Just 160 years ago, in 1843, the bakeries of Paris were beset by contamination of their bread by a pink mold. That's how the filamentous fungus Neurospora crassa entered the history books.
Fast forward 25 years to the late 1860s. That's when an Austrian monk named Gregor Mendel (1822-1884) finished writing up his research notes, which described the first laws of heredity. As a diversion from his churchly duties, Mendel bred garden peas on his monastery premises, mixing and matching such traits as smooth or wrinkled, green or yellow. The paper he published on his botanical findings dropped out of sight till the early 20th century.
That's when the celebrated American zoologist and biologist Thomas Hunt Morgan (1866-1945) started experimenting with fruit flies (Drosophila melanogaster), and came up with the chromosome theory of heredity. Then Neurospora started its own lengthy career as a genetics research workhorse - like D. melanogaster.
Now the fungus has come into its own. Today's issue of Nature, dated April 24, 2003, carries an article titled "The genome sequence of the filamentous fungus Neurospora crassa." Its first author is computational biologist James Galagan, and senior author genomicist Bruce Birren. Both are at the Whitehead Institute Center for Genome Research in Cambridge, Mass. It took 77 co-authors from 32 centers in six countries to compile and annotate this first draft sequence.
"The legacy of over 70 years of research, coupled with the availability of molecular and genetic tools, offer enormous potential for continued discovery," Galagan told BioWorld Today. "We undertook sequencing of the N. crassa genome to maximize its potential.
"We used the whole-genome strategy' to read that initial sequence. This approach involved shattering the genome into more than 200,000 fragments, sequencing the pieces, then looking for overlaps between the text of the fragments so as to put them together in the right order. A physical map' of landmarks in the Neurospora genome is in progress," Galagan pointed out. "It seems that the Neurospora genome is about four times shorter than that of fruit flies, and 100 times shorter than humans, but the number of genes is not so different."
Not That Far From Common Pink Bread Mold
"The 90 percent-complete sequence," Galagan told BioWorld Today, "has 38.6 million base pairs and 10,082 genes. In comparison, the human genome has 3 billion base pairs and 21,000 to 39,000 genes. In this sense," he quipped, "we are truly not that far in genetic complexity from the common pink bread mold. Neurospora's genes suggest," Galagan added, "that the fungus can sense the time of day, react to blue and red light, and has developed a strategy for destroying repeated sequences of genetic information. Blue light is an important regulator of Neurospora growth and development. It affects the circadian rhythm of conidiation [asexual fungal reproduction]."
That strategy enlists a striking near-unique capability called RIP - "repeat-induced-point mutation."
"First discovered in Neurospora," Galagan recounted, "RIP is a process that efficiently detects and mutates both copies of a sequence duplication. RIP acts during the haploid dikaryotic stage of the Neurospora sexual reproductive cycle. It causes numerous CG to TA mutations within duplicated sequences. In a single passage through the sexual cycle," he continued, "up to 30 percent of the CG pairs in duplicated sequences can be mutated.
"The pattern of mutations," Galagan pointed out, "produces a characteristic skewing of dinucleotide frequencies that allows RIP-mutated sequences to be detected accurately. RIP has been proposed to act as a defense against selfish or mobile DNA. This allows it to defend its genome against naturally occurring, moving genetic elements that could subvert the fungus' genome to its own purposes." He suggested that RIP has had a powerful impact in suppressing the creation of new or partial genes through genomic duplication. "Computer simulations indicate that after a gene duplication, each copy has an 80 percent probability of acquiring an in-frame stop codon after only a single round of RIP. There is a 99.5 percent probability that RIP has mutated the copies to less than 85 percent nucleotide similarity. Only 59 of the 9,200 predicted genes encoding proteins show evidence of mutation by RIP.
"Gene duplication," Galagan continued, "is thought to have a primary role in the innovation of new genes. However, our data support the conclusion that most, if not all, paralagous [evolved in parallel within the same organism] genes in Neurospora duplicated and diverged before the emergence of RIP, and since that point the evolution of new genes through gene duplication has been virtually arrested. Our results indicate that the cost to Neurospora of increased genomic security through RIP is a significant impact on the evolution of new gene functions through gene duplication."
Fungal Genome Tells Time, Senses Red, Blue
A News & Views commentary in the issue headed "Revelations from a bread mold" asks rhetorically: "What else does the Neurospora sequence tell us?" In reply, "This fungus shares some significant physical characteristics with other complex eukaryotes, notably a biological clock. It knows how to tell the time of day, and much of what we understand about this process in other organisms comes from studies of Neurospora. The genome sequence should reveal how the biological clock connects with other cellular processes, such as metabolism and light-sensing. Furthermore, the sequence provides hints that, like some plants, Neurospora can sense both blue and red light. It was already known that it responds to blue light, and Galagan et al. have found some additional genes that may be involved in this process. But the discovery of genes that may be needed in sensing red light comes as a surprise."
"The genome sequence of Neurospora," Galagan noted, "provides only a first glimpse into the genomic basis of the biological diversity of the filamentous fungi. Many ongoing and planned Whitehead cornerstone projects will expand this view. This new era in fungal biology promises to yield insight into this important group of organisms and economically important applications in agriculture and medicine."
"Neurospora was developed as a laboratory organism in the 1920s," Birren observed, "and has been a regular workhorse in genetics laboratories since the 1940s. It seems fitting that its genome be revealed this week," he concluded, "50 years after Watson and Crick deciphered the structure of DNA."