Genetic information provided by a large group of specially designed mice could pave the way to faster human health discoveries and transform the ways people battle and prevent disease.

In 15 papers published Feb. 16 in the Genetics Society of America journals Genetics and G3:Genes/Genomes/Genetics, researchers from North Carolina State University, the University of North Carolina at Chapel Hill, The Jackson Laboratory and other universities and labs across the globe highlight a new genetic resource that could aid development of more effective treatments for any number of human diseases.

The resource, known as the Collaborative Cross (CC), is a reference manual of genetic variation contained in hundreds of specially-bred mice and their genetic sequences. The CC mice have much more genetic variation than normal lab mice, and thus more closely mirror the genetic complexity found in humans.

Dr. David Threadgill originally proposed the idea for the Collaborative Cross mice and serves as a leader of the project.

Moreover, the mice and their genetic sequences will be publicly available, allowing researchers around the world to work with mice that have particular genetic variations.

“If you can’t mimic the genetic variation in people, you can’t necessarily use mouse findings to understand more about human disease,” says Dr. David Threadgill, professor and department head of genetics at NC State who originally proposed the idea for the CC project a decade ago and who serves as one of the project leaders. Threadgill is also a member of the UNC Lineberger Comprehensive Cancer Center at UNC-Chapel Hill.

Threadgill developed the idea for the CC in order to harness the power of so-called whole genome studies that examine all genes at once instead of subsets of genes. Complex interactions between large numbers of genes frequently govern traits and behavior. Learning more about these interactions could help researchers tease out links between certain genes and certain diseases, for example.

In one of the 15 papers, Threadgill and corresponding author Dr. Francis S. Collins, director of the National Institutes of Health, identify key genes involved in red and white blood cell counts and red blood cell volume. These hematological parameters are important indicators of health and disease.

Project leaders include Dr. Fernando Pardo-Manuel de Villena of the UNC Department of Genetics, who is a member of UNC Lineberger Comprehensive Cancer Center, and Dr. Gary Churchill at The Jackson Laboratory. The international consortium participating in the development of the CC project includes NC State, UNC-Chapel Hill, The Jackson Laboratory, Tel Aviv University, Oxford University and Geniad/Australia. The mice are housed and “curated” at UNC-Chapel Hill.

The research was supported by grants from the National Institutes of Health; Ellison Medical Foundation; National Science Foundation; Australian Research Council; and the Wellcome Trust. The University Cancer Research Fund from the state of North Carolina also provided important funding.

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Scientists searching for the genomics version of the holy grail – more insight into predicting how an animal’s genes affect physical or behavioral traits – now have a reference manual that should speed gene discoveries in everything from pest control to personalized medicine.

In a paper published today in Nature, North Carolina State University genetics researchers team with scientists from across the globe to describe the new reference manual – the Drosophila melanogaster Reference Panel, or DGRP. Dr. Trudy Mackay, William Neal Reynolds and Distinguished University Professor of Genetics and one of the paper’s lead authors, says that the reference panel contains 192 lines of fruit flies that differ enormously in their genetic variation but are identical within each line, along with their genetic sequence data.

These resources are publicly available to researchers studying so-called quantitative traits, or characteristics that vary and are influenced by multiple genes – think of traits like aggression or sensitivity to alcohol. Mackay expects the reference panel will benefit researchers studying everything from animal evolution to animal breeding to fly models of disease.

Environmental conditions also affect quantitative traits. But studying the variations of these different characteristics, or phenotypes, of inbred fruit flies under controlled conditions, Mackay says, can greatly aid efforts to unlock the secrets of quantitative traits.

“Each fly line in the reference panel is essentially genetically identical, but each line is also a different sample of genetic variation among the population,” Mackay says. “So the lines can be shared among the research community to allow researchers to measure traits of interest.”

The Nature paper showed that, in general, many genes were associated with three quantitative traits studied in fruit flies – resistance to starvation stress, chill coma recovery time and startle response – and that the effects of these genes were quite large.

“Until now, we had the information necessary to understand what makes a fruit fly different from, say, a mosquito,” Mackay says. “Now we understand the genetic differences responsible for individual variation, or why one strain of flies lives longer or is more aggressive than another strain.”

The study was funded by the National Institutes of Health, the National Human Genome Research Institute and the NVIDIA Foundation’s “Compute the Cure” program. Dr. Eric Stone, associate professor of genetics at NC State, is also a lead author of the paper, along with colleagues from Baylor College of Medicine and the Universitat Autonoma de Barcelona in Spain.

