BOSTON – More than 200 scientists working on an ambitious federal project have begun to understand the complicated system of switches that regulates genes, turning some on and others off, making some glow brightly while others dim. They hope that these discoveries, described in two dozen papers released Wednesday, will eventually lead to a deeper understanding of diseases and new ways to treat or cure them.
The expectation is that by uncovering the switches and genes they control, scientists can add depth to genetic findings like those from a schizophrenia study published last summer. Researchers identified 108 scattered genes associated with the mental illness but could not explain how they were related to one another or worked in the brain. An understanding of the circuits that control these genes may give them the clues they need, the researchers said.
“How does this conspiracy of genes work?” asked Dr. Eric S. Lander, director of the Broad Institute, a genetic research center affiliated with Harvard University and Massachusetts Institute of Technology, who is not an author of the new papers. “This begins to connect the dots.”
Researchers have long known that genes are only a small part of DNA – the rest contains switches that control genes. And researchers suspect that changes in these switches may have as much to do with diseases and with traits, such as height or weight, as changes in genes themselves. Ninety percent of DNA alterations associated with diseases are turning out to be in gene-switching areas, not the genes themselves. Scientists say they urgently need a map for understanding those circuits.
To find the switches and figure out the circuits that control genes, researchers examined cells taken from healthy people and from patients suffering from a range of diseases including multiple sclerosis and diabetes. They also studied cells from different stages of life, including fetal cells and stem cells, which are present at the very earliest stage of development. Using those cells, investigators found millions of switches that control genes.
The results are published in 24 papers in the journal Nature and other journals from Nature Publishing. The authors call it a road map to the human epigenome, a collection of chemical modifications of DNA that alter the way genetic information is used in different cells.
“We now have an unprecedented view of the living human genome,” said Manolis Kellis, a computer scientist at MIT and a leader of the federally funded project.
Scientists have had trouble understanding the connections between the switches and the genes because the switches are often physically nowhere near the genes they control on the linear sequence of DNA.
“The genome hasn’t nicely arranged the regulatory elements to be cheek by jowl with the elements they regulate,” Lander said. “It can be very hard to figure out which regulator lines up with which genes.”
So the researchers sought to determine which switches were active in more than 100 human cell types, an undertaking that required thousands of genomewide experiments and the collection of huge amounts of data. For each tissue sample, they asked which regulators were turned on when different switches were turned on. That let them infer, in a sort of guilt-by-association way, whether a regulator controlled a switch. If the researchers always saw that when regulator X was turned on, switch Y was turned on, they could infer that regulator X controlled switch Y.
“Before, we did not have enough data to do that,” Lander said.
Lander explained the method the scientists used with an analogy to a Boston subway line that runs near his snow-enshrouded office in Cambridge. If you knew when service on the Red Line was disrupted and when various employees were late for work, you might be able to infer which employees lived on the Red Line, he said. Likewise, when a genetic circuit was shut down, certain genes would be turned off. That would indicate that those genes were connected, like the employees who were late to work when the Red Line shut down.
Finding the switches has already proved useful. Researchers had previously found DNA alterations associated with high blood pressure, for example, but the alterations were not in genes. Presumably they were in switches. The new research found that these switches were only active in the heart, and, it appears, in the heart muscle of the left ventricle.
In cancer, the disease may start with what Dr. John A. Stamatoyannopoulos of the University of Washington, one of the authors, called “a big bang of mutations” specific to a particular type of cell. That may help doctors figure out a mysterious sort of cancer, in which patients arrive with tumors all over the body but no one knows where the cancer started, making it difficult to find the best treatment. By looking at which switches are active they hope to figure out the tissue of origin.
While the researchers are confident that their discoveries will be revelatory, they also see a long road ahead. They will find circuits, another author, said Anshul Kundaje, an assistant professor of genetics at Stanford, but, “Making sense of them is a whole different story.”