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Comparative chromosome study
finds breakage trends, cancer ties
Barlow, Life Sciences Editor
photo to enlarge
Automated Learning Group, NCSA
multi-species chromosome comparison was aided by a
computer visualization tool – the “Evolution
Highway”– developed by collaborators in
the Automated Learning Group at the National Center
for Supercomputing Applications at Illinois.
— Breakages in chromosomes in mammalian evolution have occurred
at preferred rather than random sites as long thought, and many of the
sites are involved in human cancers, an international team of 25 scientists
The researchers, reporting in the July 22 issue of the journal Science,
also found that chromosomal evolution has accelerated, based on the
rate of breakages and reorganization, since the extinction of dinosaurs
65 million years ago.
In a study led by Harris A. Lewin of the University of Illinois at Urbana-Champaign
and William J. Murphy of Texas A&M University, the organization
of chromosomes of humans, mice, rats, cows, pigs, dogs, cats and horses
was compared at high resolution.
“This study has revealed many hidden secrets on the nature and
timing of genome evolution in mammals, and it demonstrates how the study
of basic evolutionary processes can lead to new insights into the origin
of human diseases,” said Lewin, the director of the Institute
for Genomic Biology at Illinois and a professor of animal sciences.
The multi-species comparison was aided by a computer visualization tool
– the “Evolution Highway”– developed by collaborators
in the Automated Learning Group at the National
Center for Supercomputing Applications at Illinois. Other lead participants
were from the University of California, San Diego, and the Genome Institute
photo to enlarge
of Illinois Photo
Lewin, the director of the Institute
for Genomic Biology at Illinois and a professor of
animal sciences, and colleagues at Illinois and Texas
A&M University, compared the organization of chromosomes
of humans, mice, rats, cows, pigs, dogs, cats and
horses at high resolution.
of evolution since dinosaurs disappeared surprised the researchers,
who studied a computer-generated reconstruction of genomes of long extinct
mammals, including the ancestor of the majority of living placental
mammals of 94 million years ago.
“Based on our findings of the mammalian rate speed-up, we postulate
that early mammals, with conservative body plans, retained fairly conserved
genomes, as evidenced in the striking similarities in the reconstructed
ancestral genomes,” Murphy said.
“The widespread origin and diversification of most mammalian orders
after the K-T extinction, due to exploitation of new ecological niches,
may have facilitated isolation and opportunities for the fixation of
karyotypic differences,” said Murphy, a professor of veterinary
The K-T extinction occurred 65 million years ago as the Cretaceous Period
closed and the Tertiary Period began. The Cretaceous-Tertiary Boundary,
a defining moment marked throughout the world by a thin layer of iridium-rich
clay between the rocks of the two periods, is believed to have resulted
from a massive comet or asteroid strike.
The study’s data, Murphy added, provide a potential link between
post-K-T isolation and the accelerated development of species-specific
chromosomes. Since the K-T extinction, rates of chromosomal evolution
among the species have increased from two-to-five fold, the researchers
Rates of changes were obtained by analyzing the placements of breakpoints
in the genomes of the species studied. A breakpoint is where one chromosome
has split and the DNA is rearranged by the insertion of a piece from
another chromosome or a different part of the same chromosome.
Breakpoints have been implicated as potentially major triggers for cancers
and many other human diseases. “We looked closely at these breakpoints,
asking if there are specific DNA signatures in these regions,”
Lewin said. “The answer is, we still don’t know, but in
the human there is a high frequency of segmental duplication around
the sites of breakage. We are interested in characterizing the genes
and their functions in these regions.”
The multi-species comparison showed significant overlapping with breakpoints
that occur in a variety of human cancers, Lewin said. “While more
work needs to be done to clarify this relationship, it is clear that
the overlap is real, and that there is likely to be biological significance
to this discovery.”
The researchers theorize that chromosome rearrangements that result
in the activation of cancer-causing genes are related to the propensity
of chromosomes to break and form new combinations as new mammalian species
In all, 1,159 pair-wise breakpoints were found among the genomes of
human and six non-primate species. Using a bioinformatics tool, researchers
aligned and compared the breakpoints across species and constructed
an evolutionary scenario for chromosomal rearrangements among all genomes
and ancestors. They found 492 evolutionary-specific breakpoints and
analyzed them for segmental duplication; 40 breakpoints were considered
to be primate specific.
“Understanding the features of the DNA sequence in and around
the evolutionary breakpoint regions is of key importance in determining
why chromosomes break in specific regions,” said Denis Larkin,
a visiting animal scientist at Illinois and a principal author.
The researchers found that chromosomes tend to break in the same places
as species evolve. Evidence for such a pattern had been suggested previously
by Larkin and Lewin and by study co-authors Pavel A. Pevzner and Glenn
Tesler, both of the University of California, San Diego. However, the
new study is the first to show the phenomenon on a genome-wide basis
by multi-species comparison.
“Finding rearrangement hotspots in mammalian genomes is a paradigm
shift in the study of chromosome evolution,” said Pevzner, a professor
of computer science. The next important questions, he added, involve
what it is that makes some regions fragile and how fragility in an evolutionary
context is related to fragility in cancer.
The regions immediately flanking breakpoints, they discovered, have
more genes than the rest of the genome on average.
“One of the most gene dense regions of the human genome,”
the authors wrote, “is characterized by recurrent breaks in different
mammalian lineages (dog, cat, cattle, rodents), marked by large amounts
of gene turnover and variation in centromere placement.”
(Centromere refers to highly condensed and constricted regions of chromosomes,
where spindle fiber is attached during mitosis.)
Scientists at several other institutions contributed key genome-mapping
information to the project.
Mapping data for the dog genome was provided by scientists at the U.S.
National Human Genome Research Institute and French National Center
for Scientific Research (CNRS). Cat-mapping data was contributed by
the U.S. National Cancer Institute.
Scientists at Illinois, Texas A&M University and the National Institute
for Agricultural Research in France provided genome maps of cattle,
horses and pigs. The genome maps of humans, mice and rats were available
from public sources.
“None of this would have been possible without the strategic investments
by the National Institutes of Health and by the U.S. Department of Agriculture
in the genome projects of humans, model and agriculturally important
organisms,” Lewin said. “It’s a perfect example of
the unity of biology when studied at the level of DNA. Many more surprises
await us as we relate genomes to biology, and these surprises will lead
to better understanding of how species evolve and what peculiarities
in their genomes cause one species to have a high rate of cancer and