The spectra of point mutations in vertebrate genomes

Albrecht‐Buehler, Guenter

doi:10.1002/bies.080081

Cited by 11 publications

(9 citation statements)

References 16 publications

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“…This pronounced asymmetry agrees with pol I’s known role of mediating initiation of leading-strand synthesis because if there was no strand preference, we would expect the frequency of every pair of complementary mutations to be symmetrical (Figure 3b, Scenario 5) (30). …”

Section: Discussionsupporting

confidence: 74%

Roles of DNA polymerase I in leading and lagging-strand replication defined by a high-resolution mutation footprint of ColE1 plasmid replication

Allen

Simcha

Ericson

et al. 2011

Nucleic Acids Research

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DNA polymerase I (pol I) processes RNA primers during lagging-strand synthesis and fills small gaps during DNA repair reactions. However, it is unclear how pol I and pol III work together during replication and repair or how extensive pol I processing of Okazaki fragments is in vivo. Here, we address these questions by analyzing pol I mutations generated through error-prone replication of ColE1 plasmids. The data were obtained by direct sequencing, allowing an accurate determination of the mutation spectrum and distribution. Pol I’s mutational footprint suggests: (i) during leading-strand replication pol I is gradually replaced by pol III over at least 1.3 kb; (ii) pol I processing of Okazaki fragments is limited to ∼20 nt and (iii) the size of Okazaki fragments is short (∼250 nt). While based on ColE1 plasmid replication, our findings are likely relevant to other pol I replicative processes such as chromosomal replication and DNA repair, which differ from ColE1 replication mostly at the recruitment steps. This mutation footprinting approach should help establish the role of other prokaryotic or eukaryotic polymerases in vivo, and provides a tool to investigate how sequence topology, DNA damage, or interactions with protein partners may affect the function of individual DNA polymerases.

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Section: Discussionsupporting

confidence: 74%

Roles of DNA polymerase I in leading and lagging-strand replication defined by a high-resolution mutation footprint of ColE1 plasmid replication

Allen

Simcha

Ericson

et al. 2011

Nucleic Acids Research

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“…Although this invariant pattern is "universal" only in the context of the current collection of species with well defined mutational features, because the phylogenetic diversity of this group is very substantial, it is likely to have broad applicability. The predominance of A:T → G:C and G:C → A:T changes among base-substitutional mutations in the human genome has previously been inferred by other methods, some potentially influenced by selection biases (18)(19)(20). In primates, C → T transitions arise at CpG dinucleotide sites approximately 15 times the mutation rate observed at other sites (8,21), ostensibly because of the spontaneous oxidative deamination of methylated cytosines at CpG sites.…”

Section: Resultsmentioning

confidence: 92%

Rate, molecular spectrum, and consequences of human mutation

Lynch

2010

Proc. Natl. Acad. Sci. U.S.A.

719

603

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Although mutation provides the fuel for phenotypic evolution, it also imposes a substantial burden on fitness through the production of predominantly deleterious alleles, a matter of concern from a human-health perspective. Here, recently established databases on de novo mutations for monogenic disorders are used to estimate the rate and molecular spectrum of spontaneously arising mutations and to derive a number of inferences with respect to eukaryotic genome evolution. Although the human per-generation mutation rate is exceptionally high, on a per-cell division basis, the human germline mutation rate is lower than that recorded for any other species. Comparison with data from other species demonstrates a universal mutational bias toward A/T composition, and leads to the hypothesis that genome-wide nucleotide composition generally evolves to the point at which the power of selection in favor of G/C is approximately balanced by the power of random genetic drift, such that variation in equilibrium genome-wide nucleotide composition is largely defined by variation in mutation biases. Quantification of the hazards associated with introns reveals that mutations at key splicesite residues are a major source of human mortality. Finally, a consideration of the long-term consequences of current human behavior for deleterious-mutation accumulation leads to the conclusion that a substantial reduction in human fitness can be expected over the next few centuries in industrialized societies unless novel means of genetic intervention are developed.base substitutions | human genetic disorders | introns | mutation rate | mutational spectrum D espite its central significance to matters of health and phenotypic evolution, many uncertainties still remain about the rate and spectrum of mutations spontaneously arising in the human genome (1-3). How frequently do germline and somatic mutations arise, and to what extent does this vary between the sexes? What is the relative incidence of various forms of mutations, e.g., missense and nonsense base substitutions, insertions, duplications, and deletions, especially among alterations having major phenotypic effects? How does the mutational spectrum in humans compare with that in other species? And most importantly, what are the consequences of mutation for the long-term genetic well-being of our species?In the near future, it should be possible to provide refined answers to these and many more questions by sequencing the complete genomes of well defined pedigrees and somatic tissues (4, 5). However, it is already possible to achieve a relatively complete picture of the point-mutation process from databases on mutations at loci known to underlie monogenic disorders with major phenotypic effects. In the case of autosomal-dominant and X-linked disorders, affected individuals can generally be identified as de novo mutants by comparison with the parental phenotypes, thereby providing a nearly unbiased view of the rate and spectrum of locus-specific mutations, similar to what has been achieved ...

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“…This strong bias between complementary pairs means that certain mutations can now be approximated to be physical indicators of strandedness, with the most frequent mutation of the pair representing leading-strand synthesis and the other partner representing lagging-strand synthesis. This concept, originally used by Dr. Buehler to study directional evolution in vertebrate genomes (Albrecht-Buehler 2009) is illustrated in Fig. 3 for the C→T/G→A complementary pair.…”

Section: Resultsmentioning

confidence: 99%

The mutagenic footprint of low-fidelity Pol I ColE1 plasmid replication in E. coli reveals an extensive interplay between Pol I and Pol III

et al. 2013

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ColE1 plasmid replication is unidirectional and requires two DNA polymerases: DNA polymerase I (Pol I) and DNA polymerase III (Pol III). Pol I initiates leading-strand synthesis by extending an RNA primer, allowing the Pol III holoenzyme to assemble and to finish replication of both strands. The goal of the present work is to study the interplay between Pol I and Pol III during ColE1 plasmid replication, in order to gain new insights into Pol I function in vivo. Our approach consists of using mutations generated by a low fidelity mutant of Pol I (LF-Pol I) during replication of a ColE1 plasmid as a footprint for Pol I replication. This approach allowed mapping areas of Pol I replication on the plasmid with high resolution. In addition, we were able to approximate the strandedness of Pol I mutations throughout the plasmid, allowing us to estimate the spectrum of the LF-Pol I in vivo. Our study produced the following three mechanistic insights: 1) we identified the likely location of the polymerase switch at ~200 bp downstream of replication initiation; 2) we found evidence suggesting that Pol I can replicate both strands, supporting earlier studies indicating a functional redundancy between Pol I and Pol III 3) we found evidence pointing to a specific role of Pol I during termination of lagging-strand replication. In addition, we illustrate how our strand-specific footprinting approach can be used to dissect factors modulating Pol I fidelity in vivo.

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The spectra of point mutations in vertebrate genomes

Cited by 11 publications

References 16 publications

Roles of DNA polymerase I in leading and lagging-strand replication defined by a high-resolution mutation footprint of ColE1 plasmid replication

Roles of DNA polymerase I in leading and lagging-strand replication defined by a high-resolution mutation footprint of ColE1 plasmid replication

Rate, molecular spectrum, and consequences of human mutation

The mutagenic footprint of low-fidelity Pol I ColE1 plasmid replication in E. coli reveals an extensive interplay between Pol I and Pol III

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