A handful of labs expanded this technique to isolate and manually sequence all the exons in a genome, a massive undertaking. Their success in using this method to identify genes, however, suggested that if it were made quicker and cheaper, it could be useful on a broad scale. During a six-month period in 2009, several research teams came up with an idea that made the technology more feasible, and labs across the country picked it up.

HHMI investigator Richard P. Lifton at Yale School of Medicine was among the first to realize there was a quicker way to sequence exomes. He proposed that by using a microarray to capture exomes from the genome, sequencing of the exome could be streamlined. At the same time, biologist Jay Shendure at the University of Washington, Seattle, was pursuing a similar idea.

“This was a natural next step to what else had been going on in the field of next-generation sequencing,” says Shendure. In 2008 and 2009, he adds, it cost close to $250,000 to sequence a full genome, depending on the methods used. By comparison, the first exomes were sequenced for about $10,000, plus the initial cost of the sequencing equipment.

“Close to 3,000 disease genes had been mapped at that point and the obvious fact to us was that very few of these had fallen outside the exome,” says Lifton. “So at a time when the cost of sequencing was still relatively high, it occurred to us that we could get a huge advantage if we could fish out the exomes and just sequence them.”

Lifton worked with postdoc Murim Choi and NimbleGen, a private company, to develop an exome-sequencing platform. DNA that’s been cut up into manageable sizes is screened using a microarray made with probes specific for markers throughout the exome. Then the captured DNA bits, which ideally make up the whole exome, can be sequenced.

As a proof of concept that the method could be used to discover disease-related genes, Lifton’s lab used exome sequencing to take a close look at the DNA of a five-month-old Turkish boy diagnosed with Bartter syndrome, a rare disease characterized by low levels of potassium in the blood. Exome sequencing changed the child’s diagnosis, showing that he had a mutation in a chloride channel protein involved in a different disease: congenital chloride diarrhea. Lifton’s team got the result from the DNA of a single affected patient, with no need for dozens of affected individuals. Within a month, Shendure’s team published its own proof of concept.

The power of exome sequencing was immediately clear to geneticists who had spent years toiling on linkage studies. The family pedigrees they’d built for particular diseases could be tackled in mere weeks rather than languishing on seemingly endless waiting lists.

Most recently, Lifton, in January 2012, identified two genes responsible for an inherited form of hypertension in 41 families. The genes encode components of a ubiquitin ligase complex never before linked to blood pressure; that work has advanced understanding of normal blood pressure control. Both Gleeson and HHMI investigator Christine E. Seidman at Brigham and Women’s Hospital have used exome sequencing to diagnose hard-to-pin-down diseases (see Web Extra sidebar, “Exomes in the Clinic”).

		Exomes in the Clinic Researchers are using exome sequencing—zeroing in on the genes that encode proteins—to explore the biology of certain diseases. Read More

Sequencing Tumors

Exome sequencing is proving useful for studying tumors as well. Researchers sequence the exomes from a cancer patient’s cheek swab or blood sample in addition to the patient’s tumor tissue. They can compare the sequences to see how tumor cells have accumulated genetic mutations distinct from the patient’s healthy cells.

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