In work that may lead to better understanding of genetic diseases, researchers at the Broad Institute of MIT and Harvard show that baker's yeast was created hundreds of millions of years ago when its ancestor temporarily became a kind of super-organism with twice the usual number of chromosomes and an increased potential to evolve.
The study is by postdoctoral fellow and lead author Manolis Kellis of the Broad (rhymes with "code") Institute; Eric S. Lander, Broad director; and Bruce W. Birren, co-director of the Broad's sequencing and analysis program. It will be published online by Nature on March 7.
Scientists have postulated that in a handful of instances in evolutionary history, cells may have replicated their entire genomes in events called whole genome duplication, but no definitive proof existed. The Broad Institute work shows conclusively for the first time that the well-studied organism baker's yeast originated through this little-understood phenomenon, resolving a long-standing controversy on the ancestry of the yeast genome.
Whole genome duplication (WGD) may have occurred when a cell replicated its DNA normally, as it does every time it divides, but did not split it between two resulting cells, or two cells may have fused. The result is that a yeast cell with around 5,700 genes suddenly had more than 11,000. In this scenario, while one copy of the gene performs its designated function, the other is free to perform a new and potentially valuable use. In addition, the organism is able to evolve more rapidly with natural selection acting on thousands of duplicated genes simultaneously, allowing for large-scale adaptation to new environments.
This super-organism doesn't come without drawbacks. The excess genes cause instability in the genome and are deleted through mutation, gene loss and genomic rearrangement. As a result, millennia after the event, very few duplicated genes remain.
"This is the first time we actually see that an organism underwent complete genome duplication and went back to a single-copy state," Kellis said. In the case of baker's yeast, roughly 90 percent of its duplicated genes were lost. The organism returned to having one gene per function for the vast majority of its genome, ending up with only 457 additional genes.
What's the advantage to replicating the entire genome and then losing half the genes? According to one theory, by replicating the whole genome, entire systems (networks and pathways) within the organism can evolve together and take on new functions. Yeast, which metabolizes sugar and causes fermentation, apparently evolved to fill an evolutionary niche around the time that fruit-bearing plants appeared, creating an abundance of sugar in the environment.
"It's the best fermenter out there," Kellis said of Saccharomyces cerevisiae, the species that the group studied. Many of its surviving 457 genes are devoted to sugar metabolism.
If incremental evolution over millennia is like a landscape changing through erosion, whole genome duplication is like an earthquake. "Direct study of such a cataclysmic event may provide major insights into the dynamics of genome evolution and the emergence of new functions," the authors wrote.
Uncovering the original
Given the massive gene loss and hundreds of rearrangements, little evidence of WGD remains within the genome of baker's yeast. Tracing the development of a genome over billions of years is like printing a 5,000-page book twice without page numbers, throwing away most of the duplicate pages, shuffling both copies and binding them into a single book. Uncovering the ancestral gene order, Kellis said, would be like happening upon the original book in a hidden library.
The authors found the missing link by sequencing a yeast species whose evolutionary divergence preceded the duplication. They showed that each region of this pre-duplication relative corresponds to exactly two regions of baker's yeast, providing definitive proof of duplication.
Researchers speculate that vertebrates, including human ancestors, may have undergone two rounds of complete duplication, but the evidence remains weak without comparison to a pre-duplication relative. Broad researchers used a new method to compare the complete genomes of each of the duplicated and pre-duplication yeast species, and they plan to apply this method to more species. Typical methods of genome comparison would "miss the genome duplication event if they focus on solely the best match for every gene and every region," Kellis said.
Genomic research is leading to new understanding of the connections between different types of genetic functions and which genes were paired in our ancestors to work together. For example, uncovering the duplication event provided a new link between gene silencing and the binding of DNA-replication origins.
Similarly, understanding the dynamics of genome duplication has implications in understanding disease. In certain types of cancer, for instance, cells have twice as many chromosomes as they should, and there are many other diseases linked to gene dosage and misregulation. "These processes are not much different from what happened in yeast," Kellis said.
Whole genome duplication may have allowed other organisms besides yeast to achieve evolutionary innovations in one giant leap instead of baby steps. It may account for up to 80 percent of flowering plant species and could explain why fish are the most diverse of all vertebrates.
"The results here suggest that it may also be fruitful to search for similar genomic signatures of WGD in other organisms. It will be interesting to see just how far such distant echoes of genomic upheaval may be traced," the authors said.
Kellis is also part of the MIT Computer Science and Artificial Intelligence Laboratory, and Lander is a professor of biology at MIT and a member of the Whitehead Institute for Biomedical Research.
The Broad Institute, known officially as the Eli and Edythe L. Broad Institute, is a research collaboration of MIT, Harvard University and the Whitehead Institute. The Broad's mission is to fulfill the promise of genomics for medicine.
