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. While 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 5 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 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.

Aroma Profiles of Vitis vinifera L. cv. Gewürztraminer Must Fermented with Co-Cultures of Saccharomyces cerevisiae and Seven Hanseniaspora spp.

“…The recent influx of whole-genome sequencing of representatives of each species within the Hanseniaspora genus, along with accompanying comparative studies, have revealed interesting data regarding the genomic make-up of this genus. Phylogenetic analyses have separated Hanseniaspora into two major clades, namely the fast-evolving lineage (FEL) and the slow-evolving lineage (SEL) [24,25]. Genes involved with cell cycle and genome integrity, thought to be conserved within ascomycetes, are not present within the genus.…”

Mutation bias and the predictability of evolution

“…Predicting evolutionary trajectories is further complicated by the potential for changes in the mutation spectrum itself, which can occur even on short timescales, owing to transient changes in environmental conditions [ 68 , 69 ]. Durable genetic changes in the mutation spectrum that may be important in evolution on various timescales include (i) the emergence of hypermutators with greatly enhanced mutation rates and distinct mutation spectra [ 34 , 70 ], (ii) changes that modify mutation spectra without dramatic changes in total mutation rate [ 71 , 72 ], (iii) long-term changes in DNA repaire repertoire including the loss and gain of entire pathways [ 73 ], (iv) shifts in (and long-term equilibration of) the genomic frequency of sequence contexts under the long-continued influence of context-dependent mutation [ 74 ], (v) genome-wide patterns of adaptive amelioration reducing the frequency or severity of deleterious mutations [ 75 , 76 ], and (vi) bias reversals that temporarily enhance the rate of adaptation by enhancing mutational access to previously under-sampled classes of beneficial mutations [ 50 , 53 ].…”

Mutators Enhance Adaptive Micro-Evolution in Pathogenic Microbes

“…A comparison of the genomes of ascomycete yeasts shows that DNA repair genes, including the orthologues of the MMR genes MLH1-3, are less conserved than other gene categories [37]. A comparison of 1107 species of ascomycete fungi showed that four closely related obligate plant parasites from the powdery mildew genera (Erysiphe and Blumeria) have lost a substantial number of MMR genes and exhibit accelerated sequence evolution [38].…”