Whitehead Genome Center Taps Comparative Genomics to Analyze Key Functions in Yeast

In this project, scientists generated high-quality draft sequences of the genomes of three of the Saccharomyces yeast species, S. paradoxus, S. mikatae and S. bayanus. They lined up these genomes to that of the model organism S. cerevisiae, commonly known as baker's yeast. The resulting multiple comparisons provided a great resource for understanding the yeast genome.

Highly significant is that the comparisons made it possible to more easily distinguish the "noise'' portions of the genomes--areas that appear to have little use-- from "signal," those parts that have an obvious purpose. In humans, a mere five percent of the genome is functional.

"The goal is to extract important biological signals hidden in the vast noise of non-functional regions," says Manolis Kellis (Kamvysselis), a graduate student at the Whitehead/MIT Center for Genome Research and the Department of Computer Science, Massachusetts Institute of Technology, who is the first author on the paper. "These signals include genes, the building blocks of our cells, but also regulatory motifs, tiny traffic lights that turn genes on and off."

Nature magazine cover - May 15, 2003

Not unlike attempting separating wheat from chaff with only one's fingers, extracting signal in genomes has proved a painstaking, inaccurate process, and a frustrating one, as being able to hone in on the functions of a genome has vast implications for medical science. Yeast, a relatively simple organism, has a small, compact genome containing less noise than the human genome. It provided an excellent organism to test comparative genomic techniques.

"We believe it is a good model for genome-wide comparative analysis,'' Kellis says. In principal, the approach the researchers used can be applied to any organism by choosing a set of related species to sequence and study.

Overall, the scientists found their model to be a powerful tool for identifying genes and refining gene structure, rapid and slow evolutionary changes, and facets of gene regulation.

"Comparative genomics is an extremely important tool. Trying to understand an ancient language like Egyptian hieroglyphs by simply looking at the words in one language may be hard. But by reading the same text in other languages like Latin or Greek and finding common structures, we can recognize words and grammar, and learn the meaning of each language. Similarly, by reading the same chapter in multiple species, we get to the basis of what is important in the book of life. Comparative genomics is the Rosetta stone of biology," says Kellis.

Saccharomyces is perhaps best known as the magic that makes bread rise and fruit ferment but to scientists, it is a favorite organism of study, one that for years has helped scientists answer important questions in genetics and cell biology. Now, the availability of the three, high-quality yeast sequences means biomedical researchers can better understand these organisms, some of which mutate into invasive, deadly infections in humans.

Among the findings of this analysis is that the yeast genomes hold about 5,700 genes, many fewer than the estimated 10,000 of the fruitfly and 30,000 that humans have. Because of an ancient common ancestor, humans have about 2-3,000 genes in common with the yeast, generally genes that code for basic cell machinery.

Researchers were also able to identify signals controlling gene expression that typically required complex experimentation and extensive biological knowledge to find. "One of the most important results of this analysis is that regulatory motifs can be read directly from the DNA sequence," says Kellis. "When comparing multiple genomes, these signals become apparent. We now have a complete list of the most strongly conserved regulatory motifs in yeast."

The four different species of yeast are as different from each other as mice are from humans, yet across the four yeast genomes, all but roughly 12 genes are held in common. In other words, a mere 12 genes or so separate one yeast species from the next.

"It is striking. We saw the same thing between the human and mouse genomes. It may mean that genetic differentiation across different species is the result of very subtle events," Kellis says.

Understanding what changes may turn a benign species into an invasive human pathogen will be crucial to understanding and curing disease. Studying the differences between Saccharomyces genomes offers insight as to how genes and new functions may evolve in higher organisms, including humans. "We found a small number of genes that are evolving very rapidly," says Kellis. "These are likely to be involved in speciation events."

The genomes were sequenced using the Whole Genome Shotgun (WGS) approach. For each species, sequence from the entire genome was generated and reassembled by recognizing identical segments using the ARACHNE assembler, a program developed at the Whitehead Institute/MIT Genome Center. The WGS method is standard and has been successfully applied to the fruitfly and the mouse. The Saccharomyces sequences are freely available through public sequence databases and the Saccharomyces Genome Database (SGD) maintained at Stanford University (http://genome-www.stanford.edu/Saccharomyces/). The sequence is still considered a draft because there are very small missing or ambiguous portions of the sequence.

The genome of each species of Saccharomyces is about 12 million base pairs in size. The draft sequences show the order of the DNA chemical bases A, T, C, and G along the yeasts' 16 chromosomes. It includes more than 95 percent of the genomes with long, continuous stretches of overlapping DNA and represents 7-fold coverage of the genome. This means that the location of every base, or DNA letter, in the Saccharomyces genomes was determined an average of 7 times, a frequency that assures a high degree of accuracy.

Today's research also represents a major step along the path of bioinformatics, a recent field of science that combines biology with computing--as not one test tube was used beyond the sequencing of the species. The project relied completely on computational analysis.

"We are entering a new era where computers will provide a bigger and bigger role to the understanding of biology and genomics,'' Kellis commented.

The Whitehead Institute/MIT Center for Genome Research is an international leader in the field of genomics, the study of all of the genes in an organism and how they function together in health and disease. A flagship of the Human Genome Project, the Center today houses a broad range of thriving research programs combining structural genomics, medical and population genetics and clinical medicine. The Center's annual budget is $80 million, and it employs 350 people, including scientists and medical researchers from Whitehead, MIT and Harvard.

For more information, contact:
Lisa Marinelli, 617.252.1967