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Finding Function in Genomes

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  • Title: Investigator, Genome Technology Branch, National Human Genome Research Institute
  • Education: PhD, University of Michigan, 2001; Postdoctoral fellowship, NHGRI, Eric Green's lab
  • Recommended by: Eric Green

Ever since his graduate days at the University of Michigan, Elliott Margulies has been just as interested in developing technology as he has in answering biological questions. That makes his new post in the Genome Technology Branch at NHGRI a perfect fit, he says.

His just-opened lab “focuses on trying to identify and characterize functional sequences that are in the human genome,” he says. His team is working on new approaches — both computational and experimental — to extract information from the genomes of multiple species and find patterns or alignments to indicate evolutionarily conserved sequences that are likely to be functional. “There's strong evidence that because these sequences have stayed so similar over millions of years, that those bases must be important for something,” he says. And unlike searching for protein-coding genes or other well characterized genetic elements, “it's a very unbiased way for approaching what parts of the genome might be functional,” he adds.

There is certainly no shortage of people in the field using evolutionary studies to track possible functional elements, but Margulies has plans to take the usual sequence comparisons a step further. “I'm going to be working on [trying] to develop new ways of looking at parts of the genome that have been conserved throughout evolution,” he says. Current studies focus entirely on the primary order of nucleotides, he notes, but little attention has gone toward the physical structure of the DNA in question. “We know that sequence has a three-dimensional structure to it,” Margulies says. “I'm trying to develop more sensitive methods that take the structure of the DNA into account” — in part by collaborating with scientists who specialize in DNA structure.

It's no wonder Margulies is looking for new ways to compare DNA. Comparative genomics is an approach he has well in hand, not only from his postdoc position in Eric Green's lab but also from his service, since 2004, as group leader of the ENCODE Consortium's Multi-species Sequence Analysis Group.

Looking ahead

Margulies has a short wish list for his research: more sequence data. He believes the community is poised on the brink of a major change in how much sequence data is available. Right now, he says, “there are questions that we would like to be able to ask … but they require a tremendous amount of sequencing data, so we don't even ask the questions.” But as promising new sequencing technologies ramp up output and slash costs, he says, “we're going to see a completely new revolution of how we can ask genomics questions and how we can answer them. I'm hoping to ride that wave.”

That sequencing capacity will help increase the number of genomes that can be compared in functional studies, he adds. “I think we're going to go way beyond comparing tens of genomes to comparing hundreds of genomes,” he says. “We also need newer technologies to figure out where these functions are, regardless of how they might be evolutionarily conserved.”

Publications of note

While Margulies has a number of papers currently submitted or in press,  he feels that a paper published in 2003 “laid the foundation for a lot of the work I'm doing right now.” That paper, entitled “Identification and characterization of multi-species conserved sequences,” can be found in Genome Research.

And the Nobel goes to…

Margulies hopes his crowning scientific achievement is “to find some function that the genome does that we never knew existed before.”

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