By Mary Flynn
California Health Report
Everybody carries the potential for diseases in their genes, but that potential doesn’t always result in illnesses. What flips the genetic switch to create disease in some people and not in others?
And even more critically, why is it that those who have ongoing exposure to stress—living in a violent neighborhood or below the poverty level, for example—are more prone to such diseases?
Studies have shown that people in the United States with low incomes suffer from illness in their 30s and 40s that wealthier people don’t see until they are 60 or 70. They are much more likely to be obese, have high blood pressure, suffer heart attacks and be depressed compared to people with higher incomes. People of color suffer from similar disparities in health. African Americans, for instance, are much more likely to die of heart disease than whites regardless of their income level. And Hispanics without a high school education are much more likely to die of diabetes than their white counterparts.
In the last few years, there have been some breakthroughs in the study of the genetic component that may cause these diseases. Groundbreaking findings on “junk DNA”—which scientists now call dark matter DNA—could help researchers get to the bottom of the mystery of how, exactly, stress hurts the health of poor people and people of color.
And that, in turn, could help prevent disease.
Dark matter DNA, once dismissed as evolutionary baggage or junk in our genes that served no function, has a critical role in gene expression. Scientists once thought that only the coding portion of DNA was important to genetics. In a series of research papers released in September 2012, scientists found that dark matter actually contains a complex system of switches— many more than were previously thought— that regulate the encoding portions of DNA.
The research project, called ENCODE for Encyclopedia of DNA Elements, is a huge undertaking by 442 scientists in laboratories across three continents. The ENCODE project, launched in 2003, resulted this fall in the coordinated publication of more than 30 papers in journals.
The data may help solve the mystery of what causes health disparities by revealing more about gene expression.
“This is one more step to our really understanding the mechanism by which the environment may switch the genes on and off,” says Nancy Adler, professor of psychiatry and the director of the Center for Health and Community at UCSF School of Medicine.
Adler has long examined the effects of socioeconomic influences and education on health. For the past 15 years, she has collaborated with other researchers as part of the MacArthur Research Network on Socioeconomic Status and Health to try and determine the reasons for health disparity.
The MacArthur network asks this question: Why are people who live in poverty, are poorly educated or are unemployed so widely different in their health status from those at the other end of the spectrum (with ample wealth, respected occupations and comfortable housing)? The common assumption is that people of a different socioeconomic status or lower education have limited access to health care, and that results in a lower quality of health.
Access to care, however, can’t explain the extent of disparities in health. Poor people
and people of color also don’t have genetic differences that would explain their poorer health. Instead, the culprit likely lies in a complex interaction between environment and genetics that results in gene expression.
Exactly how physical responses to stress result in worse health, however, is not fully understood. One recent study has suggested, for instance, that stress affects the body’s ability to regulate inflammation, interfering with the immune system’s response to illness, the response that allows the body to heal.
Other studies have suggested that stress causes premature aging that results in poor health—an effect researchers recently found in children as young as 10 years old.
The ENCODE data are a “very promising avenue” for understanding exactly how social and physical environments can result in disease, Adler says.
Traditionally, researchers have focused on mapping the genome and paid less attention to what some call the “exposome” or the “environome,” ingredients in one’s external environment that interact with genetic vulnerabilities. These ingredients include anything from job stress and social relation- ships to air quality and noise pollution.
The recent research puts more emphasis on this question, Adler says: “If there’s a switch, what determines what flips that switch?”
Research examining what physical mechanism flips genetic switches in people living under stress is still in its beginning phases, but preliminary experiments suggest that answers lie in dark matter.
“What ENCODE and a variety of other studies have shown is that there’s really not a lot of explanatory power within the coding region of genes,” says Steve Cole, associate professor in the Division of Hematology-Oncology at the UCLA School of Medicine. Cole, who was not involved with ENCODE, focuses his research on explaining why genes get activated or expressed in a way that facilitates disease.
Most disease-linked genetic changes happen in the stretches of DNA sequence that lie outside the coding region, where ENCODE has identified many “regulatory sites.” These regulatory portions of dark matter act like a set of dimmer switches. They determine the extent to which the gene is activated within the cell, if it’s activated at all, and they also control what kind of a cell it will be. This information provides new leads for linking the genetic variations to diseases.
Cole researches how social environments influence gene expression. His studies examine how social stress and isolation affect the expression of inflammatory genes, which play a role in many diseases, from the common cold to heart disease. As it turns out, stress and isolation affect a pathway created by what was once written off as junk.
Some of the clearest examples of dark matter DNA’s effect on the body, Cole says, have been experiments conducted using small animals. He described a study that induced a psychological-stress response in cancer-ridden mice (by placing individual mice in a box) to study the effect of that stress on the cancer cells. The stress response, researchers observed, activated particular receptors on the surface of cells in the mice, and those receptors in turn activated protein “transcription factors” within the cell to bind onto the dark matter of DNA. The transcription factors activated genes that created an inflammatory response, and the tumors grew and metastasized.
Cole says the mice experiments were revelatory. “In those kinds of models, we can see a lot,” he explains. “Once we understand those receptors, we can give the mouse a drug that blocks those receptors” by decreasing the stress signals’ ability to reach dark matter DNA and activate the genes that promote cancer metastasis.
Cole warns that although this approach may work in small animal models, humans operate very differently—some effects might occur differently or not at all in a human study. More studies will need to be conducted before researchers understand how the non-encoding regions of the DNA are affected by stress and in turn affect gene expression.
Despite the need for more research, these studies do emphasize the essential role of dark matter DNA. “It’s actually the eyes and ears of the system,” Cole says. “In terms of the basic philosophy of genetics, we need to look more at the eyes and ears, and less at the hands and feet, of the genome.”
Eventually, researchers expect, the ENCODE project will provide a blueprint of the human genome. When it is mapped in its entirety, it could pave the way for truly personalized medicine.
This story originally appeared in the California Health Report magazine’s Winter 2012/2013 issue. Read the rest of the magazine here.
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