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Jacob Kitzman: Increasing What Sequencing Can Do

Jacob Kitzman: Increasing What Sequencing Can Do
Graduate student, Shendure lab, University of Washington
Recommended by Evan Eichler, University of Washington

Kitzman.jpgThere's a lot that sequencing can do, but there are still plenty of things that it cannot do. Jacob Kitzman's work on sequencing technology in general, and on haplotype sequencing in particular, sprung in part from the desire to chip away at what sequencing can't do.

"We were motivated [by] interesting areas of biology that demanded essentially better sequencing, better continuity," Kitzman said. Indeed, better haplotype sequencing has enabled both prenatal and cancer genomic studies.

Kitzman will be starting his own lab this spring at the University of Michigan, where he plans to branch out a little bit, though he'll continue to work on developing new sequencing technologies.

He said that he and his team would focus on studying somatic variations and genetic diversity. In particular, he said he plans to focus on how to sequence difficult, diverse areas like the HLA locus, using either technology developed in house or elsewhere.

At the same time, he noted that his lab would be tackling the functional effect of such variation by coupling large-scale mutagenesis studies to functional assays.

"[We will] make essentially every possible mutation at a given locus and then see if we can apply a functional selection to select away the loss-of-function alleles from the ones that retain function," he said, adding that they would then "use sequencing to actually count at the end of selection which alleles retain function and which ones don't."

A challenge, he said, though, is to figure out how to translate the variation seen in the human genome to personalized risk scores for disease.

Paper of note

In 2011, Kitzman and his colleague published a paper in Nature Biotechnology detailing how they generated a haplotype-resolved genome sequence from a Gujarati Indian individual. To do that, they split the fosmid library into a number of pools that were sequenced predominately from one homologous chromosome and combined that with whole-genome shotgun data.

"It really was a kind of [an] 'aha! moment' … seeing the first long chunks of 30, 40 kilobases come off the sequencer and realizing that this would actually work, that we could put together a substantially complete long-range haplotype from very short and error-prone data was quite satisfying," Kitzman said.

Looking ahead

In the not-too-distant future, Kitzman would like there to be better interpretation of personal genomes. "An ideal vision would be that I have can have my genome sequenced and, at least for common diseases, I can obtain a risk score for my set variants, many of which are either rare or private to me," he said.

Such a future, he added, would be fueled by both large-scale sequencing studies and high-throughput functional assays, especially for private alleles.

The interaction of such variants would also be key. "I'm the only person in the world that has this particular combination of three different alleles, what does that mean for my disease risk for disorder X?" he said.

And the Nobel goes to…

Kitzman said that if he were to become a Nobel laureate, it would likely be for "something completely unexpected." Genome-wide association and other studies are uncovering a number of previously unknown phenomena, he says, pointing to lncRNAs, genome editing, and phage defense as examples, and the field is being blown open by these unexpected directions.

"I'm just going to keep working on what I am interested in and hope to take new and exciting directions," Kitzman added.