Multi-site co-mutations and 5’UTR CpG immunity escape drive the evolution of SARS-CoV-2

Abstract

The SARS-CoV-2 infected cases and the caused mortalities have been surging since the COVID-19 pandemic. Viral mutations emerge during the virus circulating in the population, which is shaping the viral infectivity and pathogenicity. Here we extensively analyzed 6698 SARS-CoV-2 whole genome sequences with specific sample collection dates in NCBI database. We found that four mutations, i.e., 5’UTR_c-241-t, NSP3_c-3037-t, NSP12_c-14408-t, and S_a-23403-g, became the dominant variants and each of them represented nearly 100% of all virus sequences since the middle May, 2020. Notably, we found that co-occurrence rates of three significant multi-site co-mutational patterns, i.e., (i) S_a-23403-g, NSP12_c-14408-t, 5’UTR_c-241-t, NSP3_c-3037-t, and ORF3a_c-25563-t; (ii) ORF8_t-28144-c, NSP4_c-8782-t, NSP14_c-18060-t, NSP13_a-17858-g, and NSP13_c-17747-t; and (iii) N_g-28881-a, N_g-28882-a, and N_g-28883-c, reached 66%, 90%, and nearly 100% of recent sequences, respectively. Moreover, we found significant decrease of CpG dinucleotide at positions 241(c)-242(g) in the 5’UTR during the evolution, which was verified as a potential target of human zinc finger antiviral protein (ZAP). The four dominant mutations, three significant multi-site co-mutations, and the potential escape mutation of ZAP-target in 5’UTR region contribute to the rapid evolution of SARS-CoV-2 virus in the population, thus shaping the viral infectivity and pathogenicity. This study provides valuable clues and frameworks to dissect the viral replication and virus-host interactions for designing effective therapeutics.One Sentence SummaryFour dominant mutations, three significant multi-site co-mutations, and 5’UTR CpG escape contribute to the rapid evolution of SARS-CoV-2 virus.

Short sequence motif dynamics in the SARS-CoV-2 genome suggest a role for cytosine deamination in CpG reduction

“…Our CpG net gain analysis showed a decline, indicating that the number of total CpG losses overrides their gain (Figure S4), in agreement with recently published observations (Wang et al 2020; Wei et al 2020; Zhang et al 2020). Similar to other coronavirus genomes, SARS-CoV-2 has a low CpG frequency around 1.5%, while the expected frequency is 3.6% (Wang et al 2020).…”

“…The remaining dinucleotides showed relative stability across the time period. Interestingly, recent reports showed the reduction of CpG dinucleotides in 5’-UTR and ORF1ab regions (Wang et al 2020; Wei et al 2020; Zhang et al 2020). When analyzing the context of genomic sites undergoing C>U changes we noticed an enrichment for 5’-UCG-3’ motifs (Table S2).…”

A new framework for host-pathogen interaction research

“…Multiple genetic viral mutations may also co-exist and co-evolve with the host population ( 31 ). Our recent study of 6698 SARS-CoV-2 whole-genome sequences revealed four dominant mutations, including 5’UTR_c-241-t, NSP3_c-3037-t, NSP12_c-14408-t, and S_a-23403-g ( 33 ). These mutational changes in viral genomes all contribute to the rapid viral evolution and enhance viral transmission and long-term survival rates.…”