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‘Dark Matter’ in Cat Genomes May Shed Light on Human Disease

MU researchers find cat genome resembles human genome more closely than nearly all other mammals.

While dogs may be man’s best friend, cats are more genetically similar to humans than nearly any other mammal, according to a researcher and her team at the University of Missouri. The findings, published today in Trends in Genetics, come after decades of genome DNA sequencing by Leslie Lyons, a Gilbreath-McLorn endowed professor of comparative medicine in the MU College of Veterinary Medicine.

“Comparative genetics can play a key role in precision medicine and translational medicine, particularly for inherited diseases that affect both cats and humans, such as polycystic kidney disease and hypertrophic cardiomyopathy,” Lyons said. “As researchers, anything we can learn about identifying the causes of genetic diseases in cats or how to treat them can be useful for treating humans with the same disease.”

As DNA sequencing technology has improved over time, Lyons and her team have created a cat genome assembly that is nearly 100% complete, and Lyons found the layout of the cat genome to be very similar to the human genome, even more similar than that of mice or dogs.

Lyons explains that out of the 3 billion base pairs of DNA that make up the genome of mammals, only 2% of the DNA is coded into proteins that help our bodies perform natural functions. ‘Dark matter’ DNA, or the 98% of DNA with no obvious functions, may play a regulatory role in turning certain genes on or off, but that role is not quite fully understood by researchers.

“We want to find the regulatory elements in the dark matter where there might be specific DNA that turn our genes on or off, and since cats have a genome very similar to humans, the dark matter is arranged in a similar way as well,” Lyons said. “By better understanding the cat genome, we can try to target and find those regulatory sequences and then potentially develop therapies that would turn those sequences on or off. If we can shut down a whole gene, maybe we can shut down an entire cancer or disease that the genetic mutation was causing in the first place.”

Lyons’ research improves animal welfare by discovering genetic mutations that cause disease. In a previous study, she located in a domestic cat a specific mutation in the gene responsible for causing Chediak-Higashi syndrome, a rare condition in both cats and humans that weakens the immune system and leaves the body more vulnerable to infections. Her research is also helpful in preventing inherited diseases from being passed down to future generations.

“For most rare conditions, we are getting pretty good at discovering genes where there is one single mutation that causes something good or bad, but most common diseases among the general public, such as asthma, diabetes, obesity, high blood pressure and allergies, are often more complex,” Lyons said. “Since these are all common conditions that affect cats as well as humans, more research on comparing the cat and human genomes can help us one day possibly figure out which different genes and mechanisms are interplaying to create these complex diseases.”

Lyons added that the COVID-19 pandemic highlights the importance of translational medicine. In addition to the coronavirus causing COVID-19 in humans, it also causes feline infectious peritonitis in cats, which can be fatal.

“A few years ago, we learned the drug remdesivir was effective in curing cats of feline infectious peritonitis,” Lyons said. “So, when the pandemic began, we knew we could consider it to treat humans with COVID-19 because the receptors for the virus are similar between cats and humans.”

More research is needed as there are still questions to investigate, Lyons said.

Leslie Lyons is a Gilbreath-McLorn endowed professor of comparative medicine in the MU College of Veterinary Medicine.

“There is still a lot we don’t know yet, including why do some cats get very sick but not others?” Lyons said. “Why do some humans die from COVID-19 yet others show no symptoms? Getting a better understanding of the cat’s biology and genetic makeup will help us better understand the biology of humans, too.”

Precision medicine will be a key component of the NextGen Precision Health Initiative by helping to accelerate breakthroughs for both patients in Missouri and beyond. Lyons is passionate about the role feline genetics will play in precision medicine by laying the groundwork for tailored, specific treatments according to a patient’s individual genetic makeup, regardless if the patient has two legs or four.

“Our overall goals are to make cats healthier by alleviating genetic problems and use that information to inform human medicine based off what we learn,” Lyons said. “Our work can also help reduce inheritable conditions in cats from getting passed down to their offspring.”

“Cats – telomere to telomere and nose to tail” was published today in Trends in Genetics. Co-authors include William Murphy of Texas A&M and Wes Warren of MU.

Story courtesy of MU News Bureau
Contact: Brian Consiglio, 573-882-9144, consigliob@missouri.edu

Research With Heart

MU researcher is looking for how to best prescribe exercise to treat heart failure patients.

CVM Serves as Clinical Investigation Site for Liquid Biopsy Study

The University of Missouri College of Veterinary Medicine participated in what may be the largest-ever clinical research program in veterinary cancer diagnostics.

