Mutations in our DNA can have a variety of harmful effects, which can impact us at many different stages of life. But sometimes a mutation can confer a benefit. In the case of microorganisms, those beneficial mutations can create a super-organism, like a drug-resistant bacterium. Microbes are good at tweaking their genomes and easily accumulate mutations.
New work reported in eLife has shown that a fungal pathogen harbors a genetic mutation that increases its mutation rate. The work was performed by scientists at Duke University. It describes how Cryptococcus deuterogattii, a hypermutator, can quickly become resistant to FK506 and rapamycin, two antifungal drugs.
"If there weren't mutations, there wouldn't be any raw genetic material for evolution and selection to act upon," explained the senior author of the report, Joseph Heitman, Professor and Chair of Molecular Genetics and Microbiology at Duke University School of Medicine. "These hypermutators are probably a lot more common than we think, particularly among pathogenic fungi."
A fungus called C. deuterogattii, which is rare but can cause deadly infections, has spread over the past couple of decades in the Pacific Northwest and on Vancouver Island. C. deuterogattii is different from fungi that typically infect people with compromised immunity; it has sickened hundreds of people that are otherwise in good health. It’s considered an emerging fungal pathogen and causes serious infections of the lungs and central nervous system. If untreated, it is fatal.
A former graduate student of Heitman, Blake Billmyre, sequenced the genome of three strains of C. deuterogattii. He found that all have a one base pair deletion in MSH2, a gene that plays a role in fixing errors that arise in DNA during replication, called mismatch repair. Humans that carry mutations in their MSH2 gene have a disorder called Lynch syndrome. The syndrome causes mutations to accumulate in a patient’s DNA, who then carries a 75 percent risk of developing colorectal cancer over a lifetime. They are also more likely to have a number of other types of cancer.
The researchers set out to test whether fungal MSH2 mutations cause other genetic mutations to accumulate. The growth of a wildtype strain was compared with one carrying a mutation in MSH2 under normal conditions, and they grew at an equal rate. But when the strains were grown while being exposed to antifungal drugs, the mutated strains grew far better, because they acquired resistance.
Although the newly accumulated mutations allowed these fungi to survive, they also lost their virulence, the researchers found. "We think that is because of the thousands of mutations caused by the hypermutator," said Heitman. "It seems to cause a mutational meltdown."
The investigators are now determining how many other strains might be hypermutators. "Multiple studies have come out recently indicating that hypermutators may be present in bacteria, fungi, and perhaps even higher eukaryotic populations. So it is likely to be pretty widespread and is an important consideration in terms of thinking about how antifungal drug resistance develops," said the lead author Billmyre, now a postdoctoral fellow at the Stowers Institute for Medical Research.
Learn more about Cryptococcus infections from the video.