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Functional Testing with Next-Gen Technology

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  • Title: Assistant Professor of Genome Sciences, University of Washington
  • Education: PhD, Harvard University, 2005; MD, Harvard Medical School, 2007
  • Recommended by: Alan Guttmacher, Mary-Claire King

Many in the sequencing world may already be familiar with Jay Shendure, the young investigator who, along with his colleagues in George Church's lab, helped to pioneer polony sequencing, a highly parallel, low-cost sequencing method. Now, Shendure's lab continues to advance technical elements related to sequencing — specifically in areas of experimental methods and computational tool development, including platforms for array-based, programmable DNA synthesis and massively parallelized, short-read DNA sequencing.

Shendure has also been instrumental in developing a method to selectively capture all the protein-coding sequences with a microarray as a sample prep approach to next-gen sequencing. His lab continues to work on aqueous-phase and solid-phase protocols to capture genomic subsets.

The Shendure lab is also checking out experimental methods that would enable de novo genome sequencing using next-gen technology. "A growing interest [is] in synthetic aspects — more specifically, how you use off-array synthesis of oligos in other ways, such as trying to create long synthetic constructs that can be used for various things," he says. "The particular thing we're interested in is developing very high-throughput means of doing functional testing of variants."

While there is currently a lack of quantitative models for defining cis-regulatory elements, Shendure and his team are developing a platform for high-throughput screening and high-resolution functional analysis of cis-regulatory elements. So far, they have been able to demonstrate this approach on well-characterized bacteriophage promoters, he says.

It probably goes without saying that Shendure's time in George Church's lab left an indelible mark on his approach to science. "I think it's one of these rare places where there are all kinds of those people around — biologists, physicist, engineers, all in the same working group — and also just the tremendous amount of creative freedom and flexibility very early in your career to do whatever experiment you want to do," he says. "George never told me I couldn't do an experiment, no matter how outlandish it was. It was always my choice, and I think having that sort of freedom very early on was a good thing."

Looking ahead

Peering into his crystal ball, Shendure predicts that five to 10 years down the line, he and everyone else involved in life sciences research will be able to sequence virtually anything in a cost-effective and feasible way. Shendure says the ability to accurately predict function from a sequence in a robust and accurate way would help speed things up as well. "This is something that's extremely difficult, but that certainly would be nice to have," he says. "It would be great if we're building things, if we're synthesizing things, to be able to predict what they'll do, but also, looking at variation in the human genome, to know what that does as well."

Publications of note

In the paper "Accurate multiplex polony sequencing of a bacterial genome" published in Science in 2005, Shendure, Church, and their colleagues outline their use of off-the-shelf instrumentation and reagents to perform polony sequencing. The authors describe resequencing an evolved strain of E. coli at less than one error per million consensus bases using a method to convert an epifluorescence microscope into a  nonelectrophoretic automated DNA sequencing platform.

And the Nobel goes to ...

Shendure says that if he were to be awarded the Nobel prize, he would like it be for something contributing to world peace, rather than any sort of technical innovation.

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