But a new study argues that a genetic material's arrangement—along with changes in that DNA construct, such as insertion, deletion or rearrangement of segments of code within the genome—plays a more important role.
"We think SNPs will be responsible for many phenotypes and diseases," says Michael Snyder, a professor of molecular, cellular and developmental biology at Yale University and senior author of the new report published in Science. But structural variation appears to "have a more dramatic effect because the amount of DNA that's moving around is a lot larger."
To study the prevalence of these genetic rearrangements, Snyder's team, working in conjunction with the biotechnology company 454 Life Sciences of Branford, Conn., compared the genomes of two women (one of African descent, another of European ancestry) with the reference sequence provided by the Human Genome Project. Researchers chopped each genome into fragments 3,000 bases in length and sequenced them. (If you think of the genome as a book, bases are the letters with which the book is written; there are approximately three billion bases, or nucleotides, in the human genome.) The length of each sequence was then compared with its companion in the reference genome.
"Most of the time, they match back properly," Snyder says, "but some of the time they match back differently." The mismatched sequences were either too far apart (indicating insertion of new genetic material), too close together (meaning a deletion had occurred) or organized incorrectly, signifying the material had been somehow rearranged.
All told, there were between 750 and 1,000 of these structural variations in each of the two genomes (relative to the reference). Snyder estimates about 16 percent of them affect genes, whereas "a lot of them are in areas of the genome we don't know anything about."
One known variation, he says, was found involving two genes that code for olfactory receptors, proteins that influence the way people perceive scents. In one case, two odor-receptor genes were fused, which likely caused the individual to characterize odors very differently from those who had two separate genes.
In addition, researchers found certain "hot spots," or regions in the genome more vulnerable to structural change. Among such areas were those that house genes implicated in Williams syndrome, a rare disorder marked by an elfin appearance and mental retardation, along with a heightened appreciation of language and music, as well as velocardiofacial syndrome, which can cause heart defects, a cleft palate and distorted facial features.
These types of genetic changes, which Snyder stresses are relatively rare, previously were believed to be caused by the normal shuffling of genes during germ cell division, such as in the generation of new sperm in the male's testes. But, by examining these variations at the sequence level, researchers determined that these rearrangements likely take place during DNA repair when the genome is, in essence, glued back together after breaks caused by metabolic and environmental factors, such as exposure to ultraviolet rays, toxic chemicals and smoking. These events can occur throughout a person's life, from embryonic development through to the normal wear and tear of adult life.
"This raises the hypothesis," says Jonathan Sebat, an assistant genetics professor at Cold Spring Harbor Laboratory in Long Island, N.Y., "that 'DNA damage' is a force that is driving structural evolution in the human genome."