Friday, March 14, 2008

The History of Chromosomes May Shape the Future of Diseases

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.

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