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Title: Examination of Gene Loss in the DNA Mismatch Repair Pathway and Its Mutational Consequences in a Fungal Phylum
Abstract The DNA mismatch repair (MMR) pathway corrects mismatched bases produced during DNA replication and is highly conserved across the tree of life, reflecting its fundamental importance for genome integrity. Loss of function in one or a few MMR genes can lead to increased mutation rates and microsatellite instability, as seen in some human cancers. Although loss of MMR genes has been documented in the context of human disease and in hypermutant strains of pathogens, examples of entire species and species lineages that have experienced substantial MMR gene loss are lacking. We examined the genomes of 1,107 species in the fungal phylum Ascomycota for the presence of 52 genes known to be involved in the MMR pathway of fungi. We found that the median ascomycete genome contained 49/52 MMR genes. In contrast, four closely related species of obligate plant parasites from the powdery mildew genera Erysiphe and Blumeria, have lost between five and 21 MMR genes, including MLH3, EXO1, and DPB11. The lost genes span MMR functions, include genes that are conserved in all other ascomycetes, and loss of function of any of these genes alone has been previously linked to increased mutation rate. Consistent with the hypothesis that loss more » of these genes impairs MMR pathway function, we found that powdery mildew genomes with higher levels of MMR gene loss exhibit increased numbers of mononucleotide runs, longer microsatellites, accelerated sequence evolution, elevated mutational bias in the A|T direction, and decreased GC content. These results identify a striking example of macroevolutionary loss of multiple MMR pathway genes in a eukaryotic lineage, even though the mutational outcomes of these losses appear to resemble those associated with detrimental MMR dysfunction in other organisms. « less
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Wolfe, Kenneth
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Genome Biology and Evolution
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National Science Foundation
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  1. Abstract

    DNA mismatch repair (MMR), an evolutionarily conserved repair pathway shared by prokaryotic and eukaryotic species alike, influences molecular evolution by detecting and correcting mismatches, thereby protecting genetic fidelity, reducing the mutational load, and preventing lethality. Herein we conduct the first genome-wide evaluation of the alterations to the mutation rate and spectrum under impaired activity of the MutSα homolog, msh-2, in Caenorhabditis elegans male–female fog-2(lf) lines. We performed mutation accumulation (MA) under RNAi-induced knockdown of msh-2 for up to 50 generations, followed by next-generation sequencing of 19 MA lines and the ancestral control. msh-2 impairment in the male–female background substantially increased the frequency of nuclear base substitutions (∼23×) and small indels (∼328×) relative to wildtype hermaphrodites. However, we observed no increase in the mutation rates of mtDNA, and copy-number changes of single-copy genes. There was a marked increase in copy-number variation of rDNA genes under MMR impairment. In C. elegans, msh-2 repairs transitions more efficiently than transversions and increases the AT mutational bias relative to wildtype. The local sequence context, including sequence complexity, G + C-content, and flanking bases influenced the mutation rate. The X chromosome exhibited lower substitution and higher indel rates than autosomes, which can either result from sex-specific mutationmore »rates or a nonrandom distribution of mutable sites between chromosomes. Provided the observed difference in mutational pattern is mostly due to MMR impairment, our results indicate that the specificity of MMR varies between taxa, and is more efficient in detecting and repairing small indels in eukaryotes relative to prokaryotes.

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