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Mutations01:39

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Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Simple proteins and protein complexes contain only amino acids. In contrast, many other proteins, called conjugated proteins, covalently bond with non-protein moieties.
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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
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C > U mutations generate immunogenic peptides in SARS-CoV-2.

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SARS-CoV-2 C>U mutations enhance T-cell responses by improving viral peptide binding to human leukocyte antigen class I (HLA-I). This link between C>U hypermutation and HLA-I presentation may influence COVID-19 severity.

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Area of Science:

  • Virology
  • Immunology
  • Genetics

Background:

  • SARS-CoV-2 variants pose global health challenges.
  • Understanding mutations' impact on T-cell immunity is crucial.
  • APOBEC3 enzyme-driven C>U transitions are common in RNA viruses.

Purpose of the Study:

  • To investigate how SARS-CoV-2 mutations influence HLA-restricted T-cell responses.
  • To analyze the role of C>U transitions in viral peptide presentation.
  • To explore the association between HLA-I variants, C>U mutations, and COVID-19 severity.

Main Methods:

  • Genomic analysis of SARS-CoV-2 variants.
  • Assessment of viral peptide binding to HLA-I molecules.
  • Correlation analysis between HLA-I alleles and COVID-19 outcomes.

Main Results:

  • 27% of SARS-CoV-2 mutations are C>U transitions, driven by APOBEC3.
  • C>U mutations enhance viral peptide binding to HLA-I, generating immunogenic epitopes.
  • Specific HLA-I variants, prevalent in Asia, are adept at presenting these epitopes.
  • Reduced binding of C>U-induced peptides to certain HLA-I molecules correlates with severe COVID-19.

Conclusions:

  • A link exists between C>U hypermutation and HLA-I-mediated T-cell epitope presentation.
  • This interaction may reflect evolutionary adaptations to past pandemics.
  • SARS-CoV-2 diversification generates T-cell epitopes, potentially counteracting immune escape.