In April 2000,
in Walnut Creek, California, researchers from three DOE national laboratories
completed the draft sequencing of human chromosomes 5, 16, and 19 for
the Human Genome Project. These were not the first chromosomes to be
sequenced; the first was chromosome 22, whose order of DNA bases was
published in December 1999 by a group of institutions funded by the
National Institutes of Health (NIH). However, these were the first human
chromosomes to be sequenced by DOE's Joint Genome Institute (JGI), which
integrates the genome centers at the Lawrence Berkeley, Lawrence Livermore,
and Los Alamos national laboratories with informatics and functional
genomics capabilities at ORNL.
ORNL supports
JGI by computationally analyzing DNA sequences to locate known genes,
predict unknown genes, and estimate the functions of many of these genes.
It is known that chromosomes 5, 16, and 19, which make up roughly 11%
of the human genome, contain genes that are linked to kidney disease,
various cancers, hypertension, and diabetes.
In addition, through
its Web site, called the Genome Channel,
ORNL provides new information every month on the latest DNA sequences
obtained experimentally (including partial and whole sequences of human
chromosomes) and their computationally identified genes.
The Genome Channel
is a Web browser tool that provides a comprehensive sequence-based view
of parts of the human and mouse and several complete microbial genomes.
This information resource is being used by many people worldwide, ranging
from biomedical researchers at NIH and the Massachusetts Institute of
Technology to scientists who are developing drugs at some of the world’s
largest pharmaceutical companies. The Genome Channel, which has about
100,000 hits per month, was listed among five "hot pick" Web sites in
the December
17, 1999, issue of Science magazine.
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A
view of the Genome Channel home page on the World Wide Web.
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A researcher interested
in developing a drug to control Parkinson's disease or cancer can get
relevant information from the Genome Channel by typing in a class of
genes, such as "caspase," in the search space. "Caspase genes control
cell death," says Ed Uberbacher, head of the Computational Biosciences
Section in ORNL's Life Sciences Division. "In Parkinson’s disease, cells
die when they shouldn't, and in cancer, cells grow and spread instead
of dying when they should."
Regulatory proteins are
of interest to researchers because they control the activity of a host
of genes, turning some on and others off, thus affecting the types and
levels of proteins produced. The Genome Channel provides information
on regulatory proteins as well as up-to-date lists of many important
gene types, based on the most recent ORNL analysis.
Uberbacher was
one of the developers of the Gene Recognition and Analysis Internet
Link (GRAIL) computer program. Among other things, GRAIL is known for
having helped researchers locate the gene responsible for Adrenoleukodystrophy
(related to the disease featured in the movie Lorenzo's Oil).
The updated version of GRAIL, called GRAIL EXP, is available to users
of the Genome Channel.
"Using ORNL's
IBM SP supercomputer, our programs search the databases for expressed
sequence tags," Uberbacher says. "These are fragments of gene sequences
that resemble or match DNA sequences we are interested in analyzing.
Using these sequences as evidence, we can identify and locate genes
along the human genome. By knowing the gene sequence, we can then predict
the amino-acid sequence of the gene's protein product. By matching the
sequence to known protein sequences in a database, we can often predict
the biochemical function of the protein.
"We link gene
sequences computationally to genetic maps of chromosomes showing markers,
or known locations along a chromosome, that are tied to known biological
functions. By doing this data mining, we can predict a function for
a particular gene sequence of interest."
According to Uberbacher,
ORNL researchers will estimate two-thirds of the functions of the genes
that make up the sequenced chromosomes. "We will be able to predict
that a gene's protein product catalyzes a particular biochemical reaction,"
he explains. "But to find out what the gene actually does in the organism,
we will rely on ORNL biologists studying the effects of mutations of
a similar gene in the equivalent chromosome in mice. For example, the
biologists might find that the gene affects embryonic development."
To get updates
on the latest findings concerning human chromosomes 5, 16, and 19, stay
tuned to the Genome Channel (compbio.ornl.gov).
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