Chromosome breakpoints contribute to genetic variation

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Chromosome breakpoints contribute to genetic variation

http://www.eurekalert.org/pub_releases/2009-04/uoia-cbc041709.php

A new study reveals that – contrary to decades of evolutionary thought –

chromosome regions that are prone to breakage when new species are formed are a

rich source of genetic variation.

The functions of genes found in these " breakpoint regions " differ significantly

from those occurring elsewhere in the chromosomes. This suggests that

chromosomal organization plays an important evolutionary role, the researchers

report.

The study, published in the journal Genome Research, is the first to show that

different parts of chromosomes can have very different evolutionary histories,

said University of Illinois animal sciences professor Lewin, who led the

research. Lewin directs the Institute for Genomic Biology and is part of an

international team that sequenced the cow genome.

" Our results demonstrate that chromosome breakage in evolution is non-random and

that the breakpoint regions and the more stable regions of chromosomes are

evolving in distinctly different ways, " he said.

When egg or sperm cells form in animals, maternal and paternal chromosomes first

pair up and then recombine. The chromosomes literally break and reattach to one

another. In most cases, the new chromosomes have the same arrangement of genes

as the parent cells, but with new combinations of maternal and paternal genes.

The " crossing over " of segments of maternal and paternal chromosomes to form

hybrid chromosomes has long been acknowledged as a driver of genetic variation.

Sometimes, however, the wrong chromosomes recombine, segments of chromosomes

become inverted or complete breakages and fissions occur. These rearrangements

may lead to genetic diseases or may contribute to the development of new

species.

Until now, scientists have been unable to determine how the organization of

genes along chromosomes and variation within the breakpoint regions contribute

to the evolution of an organism's genome, Lewin said. Breakages sometimes

disrupt genes or gene families that are regulated together, for example.

Deletions, insertions and inversions can cause subtle or dramatic changes in how

the genes function.

Scientists once hypothesized that chromosomal breakage and recombination

occurred randomly along the chromosomes during evolution. But in 2003, a team

from the University of California at San Diego and the Lewin laboratory reported

that the breakpoints occurred more often in specific chromosomal regions than in

others.

In 2004, Lewin and his colleagues reported a surprising finding: Breakpoint

regions also contain a higher density of genes than other parts of the

chromosome. In 2005, Lewin's team showed that breakpoint regions also have

higher numbers of segmental duplications, a type of mutation that increases the

copy number of genes and the sequences that flank them.

" To me, this was completely counterintuitive. I thought we would have these

breakpoints in gene deserts, " Lewin said. " We had to rethink the whole

evolutionary hypothesis about what was going on in breakpoints. "

In the new study, Denis Larkin, a senior scientist on Lewin's team, compared the

chromosomes of nine mammals (human, chimp, macaque, rat, mouse, pig, cattle,

dog, opossum) and a chicken. He found that the breakpoint regions contained many

more copy number variants, insertions and deletions in their sequences than the

other parts of the chromosomes. Such variations appear to make these regions

more susceptible to breakage, Lewin said. (The chromosome analysis was

facilitated by Evolution Highway, a powerful software tool developed in

collaboration with Welge and Loretta Auvil at the National Center for

Supercomputing Applications at the University of Illinois.)

The researchers also found that different classes of genes appear in the

breakpoint and break-resistant regions of chromosomes. Those in the breakpoint

regions code for proteins involved in immunity and muscle contraction, for

example. Rearrangements may cause copies of such genes to increase or change the

way they are regulated. These new sources of variation may then be subject to

natural selection, the mechanism of evolution proposed by Darwin.

The genes in more stable parts of the chromosomes are involved in growth and

development, particularly embryonic development. Disruptions to these genes

would probably be harmful to the organism as a whole, Lewin said.

" If the chromosome rearrangement is really bad for the organism, it will be

eliminated. It won't survive, " he said. " So if something persists in the genome,

it generally has to either be neutral, or it has to be of some benefit. "

Evolutionary biologists have historically focused on small changes in the genome

– such as point mutations or the insertion of viral genes – that sometimes lead

to the development of new forms, Lewin said.

" But by overlooking the importance of chromosome rearrangements, these

earthquakes in the genome, they may have missed a key component of the mechanism

for generating the variation used by natural selection, " he said.