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Studying Ribonucleotide Incorporation: Strand-specific Detection of Ribonucleotides in the Yeast Genome and Measuring Ribonucleotide-induced Mutagenesis
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Error-prone polymerase activity causes multinucleotide mutations in humans.

Kelley Harris1, Rasmus Nielsen2

  • 1Department of Mathematics, University of California Berkeley, Berkeley, California 94703, USA; kharris@math.berkeley.edu.

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|August 1, 2014
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Summary
This summary is machine-generated.

Multinucleotide mutations (MNMs) create multiple single nucleotide polymorphisms (SNPs) simultaneously, impacting human evolution. This study reveals MNMs are enriched in large human genome datasets and linked to DNA polymerase Pol ζ activity.

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Area of Science:

  • Human Genetics
  • Population Genetics
  • Molecular Evolution

Background:

  • Multinucleotide mutations (MNMs) are hypothesized to cause ~2% of human genetic polymorphisms.
  • MNMs generate multiple single nucleotide polymorphisms (SNPs) in one generation, potentially accelerating evolution and confounding population genetic studies.
  • Previous studies suggest MNMs arise from complex mutational events, but their prevalence and mechanisms in humans are not fully understood.

Purpose of the Study:

  • To investigate the prevalence and characteristics of clustered mutations, specifically multinucleotide mutations (MNMs), in a large human genome dataset.
  • To determine the relationship between SNP distance and the likelihood of simultaneous origin via MNMs.
  • To identify potential molecular mechanisms underlying MNMs in the human population.

Main Methods:

  • Analysis of clustered mutations segregating in 1092 human genomes.
  • Estimation of the proportion of linked SNP pairs generated by simultaneous mutation as a function of inter-site distance.
  • Comparison of MNM mutation signatures (transversion/transition ratios, allele distributions) with known polymerase activities.

Main Results:

  • The signature of MNMs becomes significantly enriched with increasing sample size in human genomes.
  • MNMs show a higher proportion of transversions versus transitions, consistent across multiple sequencing platforms and not attributable to sequencing error.
  • Tandem mutations exhibit a skewed allele distribution, with GC → AA and GA → TT (and reverse complements) comprising 27% of cases, implicating DNA polymerase Pol ζ.

Conclusions:

  • Multinucleotide mutations are a significant source of genetic variation in humans, becoming more apparent with larger sample sizes.
  • The observed mutation spectrum suggests that the error-prone DNA polymerase Pol ζ plays a role in generating human MNMs.
  • Statistical methods are developed to estimate MNM prevalence, crucial for correcting inferences in phylogenetic and population genetic studies.