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. Significance StatementThe DNA mismatch repair pathway corrects nucleotide base errors that occur during the replication of DNA; loss of these genes leads to cancer. We examined the conservation of the DNA mismatch repair pathways genes across more than 1,000 species in a fungal phylum and found a lineage of powdery mildews, a group of fungi that infect the leaves of plants, which have experienced extensive loss of multiple, otherwise highly conserved, genes. The genomes of these powdery mildews show elevated rates of diverse types of mutation, raising the hypothesis that these organisms have diversified while lacking genes thought to be essential for the accurate replication of DNA.