High diversity in Delta variant across countries revealed via genome-wide analysis of SARS-CoV-2 beyond the Spike protein
Rohit SuratekarPritha GhoshMichiel J.M. NiesenGregory DonadioPraveen AnandVenky SoundararajanAJ Venkatakrishnan
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Abstract The highly contagious Delta variant of SARS-CoV-2 has emerged as the new dominant global strain, and reports of reduced effectiveness of COVID-19 vaccines against the Delta variant are highly concerning. While there has been extensive focus on understanding the amino acid mutations in the Delta variant ‘s Spike protein, the mutational landscape of the rest of the SARS-CoV-2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS-CoV-2 proteins from nearly 2 million SARS-CoV-2 genomes from 176 countries/territories. Six highly-prevalent missense mutations in the viral life cycle-associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant (cosine similarity: mean Alpha = 0.94, S.D. Alpha = 0.05; mean Delta = 0.86, S.D. Delta = 0.1; Cohen ‘s d Alpha-Delta = 1.17, p-value < 0.001). Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of targetable amino acid mutations in the Delta variant ‘s proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.Keywords:
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Journal Article Vertebrate Genomes Code Excess Proteins with Charge Periodicity of 28 Residues Get access Runcong Ke, Runcong Ke * Department of Applied Physics, Graduate School of Engineering, Nagoya University, Nagoya, Japan *To whom correspondence should be addressed. Tel: +81 52 788 6218, Fax: +81 52 788 6215, E-mail: ke@bp.nuap.nagoya-u.ac.jp Search for other works by this author on: Oxford Academic PubMed Google Scholar Noriyuki Sakiyama, Noriyuki Sakiyama Department of Applied Physics, Graduate School of Engineering, Nagoya University, Nagoya, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Ryusuke Sawada, Ryusuke Sawada Department of Applied Physics, Graduate School of Engineering, Nagoya University, Nagoya, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Masashi Sonoyama, Masashi Sonoyama Department of Applied Physics, Graduate School of Engineering, Nagoya University, Nagoya, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Shigeki Mitaku Shigeki Mitaku Department of Applied Physics, Graduate School of Engineering, Nagoya University, Nagoya, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Biochemistry, Volume 143, Issue 5, May 2008, Pages 661–665, https://doi.org/10.1093/jb/mvn017 Published: 14 February 2008 Article history Received: 09 December 2007 Accepted: 01 February 2008 Published: 14 February 2008
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Abstract Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.
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The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the GJB2 missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible GJB2 missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated.
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Abstract Aims The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated. Methods and Results We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa less than 65% of wild type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (median age [IQR] at diagnosis: 28 [14-45] years, and 74% patients were male) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0-14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants which produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155). Conclusion We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis.
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Objective: CENPH, centromere protein H, is one of the constitutive kinetochore proteins. High expression of CENPH has been shown in various forms of cancers; however, studies searching the effect of CENPH mutations in cancers are limited. Therefore, the aim of this study is to investigate the potential effects of the missense mutations of CENPH that have been identified in different cancers.
Materials and Methods: Missense CENPH mutations, which have been observed in cancers, were downloaded from the COSMIC v89. The effect of missense mutations was predicted by using PredictSNP1.0. The protein structure of the CENPH protein was generated with I-TASSER and missense mutations were visualized on CENPH protein with UCSF Chimera. Structural effects of selected mutations were assessed with HOPE.
Results: 34 missense mutations were observed in human cancers. Of the 34 missense mutations 18 mutations were predicted as deleterious and 16 mutations were predicted as neutral with ranging expected accuracies. Predicted missense mutations showed a scattered pattern on 3D CENPH protein. Two of the predicted deleterious missense mutations with higher expected accuracy were further analyzed and assessed according to amino acid properties.
Conclusion: This study provided a systematic analysis and evaluation of missense mutations on a CENPH protein that have been observed in different cancers.
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