In May, PetDx, a San Diego-based company, announced the launch of OncoK9 at select sites. According to PetDx, OncoK9 is a first-in-class multi-cancer test that allows early detection of the disease in dogs with a simple blood draw. OncoK9’s clinical validation involved collecting blood samples from more than 1,600 dogs across more than 50 clinical investigation sites spanning four continents. The MU CVM was one of the sites selected to participate in the study, which exemplifies precision medicine.

In the study, blood was drawn from cancer-free dogs, dogs with cancer undergoing non-surgical treatment, and dogs with cancer receiving surgery. The drawn blood was sent to the PetDx laboratory for testing.

At Mizzou, 90 dogs were enrolled in the study beginning March 2020, including pets owned by CVM faculty and staff, as well as client-owned animals being treated at the MU Veterinary Health Center. Mizzou’s contribution made up slightly more than 5 percent of the dogs that were tested in the entire study.

Brian Flesner, DVM, MS, DACVIM-Oncology, an assistant professor of oncology at the CVM, said his connection with PetDx’s Chief Medical Officer Andi Flory, DVM, DACVIM, created the opportunity for Mizzou to act as a clinical investigation site for this study.

“The veterinary oncology community is a small world,” Flesner said. “I performed my rotating internship under the tutelage of Dr. Andi Flory. She was one of my mentors during my internship back in 2010. She’s a good friend and reached out to me personally asking if we’d like to be a trials site. She’s been impressed by the clinical trials we’ve done here at the University of Missouri.”

According to Flesner, liquid biopsies are a noninvasive alternative to other cancer screening procedures and have the potential to become even more useful. “The nice thing about this test is that it can first detect if an animal has cancer, and hopefully in the future we can use it to tell how much cancer is in the body,” Flesner said. “You could then run this test instead of having to do other invasive procedures.”

The expectation that the use of liquid biopsies will increase was shared by Flory. “In the future, we envision offering the test for additional use cases, including minimal residual disease detection, recurrence and treatment response monitoring, and targeted treatment selection, greatly expanding the veterinarian’s toolbox for the management of cancer in dogs,” she stated in a press release.

During the study, treatment for the dogs that were included was unchanged. “It didn’t affect their therapy, it didn’t affect their staging tests, everything we did was standard of care,” Flesner said. “They just received blood draws at select points with our standard staging and cancer treatment protocols.”

Additionally, Flesner said this was one of the only trials that the CVM was able to conduct during the COVID-19 pandemic, and it required vital help from the VHC staff. “A lot of people worked on it, and my nurses really kept this going,” he said. “They were integral to us being able to complete this.”

By Nick Childress

Ticking Upward: MU Researcher Studies Rise of Tick-borne Diseases in Midwest

When Ram Raghavan heard from a former colleague at the Centers for Disease Control and Prevention that a 7-year-old girl had died from Rocky Mountain spotted fever as the result of a tick bite, he thought of his own daughter, also 7 years old at the time, and the potentially fatal danger posed to vulnerable populations by tick-borne diseases.

Ram Raghavan is a professor in the MU College of Veterinary Medicine and MU School of Health Professions.

Now a professor at the University of Missouri College of Veterinary Medicine and School of Health Professions, Raghavan is an epidemiologist studying how ticks, mosquitos and other arthropods spread disease that impact people, pets and livestock over time in various geographical regions.

In a recent study, the most comprehensive of its kind in the Midwest region of the United States, Raghavan and former graduate student Ali Hroobi collected and identified various species of ticks on the outskirts of Pittsburg, Kansas, twice a month for a 3-year period. They not only found a majority of the ticks to be most active in the humid spring and summer seasons, but their comprehensive documentation of what, when and where ticks are present help public health officials better understand the threat of tick-borne diseases to humans, companion animals and livestock.

“We have seen increases recently in both the number and severity of tick-borne diseases in the Midwest, particularly in the humid climates of Missouri, Kansas, Oklahoma and Arkansas,” Raghavan said. “Since more people get infected by tick-borne diseases each year than any other vector-borne disease, it is important that we better understand what type of ticks are present in our region, where they are located and what time of year they are most prevalent. This information will help keep us, our families, pets and livestock safe.”

Raghavan explained that several factors have contributed to the rise in tick-borne diseases. Humans are increasingly relocating from densely populated urban cities to more suburban areas on the outskirts of towns near forests and grasslands where ticks are often present. Outdoor fitness activities such as hiking, biking and walking have also become more popular, especially since the COVID-19 pandemic and particularly during the warmer spring and summer seasons in the Midwest.

