Neurospora Initiative

The Neurospora Fungal Genome Initiative


Steering Committee:

SUMMARY

! The Significance: The Kingdom of the Fungi includes over 1.5 million different species and contains members central to every ecosystem on our planet,. Fungi are universally consumed as food and are used for the industrial manufacture of chemicals and enzymes, collectively representing industries that contribute ca. $35 billion to the US economy each year. Additionally fungi are major pathogens of animals (including people) and of plants, collectively costing in excess of ca. $30 billion annually on a worldwide basis. Some of the fundamental discoveries in biology have come from the study of fungi, such as what a gene does.

The Issues: We do not understand how fungi work.

The Goal: To move fungal research from the era of empiricism to the era of rational design. To achieve this we must understand how fungi work and what makes them work. The critical first step towards this goal is to catalog all the genes that constitute the repertoire of fungal physiological capacity, and to associate these genes with biological function. Since 90 percent of all fungi are filamentous,


A Closer Look - Why Fungi?

Fungi, plants, and animals represent the three phylogenetic kingdoms within the eukaryotes (non bacteria). Within the 1.5 million different species of fungi, about 75% belong to the Ascomycetes (approximately 90% of which are filamentous fungi, the remainder being yeasts), and 25% are Basidiomycetes (which form fruiting bodies or "mushrooms"). As a group, the fungi have an enormous impact on the United States and world economies: yeasts are used extensively in the brewing industry, filamentous fungi! are used both for the production of foodstuffs and indus! trial production of enzymes and chemicals, and Basidiomycetes are consumed as food all over the world. Fungi are known to infect nearly all food crops and represent the most universal and costly pathogens. Filamentous fungi are widely used as organisms for basic research.


A Closer Look - Why Determine the DNA Sequence of a Fungal Genome?

The information encoded in the genomic DNA of an organism contains the entire repertoire of the organism's metabolic and developmental capacity - everything that it can do or become. It represents the pinnacle of an organism's evolutionary growth over eons of history, where variation induced by mutation has been refined in the crucible of evolution.

By determining the sequence of a genome, all of the proteins encoded by the organism can be identified and all of the developmental and metabolic potential of an organism becomes available for manipulation both in that organism and, potentially, for re-engineering in any other organism.

The initial key to this treasury of informat! ion is the DNA sequence.

The determination of complete genomic sequences of filamentous fungi is now an important and readily achievable goal. Initially the DNA sequence itself will be most informative in proportion to extent to which the genome sequenced is already understood genetically.

A Closer Look - Why Sequence Neurospora?

A recent cover article in The Scientist (Nov. 25, 1996) hailed "Functional Genomics - unraveling how genes work" as the currently hottest area for biotechnology investment, and they found (not surprisingly) that a lot of the smart money was going into start-up companies working on model eukaryotic organisms and not on people or plants. The reason for ! this is that, although the acquisition of DNA sequences i! n any organism is now economically feasible, the true utility of the sequence cannot be fully realized until the string of A', T's, G, and C's comprising the sequence can be interpreted as a series of genes encoding the proteins that confer metabolic and developmental potential on the organism - until this connection between gene and function is made the sequence is mute.

It has been estimated that roughly 1/3 of any organisms' genetic capacity is devoted to housekeeping functions that all organisms must be able to do - metabolizing simple sugars, making proteins, replicating DNA, etc. The DNA sequences of these genes will be similar enough in all organisms that the presence of these genes in a raw DNA sequence is identifiable and interpretable. However, genes that are not highly conserved in all organisms - the truly interesting genes in terms of development of fungal spores, elaboration of mushroom fruiting bodies, synthesis and secretion of ! secondary metabolites such as penicillin, capacity for pathogenesis in plants and animals and ability of hyphae to fuse for heterokaryons, genes that function in the cell cycle, in the biological clock, in sexual development - cannot be recognized just from the DNA sequence because no other genes like them have ever been identified.

Herein lies the reason that venture capitalists are investing in functional genomics companies that can exploit the knowledge base of model organisms - and the reason why, in the context of filamentous fungi, Neurospora is ideal for launching the genome initiative. Neurospora has been a dominant force in filamentous fungal research for the past half century.


There is an enormous wealth of genetic diversity awaiting discovery in the fungi, and the legacy of Neurospo! ra genetics is the key to elucidating the biological function of this genetic diversity.Today the 50 years of forefront research on this organism constitutes a priceless legacy for interpreting what comes out of the DNA sequence - a Rosetta Stone really - and one not available in an organism chosen for its temporary, topical interest.

The Neurospora - Fungal Genome Initiative

Our Plan of Attack

We are now engaged in Phase I of an overall plan to prosecute the global sequencing effort. In this work our initial goals are twofold:
  1. to establish the unique nature of fungal genes. This goal is largely complete as the result of the ongoing work at the Neurospora Genome Center in New Mexico (see above) where sequencing of ESTs has established that over 50% of expressed genes in Neurospora are not found in either yeast or in the GenBank repository that includes all sequenced genes in the literature.!
  2. to complete the sequence of a fully functional ! chromosomal element from Neurospora. This will serve as a benchmark to establish our credibility in high through-put sequencing. This work will be completed chiefly at the Neurospora Genome Center in New Mexico and at the Fungal Genome Resource center at the University of Georgia, although we will encourage the development of four additional satellite centers .
We will then go for the funding to complete the entire sequence in Phase II, an overall effort that we expect will include the complete sequencing of Aspergillus nidulans and acquisition of partial sequences from several additional important fungal pathogens, industrial production strains, and cultured organisms.

Our Funding Base

To move forward we need your help.

Requested Action

We need your support in two ways.

First, for us to successfully educate members of Congress, it is critical that we be able to call upon your written support. An Initiative driven only by academic research interests is not likely to draw the necessary interest in Congress, whereas an Initiative supported by agricultural and industrial interests in the private sector is likely to draw attention.

Secondly, it is essential that we identify Private Sector Allies willing to financially suppo! rt the chromosomal sequencing aspect of Phase I. A commitment corresponding to one postdoctoral or technician equivalent for one year will allow us to prosecute the work immediately and to complete it is a timely manner, although partial but significant support at any level will allow the work to begin.

The Profits