Yale researchers are discussing once again the age-old question of what makes people different — this time through new genetics research that finally provides definitive answers to questions scientists have been debating since the completion of the Human Genome Project in 2003.
A team of Yale scientists, led by biology professor Michael Snyder, published a study this week that suggests large sections of similar strands of DNA occur in different arrangements from human to human. The team believes that these results will help clarify the work done to map the human genome.
“The human genome is made up of 3 billion bases,” Snyder said. “If you think of it as a book, and if you compare one person’s [book] to another’s, the most variation scientists used to think they would see would be typographical errors. With this research, we can say that from one person to the next, whole paragraphs and pages may be deleted, inserted, or flipped around.”
The researchers found that not only single units, but also potentially large sequences in the human genome undergo rearrangement — even in healthy individuals — to produce a unique genotype.
The study — which compared DNA from a woman of African descent to DNA from a woman of European descent — was feasible largely because of new technology developed by 454 Life Sciences, which is based in Branford, Connecticut, Snyder said.
“Even though some scientists had previously expected these results, they did not have the high-resolution technology to prove them,” principal author Jan Korbel said.
The researchers used a revolutionary technique called paired-end mapping, in which they broke up the DNA of each woman into strands approximately 3,000 base pairs long and then recorded the base-pair sequence at the ends of these strands. Using the map of the human genome as a reference, they “mapped back” the DNA strands, locating areas that corresponded to these ending sequences. If the areas were found more than 3,000 base pairs apart or in a reorganized form, than a structural variation could be said to exist.
The determination of so many structural variations is causing the most excitement among scientists, the authors said. Almost 1,000 variations occurred between the African woman and the reference; 750 occurred between the European woman and the reference.
Although it is still unclear what each variance may encode, the study provides two important findings, Snyder said. First, the variances are believed to be related to phenotype determination. Second, Snyder said, there is tremendous diagnostic potential in understanding the role of structural variances.
“We may be able to use [genetic arrangement] to determine things like how an individual will respond to a drug,” he said. “We can have personalized medicine.”
Dr. Maurice Mahoney, a professor at the Yale School of Medicine, said the study will help determine what specific genetic arrangements are playing a role in major illnesses ranging from cancer to heart disease. Using gene therapy, which is closely related to the idea of point mutations, scientists will be able to focus on how to manipulate and regulate the variable gene rather than substitute for it, he said.
Allen Bale, genetics professor at the School of Medicine, said from a clinical point of view there is still work to be done to avoid alarming patients if they have unusual genetic structures.
“Virtually any patient tested will have variants,” he said. “It will take some time to sort out what is normal and what is disease-related.”
Nevertheless, the research offers insight into the future of genetic testing and helps form a more complete vision of what the human genome actually looks like — or at least what it can look like on a person-by-person basis. Snyder and Korbel both said they hope to continue the research on a larger scale — perhaps with between 50 and 100 individuals — in order to guarantee a full picture of the human population.