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2005

The History of Chromosomes May Shape the Future of Diseases
The New York Times, August 30, 2005
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The common ancestor of humans and the rhesus macaque monkey lived about 25 million years ago. But despite that vast gulf of time, our chromosomes still retain plenty of evidence of our shared heritage.

A team of scientists at the National Cancer Institute recently documented this evidence by constructing a map of the rhesus macaque's DNA, noting the location of 802 genetic markers in its genome. Then they compared the macaque map to a corresponding map of the human genome. The order of thousands of genes was the same.

"About half of the chromosomes are pretty much intact," said William Murphy, a member of the team, now at Texas A&M University.

The other chromosomes had become rearranged over the past 25 million years, but Dr. Murphy and his colleagues were able to reconstruct their evolution. Periodically, a chunk of chromosome was accidentally sliced out of the genome, flipped around and inserted backward.

In other cases, the chunk was ferried to a different part of the chromosome. All told, 23 of these transformations took place, and within these blocks of DNA, the order of the genes remained intact.

"It's fairly easy to see how you can convert the chromosomes from the macaque to the human," Dr. Murphy said.

This new macaque study, which is set to appear in a future issue of the journal Genomics, is just one of many new papers charting the history of chromosomes - in humans and other species. While scientists have been studying chromosomes for nearly a century, only in the last few years have large genome databases, powerful computers and new mathematical methods allowed scientists to trace these evolutionary steps.

Scientists hope that uncovering the history of chromosomes will have practical applications to diseases like cancer, in which rearranged chromosomes play a major part.

Scientists have known for over 70 years that chromosomes can be rearranged. With a microscope, it is possible to make out the banded patterns on chromosomes and to compare the pattern in different species.

Scientists discovered that different populations of fruit fly species could be distinguished by inverted segments in their chromosomes.

Later, molecular biologists discovered how cells accidentally rearranged large chunks of genetic material as they made new copies of their chromosomes.

By the 1980's, scientists were able to identify some major events in chromosome evolution. Humans have 23 pairs of chromosomes, for example, while chimpanzees and other apes have 24. Scientists determined that two ancestral chromosomes fused together after the ancestors of humans split off from other apes some six million years ago.

But a more detailed understanding of how chromosomes had changed would have to wait until scientists had amassed more information. The mystery could not be solved with data alone. Deciphering the history of chromosomes is like a fiendishly difficult puzzle.

One well-studied version of it is known as the pancake problem. You have a stack of pancakes of different sizes, and you want to sort them into a neat pile from small to big. You can only do so by using a spatula to flip over some of the pancakes. Even a dozen pancakes make this a viciously hard problem to solve.

"Flipping chromosomes is a lot like flipping pancakes," said Pavel Pevzner of the University of California, San Diego.

In the mid-1990's, Dr. Pevzner and Sridhar Hannenhalli of the University of Pennsylvania invented a fast method for comparing chromosomes from two different species and determining the fewest number of rearrangements - the equivalent of pancake flips - that separate them.

They introduced the method with a series of talks with titles like "Transforming Cabbage Into Turnips" and "Transforming Mice Into Men."

"That opened the floodgates," said Bernard Moret of the University of New Mexico.

Scientists have used methods like Dr. Pevzner's to study different groups of species.

Dr. Pevzner himself joined with Dr. Murphy and 23 other scientists to analyze the last 100 million years of mammal evolution. They compared the genomes of humans to cats, dogs, mice, rats, pigs, cows and horses, using a program developed by Harris A. Lewin and his colleagues at the University of Illinois, called the Evolution Highway.

The program allowed them to trace how each lineage's chromosomes had become rearranged over time. They published their results in the July 22 issue of Science.

The scientists found some chromosomes barely altered and others heavily reworked. They also discovered that the rate for rearrangements was far from steady. After the end of the Cretaceous Period, when large dinosaurs became extinct, the chromosomes of mammals began rearranging two to five times as fast as before. That may reflect the evolutionary explosion of mammals that followed the dinosaur extinctions, as mammals rapidly occupied new ecological niches as predators and grazers, fliers and swimmers.

More puzzling is the fact that different lineages became rearranged faster than others.

"The dog's chromosomes have been evolving at least two to three times cats' or humans'," Dr. Murphy said. "And the mice and rats have been going even faster than the dogs."

(Rodents are by no means the record holder. A 2004 study found that sunflower chromosomes have been rearranging about three times as fast as rodents'.)

The new results raise questions about how evolution makes chromosome rearrangements part of a species' genome. In many cases, these mutations cause diseases, so natural selection should make them disappear quickly from a population.

But scientists have also documented some rearrangements that are not hazardous or that are even beneficial. This year, for example, scientists discovered that some Northern Europeans carry a large inverted segment on one of their chromosomes. This inversion boosts the fertility of women who carry it.

Chromosome rearrangements may also play a role in the origin of new species. Scientists often find that closely related species living in overlapping ranges have rearranged chromosomes. The mismatch of chromosomes may make it impossible for the two species to hybridize.

As a result, the rearrangements may then spread through the entire new species. But Dr. Murphy isn't willing to speculate whether rodents have a faster rate of chromosome rearrangements because of the way they form new species.

"There really isn't enough genome sequence to be sure," he said.

The Science study and the newer study on macaques suggest that chromosomes tend to break in certain places, a hypothesis first offered by Dr. Pevzner in 2003.

"Genomes do not play dice," Dr. Pevzner said. "Certain regions of the genome are being broken over and over again."

It is too early to say why these regions have become break points, said Evan Eichler of the University of Washington, who was not involved in the mammal study. "There's something about these regions that makes them hot, and we have to figure out what that hot factor is," he said.

Dr. Eichler argues that it is important to figure out what that is because a number of human congenital diseases are associated with chromosome rearrangements at these same break points.

"Here you have a beautiful connection," he said. "The same thing that causes big-scale rearrangement between a human and chimp or a gorilla, these same sites are often the site of deletion associated with diseases."

Some of these diseases involve chromosome rearrangements in a fertilized egg, leading to congenital disorders. Cancer cells also undergo large-scale chromosome rearrangements, often at the same break points identified in the recent evolution study.

"We could have inherited some weaknesses in our genome that we have to understand and deal with medically," said David Haussler of the University of California, Santa Cruz. "And that has to do with the history of how our genome is built."

Copyright 2005 The New York Times Company

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