Researchers trace genetic factor in life-threatening fungal disease

Nature has an ingenious way of taking advantage of advantageous situations.

Take Candida auris, for example. This yeast was not known until 2009, but it burst onto the scene when scientists learned it causes life-threatening gaseous infections in patients in hospitals and nursing care facilities. In 2019, the threat from C. auris was serious enough that the US Centers for Disease Control and Prevention called it a serious global health threat, citing the yeast’s prevalence and resistance to a range of antifungal drugs.

Last month , The CDC reports that C. auris has been detected in nearly half of the states in the United States

So how did a simple, little-known yeast suddenly become an enemy of public health? Part of the answer, biologists at the University of Iowa say, resides in the family of genes encoding adhesive properties, or adhesives, that seem central to the virulence of fungal diseases, including some that threaten humans.

In a new study, researchers report that one such sticky species, called the Hill family, was present in the common ancestor of all yeast species, but is more numerous in pathogenic than benign species. Moreover, the researchers found that some pathogenic species with a large Hill family of genes are closely related, indicating that each species with a large Hill family independently evolved family size, rather than downward transmission of genes.

“We found that this gene family was specifically and frequently expanded by gene duplications in pathogenic yeast strains,” says Ben He, assistant professor in the Department of Biology and co-author of the study. “Moreover, their sequences evolved rapidly after duplication, possibly generating functional diversity to allow the yeast to adapt to the complex host environment.”

The adaptation component is key: Hill’s genes likely encode proteins that allow an organism to stick together. More specifically, the proteins, through their structure, help yeast cells attach to host tissues and non-living surfaces (such as catheters), linking themselves together, like interlocking Legos, to form a nearly impenetrable, drug-resistant wall called a biofilm.

It is arguably natural selection at its best, or its most diabolical. Hale’s genes are either not present or are not active in a host of other yeast species, such as Saccharomyces cerevisiae, which are actually good for humans (assuming people like bread). But in the pathogenic species, the researchers found that the Hale family (short for Hyr/Iff-like) is alive and well, wreaking its sticky havoc.

“This is a convergent evolution,” he says. “You find a way to succeed in an environmental niche.”

The researchers sequenced proteins in the adhesive family, and looked across all other organisms — including the plant, animal, and bacterial kingdoms — to see if any other species had a similar protein sequence. They found the Jane Hill family in only one place, the class Saccharomyces cerevisiae, which is part of the fungi kingdom.

The analysis revealed another important clue: the Hale family appeared in species that, in taxonomic terms, had no close relatives. For example, the Hil family is present and active in C. auris and another pathogenic species, Candida albicans. But when the researchers looked at the species most closely related to each, Jane Hill’s number was either low, or none at all.

“This is the idea of ​​parallel or independent evolution,” he says. “Essentially, these genes reached the same final state, not by descending, not by heredity, but by independent evolution. And they all followed similar evolutionary paths.”

The study itself originated from a graduate-level bioinformatics chapter at Iowa State. In the fall of 2019, course instructors focused in the curriculum on C. auris, whose genome of 5,000 genes has recently been sequenced. One student group decided to investigate C. auris’ tendency to stick together.

It was a wise and fruitful choice.

explains Lindsey Snyder, who was a student in the class and pursuing a PhD in genetics at Iowa. “At that time, two small families of adductors were reported in the genome we were working with, so once we realized the size of this (Hill) family, we were pretty sure we had found something that had not yet been characterized in this species.”

Jan Fassler, a professor in the biology department who came up with the idea for the class in 2013 with fellow biology associate professor Albert Erives, says teachers would choose genomes that were new to the literature and had interesting biological features.

“We chose the recently sequenced genome so that there would be very little prior research, which allows the students to feel as though they are (and are) making new discoveries,” says Fussler, director of the Biomedical Sciences Program and co-author. In the study.

The researchers next want to investigate, through experiments, precisely how the Hill family allows H. pylori to become adhesive. This will advance research beyond identifying the genes involved and could lead to medical advances.

“Here’s the hope: We’ve identified a gene family that may play an important role in causing the disease and are specific to this group of fungi. This could be a drug target if we can figure out how to prevent it,” he says.

The study, “Parallel expansion and divergence of the adhesion family in pathogenic yeasts,” was published in the journal. Genetics.