April 19, 2004
Analysis of rat genome holds clues to mammalian
By Branwyn Stewart Wagman
UCSC Center for Biomolecular Science & Engineering
In the four years since the first draft of the human genome sequence
was made available to researchers worldwide, scientists have scrambled
to make sense of the information it contains. One of the most promising
avenues involves sequencing the genomes of other species and comparing
them with the human genome to learn what makes each species unique and
what elements are common to many species.
The brown Norway strain of the laboratory rat (Rattus norvegicus)
is the third mammalian species to have its complete genome sequenced
to high quality and described in a major scientific publication.
Comparisons with the human and mouse genomes are yielding clues
to evolutionary and biomedical questions. Photo
courtesy National Human Genome Research Institute
Researchers at UCSC, led by professor of biomolecular engineering
David Haussler, have been at the forefront of this effort. Most recently,
they have been part of an international consortium of scientists involved
in the sequencing and analysis of the genome of the common laboratory
The primary results from the Rat Genome Sequencing Project Consortium
were published in the April 1 issue of Nature, and an additional
30 papers describing further detailed analyses appear in the April issue
of Genome Research.
The entire project involved an extensive network of research centers.
After the genome was assembled, an international team, representing
more than 20 groups in six countries, analyzed the results.
Haussler, who directs UCSC's Center for Biomolecular Science &
Engineering (CBSE), co-led the evolutionary analysis group, which also
included scientists at Stanford University, UC San Diego, UC Berkeley,
and Pennsylvania State University. Jim Kent, a CBSE research scientist,
directed the UCSC group that worked on the genome alignments and built
a rat genome browser. Haussler and Kent, along with nine others at UCSC,
joined more than 220 coauthors on the Nature paper.
Only two other mammalian genomes--the human and the mouse--have been
sequenced and analyzed to this extent. The study found the rat genome
contains some 2.75 billion DNA bases, which is intermediate in size
between the human genome (2.9 billion) and the mouse genome (2.6 billion).
"The sequencing and initial analysis of the rat genome confirms
some recent thinking about mammalian evolution and offers new insights,"
For example, the evolutionary analysis of the rat genome confirmed
earlier evidence that species evolve at different rates. As genomes
evolve, they accumulate changes such as insertions, deletions, and substitutions
of DNA bases. The idea of the molecular clock, introduced in 1967, assumed
that changes in DNA accumulate at approximately constant rates over
time. But this idea is contradicted by the comparison of the human and
rodent genomes, Haussler said.
"In the 75 million years since divergence from their common ancestor
with humans, the rodent line has accumulated substitutions at a faster
clip than the human line--almost 3 to 1," he said.
The researchers also found that the rat changes slightly faster than
the mouse, so there is not even a constant molecular clock among rodents.
Even though the mouse and rat have evolved independently, the changes
that have occurred in corresponding regions of their genomes are surprisingly
related between the two species. At present there is no clear explanation.
With three genomes to compare, researchers can now trace the evolutionary
history of each of the DNA bases with more accuracy. According to Krishna
Roskin, a graduate student in computer science, this gives scientists
new insights into evolutionary events.
"When something shows up in the genome of the rat, but not in
the mouse and the human, we can be fairly certain that it was a new
insertion in the rat DNA. On the other hand, when it shows up in both
the mouse and the human, but not in the rat, it was probably deleted
from the rat," Roskin said.
Rodents showed more substitutions, insertions, and deletions than the
human line. The evolutionary analysis team at UC San Diego also found
that as rodents have evolved, their genomes have been scrambled by large
segments moving from one chromosome to another. In contrast, the evolution
of the human genome during this time shows little evidence of such scrambling.
The actual mechanism whereby the genomes are scrambled is not fully
Not everything is faster to change in rodent DNA, though. The evolution
in the human lineage features more duplications of DNA segments.
Evolutionary analysis group members at Pennsylvania State University
found that about 1 billion of the 3 billion bases in each of the genomes
of rats, mice, and humans align with each other. These are thought to
be an "ancestral core" that has been retained in the three
species. These core 1 billion bases encode nearly all the genes and
their regulatory signals, accounting for the similarities among mammals.
In addition, 5 to 6 percent of the rat, mouse, and human genomes contain
specific regions that have stayed relatively free of changes. This confirms
an earlier estimate from comparing the mouse and human genomes before
the rat genome was available. While this portion of the genome appears
to be under constraint in rodents and primates, the rest of the genome
appears to be evolving neutrally. The conserved segments are thought
to code for and regulate critical functions of the organisms.
The three genomes encode similar numbers of genes, most of which have
persisted without deletion or duplication since the last common ancestor.
A selected few families of genes have been expanded in the rat, including
smell receptors and genes for dealing with toxins. These give clues
to the distinctive physiology of the species.
Almost all human genes known to be associated with diseases have counterparts
in the rat genome and appear highly conserved through mammalian evolution.
Biomedical researchers can mine this information for clues that could
lead to improvements in the diagnosis, prevention, and cure of disease.
"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."
Currently, the rat plays a major role in many areas of human medical
research, including surgery, transplantation, cancer, diabetes, psychiatry,
neural regeneration, wound and bone healing, space motion sickness,
and cardiovascular disease. In drug development, researchers use the
rat both to demonstrate therapeutic efficacy and to assess toxicity
of novel therapeutic compounds before human clinical trials. The rat
genome sequence will facilitate research in all of these areas.
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