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Genome Road Map Points the Way

By Sean Henahan, Access Excellence

Washington, DC (2/12/01)- The historic publication of the human genome sequence in two leading science journals, Science and Nature, on Charles Darwin's birthday, offers a new and improved road map of the genetic structure of Homo Sapiens. While the road map highlights some well known genetic landmarks there are still many roads to explore that will help elucidate everying from the causes of cancer to heart disease to the origins of humanity itself.

"This stunning accomplishment, representing the most accurate human genome sequence ever completed, offers new and exciting prospects for targeting new medical improvements. It can tell us much our place in the diverse panorama of life," said Donald Kennedy, Editor-in-Chief of the journal Science.

The latest human genome data reveals that the total number of genes for our species is around 30,000, far fewer than previously predicted. Indeed this is only 13,000 more genes than are contained in the the common fruitfly genome. The data confirm that humans of all races and ethnic backgrounds share 99.99 percent of the same genetic code. Individual variations comprise only 0.01 percentof the entire sequence, which includes 2.91 billion base pairs.

Junk DNA?

So far it appears that genes tend to cluster along just a few of the chromosomes (e.g. 17, 19, 22) while others appear quite barren. Researchers have long been puzzled by that fact that nearly one quarter of the human genome contains sequences that lack protein-coding genes, so-called junk DNA. . About one-fourth of the genome could be considered deserts, with lengthy gene-free segments. More than a third of the genome (35.3 percent) contains repetitive sequences, suggesting that this so-called "junk DNA" deserves further study. In addition to repeated segments, there is also renewed interest in the 2.1 million scraps of DNA known as SNPs, or single nucleotide polymorphisms. While the new data suggest most of these are harmless, some may underlie certain disease processes.

The discovery that the human genome may only contain around 30,000 genes is one of the most surprising findings of the world wide research effort. The good news is that this may make it easier to identify the functions of the genes, any of which could be promising targets for drug development. However researchers are already moving away from the 'one gene- one protein' idea to the study of complex interactions between genes that appear to have different functions in different contexts. Now that the basic structure of the genome has been identified, it opens the way for an even more complex area of study functional genomics, dedicated to finding out the function of single and multiple interactive genes.

Some 90 percent of structural units found in human proteins, are also found in fruitfly and worm proteins. Yet more than a third of the proteins in yeast, fruitflies, worms and humans show no strong similarity across species. This suggests that these proteins might have similar functions but different structure; or they might show species-specific functions. Another possibility is that these proteins could have an as yet unidentified evolutionary mechanism for maintaining themselves that is independent of their precise sequence, notes Gerald M. Rubin, Vice-President for biomedical research at the Howard Hughes Medical Institute and director of the Berkeley Drosophila Genome Project, in a commentary in Nature.

"A good analogy is that these genes are like a set of LEGOs, the children's blocks. With the same simple set of units, you could build a complete scale model of the Vatican or you could build a log cabin," said Rubin..

Taking a broader view, other investigators are beginning to look at how tens of thousands of genes eventually form an organism. This field, known as proteomics, is considered to be the next big step beyond structural and functional genomics. Researchers in this field will build on the discoveries produced by the structural and functional genomics investigators. The challenge now will be to stop thinking about one gene at a time and start trying to understand the whole set at once as a complex system- to think about how such a small number o f genes can generate a fly or a person. Ongoing research should further investigate the functions of repetitive DNA, the regulation of gene expression, protein interactions, signaling, effects of the environment, and other mechanisms that may contribute to an organism's complexity," Barbar Jasny, senior editor at Science.

Science vs Nature?

The simultaneous publications in the journals Science and Nature reflect the ongoing, sometimes competitive, efforts of two separate research coalitions. The report in Science is the result of work done by the commercial biotech company Celera, who hope to profit someday by patenting and selling genomic data. The group includes 282 investigators from the US, Australia and Spain. Using a 'whole genome shot gun' strategy, the Celera team first break apart the genome with restriction enzymes, and then piece it together with the help of massive arrays of DNA sequencers and super computers, linking overlapping sequences to known locations on the genome.

At the same time another international collaboration published data in Nature of the human genome sequence arrived at by a different approach. The international nonprofit effort approached the challenge by duplicating pieces of the genome using bacterial artificial chromosomes (BACs). These human DNA clones can be copied and analyzed. These sequences are placed in an overlapping series that covers most of the gene-containing portion of the 3.2 billion base pairs of the genome.To ensure accuracy in the final map, the researchers created enough overlapping clones to cover the entire genome roughly 20 times.

"If you have a large, complicated jigsaw puzzle of, say, a forest scene, a number of trees may look alike," says John D. McPherson, Ph.D., corresponding author of the paper. "Making this map was like simplifying that large puzzle by dividing it up into many small puzzles, each containing one tree, then putting all the pieces of the small puzzles together, and in turn putting all the small puzzles together to make the whole forest. That way, you can build one tree at a time, and then integrate them into the whole picture." explained John D. McPherson, Ph.D., co-director of the Washington University Genome Sequencing Center, whose work appears in the Nature human genome issue.

How do the two approaches compare? In the same issue of Science another group of researchers compared the data compiled by the battling groups at Celera and the Human Genome Project. That work suggests that the two approaches may well be complementary. Michael Olivier and colleagues prepared a physical map of the human genome, called a radiation hybrid map, that places the genetic sequence in order along each chromosome. Interestingly, this physical map revealed that although there was good agreement in parts of the sequencing efforts. significant differences in the two maps did exist. Moreover, in some cases the Celera data appeared to be more accurate, while in other cases the HGP data appeared more precise.

That research underscores the point that, as impressive as the human genome sequence data is, it is still a fairly rough draft of 95% of the genome. The sequence is not a a complete end-to-end sequence of every gene on every chromosome. Both the version produced by the Celera group and the Human Genome Project team contain notable gaps that still need to be filled, meaning that there is still plenty of work to be done. Indeed, it seems that this may be one benefit of having two competing of researchers producing results using different approaches.

Nonetheless, the sequencing of the human genome, albeit incomplete, is already helping researchers to understand the genetic component of cancer, heart disease and other human ailments. New genetic screening tests will probably be the first commercial products of the genomic revolution. Researchers are also in the early stages of developing more specific treatment approaches based on individual genetic data. Ultimately, it is likely that genomic research will produce a variety of new vaccines and genetic therapies.

Handle with Care

Politicians and civil libertarians are also following the latest genomic developments. Concerns are already growing about individual privacy rights, ethical issues about how genetic data is gathered and compiled and the risks of genetic discrimination by employers and insurers. Writing in the special genome issue of Science, two US Senators (J. M. Jeffords (R-Vermont) and Senator T. Daschle (D-South Dakota)). warn: "Without adequate safeguards, the genetic revolution could mean one step forward for science and two steps backwards for civil rights."

"This assembly of the human genome sequence is but a first hesitant step on the long and exciting journey towards understanding the role of the genome in human biology. There are two fallacies to be avoided: determinism, the idea that all characteristics of a person are 'hard wired' by the gebnome; and reductionism, that now the human sequence is completely known it is just a matter of time before our understanding of gene functions and interactions will provide a complete causal description o f human variability," note the Celera researchers.

The human genome research appears in the February 15, 2001 issue of Nature and the February 16 issue of Science. Both issues were released early.


Related information on the Internet
Science Journal Online
(Free Access to Genome Articles)
Nature Journal Online
(Free Access to Genome Articles)

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