For Immediate Release
BETHESDA, Md. - Researchers today published a detailed, physical map of human chromosome 22. It provides sequence markers over an estimated 70 percent of the chromosome. With this map, scientists have gained a vastly improved roadmap to explore this gene-rich chromosome that holds important clues into the causes of several cancers and numerous syndromes of embryonic development.
Today's paper also marks the publication of the third, comprehensive physical map of a human chromosome, a major goal of the international Human Genome Project (HGP). Similar chromosome-wide maps have been published for chromosomes Y and 21, and several other physical maps will be published in the near future.
A physical map establishes the connections between two recognized sequences on a chromosome. These sequences, like mileage signs on a highway, tell researchers where they are on the chromosome and how far they need to travel to reach another tagged sequence. The shorter the distance is between tagged sequences, the easier it is for scientists to find their way around the chromosome in search of disease-causing gene mutations.
Constructed in overlapping, cloned segments of the chromosome, called YAC contigs, a physical map offers greater resolution than the initial genetic map, which yields general marker order, but much less resolution than the actual sequencing of the chromosome.
The new map, published in this month's Human Molecular Genetics, is the product of an ongoing collaborative effort between researchers at The Children's Hospital of Philadelphia and the Whitehead Institute, two of the National Human Genome Research Institute's (NHGRI) Genome Science and Technology Centers (GESTEC). Data used to construct the map may be viewed on the World Wide Web.
"Our map provides information that is of immediate use to anyone who is looking for genes and disease-causing rearrangements on this chromosome," said Beverly Emanuel, Ph.D., one of the paper's authors who heads the GESTEC and the Division of Human Genetics and Molecular Biology at The Children's Hospital of Philadelphia.
Eric Lander, Ph.D, director of the Whitehead Institute/MIT Center for Genome Research, added, "All of the long hours spent screening DNA sequences has really paid off nicely in this chromosome map."
Chromosome 22 is the third smallest human chromosome, spanning an estimated 50 million base pairs. It contains genes involved in numerous cancers, including Ewing's sarcoma, Burkitt's lymphoma, meningiomas, acoustic neuromas and acute lymphoblastic leukemia. Recent reports also have suggested that the chromosome may contain a tumor suppressor gene involved in breast cancer.
The chromosome also is of great research interest because of the many developmental conditions already linked to it. These include Cat Eye Syndrome, DiGeorge Syndrome, isolated congenital heart defects and velocardiofacial syndrome.
To date, over 100 genes and pseudogenes have been mapped to chromosome 22, but researchers estimate that the chromosome may contain as many as 2,000 genes. "In one 250 kb region, there are at least nine genes closely packed together," said Dr. Emanuel.
In December 1993, a group of French investigators published a first generation, or rough draft, physical map of the entire human genome. Today's published map builds on this baseline effort, providing considerably more mileage signs, or sequence tagged sites (STSs), on chromosome 22. It consists of 15 contigs, with each contig containing between two and 74 STSs.
The map is most densely tagged between chromosome bands 11.2 and 13.1 on the long arm of the chromosome. This area contains genes for Cat Eye Syndrome, DiGeorge Syndrome, Ewing's sarcoma, neurofibromatosis 2, isolated congenital heart defects, velocardiofacial syndrome and perhaps a form of schizophrenia.
"This physical map will greatly facilitate the study of this gene-rich region of chromosome 22," said Dr. Francis Collins, director of the National Center for Human Genome Research, which supported this project. "It should lead to gene discoveries and ultimately to better treatment of human disease."
Although chromosome 22 represents a small piece of the human genome, like Pennsylvania to the entire United States, the researchers found that traversing its complex, molecular terrain was no Sunday stroll through Independence Square.
The group relied heavily on STS-content mapping, a strategy akin to piecing together a jigsaw puzzle made up of hundreds of chromosome 22-specific STSs. Knowing ahead of time the approximate location on the chromosome of most STSs, like knowing the pattern and shape of a given puzzle piece, the researchers tried to order these markers on larger segments of the chromosome. By eventually joining together these larger segments, the researchers can form even longer, overlapping stretches (contigs) of the chromosome that contain numerous STSs.
Callum Bell, Ph.D., the paper's lead author, said that chromosome 22, like other human chromosomes, contains several regions that are unstable when cloned into existing vectors. This instability manifests itself in deletions and permutations that can complicate contig construction.
To streamline this process, Dr. Bell and colleagues used simulated annealing, a computer algorithm developed by David Searls of the University of Pennsylvania Medical School. Using Searls' algorithm, the researchers performed various computer runs that showed a series of possible marker orders, each equally valid. This approach helps to minimize "holes" in the map, while also showing the possible ambiguities in assigning marker order. Dr. Bell gave high marks to this approach.
Over the coming months, Dr. Emanuel said that the group will attempt to fill in the gaps in the map as efficiently as possible, in preparation for the sequencing of the chromosome.
Whitehead Institute Center for Genome Research [broadinstitute.org]
Editor's Note: Whitehead Institute/MIT Center is now Broad Institute.
National Human Genome Research Institute (NHGRI)
Last Updated: April 20, 2010