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Clusters of mutations from transient hypermutability.

John W Drake1, Anna Bebenek, Grace E Kissling

  • 1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. drake@niehs.nih.gov

Proceedings of the National Academy of Sciences of the United States of America
|August 25, 2005
PubMed
Summary

Excess multiple mutations in organisms, including viruses, arise from transient hypermutability, not just mutator genes. This phenomenon impacts genetic fidelity and may drive evolution, cancer, and pathogen adaptation.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Evolutionary Biology

Background:

  • Collections of mutants often show more individuals with multiple mutations than random distribution predicts.
  • This excess is observed across diverse organisms and in vitro DNA synthesis experiments.

Purpose of the Study:

  • To investigate the origins of excess multiple mutations.
  • To model mutation spectra as populations with varying mutation frequencies.
  • To understand the implications of excess multiple mutations in biological processes.

Main Methods:

  • Modeling mutation spectra as a mix of low and high mutation frequency subpopulations.
  • Analyzing mutants generated by bacteriophage RB69 mutator DNA polymerase.
  • Examining phenotypically undetectable mutations as indicators of subpopulations.

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Main Results:

  • Mutants with two or three mutations are found in significant excess (10-fold and higher).
  • Undetectable mutations are 5-fold more frequent than detectable ones, suggesting a higher-frequency subpopulation.
  • Rapidly mutating riboviruses show a bimodal distribution with a low-frequency majority and a high-frequency minority.

Conclusions:

  • Excess multiple mutations likely stem from transient hypermutability due to genetic fidelity perturbations.
  • This phenomenon may play a critical role in carcinogenesis and adaptive evolution.
  • Viral populations can comprise distinct subpopulations with vastly different mutation rates.