Abstract
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.
Highlights
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We classify each estimate as using either germline or somatic cells, there is no distinction for most unicellular eukaryotes, and some organisms, e.g., hyphal fungi and many plants, lack dedicated germlines
Wild-type, whole-genome mutation rates were previously compared across kingdoms [1], and here we confine the discussion to the eukaryotic nuclear genome
Summary
We considered 123 independent nuclear genome mutation rate measurements, gathered from over 90 studies performed in either wild-type or MMR-deficient strains of 48 eukaryotic species. We confined the analysis to whole-genome studies that explicitly report rates or, rarely, to studies from which rates may be calculated. We present mean mutation rates for similar systems that are either MMR-proficient (Table 1) or MMRdeficient (Table 2). Rates per generation and per cell division are both presented. We classify each estimate as using either germline or somatic cells, there is no distinction for most unicellular eukaryotes, and some organisms, e.g., hyphal fungi and many plants, lack dedicated germlines. We highlight trends and extremes, and comment on how whole-genome rates elucidate mechanisms of MMR
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