As science moves faster, the world gets smaller

In a giant leap forward for personalized medicine—one of the most highly anticipated benefits of the Human Genome Project—Yale researchers have applied new technology to diagnose and recommend therapy for a rare intestinal disorder in a seriously ill baby half a world away.

Doctors in Ankara, Turkey, were stumped as to the cause of chronic dehydration in a 5-month-old baby boy, and they called on the School of Medicine’s Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics, for help. After obtaining samples of the baby’s DNA from the Turkish doctors, Lifton and colleagues at the newly launched Yale Center for Genome Analysis (YCGA) used an emerging technique to quickly and completely map the “exome,” those regions of the boy’s genome that contain protein-coding genes and their associated regulatory sequences.

In just 10 days, the Lifton team was able to determine that the baby harbored a rare mutation in an intestinal protein which causes congenital chloride diarrhea, a disorder in which the gastrointestinal tract fails to properly absorb chloride and water. Armed with this information, the baby’s doctors were able to tailor a successful treatment program.

The feat was a landmark in personal genetics, marking the first time that a patient has been diagnosed, and treated, based on a comprehensive genetic scan. Moreover, it provided a preview of things to come from the YCGA, a centerpiece of the School of Medicine’s research expansion onto Yale’s West Campus.

“We believe this heralds the dawn of a new era in genetics and personalized medicine,” says Lifton, also professor of medicine and a Howard Hughes Medical Institute investigator. “The results show that new technology can generate clinically useful results quickly, bringing doctors and patients closer to the day when comprehensive sequencing information will be a routine part of medical care.”

Though the exome comprises only 1 to 2 percent of the genome, it includes crucial protein-coding regions where disease-causing mutations are most likely to occur. The Lifton group—which included ycga Director Shrikant Mane, Ph.D.; Postdoctoral Associates Murim Choi, Ph.D., and Ute I. Scholl, M.D.; and Research Associate Irina R. Tikhonova, Ph.D., of the medical school’s W.M. Keck Foundation Biotechnology Resource Laboratory—worked out an exome sequencing method that combines gene-chip technology to isolate the target DNA with the latest high-throughput sequencing techniques and hardware to decode it.

The approach yields a quick and comprehensive view of an individual’s genes for a few thousand dollars, or 10 to 20 times cheaper than sequencing the entire genome.

This “capture and sequence” method can be applied to virtually any disease and will accelerate the pace of discovery of new genes related to both rare and common conditions.

Even as they were developing the technology, Lifton and Mane could already envision how large-scale sequencing tools would transform the work of researchers across the medical school. They established the ycga, a core resource that will not only accommodate a growing demand for genomic sequencing, but also keep Yale researchers at the forefront of human genetics.

With support from the American Recovery and Reinvestment Act (ARRA; see related story), 12 of the latest-generation Illumina gene-sequencing machines, which will vastly increase medical school researchers’ ability to perform high-throughput genomic analysis, are being installed at the ycga.

The medical school’s early investment in this approach has already jump-started a substantial amount of new research: of six major ARRA research grants the School of Medicine received recently, five were based on this new sequencing technology.

“This is an area where we are leaders,” Lifton says, “and we want to take advantage of that.”