolved in the first phase and has already transmitted around the globe indicating the positive selection pressure. Among the 26 SARS-CoV-2 proteins, nucleocapsid protein, ORF3a, ORF8, RNA dependent RNA polymerase and spike exhibit a higher heterogeneity compared with the rest of the proteins. However, NSP9, NSP10, NSP8, the envelope protein and NSP4 are highly resistant to mutations and can be exploited for drug/vaccine development.

Mutation Profile of SARS-CoV-2 Genome Sequences Originating from Eight Israeli Patient Isolates

“…Apart from the abundant D614G replacement, six other nonsynonymous abundant replacements found in this study (i.e., T85I, L37F, S25L, P323L, A320V, and Q57H; Fig. 1 ) were previously reported as a result of hot spot mutations ( 8 – 10 ).…”

An outbreak of SARS-CoV-2 with high mortality in mink (Neovison vison) on multiple Utah farms

“…Twelve nonsynonymous sequence mutations were identified in the SARS-CoV-2 genome from the Utah mink isolates. The polyprotein ORF1ab T85I-NPS2 mutation is most common in the USA (56% of phase 2 viruses) and has spread to at least 37 countries during phase 2 of the pandemic [46]. The P323L-NSP12 mutation in the viral polymerase gene coevolved with the D614G-spike mutation also present in this mink strain to become the most prevalent variant in the world.…”

One Year of SARS-CoV-2: How Much Has the Virus Changed?

“…SARS-CoV-2 is an RNA virus, which is a family with significant adaptive evolution [ 10 ]. Although the changes in coronaviruses are slower than most RNA viruses, there are some viral components in SARS-CoV-2 that already yielded relevant mutations [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In addition, there are differences in the behavior of the multiple viral components.…”