The Slowing Rate of CpG Depletion in SARS-CoV-2 Genomes Is Consistent with Adaptations to the Human Host

Kumar, Akhil; Goyal, Nishank; Saranathan, Nandhini; Dhamija, Sonam; Saraswat, Saurabh; Menon, Manoj B.; Vivekanandan, Perumal

doi:10.1093/molbev/msac029

Cited by 15 publications

(21 citation statements)

References 39 publications

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“…If meaningless, then each of the six dinucleotide pairs should have the same mutation frequency (CG=GC, CT=TC, CA=AC, GA=AG, GT=TG, AT=TA). However, our results showed CG dinucleotides have a significantly higher mutation rate than GC dinucleotides (p < 0.01, t-test) (Figure S2 and Table 1), which is consistent with previous reports [34][35][36] . Since ZAP is able to specifically bind CpG dinucleotides in single-stranded RNA for targeted degradation, a reduction in the number of CG dinucleotides likely reflects an evasion mechanism resulting from virus evolution.…”

Section: Sequence Context Affects the Mutation Frequency Of Sars-cov-2supporting

confidence: 93%

Massive‐scale genomic analysis reveals SARS‐CoV‐2 mutation characteristics and evolutionary trends

Sun

Wang

Lin

et al. 2022

mLife

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The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic resulted in significant societal costs. Hence, an in‐depth understanding of SARS‐CoV‐2 virus mutation and its evolution will help determine the direction of the COVID‐19 pandemic. In this study, we identified 296,728 de novo mutations in more than 2,800,000 high‐quality SARS‐CoV‐2 genomes. All possible factors affecting the mutation frequency of SARS‐CoV‐2 in human hosts were analyzed, including zinc finger antiviral proteins, sequence context, amino acid change, and translation efficiency. As a result, we proposed that when adenine (A) and tyrosine (T) bases are in the context of AM (M stands for adenine or cytosine) or TA motif, A or T base has lower mutation frequency. Furthermore, we hypothesized that translation efficiency can affect the mutation frequency of the third position of the codon by the selection, which explains why SARS‐CoV‐2 prefers AT3 codons usage. In addition, we found a host‐specific asymmetric dinucleotide mutation frequency in the SARS‐CoV‐2 genome, which provides a new basis for determining the origin of the SARS‐CoV‐2. Finally, we summarize all possible factors affecting mutation frequency and provide insights into the mutation characteristics and evolutionary trends of SARS‐CoV‐2.

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Section: Sequence Context Affects the Mutation Frequency Of Sars-cov-2supporting

confidence: 93%

Massive‐scale genomic analysis reveals SARS‐CoV‐2 mutation characteristics and evolutionary trends

Sun

Wang

Lin

et al. 2022

mLife

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“…Depletion of CpG dinucleotides in genomes of wild viruses from field samples has been linked to virus evolution, host-switching, pathogenicity, and innate immune responses ( 66 , 67 ). However, depletion of CpG dinucleotides in genomes of synthetic recoded viruses during in vivo infection is not well studied.…”

Section: Discussionmentioning

confidence: 99%

CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes

Udenze

Trus²,

Bérubé³

et al. 2022

Front. Immunol.

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Increasing the number of CpG dinucleotides in RNA viral genomes, while preserving the original amino acid composition, leads to impaired infection which does not cause disease. Beneficially, impaired infection evokes antiviral host immune responses providing a cutting-edge vaccine approach. For example, we previously showed that CpG-enriched Zika virus variants cause attenuated infection phenotypes and protect against lethal challenge in mice. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo, particularly in non-rodent species. Here, we used well-established mouse and porcine models to study infection phenotypes of the CpG-enriched neurotropic and congenital virus—Zika virus, directly in the target tissues—the brain and placenta. Specifically, we used the uttermost challenge and directly injected mice intracerebrally to compare infection phenotypes caused by wild-type and two CpG-recoded Zika variants and model the scenario where vaccine strains breach the blood-brain barrier. Also, we directly injected porcine fetuses to compare in utero infection phenotypes and model the scenario where recoded vaccine strains breach the placental barrier. While overall infection kinetics were comparable between wild-type and recoded virus variants, we found convergent phenotypical differences characterized by reduced pathology in the mouse brain and reduced replication of CpG-enriched variants in fetal lymph nodes. Next, using next-generation sequencing for the whole virus genome, we compared the stability of de novo introduced CpG dinucleotides during prolonged virus infection in the brain and placenta. Most de novo introduced CpG dinucleotides were preserved in sequences of recoded Zika viruses showing the stability of vaccine variants. Altogether, our study emphasized further directions to fine-tune the CpG recoding vaccine approach for better safety and can inform future immunization strategies.

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“…These findings suggest a role for CpG depletion in shaping the evolution of HCV. Previous studies have shown that CpG depletion in virus genomes is pronounced during host adaptations [ 7 , 27 ]. In addition, CpG content remains stable for well-adapted human viruses such as influenza B virus [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…The abundance of the CpG dinucleotides in viruses and their association with virus evolution and host-evasion strategies have been explored for both RNA [ 7 , 8 ] and DNA viruses [ 9 , 10 ]. The CpG content differs significantly amongst viruses [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Selective Depletion of ZAP-Binding CpG Motifs in HCV Evolution

et al. 2022

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Hepatitis C virus (HCV) is a bloodborne pathogen that can cause chronic liver disease and hepatocellular carcinoma. The loss of CpGs from virus genomes allows escape from restriction by the host zinc-finger antiviral protein (ZAP). The evolution of HCV in the human host has not been explored in the context of CpG depletion. We analysed 2616 full-length HCV genomes from 1977 to 2021. During the four decades of evolution in humans, we found that HCV genomes have become significantly depleted in (a) CpG numbers, (b) CpG O/E ratios (i.e., relative abundance of CpGs), and (c) the number of ZAP-binding motifs. Interestingly, our data suggests that the loss of CpGs in HCV genomes over time is primarily driven by the loss of ZAP-binding motifs; thus suggesting a yet unknown role for ZAP-mediated selection pressures in HCV evolution. The HCV core gene is significantly enriched for the number of CpGs and ZAP-binding motifs. In contrast to the rest of the HCV genome, the loss of CpGs from the core gene does not appear to be driven by ZAP-mediated selection. This work highlights CpG depletion in HCV genomes during their evolution in humans and the role of ZAP-mediated selection in HCV evolution.

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The Slowing Rate of CpG Depletion in SARS-CoV-2 Genomes Is Consistent with Adaptations to the Human Host

Cited by 15 publications

References 39 publications

Massive‐scale genomic analysis reveals SARS‐CoV‐2 mutation characteristics and evolutionary trends

Massive‐scale genomic analysis reveals SARS‐CoV‐2 mutation characteristics and evolutionary trends

CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes

Selective Depletion of ZAP-Binding CpG Motifs in HCV Evolution

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