A Gene Map of the Human Genome: International Group Maps a Fifth of all Genes on the Human Genome

CAMBRIDGE, Mass.  — An international consortium of genome laboratories from North America, Europe, and Japan has created a unified gene map that establishes the location of more than 16,000 human genes. The unified gene map represents the first edition of the quintessential goal of the Human Genome Project—a catalog of all the genes that make up a human being—and provides the location of one in five of all human genes.

"This gene map and its future editions will provide geneticists the biological equivalent of a chemists' periodic table—a systematic and universal frame of reference that will speed the discovery of genes underlying inherited human diseases," says Dr. Eric Lander, a member of this consortium and director of the Whitehead/MIT Center for Genome Research. "With such a map, searching for a disease gene should no longer take years of painstaking effort. Instead, geneticists will be able to simply scan the human genome for an inventory of all the genes, or candidates, in a suspected region and identify the culprit."

Gene maps will also become essential for searching the genetic basis of complex diseases, such as diabetes and cancer, that are caused by the interaction of several genes and the environment. The new gene map is described in the October 25 issue of Science by more than 100 authors representing the international consortium. The National Library of Medicine will also release that day a newly constructed World Wide Web site that incorporates this information in a consumer-friendly format. (http://www.ncbi.nlm.nih.gov/Science96).

"A map like this has tremendous value for identifying disease-genes and provides extraordinary opportunities for a new era of medicine. Given this, and the wealth of information we have collected so far on the human genome, it seemed a shame to wait until the entire genome is sequenced to put together a gene map," says Dr. Thomas Hudson, senior author on the paper and head of the Whitehead mapping team. "It made more sense to construct a series of increasingly comprehensive gene maps that geneticists around the world can put to good use."

In a separate article appearing in the same issue of Science, Dr. Lander explores further the significance of this new resource and speculates about the "post-genome world," proposing 10 goals for the future of biology. (For details see release "Beyond Sequencing.")

The U.S. Human Genome Project has established a goal of completing the gene map and sequencing the 3 billion DNA building blocks by year 2005. The unified gene map, put together in the past 18 months, attains one fifth of this goal and ensures that researchers will be able to achieve the goal comfortably.

A major contribution to this effort came from the Whitehead Institute. Last year, the Whitehead Institute and Genethon announced a comprehensive map of more than 15,000 landmarks called sequence tagged sites or STSs that span 95 percent of the human genome. The integrated map provided researchers the framework for the gene map. Of the 16,000 human genes mapped in this paper, more than 9,000 were mapped at the Whitehead Institute.

The work reported in this paper greatly increases the number of mapped human genes. At the end of 1994 there were a little more than 5000 mapped human genes according to the Genome Data Base. The number of mapped genes has tripled in the last 22 months since this project started.

This first edition map also reveals some interesting, albeit preliminary, details about the distribution of human genes among the 23 chromosomes. The researchers observed, for example, that chromosomes 1, 17 and 19 were gene-rich and that chromosomes 4, 13, 18, 21, and X were gene-poor—a finding consistent with those of the earlier Whitehead map.

One of the foremost applications of the gene map will be in positional cloning--a method commonly used for searching disease genes. In this time-consuming method, researchers study a number of affected families to narrow the location of the disease gene to a specific region on a given chromosome. They then use the several pieces of overlapping DNA clones within the suspected region to identify genes contained in the region. These genes are then scrutinized for the presence of sequence mutations in affected individuals. "By providing an inventory of all candidate genes within that region, gene maps will make positional cloning more efficient," says Dr. Lander. But the value of gene maps will extend beyond facilitating gene searches. They will shed light on genome organization, provide information about clustering of related genes, and tell us more about conservation of gene order among species.

Raw Material for the Periodic Table

In the decade since the Human Genome Project was launched, dozens of genome centers and labs around the world have been working on diverse aspects of the genome project, using a variety of approaches. The result has been an explosion of information in the form of banks of DNA sequences, collections of clone libraries, varieties of mapping techniques, and comprehensive genetic and physical maps. By early 1995 these resources had reached a stage where they provided scientists the tools needed to construct a preliminary gene map. "But creating this gene map meant integrating the rich, diverse, and often redundant information into a unified and common frame of reference," says Dr. Lander. In 1995, an international consortium was formed to tackle this formidable task.

Creating the Gene Map

To construct the gene map, researchers needed two tools: a large database of genes and an efficient mapping methodology. The consortium began by organizing the collection of more than 450,000 random pieces of DNA sequences called expressed sequence tags or ESTs from GenBank. The researchers grouped similar sequences into unique families called unigenes, with one unigene representing one gene. To make mapping more efficient and cost effective, researchers selected a single "signature" sequence from each unigene, compared these signature sequences with sequences of known genes and developed an information resource—a catalog called Unigene.

Next, the scientists developed a global mapping methodology by integrating the various mapping efforts and approaches into a common framework map based on STS or sequence tagged sites. STS are short fragments of DNA that tag a unique position in the human genome. Each STS landmark is defined by a special chemical test called a polymerase chain reaction (PCR) assay. "The great 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.

"We selected reference genetic markers from the Whitehead-Genethon map to create a framework or skeleton map and divided the genome into 1000 intervals," says Dr. Hudson. "The physical mapping data obtained for each unigene (gene-based STS marker) was used to identify the genetic interval and the radiation hybrid and yeast artificial chromosome or YAC maps helped verify the proximity and order of the genes." The whole project was completed in 18 months.

The Human Genome Project

The human genome—the full set of genetic instructions that make up a human being—is estimated to have 50,000 to 100,000 genes. These genes, spelled in the 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. A decade ago, the U.S. government launched the Human Genome Project (HGP), a 15-year, $3 billion effort to decipher the location and sequence of all these genes. The reasoning was that a catalog of all human genes would usher in a new era of molecular medicine, with extraordinary opportunities to diagnose, treat, and prevent disease. Already, the Human Genome Project has led to the discovery of genes responsible for Alzheimer's disease, Huntington's disease, cystic fibrosis, breast cancer, colon cancer, Lou Gehrig's disease, and many other disorders.