A major new effort to uncover the medium- and large-scale genetic differences within the human species may soon reveal DNA sequences that contribute to a wide range of diseases, according to a paper by Evan Eichler, UW associate professor of genome sciences, and 17 colleagues published in the May 10 issue of Nature. The undertaking will help researchers identify structural variations in DNA sequences, which Eichler says amount to as much as 5 to 10 percent of the human genome.
Past studies of human genetic differences usually have focused on the individual letters, or bases, of a DNA sequence. However, structural changes such as insertions, duplications, or deletions of the DNA sequence, are more common than single base-pair changes, according to Eichler, a Howard Hughes Medical Institute investigator. 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.
These structural differences can influence disease susceptibility and the normal functioning of the human body. Deletions of particular genes or parts of genes can result in color-blindness, higher prostate cancer risk, or higher risk for some forms of cardiovascular disease. Variation in the number of genes or in gene regulation caused by structural rearrangements may also contribute to more common diseases, but researchers do not yet know the effect of those 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 will be a tool that geneticists can use to associate structural variation with particular diseases. 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.