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From Duplication to Disease Variants

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  • Title: Postdoctoral Fellow, University of Washington, Eichler lab
  • Education: PhD, University of Washington, 2004
  • Recommended by: Evan Eichler

The fascination with duplication-rich regions of the human genome hit Tera Newman during graduate school. “That was before everything had been sequenced, but it was obvious that there were these regions of the genome that were duplicated,” she says. “I came to realize that these were incredibly plastic and dynamic regions of the genome, and they were likely to be associated with large-scale structural changes.”

After completing her PhD, that fascination led her to the recognized expert in the duplication field: Evan Eichler. She joined his lab as a postdoc and is currently conducting a nucleotide-level analysis of the break points of common structural variation in humans. She is particularly interested in the mechanisms behind the creation and insertion of these deletions and inversions. “On average there may be as many as 150 to 200 structural variant sites that differ between any two humans. These can range in size from 8 kb all the way up to 200 kb,” Newman says. She adds that anywhere from half to two thirds of those sites are most likely common among humans. “What we are talking about here is really common changes that are potentially very large [and] that have some genetic impact in the population,” she says. “These are genes that may play a role in phenotype such that one person can better tolerate the carcinogens from smoking compared to another person; it's fine-scale variation leading to subtle differences in phenotype.”

The practical applications of her work immediately point to answering questions about which segment of the population will respond favorably to a particular drug and why. “The most important thing we want to try and decide is which of these changes are going to be important at a phenotypic level, so which of these changes really make a difference for how someone metabolizes a drug, for example,” she says.

“We're good at finding these variant structures,” she adds. “But tying the structures to function is difficult because there are a lot of variables in the biology.” Taking one change in the DNA and discerning what it means to an organism at the molecular level is the real challenge, she says. 

Looking ahead

Newman expects that the next three to five years will be spent cataloguing all structural variation sites that exist between humans. After the discovery phase, the next step will be pinning down which structural variant connects to which biological trait. “I think we're going to spend a lot of time out front figuring out what they are and then we're going to spend a lot more time figuring out why they matter,” she says.

In thinking about technology needs, she says that both faster sequencing — getting a genome in two hours — and a nanotechnology that would follow a protein or chemical through the body to provide a glimpse of all the interactions that it has with a cell in its normal life cycle would be vast improvements for the field.

Publications of note

In the paper “High-throughput genotyping of intermediate-size structural variation,” published in Human Molecular Genetics, Newman and her colleagues describe a pilot study to launch a high-throughput method to correlate differences in individuals with various phenotypes. The study attempted to answer whether structural variation between humans relates to disease susceptibility or other important traits.

And the Nobel goes to…

Newman says discovering structural variants might not warrant a Nobel Prize. But she does think that investigating structural variation could get us closer to big questions about why species diverge from each other. “A goal of my future is to try and see whether or not structural variation has been a factor in speciation in the past,” she says.

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