Whitehead Human Genome Map Ushers in Final Phase of U.S. Human Genome Project
CAMBRIDGE, Mass. — For the first time, scientists have created a map of the human genome that will allow them to begin the final phase of the Human Genome Project: decoding the exact sequence of all 3 billion DNA letters that make up the genetic instructions for building a human being. This powerful new map, described in the December 22 issue of Science, contains more than 15,000 distinct markers and covers virtually all of the human genome. It was created by scientists at the Whitehead Institute for Biomedical Research in Cambridge, Mass., with support from the National Institutes of Health (NIH) and major input from the genetic mapping group at Généthon in France.
The new map is composed of landmarks called sequence tagged sites, or STSs. Each landmark is a short stretch of DNA that tags a unique position in the human genome. Together, the landmarks form a long-awaited scaffold needed to begin reading the full set of genetic instructions in human chromosomes. These instructions, composed in an alphabet of four DNA letters (A, T, C, and G), determine everything from hair and eye color to increased susceptibility to heart disease and cancer.
"Generating the complete sequence of human DNA is the most exciting adventure in modern science," says Dr. Eric Lander, director of the Whitehead/MIT Center for Genome Research. "In the 19th century, chemists defined the periodic table of elements and it forever changed the practice of chemistry. Sequencing the human genome will have the same impact on human biology and medicine. It will give us a new understanding of human development and a broad array of new tools for fighting human disease."
One of the primary goals of the U.S. Human Genome Project has been to establish a physical map of the human genome with 30,000 STS landmarks by 1998. The Whitehead map represents half that goal and is sufficient to initiate sequencing on 75 percent of the human genome. Placement of the remaining 15,000 STSs, now expected to be completed by the end of 1996, will allow access to the rest of the genome.
"This is an extraordinary achievement," says Dr. Francis Collins, director of the National Center for Human Genome Research (NCHGR) at NIH, which supports the Whitehead/MIT Center for Genome Research. "In little more than twelve months, the Whitehead scientists produced a scaffold that is sufficiently dense to begin sequencing the majority of human DNA. To accomplish this goal, they developed automation technologies that will change the practice of science in universities and biotechnology companies throughout the world."
Dr. Lander says, "The STSs give us reference points so we can move through the genome without losing our way. When explorers Lewis and Clark first made maps of the continental United States, they made thousands of notations about physical landmarks—rivers, unique rock formations, streams—to help others follow their path. We're doing the same thing with STSs; scientists anywhere in the world can use our STS map to navigate through the human genome (All of the information produced by the Whitehead/MIT Center for Genome Research is available free-of-charge to the public via the World Wide Web.)
Understanding the complete set of genes spelled out in human DNA promises to usher in a new era of molecular medicine, with precise new approaches to the diagnosis, treatment, and prevention of disease. The Human Genome Project already has led to the discovery of genes responsible for Alzheimer's disease, colon cancer, breast cancer, Lou Gehrig's disease, and dozens of other disorders.
Dr. Thomas Hudson, head of the Whitehead's human genome mapping group, explains that each STS landmark in the Whitehead map is defined by a special chemical test called a polymerase chain reaction (PCR) assay.
"The wonderful feature of an STS-based map is that any scientist can find a specific location in the human genome by setting up the appropriate PCR assay," Dr. Hudson says. "All of the information necessary to locate an STS from our map is freely available by computer through our World Wide Web site. In one recent week, we had 53,000 accesses to that site."
To establish the relative positions of the 15,086 markers, the Whitehead scientists and their collaborators integrated three different kinds of maps: an STS-content map, a radiation hybrid map, and a genetic map.
"The three maps are very different in scale," Dr. Lander says. "If you wanted to find five historic American sites, you would first look at a United States map to find if they were in the same state. If three were in Massachusetts, you could then check a state map to find if they were in the same city. If two were in Boston, you could check a street map to find out how long it would take you to walk from one site to the other in Boston's old North End."
The genetic map, radiation hybrid map, and STS-content map play the role of the national, state, and city maps, Dr. Lander explains.
- the genetic map (similar to the national map) was produced by Dr. Jean Weissenbach and his group at the French research institution Généthon. It consists of 5,264 markers used to trace inheritance in human populations.
- the radiation hybrid map (similar to the state map) was produced by Dr. Hudson and his group at the Whitehead. It consists of 6,193 landmarks and is the first radiation hybrid map ever made of the human genome. (Radiation hybrid mapping is a new technology that involves breaking human DNA into large chunks using radiation and then ordering the chunks based on easily identifiable markers.)
- the STS-content map (the city map) was produced by screening 10,850 landmarks against human DNA fragments carried in yeast. It also was produced by Dr. Hudson's group and represents the first STS-content map of the entire human genome.
"Each of the physical genome maps has specific advantages," Dr. Hudson says. "The genetic and radiation hybrid maps help us determine the long-range order of the STS landmarks, while the STS-content map is best suited for estimates of fine-structure order. Integration of the three strategies allowed us to check and recheck the accuracy of our data, producing a detailed product with a high level of precision."
"All together, these efforts required more than 15 million PCR reactions," Dr. Lander says. "We were successful because at the very beginning we made a strong commitment to laboratory automation."
Over the past two and a half years, Whitehead scientists:
- built two successive generations of robots to set up and carry out PCR reactions (in collaboration with a corporate partner, Intelligent Automation Systems)
- developed mathematical pooling schemes to reduce the number of tests required to place STS markers
- generated a bar coding system, like that used in supermarkets, to accurately identify and track samples
- adapted camera technologies from the aerospace industry to read the results of PCR tests directly into the computer database
- created computer programs that automatically check the data and design new sets of experiments based on existing results
Today, the Genomatron, the Whitehead's premier robotics system, allows scientists to run 300,000 PCR reactions per day, compared with 6,000 per day when the Center first opened.
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