Ten years on: a new genomic revolution

In June 2000, the human genome revolution began with a bang. At a White House ceremony, genome pioneers Francis S. Collins, M.D., Ph.D., and J. Craig Venter, Ph.D., joined then-president Bill Clinton and British Prime Minister Tony Blair to announce the completion of a “working draft” of the 3 billion base pairs of DNA that comprise our genetic endowment. That effort took 10 years, $3 billion, and the work of 900 automated DNA sequencing machines scattered in laboratories around the world.

Ten years later, one technological advance after another has driven the speed of genomic analysis up and the cost down: the latest DNA sequencing technology is eight orders of magnitude faster than that used in 1987; over the last decade, costs have plummeted 14,000-fold. In a recent issue of the journal Nature that marked the 10th anniversary of the human genome’s first draft, Collins, now director of the National Institutes of Health, provided a vivid description of what these developments mean for biomedical research. “For example,” Collins writes, “the search for the cystic fibrosis gene finally succeeded in 1989 after years of effort by my lab and several others, at an estimated cost of US$50 million. Such a project could now be accomplished in a few days by a good graduate student with access to the Internet, appropriate DNA samples, some inexpensive reagents, a thermal cycler and a DNA sequencer.”

As a result of this stunning progress, DNA sequence information has become a common currency for scientific discovery—every life scientist seems to be making use of it in one way or another, and it is hard for those who oversee sequencing facilities to keep up with the demand. For researchers today, a single human genome won’t do—they want many, and they want to be able to compare them in detail.

At Yale, scientists can now obtain this 21st century research staple from the Yale Center for Genome Analysis (YCGA), a new high-speed sequencing facility that opened in January. Housed in a newly renovated space perched atop a hill at Yale’s West Campus, the YCGA is home to 13 state-of-the-art sequencers that churn out more than 900 billion base pairs of new information every 30 days, or the equivalent of more than 300 complete human genomes per month.

“Advancing science in these areas now requires the ability to produce very large volumes of sequence data and analyze them efficiently,” says Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics, who chairs YCGA’s Advisory Board. “The YCGA permits us to do this at a scale that has been matched by few places in the country.”

The immense computational power of the medical school’s newest sequencers is belied by the machines’ quiet operation and unremarkable appearance. Lined up behind a glass wall, through which YCGA Director Shrikant Mane, Ph.D., keeps a watchful eye, these multimillion dollar marvels could be mistaken for a group of blue dorm fridges.

The YCGA had its beginnings in a much smaller DNA sequencing core Mane launched at Yale’s Keck Foundation Biotechnology Resource Lab in 2006. Through the Keck facility, for which he remains director of microarray services, Mane provided sequencing services to Yale researchers using just three automated machines.

Last fall, Yale University made the decision to invest significantly in large-scale DNA sequencing technologies, to support research by investigators across the entire campus. Mane was named to head the new facility. He moved rapidly to acquire seven new Illumina Genome Analyzers, three machines at various campus locations, and three sequencers housed at the Keck facility, and to consolidate all the equipment at the West Campus. But that was just the beginning. “Scaling up an operation of this size by a factor of at least 100 in data output over the course of several months is a Herculean task,” Lifton said. The job included building “wet bench” infrastructure to prepare samples as well as other building modifications to accommodate high-performance computing; hiring and training new personnel; and developing and refining bioinformatics techniques and software. With round-the-clock efforts from Mane and his staff, the pieces fell into place quickly, and the facility was up and running within two days after the move to West Campus.

These labors have already yielded a significant scientific payoff. In a pilot project last fall, Lifton and Mane used whole-exome sequencing—a genomic shortcut in which researchers sequence only the few percent of a person’s DNA that actually encodes proteins, where disease-causing mutations are most likely to occur—to pinpoint the cause of a baby’s rare kidney disease. Their success marked the first use of whole-exome scanning to diagnose a patient, an important new milestone in personalized medicine.

The investment in large-scale sequencing has also enabled a raft of new research projects. In last year’s competition for research funds under the American Recovery and Reinvestment Act, Yale received five major NIH awards totaling $21 million, all dependent on the resources of the YCGA.

In his 25 years in science, Mane has not witnessed the level of enthusiasm among researchers for any technology as he sees now for large-scale sequencing. “When I wrote a grant to purchase our first genome analyzer back in 2005, I had 38 investigators sign on. Now, for my latest grant I have 150 interested. That kind of response tells you how important this technology is. It’s the most exciting thing I’ve ever been involved in.”

In just a few years, researchers predict, it will take only 15 minutes and a few hundred dollars to decode an individual’s genome. Sequencing will be a routine part of medical care, and doctors will use genetic information to drive the diagnosis and treatment of many diseases. As Lifton sees it, “We have already had innumerable new insights into disease biology from having the genome sequence, but I think the best is yet to come.”