Scientists Compare Rat Genome With Human, Mouse|
Analysis Yields New Insights into Medical Model, Evolutionary Process
Bethesda, Maryland 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
"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
"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
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
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
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.