Web address:
http://www.sciencedaily.com/releases/2007/05/
070509161020.htm
Cataloging The Structural Variations In Human Genetics
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Computer-generated image of DNA double helix. (Credit: National Human Genome
Research Institute)
ScienceDaily (May 10, 2007) — A major new effort to uncover the medium- and
large-scale genetic differences between humans may soon reveal DNA sequences
that contribute to a wide range of diseases, according to a paper by Howard
Hughes Medical Institute investigator Evan Eichler and 17 colleagues published
in the May 10, 2007, Nature. The undertaking will help researchers identify
structural variations in DNA sequences, which Eichler says amount to as much as
five to ten percent of the human genome.
Past studies of human genetic differences usually have focused on the
individual “letters” or bases of a DNA sequence. But the genetic differences
between humans amount to more than simple spelling errors. “Structural changes
— insertions, duplications, deletions, and inversions of DNA — are extremely
common in the human population,” says Eichler. “In fact, more bases are
involved in structural changes in the genome than are involved in
single-base-pair changes.”
In some cases, individual genes appear in multiple copies because of
duplications of DNA segments. In other cases, segments of DNA appear in some
people but not others, which means that the “reference” human genome produced
by the Human Genome Project is incomplete. “We're finding new sequence in the
human genome that is not in the reference sequence,” Eichler says.
These structural changes can influence both disease susceptibility and the
normal functioning and appearance of the body. Color-blindness, increased risk
of prostate cancer, and susceptibility to some forms of cardiovascular disease
result from deletions of particular genes or parts of genes. Extra copies of a
gene known as CC3L1 reduce a person's susceptibility to HIV infection and
progression to AIDS. Lower than normal quantities of other genes can lead to
intestinal or kidney diseases.
Variation in the number of genes or in gene regulation caused by structural
rearrangements may also contribute to more common diseases. “The million dollar
question is what is the genetic basis of diseases like diabetes, hypertension,
and high cholesterol levels?” says Eichler. “ We know there is a genetic
factor, but what is the role of single base pair changes versus structural
changes?”
The project Eichler and his colleagues describe in their paper will help answer
this question. Using DNA from 62 people who were studied as part of the
International HapMap Project, they are creating bacterial “libraries” of DNA
segments for each person. The ends of the segments are then sequenced to
uncover evidence of structural variation. Whenever such evidence is found, the
entire DNA segment is sequenced to catalog all of the genetic differences
between the segment and the reference sequence.
The result, says Eichler, will be a tool that geneticists can use to associate
structural variation with particular diseases. “It might be that if I have an
extra copy of gene A, my threshold for disease X may be higher or lower.”
Geneticists will then be able to test, or genotype, large numbers of
individuals who have a particular disease to look for structural variants that
they have in common. If a given variant is contributing to a disease, it will
occur at a higher frequency in people with the disease.
Knowing about structural variation in the human genome will also allow
geneticists to analyze single-base-pair changes more effectively, according to
Aravinda Chakravarti, a geneticist at The Johns Hopkins University School of
Medicine who was not a coauthor of the paper. “We have to look at structural
variants from a different perspective, because they are adding or subtracting
something from the genome,” Chakravarti says. By understanding the patterns of
both structural variants and single-base-pair changes in the population, “we'll
learn a lot.” To use both kinds of information in tandem, Eichler and his
colleagues plan to incorporate the structural information they gather into
existing databases on single-base-pair changes.
The project, which is being funded by the National Human Genome Research
Institute at the National Institutes of Health, is difficult and expensive,
Eichler admits. “It's a lot of work, because it's essentially doing 62
additional human genome projects,” he says. “Having been involved in the first
one, I swore I would never do it again. But in this case we're looking at the
coolest parts of the genome.”
Adapted from materials provided by Howard Hughes Medical Institute.
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Howard Hughes Medical Institute (2007, May 10). Cataloging The Structural
Variations In Human Genetics. ScienceDaily. Retrieved February 13, 2009, from
http://www.sciencedaily.com /releases/2007/05/070509161020.htm
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