Comparative chromosome study finds breakage trends and cancer ties

Urbana-Champaign 25 July 2005Breakages 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 has discovered. 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 reorganisation, since the extinction of dinosaurs 65 million years ago.

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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 organisation 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", stated Harris 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 at San Diego and the Genome Institute of Singapore.

The acceleration 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", William Murphy stated. "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", stated William Murphy, a professor of veterinary integrative biosciences.

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, Professor 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 reported.

Rates of changes were obtained by analysing 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", Professor Lewin stated. "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, Professor Lewin stated. "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 evolve.

In all, 1159 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 analysed 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", stated 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 Denis Larkin and Harris Lewin and by study co-authors both of the University of California at 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", stated Pevzner, a professor of computer science at the University of California at San Diego. 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 United States National Human Genome Research Institute and French National Center for Scientific Research (CNRS). Cat-mapping data was contributed by the United States 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 United States Department of Agriculture in the genome projects of humans, model and agriculturally important organisms", Professor Lewin stated. "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 others not."


Leslie Versweyveld

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