Personalized Medicine From Genomics and Bioinformatics Highlighted at UCSF Genetics Symposium

Speakers described clinical research that has resulted in the identification of gene mutations that often drive deadly breast cancers in black populations; explained how rare mutations responsible for devastating developmental defects in infants can now be discovered in studies of just a handful of individuals from affected families; offered a preview of results expected to emerge from studies of genes and environment in hundreds of thousands of patients through a Kaiser Permanente-UCSF project; and described technical advances that continue to increase scientists’ ability to identify links between DNA and disease.

All the speakers “are at the cutting edge of applying genomics and informatics to precision medicine,” said the institute’s director Neil Risch, MD, referring to an emerging trend in medicine in which treatment is tailored to the patient through a more precise diagnosis of disease.

At UCSF — a crucible of biotechnology and home to Nobel laureates who identified a role for the mutation of normal genes in cancer — major new initiatives are underway in clinical genetics and bioinformatics, Risch said.

The symposium led off with geneticist Eddy Rubin, MD, PhD, whose presentation demonstrated that genetic studies are being applied to human problems that extend even beyond the realm of medicine.

Rubin – a scientist who oversaw the sequencing and analysis of 13 percent of the human genome as part of the original Human Genome Project – has taken his research from studying abnormalities in DNA “enhancers” that may contribute to disease susceptibility or birth defects, to cutting global greenhouse gas emissions by manipulating gut microbes in sheep.

Early in his career, Rubin completed a medical genetics fellowship under the late Charles Epstein, MD, a founding director of the UCSF Institute for Human Genetics and a driving force behind medical genetics becoming an accredited medical specialty. Rubin was featured at the symposium as the named 2012 Charles J. and Lois B. Epstein Visiting Professor at UCSF.

Rubin, director of the Department of Energy’s Joint Genome Institute and director of the Genome Sciences Division at Lawrence Berkeley National Laboratory, is a pioneer in exploring DNA beyond genes, which until recently was a poorly understood realm that may nonetheless prove to be key to understanding fundamental aspects of biology and disease.

Researchers were for decades focused on DNA that encodes proteins – the genes. But the sequencing and analysis of the genome has revealed that genes account for less than 2 percent of the DNA on the 46 human chromosomes. Within the universe of DNA, the stuff beyond the genes is comparable to the poorly understood dark matter of the cosmos.

DNA 'Enhancers' Guide Development

Rather than working under the lamppost where the genes are, Rubin explores DNA within these dark regions of the chromosomes. He focuses on bits of DNA called “enhancers,” which play an important role in determining how much protein is made from a gene at a particular time and place within an organism – with great implications for how a creature develops.

Rubin wondered: Could abnormal enhancers or unusual variations in specific enhancers be playing a role in disease susceptibility or birth defects?

Some enhancers are similar across many organisms, while others are more specific to humans or to other species, Rubin said. Within the cell’s DNA, the enhancers often are nowhere near the genes they affect, but Rubin has developed new ways to find them.

Enhancers switch on and off as an organism develops, and some are uniquely activated within particular tissues. Many enhancers are the same in different species, “conserved” through the course of evolution.

But the enhancers that switch on later in development are more likely to be unique to that species. “Early in development, we see very conserved enhancers, but later on during development we see enhancers that are not conserved,” Rubin said.

Thus the developing human heart, which forms early during embryogenesis, shares many enhancers with the developing hearts of other species. Brains, which form later, share fewer enhancers across species.

Working with mice, Rubin has identified 4,400 enhancers involved in shaping the face and the bones of the head and found that some abnormal enhancer DNA appears to play a role in facial abnormalities. “We’re seeing subtle effects … with many variants causing small effects,” he said.

Sheep Flatulence and Global Warming

At the DOE Joint Genome Institute, Rubin has begun to devote more of his research effort to the study of global greenhouse gases, specifically the contributions from livestock such as cows and sheep. These barnyard beasts harbor gut microbes that produce methane while helping the sheep to digest grass and other sources of cellulose.

As countries with large populations become wealthier, their citizens not only aspire to drive more cars and own more appliances, they also want to eat more meat, Rubin said, which is likely to lead to yet more greenhouse gas production as more of these domestic animals are raised to meet the growing demand.

In New Zealand, Rubin said, “They do believe in climate change, and they are putting in place a carbon tax, and they’re going to be charging their sheep farmers. So the sheep farmers are very interested in how the sheep produce methane and whether they can mitigate it at all.”

Rubin and his New Zealand colleagues studied 23 age- and size-matched members of a flock of sheep raised in the same pasture. The gut, or more precisely the “rumen” of a sheep contains massive amounts of bacteria, protozoa and fungi that ferment cellulose in grass and convert it into nutrients for the sheep. But sheep also house another type of microbe called Archaea. Archaea produce methane, which the sheep burp and fart out, Rubin said.

Genetic analysis permitted the researchers to figure out why methane emissions varied among sheep and to determine how Archaea might be a suitable target of efforts to lower methane release.

Rubin and colleagues did not find differences in the numbers of methane-producing microbes between the high-methane and low-methane producing sheep, but they did find that the methane-producing microbes within high-methane-emitting sheep were better at making methane, as evidenced by the increased activation of genes involved in the biochemical steps of methane production.