Climate change has played a role as well, as the warmer temperatures and humidity seem to be creating perfect conditions for ticks and the pathogens they carry to thrive. Finally, a sharp increase in population of white-tailed deer, the primary animal host for the most common tick found in the Midwest, Amblyomma Americanum, is another contributing factor.

“This comprehensive research study helps us create a baseline understanding of the current situation from a public health perspective,” Raghavan said. “These contributing factors will likely continue to play a role going forward, and now we have meaningful, relevant data to look back on for comparisons to see if certain trends continue in the future.”

Raghavan added that because there are currently no vaccines for tick-borne diseases, prevention practices and tick awareness are the best ways to avoid tick bites.

“Wearing protective clothing such as long sleeve shirts and pants when walking outdoors or on hiking trails is highly recommended, and spraying permethrin insect repellent can help as well,” Raghavan said. “Other common sense safety practices such as staying on the main trails away from vegetation and keeping dogs on leash can help protect you and your pets from ticks. Always check oneself and pets for any attached ticks after being outdoors. Also, visit with your doctor if you start to have any flu-like symptoms, as most tick-borne diseases are entirely curable, but early diagnosis is crucial.”

The research can help inform future studies to better identify when and where specific pathogens amplify within various ticks, their effects on disease severity, and the impact of climate change and land use change on the prevalence of tick-borne diseases.

“It is important to remember health does not operate separately for humans compared to animals or the environment,” Raghavan said. “This is a ‘One Health’ issue, and as humans, we are just a small part of an enormous ecosystem. The more we learn and understand the problems, the better we can protect ourselves against these preventable diseases.”

“Diversity and seasonality of host-seeking ticks in a periurban environment in the Central Midwest (USA)” was recently published in PLOS One.

Story courtesy of Show Me Mizzou
Story contact: Brian Consiglio, 573-882-91444, consigliob@missouri.edu

Lighting Up Biology From Within

Researchers at the University of Missouri have created a low-cost, portable device that can apply non-invasive bioluminescent imaging technology to many uses in animals, humans.

A biochemical reaction between an enzyme called luciferase and oxygen causes fireflies to glow and is considered one of the most well-known examples of bioluminescence in nature. Now, an international team of researchers led by Elena Goun at the University of Missouri is working to harness the power of bioluminescence in a low-cost, noninvasive portable medical imaging device that could one day be applied to many uses in biomedical research, translational medicine and clinical diagnoses.

Potential uses include developing better treatments for cancer, diabetes and infectious diseases, along with monitoring various metabolic functions, such as gut health, in both animals and humans, said Goun, an associate professor of chemistry in the College of Arts and Science and corresponding author on the study published in Nature Communications.

“This is the first example of a low-cost, portable bioluminescence imaging tool that can be used in large non-transgenic animals such as dogs,” Goun said. “The mobility and cost-effectiveness of this technology also makes it a powerful tool for use in many areas of preclinical research, clinical research and diagnostics.”

Once the imaging probe is inserted into the body and reaches a targeted internal organ, such as the liver, the level of biological activity, such as liver toxicity, determines the amount of luciferin that is released into the bloodstream. Eventually, it reaches the area of the device, setting off a biochemical reaction that creates light. A portable light detector — about 10 millimeters, smaller than the diameter of a penny — is then placed on the surface of the body near the inserted device and measures the intensity of the light. The level of detected light correlates with the amount of luciferin present, which scientists can then use when determining the health of the targeted organ.

Jeffrey Bryan, a professor of veterinary oncology in the College of Veterinary Medicine and a co-author on the study, said this technology will be helpful in a clinical setting — both in animal and human medicine — where medical professionals can determine if a treatment is working inside a patient.

“This is a way we can monitor, in a minimally invasive way, a patient’s physiological response to whatever treatment is administered to him or her,” said Bryan, who is also an associate director of comparative oncology at MU’s Ellis Fischel Cancer Center. “Right now, most of the time we are looking for responses to treatment by asking the patient how they feel and then doing big, invasive, expensive tests to see if the treatment is working. Sometimes, that requires multiple procedures. But, if we can monitor for the desired effect in a minimally invasive manner and continue monitoring the progress over a long time period with this technology, that would probably reduce the need for more invasive testing.”

In addition to the diagnostic testing benefits of this technology, Goun said their approach could have the potential to significantly reduce the number of dogs, cats and non-human primates being used for experimental testing purposes by commercial drug development companies.

“Portable bioluminescent platform for in vivo monitoring of biological processes in non-transgenic animals,” was published in Nature Communications.

Story courtesy of Show Me Mizzou
Contact: Eric Stann, 573-882-3346, StannE@missouri.edu