Alzheimer’s disease may involve the immune system, and researchers might have figured out how to pinpoint the origin of a cancer that has spread prior to diagnosis. These are just some of the findings reported today in a series of studies published in the Nature journals, which detail a largely unmapped portion of human genetics — and could lead to new treatments for everything from high blood pressure to arthritis and cancer.

Whether or not a gene is expressed in your body is the product of two layers of biology: the genome and the epigenome. The genome is the collection of genes contained in DNA; these are more or less the same throughout the cells in the body. The epigenome, on the other hand, is the traffic light of genetics; it provides the various signals that control whether or not a gene is active in a type of cell — so it’s way more variable. And unlike the genome, the human epigenome has yet to be fully mapped by scientists. The findings announced in Nature today by the Roadmap Epigenomics Program bring us closer to that goal, however, as they describe epigenetic processes that occur in over 100 different human cell types — and may lead to drugs that can reverse the actions of chemical modifications that regulate genes associated with disease.

In the first study, researchers figured out in which type of cell genetic mutations are active for 58 different biological traits. Some of the findings weren’t entirely unexpected. Mutations associated with blood pressure, for instance, are active in the heart. But the researchers were surprised to see that the mutations linked to Alzheimer’s disease are active in immune cells as well as in neurons. If the finding — in mice — holds, that means that genetic mutations linked to Alzheimer’s disease affect the immune system as well as neural processes, says Manolis Kellis, a molecular biologist at MIT and a co-author of the study.

The Alzheimer’s finding is the product of a mouse study, so it’s possible that it doesn’t represent an exact replica of what’s going on in humans with the condition. Still, Kellis thinks that the mouse model of Alzheimer’s that they used — developed by MIT — is a good one, because the researchers were able to show that the genes that are turned on and off in the mouse match very closely those seen in the brain of a human with Alzheimer’s. This is one of the consequences of the epigenome roadmap program, Kellis says; it provides a “more robust model of the mouse for Alzheimer’s disease,” which could in turn lead to new drugs that target the immune cells that “perhaps” contribute to the predisposition for Alzheimer’s disease.

“There is still a tremendous amount of work to be done — don’t get me wrong, drug development takes many years — but the new directions are promising,” Kellis says.

A second study showed that sometimes one parent’s influence outweighs the other on the genetic level. People inherit chromosomes from both parents to make up their double-stranded DNA. But genes from both parents at the same area on the chromosome aren’t expressed at the same level. “One of the parents tends to dominate over the other in the expression of the same gene,” says Bing Ren, a cellular biologist at the University of California at San Diego and co-author of the study. This finding “has a profound implication for basic biology and genetic disease,” because determining which parent dominates for a given gene could one day help us determine a person’s risk for developing a disease that runs in their family with a high degree of accuracy.

The researchers also developed a method that can pinpoint the cell of origin of a particular tumor in a cancer that has spread to many different parts of the body. In some forms of metastatic cancer, that location can only be approximated. “Most of the time those patients are treated empirically, in other words, based on certain features that the oncologist can use to guess what that cancer might be,” says John Stamatoyannopoulos, a geneticist at the University of Washington and a co-author of the study. “Typically, the patients have very bad outcomes.”

But looking at what happens in the body in the early stages of cancer through an epigenetic lens might change that. Cancer-associated genetic mutations closely match the epigenetic features of the type of cell that originated the cancer, the researchers found. And that information can be used to determine the source of the cancer with an accuracy of “close to 90 percent,” Stamatoyannopoulos says.

This could change tumor analysis, as well as change our understanding of cancer mutations in general, Stamatoyannopoulos says — mutations that likely “hold additional information that we haven’t tapped yet.”

More to come

The findings described in each of the studies are early, and will need to be validated by other research groups. They should be viewed as a starting point, especially since they didn’t take aging into account. Certain processes in the epigenome change over time, so “future work should try to address the changing relationship between the epigenome and genome,” says Henrik Stunnenberg, a molecular biologist at Radboud University, in a Nature news article published alongside the studies. Even with that limitation, “these papers and the associated data sets provide an unprecedented resource for understanding relationships between cells and tissues, and for delineating how cell-specific programs of gene expression are achieved,” write Casey Romanoski and Christopher Glass, both molecular biologists at the University of California, San Diego, who didn’t participate in the program, in a second news article published in Nature.

Now that the studies have been published, Kellis thinks that researchers should try to look at other cell types. “We have made all these maps freely available as a public resource … to help guide the studies of the epigenome,” he says. Armed with a more complete map of the epigenome, researchers will be better able to study variation among people. And scientists will also be able to delve deeper into the relationship between gene activation and disease. “Just as genetic inheritance predisposes us to disease, the epigenomic variation that we see between individuals can also be associated with disease,” Kellis says. This means that figuring out how and where chemical alterations act on gene expression could help us determine which drugs work on which individuals and why.

“We expect that this map will be of broad use to the scientific and biomedical communities” for studies of gene regulation, evolution variation, as well as for studies of human disease, the researchers write in one of the Nature studies. In the meantime, however, these findings serve as an excellent demonstration of how far we’ll have to go to really get a handle on human genetics.