EECS faculty member Manolis Kellis, associate professor of Computer Science in the area of Computational Biology and a member of the Computer Science and Artificial Intelligence Laboratory, CSAIL, and of the Broad Institute of MIT and Harvard, is one of two senior authors in a major international effort reported in Nature this week, May 24, 2009. The paper reports the findings of one of the largest comparative genomics studies to date--yielding insights into the group of pathogen species, Candida albicans, a group of fungi related to the otherwise harmless baker's yeast. The study will significantly extend the arsenal of genomic information on these organisms--both pathogens and non-pathogens--allowing, for the first time, the systematic study of the genomic basis for pathogenicity.
As Kellis points out, the pathogenic species of Candida albicans account for 95% of fungal infections, an increasingly alarming situation in hospitals--especially given the similarities between fungal and mammalian cells which make most anti-bacterial drug targets inapplicable.
“Most of what we know about Candida comes from the study of a single species, C. albicans,” said Christina Cuomo, a senior author of the study and a research scientist at the Broad Institute. “But there are at least six other species that together account for nearly half of all Candida infections. Our work is a key step toward deepening our knowledge of these medically important fungi.”
Together with their colleagues, Manolis and Cuomo chose six additional Candida species for whole genome sequencing. These include established and emerging pathogens (C. tropicalis, C. parapsilosis, L. elongisporus, C. guilliermondii, and C. lusitaniae) as well a second strain of C. albicans. To help interpret the information within these genomes, the researchers compared them to eleven previously sequenced fungal genomes, illuminating a broad spectrum of biological and evolutionary diversity--spanning more than 500 million years of evolution.
As reported by the Broad Institute May 24, 2009 article, the most significant of the new findings, from the standpoint of human health, involves genes associated with Candida virulence. Because the researchers compared the genomes of both pathogenic and non-pathogenic fungi, they were able to identify groups of genes that track with species’ capacities to cause disease. Matthew Rasmussen, an MIT graduate student and co-author of the study, conducted analyses that highlighted 21 gene families enriched in pathogenic Candida species from among the more than 9,000 Candida gene families. These genes function in processes ranging from cell wall formation and cell adhesion to fungal growth and extracellular transport, as well as several novel families whose roles remain unclear. In addition to interesting biology, these findings suggest potential new therapeutic approaches.
Although future work is needed to extend the findings of this “phylogenomic” approach, the work of Cuomo, Kellis and their collaborators is a critical first step to fully dissect the molecular underpinnings of opportunistic fungal infections. On a broader scale, Kellis commented, "Implications are many, and methods should apply to viruses [for example], though their evolutionary dynamics are likely to be very different."
The work is part of the Fungal Genome Initiative at the Broad Institute and was funded by the National Human Genome Research Institute and the National Institute of Allergy and Infectious Diseases among other organizations. Researchers from the Broad Institute who contributed to this research include Bruce Birren, Christina Cuomo, Manfred Grabherr, Manolis Kellis, Chinnappa Kodira, Michael Lin, Sharadha Sakthikumar, and Qiandong Zeng, and members of the Broad Institute’s Genome Sequencing Platform.
- MIT News Office June 18, 2009 article: "Study takes aim at opportunistic fungal pathogens: Research provides genome sequences and critical analyses of key Candida species"
- Nature advance online publication 24 May 2009: "Evolution of pathogenicity and sexual reproduction in eight Candida genomes"