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Comparative Genomics Broad’s Kellis Stumbles onto Yeast Duplication

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Manolis Kellis didn’t set out to show that a particular species of yeast had long ago duplicated its entire genome and then very rapidly shed almost all of the extra genes. In fact, when preliminary evidence seemed to suggest this, he immediately suspected a lab error or data-handling problem and wondered what he had done wrong.

But the computer scientist who’s spent some four years at the Broad Institute hadn’t run a sloppy experiment after all. It all stemmed from two projects, he says: in the first, he and his colleagues were trying to figure out just how much they could learn from comparing genomes, and set out with a pilot project on yeast. After sequencing three close relatives of baker’s yeast, Kellis says, they gleaned a great deal of information about regulatory motifs, among other things, and that led to a second project, which involved studying relatives that were much more distant on the organism’s path of evolution.

But in comparing those genomes, “I basically started noticing very funny patterns,” Kellis says. Using the ancestral genome as the template, it looked like half the genes were missing in the more modern species — but, Kellis says, the missing genes always turned up in the correct order in another region of that species. “At first glance, it was that half the genes were missing in one region,” Kellis says. “The second observation [was that] every region has exactly two matches. That’s where the idea of duplication came in.”

Like any good scientist, Kellis headed straight for the literature, where he discovered that the question of duplication of the yeast genome had actually been raised seven years earlier and had unleashed a flurry of papers contesting the idea.

“We are now in a place to settle the controversy,” Kellis says. Based on the interleaving of the genes in the exact order of their pattern in the ancestral genome, he was able to show that the entire genome did duplicate and that afterward, due to massive gene loss, “92 percent of the genes were kept in only one copy.”

Kellis says there are several theories for how the duplication occurred, including basic cell mitosis or meiosis gone awry. It’ll be another endeavor to study the “very subtle signals” scattered throughout the yeast genome that may indicate exactly how the duplication took place, and how the organism kept functioning properly throughout.

A computer scientist by training, Kellis says he was drawn into genomics in part through being “fascinated with the ultimate machine. The cell is nothing but a perfect robot … the most basic computer.” And through early research initiatives in his undergrad days at MIT, he encountered a text file of As, Cs, Ts, and Gs that provided his first glimpse into the human genome. “My own program was in front of my eyes,” Kellis remembers. “I could never go back after I saw that. I [thought], ‘This is it, sign me up.’”

— Meredith Salisbury

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