Raking the Family Tree for Disease-Causing Variations

Silhouettes of people with nucleic acid sequences and a stethoscope.
A new software tool analyzes disease-causing genetic variations within a family. Credit: NIH’s National Human Genome Research Institute.

Changes in your DNA sequence occur randomly and rarely. But when they do happen, they can increase your risk of developing common, complex diseases, such as cancer. One way to identify disease-causing variations is to study the genomes of family members, since the changes typically are passed down to subsequent generations.

To rake through a family tree for genetic variations with the highest probabilities of causing a disease, researchers combined several commonly-used statistical methods into a new software tool called pVAAST. The scientific team, which included Mark Yandell and Lynn Jorde of the University of Utah and Chad Huff of the University of Texas MD Anderson Cancer Center, used the tool to identify the genetic causes of a chronic intestinal inflammation disease and of developmental defects affecting the heart, face and limbs.

The results confirmed previously identified genetic variations for the developmental diseases and pinpointed a previously unknown variation for the intestinal inflammation. Together, the findings confirm the ability of the tool to detect disease-causing genetic changes within a family. Another research team has already used the software tool to discover rare genetic changes associated with family cases of breast cancer. These studies are likely just the beginning for studying genetic patterns of diseases than run in a family.

This work also was funded by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute; National Human Genome Research Institute; National Heart, Lung, and Blood Institute; and National Institute of Mental Health.

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Meet Elizabeth Grice

Elizabeth Grice
Elizabeth Grice
First job: Detasseling corn
Favorite food: Chocolate
Pets: An adopted shelter cat, Dolce
Favorite city: Athens, Greece
Hidden talent: Baking creative desserts
Credit: Bill Branson, NIH

Imagine a landscape with peaks and valleys, folds and niches, cool, dry zones and hot, wet ones. Every inch is swarming with diverse communities, but there are no cities, no buildings, no fields and no forests.

You’ve probably thought little about the inhabitants, but you see their environment every day. It’s your largest organ—your skin.

Elizabeth Grice, an assistant professor at the University of Pennsylvania, studies the skin microbiome to learn how and why bacteria colonize particular places on the body. Already, she’s found that the bacterial communities on healthy skin are different from those on diseased skin.

She hopes her work will point to ways of treating certain skin diseases, especially chronic wounds. “I like to think that I am making discoveries that will impact the way medicine is practiced,” she says.

Grice’s Findings

To investigate what role bacteria play in diabetic wounds, Grice and her colleagues took skin swabs from both diabetic and healthy mice, and then compared the two. They found that diabetic mice had about 40 times more bacteria on their skin, but it was concentrated into few species. A more diverse array of bacteria colonized the skin of healthy mice.

The researchers then gave each mouse a small wound and spent 28 days swabbing the sites to collect bacteria and observing how the skin healed. They found that wounds on diabetic mice started to increase in size at the same time as wounds on healthy mice began to heal. In about 2 weeks, most healthy mice looked as good as new. But most of the wounds on diabetic mice had barely healed even after a month.

Interestingly, bacterial communities in the wounds became more diverse in both groups of mice as they healed—although the wounds on diabetic mice still had less diversity than the ones on healthy mice.

“Bacterial diversity is probably a good thing, especially in wounds,” says Grice. “Often, potentially infectious bacteria are found on normal skin and are kept in check by the diversity of bacteria surrounding them.”

Grice and her colleagues also found distinctly different patterns of gene activity between the two groups of mice. As a result, the diabetic mice put out a longer-lasting immune response, including inflamed skin. Scientists believe prolonged inflammation might slow the healing process.

Grice’s team suspects that one of the main types of bacteria found on diabetic wounds, Staphylococcus, makes one of the inflammation-causing genes more active.

Now that they know more about the bacteria that thrive on diabetic wounds, Grice and her colleagues are a step closer to looking at whether they could reorganize these colonies to help the wounds heal.

Content adapted from the NIGMS Findings magazine article Body Bacteria.

