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 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 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 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," 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 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, 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 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 evolve.
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.