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Related Concept Videos

Mismatch Repair01:20

Mismatch Repair

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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
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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.
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DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their  survival. Therefore, the copying errors are checked and repaired at three levels.
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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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Gene Evolution - Fast or Slow?02:05

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The genomes of eukaryotes are punctuated by long stretches of sequence which do not code for proteins or RNAs. Although some of these regions do contain crucial regulatory sequences, the vast majority of this DNA serves no known function. Typically, these regions of the genome are the ones in which the fastest change, in evolutionary terms, is observed, because there is typically little to no selection pressure acting on these regions to preserve their sequences.
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Other than maintaining genome stability via DNA repair, homologous recombination plays an important role in diversifying the genome. In fact, the recombination of sequences forms the molecular basis of genomic evolution. Random and non-random permutations of genomic sequences create a library of new amalgamated sequences. These newly formed genomes can determine the fitness and survival of cells. In bacteria, homologous and non-homologous types of recombination lead to the evolution of new...
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Updated: Jun 4, 2025

Assessing Somatic Hypermutation in Ramos B Cells after Overexpression or Knockdown of Specific Genes
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Mutability and hypermutation antagonize immunoglobulin codon optimality.

Joshua J C McGrath1, Juyeon Park2, Chloe A Troxell1

  • 1Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.

Molecular Cell
|December 21, 2024
PubMed
Summary
This summary is machine-generated.

Antibody diversity, crucial for immune response efficacy, is shaped by genetic mechanisms that reduce codon optimality. This trade-off prioritizes diversity over optimal gene expression for effective antibody function.

Keywords:
IGHVantibodycodon optimalityevolutionimmunogeneticsmutabilitysomatic hypermutation

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Antibody efficacy depends on paratope diversity generated by V(D)J recombination and somatic hypermutation.
  • The interplay between genetic diversification mechanisms and codon optimality in antibody expression remains poorly understood.

Purpose of the Study:

  • To investigate how codon optimality influences antibody expression through analysis of germline immunoglobulin genes and natural repertoires.
  • To explore the relationship between genetic diversification, codon optimality, and antibody efficacy in various biological contexts.

Main Methods:

  • Analysis of germline immunoglobulin variable (IGV) genes and natural V(D)J repertoires.
  • Assessment of codon optimality in heavy-chain (IGH) VDJ repertoires from human and animal tissues, including specific immune responses.
  • Correlation of germline IGHV optimality with serum variable fragment (VH) usage and evaluation of synonymous deoptimization effects on monoclonal antibody (mAb) yield.

Main Results:

  • Germline IGV genes show varied optimality inversely related to mutability.
  • Somatic hypermutation deoptimizes IGH VDJ repertoires across diverse human and animal immune sites and specific clones (e.g., SARS-CoV-2, HIV-1).
  • Targeting mutations to complementarity-determining regions limits deoptimization; germline IGHV optimality correlates with VH usage post-influenza vaccination, and deoptimization reduces mAb yield.

Conclusions:

  • An antagonistic relationship exists between antibody diversification mechanisms and codon optimality.
  • The evolutionary requirement for antibody diversity supersedes the need for maximal codon optimality.
  • Understanding this trade-off offers insights into antibody engineering and immune response regulation.