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Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair

We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms a...

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Autores principales: Lujan, Scott Alexander, Kunkel, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156620/
https://www.ncbi.nlm.nih.gov/pubmed/34067668
http://dx.doi.org/10.3390/cells10051224
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author Lujan, Scott Alexander
Kunkel, Thomas A.
author_facet Lujan, Scott Alexander
Kunkel, Thomas A.
author_sort Lujan, Scott Alexander
collection PubMed
description We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on Saccharomyces cerevisiae and human tumors. Well-studied organisms include Drosophila melanogaster and Mus musculus, while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring–parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, Arabidopsis thaliana, Caenorhabditis elegans, and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays.
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spelling pubmed-81566202021-05-28 Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair Lujan, Scott Alexander Kunkel, Thomas A. Cells Review We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on Saccharomyces cerevisiae and human tumors. Well-studied organisms include Drosophila melanogaster and Mus musculus, while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring–parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, Arabidopsis thaliana, Caenorhabditis elegans, and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays. MDPI 2021-05-17 /pmc/articles/PMC8156620/ /pubmed/34067668 http://dx.doi.org/10.3390/cells10051224 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Lujan, Scott Alexander
Kunkel, Thomas A.
Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair
title Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair
title_full Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair
title_fullStr Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair
title_full_unstemmed Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair
title_short Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair
title_sort stability across the whole nuclear genome in the presence and absence of dna mismatch repair
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156620/
https://www.ncbi.nlm.nih.gov/pubmed/34067668
http://dx.doi.org/10.3390/cells10051224
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