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Cataloging The Structural Variations In Human Genetics

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 

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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Variations In Human Genetics. ScienceDaily. Retrieved February 13, 2009, from 
http://www.sciencedaily.com­ /releases/2007/05/070509161020.htm

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