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Genome of Virulent Fungus Missing Parts of RNAi Pathways Present in Related Species

NEW YORK (GenomeWeb) – A fungus that's been infecting otherwise healthy people is missing parts of its RNAi silencing pathway, according to a study appearing today in PLOS Genetics.

Unlike the related Cryptococcus neoformans, which typically only infects people with compromised immune systems, C. deuterogattii has been infecting people in the Pacific Northwest and Vancouver Island who have no such problems with their health.

By comparing the genomes of related Cryptococcus species, researchers from Duke University found that C. deuterogattii lacks more than two dozen genes, including ones that make up part of the RNAi pathway present in other Cryptococcus species, like C. neoformans, that defends the fungal genome against mobile elements and transgene repeats.

"Genome instability is a bad thing in terms of human health, because it is linked to cancer and other diseases," lead author Blake Billmyre, a graduate student at Duke University School of Medicine, said in a statement. "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."

This also enabled the researchers to investigate the roles that four of those missing genes play when present in either the sex-induced silencing or the mitotic-induced silencing pathways.

An initial exploration of the C. deuterogattii reference genome found that it is missing both Argonaute genes, AGO1 and AGO2, which are essential parts of the RNAi-induced silencing complex. A deeper dive further uncovered that the C. deuterogattii reference genome also lacks DCR1 and RDP1, other canonical members of the RNAi pathway.

Billmyre and his colleagues surveyed the genomes of strains of C. deuterogattii, C. gattii, C. neoformans, and C. deneoformans strains to find 14 otherwise conserved genes that are missing or severely shortened in C. deuterogattii. Seven of these genes were not annotated in the C. deuterogattii lineage, while the other seven were less than half their usual length.

Of these 14 genes, one — AGO1 — was known to be a part of RNAi pathway, but seven others had been previously linked to the degradation of unspliced mRNA through RNAi or to unisexual or bisexual reproduction.

The team focused in particular on the CPR2, FZC28, QIP1, and ZNF3 genes. CPR2 encodes a seven transmembrane domain GPCR; FZC28 is a transcription factor with an unknown role; QIP1 binds RISC to spur the cleavage of duplex siRNA; and ZNF3 is needed for hyphal development during unisexual and bisexual reproduction in C. deneoformans.

Through a combination of knockout crosses, transgene studies, silencing assays, and other studies, the researchers found that QIP1 and ZNF3 are needed for either form of RNAi, while CPR2 and FZC28 are only involved in sex-induced silencing. This, Billmyre and his colleagues noted, indicates that the mitotic and sex-induced RNAi pathways share core components, though sex-induced silencing may involve additional parts.

The researchers further suggested that this loss of RNA silencing could be linked to the higher virulence of C. deuterogattii.

"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," senior author Joseph Heitman at Duke said in a statement. "Instead, the one glaring difference between these more and less virulent species seems to be the loss of the RNAi pathway."