On the Trail of Drug-Defying Superbugs

Antibiotic-resistant strains of Staphlyococcus aureus bacteria (purple) have become the most common cause of skin infections seen in hospital emergency departments. Credit: NIH’s National Institute of Allergy and Infectious Diseases.
Antibiotic-resistant strains of Staphlyococcus aureus bacteria (purple) have become the most common cause of skin infections seen in hospital emergency departments. Credit: NIH’s National Institute of Allergy and Infectious Diseases.

In the United States alone, at least 2 million people each year develop serious infections with bacteria that have become resistant to the antibiotics we use to combat them, and about 23,000 die, according to the Centers for Disease Control and Prevention. Antibiotic resistance can turn once-manageable infections into “superbug” diseases that are difficult—and sometimes impossible—to treat.

Scientists funded by the National Institutes of Health are studying many aspects of antibiotic resistance, including how it spreads. Read this Inside Life Science article for just a few research examples and how the work could aid efforts to curb the emergence of resistance.

Revealing the Human Proteome

An artistic interpretation of the human proteome. Credit: Corinne Sandone and Jennifer Fairman, Johns Hopkins University.
An artistic interpretation of the human proteome. Credit: Corinne Sandone and Jennifer Fairman, Johns Hopkins University.

Genes control the most basic functions of the cell, including what proteins to make and when. In 2003, the Human Genome Project created a draft map of our genes, and now researchers have completed a draft map of the human proteome—the set of all our proteins. The map, which includes proteins encoded by more than 17,000 genes as well as ones from regions of the genome previously thought to be non-coding, will help advance a broad range of research into human health and disease.

Read more about the proteome map in this NIH Research Matters article.

Cool Image: Researching Regeneration in a Model Organism

The isolated feeding tube of a flatworm.

The feeding tube, or pharynx, of a planarian worm with cilia shown in red and muscle fibers shown in green. Credit: Carrie Adler/Stowers Institute for Medical Research.

This rainbow-hued image shows the isolated feeding tube, or pharynx, of a tiny freshwater flatworm called a planarian, with the hairlike cilia in red and muscle fibers in green. Scientists use these wondrous worms, which have an almost infinite capacity to regrow all organs, as a simple model system for studying regeneration. A research team led by Alejandro Sánchez Alvarado of the Stowers Institute for Medical Research exploited a method known as selective chemical amputation to remove the pharynx easily and reliably. This allowed the team to conduct a large-scale genetic analysis of how stem cells in a planaria fragment realize what’s missing and then restore it. The researchers initially identified about 350 genes that were activated as a result of amputation. They then suppressed those genes one by one and observed the worms until they pinpointed one gene in particular—a master regulator called FoxA—whose absence completely blocked pharynx regeneration. Scientists believe that researching regeneration in flatworms first is a good way to gain knowledge that could one day be applied to promoting regeneration in mammals.

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Learning How Mosquito-Borne Viruses Use Knot-like RNA to Cause Disease

A knot-like structure in a section of RNA from a flavivirus
A knot-like structure in RNA enables flaviviruses to cause diseases like yellow fever, West Nile virus and dengue fever, which threaten roughly half the world’s population. Credit: Jeffrey Kieft.

Roughly half the world’s population is now at risk for mosquito-borne diseases other than malaria, such as yellow fever, West Nile virus and dengue fever. These three diseases are caused by flaviviruses, a type of virus that carries its genetic material as a single strand of RNA.

Flaviviruses have found a way not only to thwart our bodies’ normal defenses, but also to harness a human enzyme—paradoxically, one normally used to destroy RNA—to enhance their disease-causing abilities. A team of scientists led by Jeffrey Kieft at the University of Colorado at Denver found that flaviviruses accomplish both feats by bending and twisting a small part of their RNA into a knot-like structure.

The scientists set out to learn more about this unusual ability. First, they determined the detailed, three-dimensional architecture of the convoluted flaviviral RNA. Then, they examined several different variations of the RNA. In doing so, they pinpointed parts that are critical for forming the knot-like shape. If researchers can find a way to prevent the RNA from completing its potentially dangerous twist, they’ll be a step closer to developing a treatment for flaviviral diseases, which affect more than 100 million people worldwide.

