The news that researchers had sequenced the first human chromosome (22) marks the first milestone in the Human Genome Project (HGP), which is now racing to map the entire genome (Nature 1999;402:489-95). The announcement, made Dec. 2, may seem esoteric to physicians in everyday clinical practice, but it is a portent of the genetic knowledge that is going to transform medicine. Ultimately, human genome sequencing will allow physicians to concentrate on prevention instead of focusing on treatment.
"The 21st century will be the era of genetic medicine," says Dr. Richard Bruskiewich, a Canadian medical geneticist working at the Sanger Centre in Cambridge, UK, where a third of the international HGP sequencing research is being done. "Sequencing now allows us to 'look under the hood' to identify all the components of the biological system, and hence their interactions with each other and the environment." Bruskiewich, who specializes in bioinformatics, the computational analysis of biological systems, is a coauthor of the Nature paper. FIGURE
Chromosome 22, the second smallest human chromosome, is thought to be associated with at least 27 human disorders (see sidebar); causative genes in 8 of them - including schizophrenia - remain to be discovered.
By summer, the draft sequence of about 90% of the entire human genome is slated to be finished; refining the draft sequences into a finished reference sequence and sequencing the remaining 10% - the most difficult - will take another 2 to 3 years. The full sequence will identify the 200 000 to 300 000 proteins that direct the formation of a human being.
The 5-year-old HGP involves hundreds of researchers, mainly in 5 sequencing centres in the US and England but also in smaller centres in Europe, Japan and China. Canada will soon play a larger role with the start-up of the BC Cancer Agency's Vancouver Millennium Genome Sequence Centre.
In the HGP's clone-by-clone sequencing strategy, each DNA fragment is cloned and propagated by inserting it into the genome of a bacterial artificial chromosome (BAC) or a bacteriophage P1 artificial chromosome (PAC). Each BAC or PAC is 40 000 to 400 000 base pairs long, and these base pairs are then sequenced - or rearranged in the order in which they occur on the chromosome. During the mapping of chromosome 22, researchers sifted through 33.4 million base pairs of DNA and identified 545 genes, which contain instructions on creating specific proteins. The sequence is not quite complete; for technical reasons there are 11 gaps.
Although the number and location of the vast majority of genes are the same, sequence variation - for example, single nucleotide polymorphisms (SNPs) - give humans individual characteristics and genetic disorders, including predisposition to various diseases. Once researchers know which genetic variations of the estimated 3 million SNPs are involved in a particular disorder such as diabetes, heart disease or stroke, they can warn people who are at risk to avoid environmental triggers. Prevention, rather than treatment, will become the cornerstone of modern medicine. Information from the human genome sequence may also eventually allow researchers to predict and correct some developmental disorders.
"A complete patient history will eventually include a characterization of the patient's genotype that contributes to disease susceptibility and modulates the patient's response to therapies," says Bruskiewich. "The biggest challenge lying ahead for physicians is how to integrate this overwhelming body of new genetic knowledge effectively into daily practice. I would like to know what physicians think they need to achieve this task."
Geneticist Heather McDermid, who led the only Canadian research team contributing to the Nature paper, believes that "this is the start of a big boom in genetic research." McDermid, along with a technician and graduate student at the University of Alberta, mapped the cat-eye syndrome region, associated with a genetic duplication, and the 22q13 deletion syndrome region, associated with a genetic deletion. Cat-eye syndrome can lead to heart, eye, kidney and facial defects, anal atresia and mild mental retardation. The deletion syndrome causes mental retardation and loss of expressive speech.
The HGP is 1 of 2 research groups racing to complete the sequencing of the human genome. Celera Genomics Systems, a private company in Rockville, Md., started sequencing in September using the "whole genome shotgun" method. With this aproach, researchers shatter the entire genome into fragments and read them simultaneously by feeding them into a supercomputer. Aside from methodology, the other major difference between the 2 groups is that Celera sells its information, while the HGP presents all its findings free to the public (www.ncbi.nlm.nih.gov/genemap99/). "The human genome is the common property of all humankind, not just of those who can afford to pay for the information," emphasizes Bruskiewich. "The imposition of any embargo upon that free exchange stifles the progress of scientific understanding."