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Cataloging the Structural Variations in Human Genetics

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 millio
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