Creative Minds: Building the RNA Toolbox

Mice

Caption: Genetically identical mice. The Agouti gene is active in the yellow mouse and inactive in the brown mouse.
Credit: Dana Dolinoy, University of Michigan, Ann Arbor, and Randy Jirtle, Duke University, Durham, NC

Step inside the lab of Dana Dolinoy at the University of Michigan, Ann Arbor, and you’re sure to hear conversations that include the rather strange word “agouti” (uh-goo-tee). In this context, it’s a name given to a strain of laboratory mice that arose decades ago from a random mutation in the Agouti gene, which is normally expressed only transiently in hair follicles. The mutation causes the gene to be turned on, or expressed, continuously in all cell types, producing mice that are yellow, obese, and unusually prone to developing diabetes and cancer. As it turns out, these mutant mice and the gene they have pointed to are more valuable than ever today because they offer Dolinoy and other researchers an excellent model for studying the rapidly emerging field of epigenomics.

The genome of the mouse, just as for the human, is the complete DNA instruction book; it contains the coding information for building the proteins that carry out a variety of functions in a cell. But modifications to the DNA determine its function, and these are collectively referred to as the epigenome. The epigenome is made up of chemical tags and proteins that can attach to the DNA and direct such actions as turning genes on or off, thereby controlling the production of proteins in particular cells. These tags have different patterns in each cell type, helping to explain, for example, why a kidney and a skin cell can behave so differently when they share the same DNA.

Some types of genes, including Agouti, are particularly vulnerable to epigenomic effects. In fact, Dolinoy has discovered that exposing normal, wild-type (brown) mice to certain chemicals and dietary factors during pregnancy can switch on the Agouti gene in their developing offspring, turning their coats yellow and their health poor. Dolinoy says these experiments raise much larger questions: If researchers discover populations of humans that have been exposed to lifestyle or environmental factors that modify their epigenomes in ways that may possibly contribute to risk for certain diseases, can the modification be passed on to their children and grandchildren (referred to as transgenerational epigenetic inheritance, a controversial topic)? If so, how can we develop the high-precision tools needed to better understand and perhaps even reduce such risks? The University of Michigan researcher received a 2015 NIH Director’s Transformative Research Award to undertake that challenge.

Continue reading

Flipping a Genetic Switch on Obesity?

Illustration of a DNA switchWhen weight loss is the goal, the equation seems simple enough: consume fewer calories and burn more of them exercising. But for some people, losing and keeping off the weight is much more difficult for reasons that can include a genetic component. While there are rare genetic causes of extreme obesity, the strongest common genetic contributor discovered so far is a variant found in an intron of the FTO gene. Variations in this untranslated region of the gene have been tied to differences in body mass and a risk of obesity [1]. For the one in six people of European descent born with two copies of the risk variant, the consequence is carrying around an average of an extra 7 pounds [2].

Now, NIH-funded researchers reporting in The New England Journal of Medicine [3] have figured out how this gene influences body weight. The answer is not, as many had suspected, in regions of the brain that control appetite, but in the progenitor cells that produce white and beige fat. The researchers found that the risk variant is part of a larger genetic circuit that determines whether our bodies burn or store fat. This discovery may yield new approaches to intervene in obesity with treatments designed to change the way fat cells handle calories.

Continue reading

What Makes Our Brain Human? The Search for Answers

The Thinker

“The Thinker” by Auguste Rodin (photo by Brian Hillegas)

Humans’ most unique traits, such as speaking and abstract thinking, are rooted in the outer layer of our brains called the cerebral cortex. This convoluted sheet of grey matter is found in all mammals, but it is much larger and far more complex in Homo sapiens than in any other species. The cortex comprises nearly 80 percent of our brain mass, with some 16 billion neurons packed into more than 50 distinct, meticulously organized regions.

In an effort to explore the evolution of the human cortex, many researchers have looked to changes in the portion of the genome that codes for proteins. But a new paper, published in the journal Science [1], shows that protein-coding DNA provides only part of the answer. The new findings reveal that an even more critical component may be changes in the DNA sequences that regulate the activity of these genes.

Continue reading

NIH Common Fund: 10 Years of Transformative Science

Common Fund 10th Anniversary LogoHappy 10th Anniversary to the Common Fund! It’s hard to believe that it’s been a decade since I joined then-NIH Director Elias Zerhouni at the National Press Club to launch this trans-NIH effort to catalyze innovation and speed progress across many fields of biomedical research.

We’re marking this milestone with a special celebration today at NIH’s main campus. And, for those of you who can’t make it to Bethesda to join in the festivities, you can watch the videocast (live or archived). But allow me also to take this opportunity to share just a bit of the history and a few of the many achievements of this bold new approach to the support of science.

Continue reading

Creative Minds: Interpreting Your Genome

Artist's rendering of a doctor with a patient and a strand of DNA

Credit: Jane Ades, National Human Genome Research Institute, NIH

Just this year, we’ve reached the point where we can sequence an entire human genome for less than $1,000. That’s great news—and rather astounding, since the first human genome sequence (finished in 2003) cost an estimated $400,000,000!  Does that mean we’ll be able to use each person’s unique genetic blueprint to guide his or her health care from cradle to grave?  Maybe eventually, but it’s not quite as simple as it sounds.

Before we can use your genome to develop more personalized strategies for detecting, treating, and preventing disease, we need to be able to interpret the many variations that make your genome distinct from everybody else’s. While most of these variations are neither bad nor good, some raise the risk of particular diseases, and others serve to lower the risk. How do we figure out which is which?

Jay Shendure, an associate professor at the University of Washington in Seattle, has an audacious plan to figure this out, which is why he is among the 2013 recipients of the NIH Director’s Pioneer Award.

Continue reading