Ó³»­´«Ã½

James Galagan

Although you may not suspect it, the pink mold growing on that stale bread in your pantry has expanded our conception of how eukaryotic genomes evolve. This mold, a fungus called Neurospora crassa, is one of the key model organisms of the twentieth century. Earlier work on Neurospora laid the foundation for modern genetics and molecular biology and contributed to our knowledge of fundamental eukaryotic processes like RNAi and circadian rhythms. Now, Ó³»­´«Ã½'s sequencing and analysis of the complete genome sequence of Neurospora crassa has led to a surprising discovery about this well known organism: Neurospora does not appear to be evolving new genes the way we thought all organisms do.

Neurospora is a filamentous fungus and is second only to baker's yeast as a fungal model for eukaryotic biology. It was work on Neurospora by George Wells Beadle and Edward Lawrie Tatum that led to the "one-gene-one-enzyme" hypothesis that established the fundamental relationship between proteins and genes. This discovery garnered Beadle and Tatum the Nobel Prize in Physiology or Medicine in 1958. Work since has continued to expand our knowledge of eukaryotic biology. For example, the molecular mechanisms of RNAi (a process that has received widespread attention as a tool for selectively silencing genes) and circadian rhythms (how our cells maintain daily rhythms and consequently contribute to jet lag) were initially dissected in Neurospora. To continue this legacy of over half a century of research, we sequenced the genome of Neurospora crassa with support from NSF, and in collaboration with the Neurospora scientific community analyzed the sequence. What we discovered surprised us.

It is widely held that organisms evolve new genes by duplicating old ones. Essentially, the duplicate gene can act as a "spare" that is free to mutate into a new function, while the original gene continues to provide the old function. Many examples of this process have been documented, most recently in an analysis here at the Ó³»­´«Ã½ of an ancient duplication of the yeast genome. However, our analysis shows that Neurospora took a different evolutionary pathway. Indeed, it appears to be stuck in an evolutionary slow lane, totally unable to create new genes by this mechanism that almost every other organism relies on to evolve. Although we are still trying to understand why, we have a pretty good grasp of how this happens: a process called Repeat Induced Point Mutation (RIP).

RIP protects Neurospora against mobile genetic elements. These are "selfish" DNA elements that parasitize the genomes of virtually all known organisms and proliferate by a process of self duplication. Nearly 50% of the human genome consists of these genetic hitchhikers. In Neurospora however, RIP successfully prevents selfish DNA from gaining a foothold. Essentially, RIP acts during sex in Neurospora to detect duplicated selfish DNA and destroys both copies of the duplication with a barrage of point mutations. RIP also modifies the mutated sequences by methylating them, preventing them from being transcribed. In short, RIP both mutates and silences duplicated DNA. This has the apparent beneficial effect of protecting against selfish DNA, and indeed not a single intact mobile genetic element was detected in the genome. But RIP is indiscriminate. Any duplicated sequence gets targeted — even those arising from the duplication of genes.

The consequence of this indiscriminate nature of RIP is drastic: RIP effectively prevents Neurospora from creating new genes through gene duplication. A duplicated gene on its way to acquiring a new, possibly beneficial, function is indistinguishable to RIP from a parasitic mobile element attempting to spread. In both cases, RIP moves in for the kill. Consequently, Neurospora has many fewer duplicated genes than expected as compared with other sequenced eukaryotes. The duplicated genes that are present appear to be ancient duplications that predate RIP. But since the emergence of RIP, gene evolution through gene duplication — and thus, as far as we know, the primary mechanism for evolving new genes — has been all but arrested in Neurospora.

This result raises a host of questions: How important is gene duplication as a mechanism of evolutionary adaptation? Does Neurospora need to compensate for the lack of gene dosage control? Does Neurospora create new genes using different mechanisms? We do not yet have answers, but a collaborative project — between the Ó³»­´«Ã½, Dartmouth, UCLA, UC Berkeley, UC Riverside, the University of New Mexico, and the Oregon Health & Sciences University with support from NIH — is now putting into place the functional genomics resources for Neurospora that will help us to start to address these and many other questions. Ultimately, our results add the topic of Genome Evolution to the long list of topics that Neurospora, the humble pink bread mold, is helping science to better understand.

Neurospora crassa

The results from Neurospora, the first filamentous fungus to be sequenced, underscore how much remains to be discovered through genomic studies of the fungal kingdom. To take advantage of this opportunity, we are collaborating with the fungal scientific community in exciting project called the Fungal Genome Initiative. The goals of this project are to comprehensively sequence organisms spanning the fungal kingdom and thereby lay the foundation for work in medicine, agriculture, and industry through comparative studies. Check back in future "Spotlights" for the findings coming out of these studies!