scholarly journals Differential DNA mismatch repair underlies mutation rate variation across the human genome

Nature ◽  
2015 ◽  
Vol 521 (7550) ◽  
pp. 81-84 ◽  
Author(s):  
Fran Supek ◽  
Ben Lehner
Keyword(s):  
Human Genome ◽  
Mismatch Repair ◽  
Mutation Rate ◽  
Dna Mismatch Repair ◽  
Rate Variation ◽  
Dna Mismatch ◽  
Mutation Rate Variation

scholarly journals Nucleosome positioning stability is a significant modulator of germline mutation rate variation across the human genome

2018 ◽  
Author(s):  
Cai Li ◽  
Nicholas M. Luscombe
Keyword(s):  
Human Genome ◽  
Genome Evolution ◽  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Mutation Rates ◽  
Rate Variation ◽  
Nucleosome Organization ◽  
Local Sequence ◽  
Mutation Rate Variation

AbstractUnderstanding the patterns and genesis of germline de novo mutations is important for studying genome evolution and human diseases. Nucleosome organization is suggested to be a contributing factor to mutation rate variation across the genome. However, the small number of published de novo mutations and the low resolution of earlier nucleosome maps limited our understanding of how nucleosome organization affects germline mutation rates in the human genome. Here, we systematically investigated the relationship between nucleosome organization and fine-scale mutation rate variation by analyzing >300,000 de novo mutations from whole-genome trio sequencing and high-resolution nucleosome maps in human. We found that de novo mutation rates are elevated around strong, translationally stable nucleosomes, a previously under-appreciated aspect. We confirmed this observation having controlled for local sequence context and other potential confounding factors. Analysis of the underlying mutational processes suggests that the increased mutation rates around strong nucleosomes are shaped by a combination of low-fidelity replication, frequent DNA damage and insufficient/error-prone repair in these regions. Interestingly, strong nucleosomes are preferentially located in young SINE/LINE elements, implying frequent nucleosome re-positioning (i.e. shifting of dyad position) and their contribution to hypermutation at new retrotransposons during evolution. These findings provide novel insights into how chromatin organization affects germline mutation rates and have important implications in human genetics and genome evolution.

scholarly journals Inactivation of DNA Mismatch Repair by Increased Expression of Yeast MLH1

2001 ◽  
Vol 21 (3) ◽  
pp. 940-951 ◽  
Author(s):  
Polina V. Shcherbakova ◽  
Mark C. Hall ◽  
Marc S. Lewis ◽  
Samuel E. Bennett ◽  
Karla J. Martin ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Mutation Rate ◽  
Analytical Ultracentrifugation ◽  
Dna Mismatch Repair ◽  
Genome Instability ◽  
Spontaneous Mutation ◽  
Moderate Increase ◽  
Spontaneous Mutation Rate ◽  
Dna Mismatch ◽  
Mutator Effect

ABSTRACT Inactivation of DNA mismatch repair by mutation or by transcriptional silencing of the MLH1 gene results in genome instability and cancer predisposition. We recently found (P. V. Shcherbakova and T. A. Kunkel, Mol. Cell. Biol. 19:3177–3183, 1999) that an elevated spontaneous mutation rate can also result from increased expression of yeast MLH1. Here we investigate the mechanism of this mutator effect. Hybridization of poly(A)+ mRNA to DNA microarrays containing 96.4% of yeast open reading frames revealed that MLH1overexpression did not induce changes in expression of other genes involved in DNA replication or repair. MLH1overexpression strongly enhanced spontaneous mutagenesis in yeast strains with defects in the 3′→5′ exonuclease activity of replicative DNA polymerases δ and ɛ but did not enhance the mutation rate in strains with deletions of MSH2, MLH1, orPMS1. This suggests that overexpression ofMLH1 inactivates mismatch repair of replication errors. Overexpression of the PMS1 gene alone caused a moderate increase in the mutation rate and strongly suppressed the mutator effect caused by MLH1 overexpression. The mutator effect was also reduced by a missense mutation in the MLH1 gene that disrupted Mlh1p-Pms1p interaction. Analytical ultracentrifugation experiments showed that purified Mlh1p forms a homodimer in solution, albeit with a K d of 3.14 μM, 36-fold higher than that for Mlh1p-Pms1p heterodimerization. These observations suggest that the mismatch repair defect in cells overexpressingMLH1 results from an imbalance in the levels of Mlh1p and Pms1p and that this imbalance might lead to formation of nonfunctional mismatch repair complexes containing Mlh1p homodimers.

scholarly journals Mutation Rate, Spectrum, Topology, and Context-Dependency in the DNA Mismatch Repair-Deficient Pseudomonas fluorescens ATCC948

2014 ◽  
Vol 7 (1) ◽  
pp. 262-271 ◽  
Author(s):  
Hongan Long ◽  
Way Sung ◽  
Samuel F. Miller ◽  
Matthew S. Ackerman ◽  
Thomas G. Doak ◽  
...  
Keyword(s):  
Pseudomonas Fluorescens ◽  
Mismatch Repair ◽  
Mutation Rate ◽  
Dna Mismatch Repair ◽  
Context Dependency ◽  
Dna Mismatch
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