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Broad-Led Team Sequences and Compares Candida Genomes

NEW YORK (GenomeWeb News) – An international research team has sequenced and compared the genomes of six yeast species in the Candida clade, identifying gene families that appear to contribute to pathogenicity and shedding light on the genetics and evolution of fungal reproduction.

The research, appearing online yesterday in Nature, suggests Candida-related pathogenicity often involves expansions and duplications in gene families involved in processes such as cell wall production, adhesion, secretion, and transport. In addition, the work turned up new clues about sexual reproduction in this branch of yeast, showing that Candida species have lost many mating and meiosis genes found in other fungi.

Candida yeast species cause a variety of opportunistic infections that can range from superficial to systemic. Although C. albicans is the most common culprit, the relative contributions of other species in the Candida clade in causing infections are also on the rise, co-senior author Christina Cuomo, a researcher with the Broad Institute's Fungal Genome Initiative, told GenomeWeb Daily News.

A draft genome sequence for C. albicans was first published in the Proceedings of the National Academy of Science in 2004. For the latest paper, the researchers sequenced a second C. albicans isolate, along with the genomes of five other closely related species — C. tropicalis, C. parapsilosis, C. guilliermondii, C. lusitaniae, and Lodderomyces elongisporus — using high-throughput Sanger sequencing.

The Candida genome sizes varied from around 10.6 to 15.5 million bases in the six species. Even so, the researchers noted, the number of protein-coding genes didn't increase with increasing genome size — all of the genomes contained roughly 5,700 to 6,300 protein-coding genes. Instead, the size difference seemed to reflect differences in intergenic regions.

With the sequence data in hand, the researchers were able to compare the newly sequenced strains with several previously sequenced yeast — including nine Saccharomyces species, a C. albicans strain, and the non-pathogenic marine yeast Debaryomyces hansenii.

Using phylogenomic analyses to determine which Candida gene families contribute to pathogenesis in the clade, the team found 21 gene families that were enriched in common pathogens. Among them: gene involved in cell wall production, adhesion, secretion, and transport into and out of the cell.

Along with offering insights into Candida pathogenicity, the genome sequences are also providing a new view of sexual reproduction in this clade. Whereas species such as S. cerevisiae have a mating type locus that defines mating idiomorphs ("a" and "alpha"), Candida species were found to have variable gene content at this locus.

Indeed, the researchers found that some or all of the genes in the locus missing, even in species undergoing sexual reproduction. For instance, the team noted that L. elongisporus completely lacks all four mating-type genes. Their analysis suggests the shared common ancestor to Candida and Saccharomyces had the full mating type locus but that it was subsequently lost in Candida.

The genome sequences also revealed other reproductive peculiarities, including a dearth of meiosis-related genes. A search for 227 S. cerevisiae meiosis-related genes turned up no matches in Candida, suggesting species in the clade may use their own, alternative meiotic method.

"These findings suggest considerable plasticity and innovation of meiotic pathways in Candida," they authors wrote. "Overall, if Candida species undergo meiosis it is with reduced machinery, or different machinery, suggesting that unrecognized meiotic cycles may exist in many species, and that the model of meiosis developed in S. cerevisiae varies significantly, even among yeasts."

The comparison offered insights into other evolutionary mysteries in the clade as well, such as shifts in the way the CUG codon is translated.

It also gave the researchers an opportunity to tweak the existing C. albicans genome sequence using sequence information gleaned from comparisons between different Candida genomes. Using this approach, they found 91 genes that were previously overlooked or needed to be updated. They also detected 222 bogus genes, 190 frame shifts, and dozens of nonsense sequencing errors.

"The genome sequences reported here provide a resource that will allow current knowledge of C. albicans biology, the product of decades of research, to be applied with maximum efficiency to the other pathogenic species in the Candida clade," Cuomo and her co-authors concluded.

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