[Paleopsych] NYT: The History of Chromosomes May Shape the Future of Diseases

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The History of Chromosomes May Shape the Future of Diseases
http://www.nytimes.com/2005/08/30/science/30gene.html

    By [3]CARL ZIMMER

    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."