This work also was supported by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.

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The Inner Life of Nerve Cells

“Before this research, we didn’t even know that neurons had this special mechanism to control neuropeptide function. This is why we do basic research. This is why it’s important to understand how neurons work, down to the subcellular and molecular levels.”—Kenneth Miller

Nerve cells (neurons) in the brain use small molecules called neuropeptides to converse with each other. Disruption of this communication can lead to problems with learning, memory and other brain functions. Through genetic studies in a model organism, the tiny worm C. elegans, a team led by Kenneth Miller Exit icon of the Oklahoma Medical Research Foundation has uncovered a previously unknown mechanism that nerve cells use to package, move and release neuropeptides. The researchers found that a protein called CaM kinase II, which plays many roles in the brain, helps control this mechanism. Neuropeptides in worms lacking CaM kinase II spilled out from their packages before they reached their proper destinations. A more thorough understanding of how neurons work, provided by studies like this, may help researchers better target drugs to treat memory disorders and other neurological problems in humans.

This work also was funded by NIH’s National Institute of Mental Health.

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Two Proteins That Regulate Energy Use Play Key Role in Stem Cell Development

Stem cells. Credit: Julie Mathieu, University of Washington.
The protein HIF1 alpha is beneficial for creating induced pluripotent stem cells (green) from adult human cells. Credit: Julie Mathieu, University of Washington.

Hannele Ruohola-Baker and a team of researchers at the University of Washington recently discovered that two proteins responsible for regulating how cells break down glucose are also essential for stem cell development. The scientists showed that the proteins HIF1 alpha and HIF2 alpha are both required to reprogram adult human cells into pluripotent stem cells, which have the ability to mature into any cell type in the body. Taking a closer look at what each protein does on its own, the researchers found that HIF1 alpha was beneficial for reprogramming throughout the process, whereas HIF2 alpha was required at early stages but was detrimental at later stages of reprogramming. Because the two proteins also play a role in transforming normal cells into cancer cells, the findings could lead to future advances in cancer research.

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Once Upon a Stem Cell Article from Inside Life Science
Learning About Cancer by Studying Stem Cells Article from Inside Life Science
Sticky Stem Cells Article from Inside Life Science

Basic Research Fuels Medical Advances

Genetic defect that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University.
Scientists revealed a detailed image of the genetic change that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University. View larger image

This image may look complicated, but it tells a fairly straightforward tale about basic research: Learning more about basic life processes can pave the way for medical and other advances.

In this example, researchers led by Matthew Disney of the Scripps Research Institute’s Florida campus focused on better understanding the structural underpinnings of myotonic dystrophy type 2, a relatively rare, inherited form of adult-onset muscular dystrophy. While this work is still in the preliminary stages, it may hold potential for someday treating the disorder.

Some 300,000 NIH-funded scientists are working on projects aimed at improving disease diagnosis, treatment and prevention, often through increasing understanding of basic life processes.

Read the complete Inside Life Science article.

Learning More About Our Partners in Digestion

Bacteroides ovatus
Bacteroides ovatus. Credit: Eric Martens, University of Michigan Medical School.

After eating, we don’t do all the work of digestion on our own. Trillions of gut bacteria help us break food down into the simple building blocks our cells need to function. New research from an international team co-led by Eric Martens of the University of Michigan Medical School has uncovered how a strain of beneficial gut bacteria, Bacteroides ovatus, digests complex carbohydrates called xyloglucans that are found in fruits and vegetables. The researchers traced the microorganism’s digestive ability to a single piece of the genome. They also examined a publicly available set of genomic data, which included information from both humans and their resident bacteria, and found that more than 90 percent of 250 adults harbored at least one Bacteroides strain with xyloglucan-digesting capabilities. These results underscore the importance of the bacteria to human health and nutrition.

This work also was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

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Gut Reactions and Other Findings About Our Resident Microbes from Inside Life Science
Body Bacteria from Findings Magazine