Spores on the surface of a fruiting structure from the fungus Cryptococcus deuterogattii, a deadly strain that emerged in the Pacific Northwest. (Credit: Edmond Byrnes III, Joseph Heitman — Duke Department of Molecular Genetics and Microbiology; Valerie Knowlton — North Carolina State University, Center for Electron Microscopy)
“Genome instability is a bad thing in terms of human health, because it is linked to cancer and other diseases,” said Blake Billmyre, lead study author and a graduate student in Joseph Heitman’s lab at Duke University School of Medicine. “But it could be good thing for single-celled organisms like Cryptococcus, because it enables them to mutate, evolve and adapt to survive under different conditions.”
Five years ago, researchers in the Heitman lab participated in an international collaborative consortium to sequence the genome of this outbreak species and discovered that it had lost two genes involved in RNAi, a process previously thought to be key to its survival.
The RNAi gene-silencing machinery normally shreds the genetic instructions for harmful viruses or silences rogue genes that might contaminate the fungus’ genome. But Cryptococcus deuterogatti had holes in its genome where the two RNAi genes should have been.
Armed with this information, Billmyre hypothesized that other genes in this missing set of genes might also function in RNAi. He and his colleagues compared the genomes of Cryptococcus deuterogatti with less potent cousins like Cryptococcus neoformans, which predominantly infects immunocompromised individuals. They found that C. deuterogatti has lost 14 genes compared to the other, less pathogenic, species.
“We could have imagined that the species lost a couple of RNAi genes, and then a smattering of genes involved in all other kinds of processes,” said Heitman. “Instead, the one glaring difference between these more and less virulent species seems to be the loss of the RNAi pathway.”
Though the researchers don’t know why shedding the RNAi machinery could help Cryptococcus assume a deadlier form, they do have some ideas. It could enable the fungi to cohabitate with killer viruses that pump out powerful toxins to poison competing organisms. Or it could allow them to accumulate mutations or even extra chromosomes to gain resistance against antifungal medications.
Whatever the reason, the discovery could pave the way for future studies using comparative genomics to identify other sets of related genes. Once one gene in a pathway is lost, the researchers hypothesize that an organism can find itself on a slippery evolutionary slope as other genes that are no longer of benefit are lost in quick succession. Only a few other examples of this system-wide pattern of gene loss, called systems polymorphisms, have been described so far.