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A tough cancer survivor named Cyrano will receive a brand new knee today at NC State, making him the first ever feline recipient of an osseointegrated knee implant.

Cyrano is a 10-year-old tabby cat who was treated for bone cancer last year and is now in total remission. However, the disease and treatment weakened the bone in his affected back leg and Cyrano’s knee

Cyrano's implant is about the same size as a tube of lip balm

deteriorated as a result. His owner, Sandy Lerner, felt that amputation would negatively affect the cat’s quality of life, and her search for other options brought them both to NC State and the team of orthopedic surgeon Dr. Denis Marcellin-Little and industrial and systems engineer Dr. Ola Harrysson.

Marcellin-Little and Harrysson are pioneers in osseointegration, a process that fuses a prosthetic limb with an animal’s (or human’s) bones. The NC State team, in collaboration with veterinarians and engineers from around the U.S. and abroad, will provide Cyrano with the first ever custom-made, osseointegrated feline knee replacement.

“Although total knee replacements in dogs are increasingly common, a cat poses some additional challenges, particularly regarding the size of the implant,” Marcellin-Little says. “Additionally, Cyrano’s existing leg bones were weakened by the cancer, so we must take care to be sure that the implant does not place undue stress on the remaining bone.”

If all goes well, Cyrano should be back to mousing at the family farm in about three months.

Cyrano’s case is unique, but Marcellin-Little hopes that this surgery will pave the way toward making feline knee replacements more commonly available. “This collaboration between NC State’s College of Veterinary Medicine,  College of Engineering, and outside implant designers and manufacturers allows us to design and make implants that we could only dream of, in the past. I am sure that this technology will help other patients with tumors, in the future.”

Other than Olympic race walkers, people generally find it more comfortable to run than walk when they start moving at around 2 meters per second – about 4.5 miles per hour.

North Carolina State University biomedical engineers Dr. Gregory Sawicki and Dr. Dominic Farris have discovered why: At 2 meters per second, running makes better use of an important calf muscle than walking, and therefore is a much more efficient use of the muscle’s – and the body’s – energy.

Published online in Proceedings of the National Academy of Sciences, the results stem from a first-of-its-kind study combining ultrasound imaging, high-speed motion-capture techniques and a force-measuring treadmill to examine a key calf muscle and how it behaves when people walk and run.

The study used ultrasound imaging in a unique way: A small ultrasound probe fastened to the back of the leg showed in real time the adjustments made by the muscle as study subjects walked and ran at various speeds.

The high-speed images revealed that the medial gastrocnemius muscle, a major calf muscle that attaches to the Achilles tendon, can be likened to a “clutch” that engages early in the stride, holding one end of the tendon while the body’s energy is transferred to stretch it. Later, the Achilles – the long, elastic tendon that runs down the back of the lower leg – springs into action by releasing the stored energy in a rapid recoil to help move you.

The study showed that the muscle “speeds up,” or changes its length more and more rapidly as people walk faster and faster, but in doing so provides less and less power. Working harder and providing less power means less overall muscle efficiency.

When people break into a run at about 2 meters per second, however, the study showed that the muscle “slows down,” or changes its length more slowly, providing more power while working less rigorously, thereby increasing its efficiency.

“The ultrasound imaging technique allows you to separate out the movement of the muscles in the lower leg and has not been used before in this context,” Farris says.

The finding sheds light on why speed walking is generally confined to the Olympics: muscles must work too inefficiently to speed walk, so the body turns to running in order to increase efficiency and comfort, and to conserve energy.

“The muscle can’t catch up to the speed of the gait as you walk faster and faster,” Sawicki says. “But when you shift the gait and transition from a walk to a run, that same muscle becomes almost static and doesn’t seem to change its behavior very much as you run faster and faster, although we didn’t test the muscle at sprinting rates.”

The research could help inform the best ways of building assistive or prosthetic devices for humans, or help strength and conditioning professionals assist people who have had spinal-cord injury or a stroke, Sawicki and Farris say.

The researchers are part of NC State’s Human PoWeR (Physiology of Wearable Robotics) Lab, directed by Sawicki. The joint Department of Biomedical Engineering is part of NC State’s College of Engineering and the University of North Carolina-Chapel Hill’s School of Medicine.

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