Ó³»­´«Ã½

Fungi are well known as the trespassers that blemish or contaminate food. But it is perhaps less appreciated that our existence is forever intertwined with and even dependent upon them. In three articles published in the December 22 issue of Nature, an international group of scientists report new genetic data and tools that help define what makes a fungus friend or foe.

It is humbling to realize that we live in a world inextricably tied to fungi. Not quite plants, yet more similar to animals, fungi have been crowned with their own kingdom, which doles out benefits and woes equally to humankind. These microorganisms degrade dead animal and plant material, an essential step for recycling organic compounds through the planet's ecosystem. Fungi are also welcome sidekicks for many plants and supply the nutrients critical for growth. Moreover, fungi provide life-saving medicines (penicillin, cyclosporine), nourishment (mushrooms) and important food additives, like the citric acid found in soft drinks or the bubbles in champagne and beer. Fungi can also threaten human health: some species are potent allergens as well as devious opportunistic pathogens that thrive when an individual's immune system is distracted or weak.

These extraordinary differences are reflected in the three fungal species of the genus Aspergillus examined by Ó³»­´«Ã½ researchers and an international group of scientific colleagues. A. nidulans, with its well-characterized sexual cycle, has been an important scientific model organism for several decades. A. oryzae acts as a fermenting agent in the production of sake, soy sauce and miso. A. fumigatus can spur allergic reactions and sometimes, lethal infections in humans.

A detailed understanding of these fungal genomes will help researchers identify the genetic determinants that make one species beneficial and another detrimental. To that end, Ó³»­´«Ã½ scientists focused on deciphering the genetic code of A. nidulans, while collaborating institutions sequenced the DNA of its brethren, A. oryzae and A. fumigatus.

"Scientists have relied on A. nidulans to teach us about how eukaryotic cells work," said Bruce Birren, co-director of the Genome Sequencing and Analysis Program at the Ó³»­´«Ã½ and leader of the A. nidulans sequencing project. "Now the genome sequences are accelerating that process, and are also helping us understand what makes one fungus indispensable for food production, while its relative can cause fatal disease."

Having the A. nidulans sequence in hand, the Ó³»­´«Ã½ scientists and their collaborators, led by James Galagan, associate director of Ó³»­´«Ã½'s Microbial Genome Analysis and Annotation Program, compared the A. nidulans genome to those of A. fumigatus and A. oryzae."The comparison of these organisms gives us a wealth of information about gene regulation and genome evolution that apply to the study of all eukaryotes, including humans," said Galagan.

Reflecting the 200 million years of Aspergillus evolution, researchers noted substantial differences in the genomes of the three species. For example, comparing genome sizes revealed that A. oryzae is approximately 36 million bases in length, making it the largest of the three genomes, followed by A. nidulans at 30 million bases, then A. fumigatus with a diminutive 28 million bases. Although these species are members of the same genus, Ó³»­´«Ã½ scientists also found significant variability contained within their genome sequences. As a result, comparable proteins in the three species are only about 66-70% identical — a level akin to that shared between humans and fish.

The researchers discovered that genome reorganization is occurring more rapidly in A. oryzae than A. fumigatus, despite similar rates of amino acid substitutions in their proteins. This decoupling between the rates of structural and molecular change in aspergilli is a departure from the association that is typically found in other organisms.

The aspergilli have also undergone extensive shuffling at the ends, or telomeres, of their chromosomes. These rapidly evolving regions are the residences for many secondary metabolite genes, which encode products that are not essential to fungi but that are sometimes valuable (like the antibiotic penicillin) or harmful (like the potent carcinogen aflatoxin) to humans. In the future, understanding how fungi exploit these genetic changes to generate compounds with unique chemical structures and bioactivities may provide insight into fungal biology and evolution.

By looking for pieces of DNA shared across all three Aspergillus genomes, Ó³»­´«Ã½ researchers identified the most highly conserved sequences that, owing to their careful preservation, are likely to be functionally important. Nearly one third of these sequences lie within genes, confined to special end-regions that can influence gene expression. A specific class of modulators is the short upstream open reading frames (uORFs) that sit ahead of protein-coding genes in fungi and other eukaryotes. Ó³»­´«Ã½ researchers compiled the first genome-wide list of predicted uORFs and in preliminary studies, found that two candidates can inhibit gene activity by repressing protein synthesis in vitro. Thus, uORFs could play a key role in regulating gene expression in Aspergillus.

Perhaps the most surprising finding to emerge from the comparative analysis of the three apergilli is that the presumed asexual fungi A. oryzae and A. fumigatus may in fact be capable of sexual reproduction. "We were most excited about being able to relate genome evolution to sexual reproduction, a very specific — and important — physiological difference between the three aspergilli," said Galagan. After examining the genetic machinery in A. nidulans — a species that reproduces sexually — Ó³»­´«Ã½ scientists found similar, though slightly rearranged, remnants in its asexual relatives. The potential for mating would make genetic studies of these critical species a straightforward task. In turn, this feasibility would dramatically boost efforts to understand the properties that render A. oryzae safe for synthesizing food and beverages, but make A. fumigatus harmful for human health, and would also shed light on the underlying physiologies of other closely related fungi.