Hidden secrets on the nature and timing of genome evolution in mammals revealed

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News-Medical.Net 21-Jul-2005

Hidden secrets on the nature and timing of genome evolution in

mammals revealed

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 A. Lewin of the University of Illinois at

Urbana-Champaign and J. 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, " 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 , 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, 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.

" 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 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, " said 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

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 others not. "

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