2003: the first genome of a filamentous fungus

In April 2003 Nature published a high-quality draft of the Neurospora crassa genome, produced by James Galagan's team. The species was already one of the pillars of twentieth-century genetics, biochemistry and molecular biology — it was in Neurospora that George Beadle and Edward Tatum formulated the "one gene, one enzyme" principle. The sequence gave that toolkit a complete map.

The numbers were a surprise. A genome of about 40 megabases encodes roughly 10,000 protein-coding genes — more than twice as many as the fission yeast Schizosaccharomyces pombe and only about 25 per cent fewer than the fruit fly. A filamentous fungus turned out to have a genetic richness comparable to animals rather than being a scaled-up yeast.

Analysis of the gene set also produced unexpected findings: genes potentially associated with red-light photobiology, genes implicated in secondary metabolism, and important differences in calcium signalling compared with plants and animals. The strongest result, however, concerned genome defence. Neurospora possesses the widest array of such mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation, or RIP.

RIP detects duplicated stretches of DNA and riddles them with mutations. The consequence is evolutionary: if duplicating a gene usually ends in its destruction, then the route to new genes through copying old ones is largely closed in this genome. The authors showed that the effect is visible in the genome's structure — it contains an unusually low proportion of closely related genes.

A genome that exposed the cost of repeat defence

The Neurospora crassa project reported a genome of about 40 Mb and predicted 10,082 protein-coding genes. As many as 4,140 predicted proteins—41% of the set—had no significant match in the public protein databases then available, while 5,805 had no significant match in either of the two sequenced yeast genomes. The figures made clear how little yeast genomics alone captured the biology of filamentous fungi.

The strongest evolutionary result concerned repeat-induced point mutation, or RIP. Repeated sequence made up 10% of the assembly; 81% of those repeats carried the RIP signature, as did more than 97% of repeats longer than 400 base pairs. No intact mobile elements were identified. The authors interpreted this as an effective genome-defence system with a trade-off: RIP appeared to have greatly slowed the origin of new genes through duplication. These are sequence-based evolutionary inferences, not direct observations of every historical mutation.