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Researchers Find Value in Exomes

Jane Ades, NHGRI.

In a pioneering effort, researchers have demonstrated the value of a new strategy for identifying relatively rare genetic variants that may cause or contribute to disease.

The human genome—all the DNA in a human being—is massive. A team of scientists from the University of Washington in Seattle and Agilent Technologies reasoned that the important genetic information about a person might be obtained more quickly and at lower cost by isolating and sequencing exons. Exons are the parts of the human genome that contain the information needed to produce proteins, the building blocks of the body. The complete set of exons, referred to as the "exome," makes up just a small fraction of the human genome-about 1%.

To test this approach, the researchers focused on the exomes of 8 people (4 Yoruba, 2 East Asians, 2 European-Americans) whose DNA had previously been characterized by the International HapMap Project, which produced a comprehensive catalog of common human genetic variation. The researchers also included 4 unrelated people with Freeman-Sheldon syndrome, a rare inherited disorder, to see if exome sequencing had the power to detect the mutations known to exist in their DNA.

The study was funded by NIH's National Heart, Lung and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) as part of the Exome Project, a program jointly managed by NHLBI and NHGRI to develop, validate and begin to apply a cost-effective, high-throughput approach for exome sequencing.

The researchers began by shearing the 12 samples of genomic DNA into fragments and then used special probes to capture only those fragments that contained exons. The resulting 12 exomes were then sequenced and analyzed. The researchers reported in the online edition of the journal Nature on August 16, 2009, that they analyzed 300 million bases of DNA sequence altogether.

When they compared the exome sequences to publicly available human genome sequence, the researchers found the new technique was sensitive enough to detect genetic variations both common and rare. They were also able to pinpoint the causal genetic variant in the DNA of the 4 people with Freeman-Sheldon syndrome.

These findings demonstrate that, for now, exome sequencing offers a faster, more cost-effective method for pinpointing genetic variants than sequencing entire genomes. Ultimately, researchers and clinicians would prefer a whole genome sequence. Recent research has shown that other parts of the genome can influence a person's risk of disease. However, exome sequencing will remain useful until the sequencing of entire genomes becomes quicker and more affordable.

“We have great hope that targeted sequencing, when applied to a larger number of individuals, will be used to discover the genetic underpinnings of common conditions such as high blood pressure and high cholesterol,” says NHLBI Director Dr. Elizabeth G. Nabel. “The current findings provide the fundamental groundwork for pursuing this important goal.”