Scientists Compare Rat Genome
With Human, Mouse
Analysis Yields New Insights into Medical
Model, Evolutionary Process
BETHESDA, Md., Wed., March 31, 2004 – An international
research team, supported by the National Institutes
of Health (NIH), today announced it has completed
a high-quality, draft sequence of the genome of the
laboratory rat, and has used that data to explore
how the rat’s genetic blueprint stacks up against
those of mice and humans.
In a paper published in the April 1 issue of the journal
Nature, the Rat Genome Sequencing Project
Consortium describes its efforts to produce and analyze
a draft sequence of the Brown Norway strain of the
laboratory rat (Rattus norvegicus). The project,
led by the Human Genome Sequencing Center at Baylor
College of Medicine in Houston, was primarily funded
by the National Heart, Lung and Blood Institute (NHLBI),
$58.5 million, and the National Human Genome Research
Institute (NHGRI), $60 million.
“This is an investment that is destined to yield
major payoffs in the fight against human disease,”
said NIH Director Elias A. Zerhouni, M.D. “For
nearly 200 years, the laboratory rat has played a
valuable role in efforts to understand human biology
and to develop new and better drugs. Now, armed with
this sequencing data, a new generation of researchers
will be able to greatly improve the utility of rat
models and thereby improve human health.”
Areas in which rat models have already helped to advance
medical research include: cardiovascular diseases
(hypertension); psychiatric disorders (studies of
behavioral intervention and addiction); neural regeneration;
diabetes; surgery; transplantation; autoimmune disorders
(rheumatoid arthritis); cancer; wound and bone healing;
and space motion sickness. In drug development, the
rat is routinely employed to demonstrate therapeutic
efficacy and assess toxicity of drug compounds prior
to human clinical trials. The genome sequence will
facilitate all of these studies, as well as help researchers
better pinpoint the crucial areas of biological difference
between rats and humans.
“This is an era of extraordinary biomedical opportunities
in genomic research. As a result of this significant
achievement, the rat model is poised to be at the
forefront of discovery, providing insight into human
health and new treatments for human diseases,"
said NHLBI Acting Director Barbara Alving, M.D.
The rat sequence draft, which covers more than 90
percent of the genome, represents the third mammalian
genome to be sequenced to high quality and described
in a major scientific publication. A draft of the
human genome sequence was published in February 2001,
and the completed human sequence was announced in
April 2003. A draft of the mouse genome sequence was
published in December 2002. The availability of a
third mammalian genome sequence gives scientists the
ability to triangulate data to better resolve details
of human biology, as well as mammalian evolution.
“The sequencing of the rat genome constitutes
another major milestone in our effort to expand our
knowledge of the human genome,” said NHGRI Director
Francis S. Collins, M.D., Ph.D. “As we build
upon the foundation laid by the Human Genome Project,
it’s become clear that comparing the human genome
with those of other organisms is the most powerful
tool available to understand the complex genomic components
involved in human health and disease.”
In addition to Baylor College of Medicine, the Rat
Genome Sequencing Project includes: Celera Genomics
Group of the Applera Corp., Rockville, Md.; Genome
Therapeutics Corp., Waltham, Mass.; the Genome Sciences
Centre, British Columbia Cancer Agency, Vancouver,
British Columbia; The Institute for Genomic Research,
Rockville, Md.; The University of Utah, Salt Lake
City; Medical College of Wisconsin, Milwaukee; The
Children’s Hospital of Oakland Research Institute,
Oakland, Calif.; and the Max Delbrück Center
for Molecular Medicine, Berlin. In addition to the
NIH funding, additional private funding was provided
to Baylor by the Kleberg Foundation.
After the rat genome sequence was assembled at Baylor,
an international team, comprised of more than 20 groups
in six countries, conducted a three-way analysis comparing
the rat sequence data with similar data from the mouse
and the human. In addition to the paper in Nature,
the team is publishing an additional 30 papers in
the April issue of the journal Genome Research,
which describe the analyses in greater detail.
“Future work aimed at identifying the genomic
differences that contribute to the evolution of physical
traits may benefit from analyses such as these, which
will become more powerful as the repertoire of mammalian
genome sequences expands,” said Richard Gibbs,
Ph.D., director of the Baylor College of Medicine’s
Genome Sequencing Center and principal investigator
of the Rat Genome Sequencing Project.
In their Nature paper, the researchers reported
that, at approximately 2.75 billion base pairs, the
rat genome is smaller than the human genome, which
is 2.9 billion base pairs, and slightly larger than
mouse genome, which is 2.6 billion base pairs. However,
they also found that the rat genome contains about
the same number of genes as the human and mouse genomes.
Furthermore, almost all human genes known to be associated
with diseases have counterparts in the rat genome
and appear highly conserved through mammalian evolution,
confirming that the rat is an excellent model for
many areas of medical research.
Comparison of the rat genome to those of the human
and mouse also opens a new and unique window into
mammalian evolution. The rodent lineage, which gave
rise to the rat and mouse, and the primate lineage,
which gave rise to humans, diverged about 80 million
years ago. Humans have 23 pairs of chromosomes, while
rats have 21 and mice have 20. However, the new analysis
found chromosomes from all three organisms to be related
to each other by about 280 large regions of sequence
similarity – called “syntenic blocks”
– distributed in varying patterns across the
organisms’ chromosomes.
The sequence data also confirms that the rodent lineage
split 12 to 24 million years ago into the separate
lines that gave rise to the rat and to the mouse.
Researchers estimate about 50 chromosomal rearrangements
occurred in each of the rodent lines after divergence
from their common ancestor. The number of chromosomal
rearrangements, as well as other types of genome changes,
was found to be much lower in the primate lineage,
indicating that evolutionary change has occurred at
a faster rate in rodents than in primates.
The new analysis also underscores the fact that while
rats and mice look very similar to the human eye,
there are significant genomic differences between
the two types of rodents. For example, some aspects
of genomic evolution in the rat appear to be accelerated
when compared to the mouse. According to the new analysis,
due to the unusually rapid expansion of selected gene
families, rats possess some genes not found in the
mouse, including genes involved in immunity, the production
of pheromones (chemicals involved in sexual attraction),
the breakdown of proteins and the detection and detoxification
of chemicals.
To achieve its goal of producing a high-quality draft
sequence, the Rat Genome Sequencing Project developed
a new, “combined” approach that used both
whole genome shotgun (WGS) and bacterial artificial
chromosome (BAC) clone sequencing techniques. To merge
these into the final draft sequence, the Baylor group
developed the Atlas software package for
genome assembly. The resulting genome sequence was
contained in 291 large segments, with a typical length
of 19 million bases. Moreover, the structure of the
3 percent of the genome that contains recent duplications
– thought to be the regions in which many genes
are “born” – was determined by the
Atlas assembler. These statistics match or
exceed other draft genome sequences. Overall, the
combined approach takes advantage of strengths of
both the WGS and BAC methods.
A high-resolution photo of the Brown Norway strain
of the laboratory rat is available at: www.genome.gov/10005141.
NHGRI and NHLBI are two of the 27 institutes and centers
at the NIH, which is an agency of the Department of
Health and Human Services. For more on comparative
genomic analysis, go to: www.genome.gov/10005835.
Additional information about NHGRI can be found at
its Web site: www.genome.gov.
Additional information about NHLBI can be found at
its Web site: www.nhlbi.nih.gov.
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