Tailoring medicine by reading the code for life

Rebecca Bellone, PhD, became a geneticist to understand the causes of Appaloosa spotting coat patterns in horses.

Her work helped identify links between spotting and congenital stationary night blindness, which is caused by abnormal signaling from cells in the retina. Dr. Bellone, who is director of the veterinary genetics laboratory at the University of California-Davis and professor of population health and reproduction, attributes part of her team’s success in identifying the genetic cause of the disease to access to the horse reference genome.

The horse was among the first animals with full genome sequences after the first human genome was published. That let Dr. Bellone and her team compare genes between humans and horses.

The team found that a gene, known as TRPM1, for calcium ion channel function was downregulated in Appaloosa horses with night blindness.

“That work led scientists looking at human night blindness to start to look at that gene as a cause for night blindness in humans,” she said. “It turns out that gene has more mutations causing human night blindness than any of the other genes that they had previously discovered.”

Dr. Bellone said the publication of a human genome 20 years ago transformed the scientific community’s ability to identify genetic causes of diseases and animal traits as well as enabled genetic testing for animal breeding and disease management. Access to a published human genome led to work on animal genomes for comparative genomics, which helped demonstrate the roles of genetic sequences across species and advance human and veterinary medicine, she said.

“Veterinary medicine really benefited from the push for comparative genomics because then there was a push to sequence the genomes of other species like dogs and horses,” Dr. Bellone said. “Having those genomes and making comparisons to humans has really accelerated the rate at which we can make discoveries to find causes for genetic diseases, and that has enabled diagnostic testing for genetic diseases across species.”

A major milestone

On Feb. 12, 2001, the International Human Genome Sequencing Consortium announced the publication of a draft sequence and initial analysis of the human genome in the journal Nature. A wealth of information was obtained from the initial analysis of the human genome draft, according to the National Institutes of Health. For instance, the number of human genes was originally estimated to be about 35,000. This was later revised to about 20,000.

The tools and techniques from the Human Genome Project have given the world continuously faster access to genetic information with precipitous drops in price, and the collective information on genetic links to disease and gene function make that information accessible and useful to clinicians.

Leslie A. Lyons, PhD, who is director of the Feline Genetics and Comparative Medicine Laboratory at the University of Missouri College of Veterinary Medicine and a professor of comparative medicine, said the Human Genome Project provided the technologies to better sequence cat genomes, analyze genomic data, and provide the infrastructure to hold and manipulate those data.

“Everything that has been learned in humans, including advancing the technologies, has been translated down into what we do in our cats and dogs and even our farm animal species,” Dr. Lyons said.

Today, whole genome sequencing available at the University of Missouri’s Veterinary Health Center can identify the genetic causes of inherited disease within a few days to a few weeks of collecting a blood sample. The cost for sequencing an animal’s genome has dipped below the cost of an MRI, she said.

“We can now do precision medicine in cats because of what was done in the Human Genome Project,” Dr. Lyons said.

Cost, time to sequence plunge

In his 2021 book “Genome Odyssey,” Stanford University medicine and genetics professor Euan Angus Ashley, MD, noted that the Human Genome Project had a budget of $3 billion and published a draft human genome in 2001. By 2009, a three-person team at Stanford sequenced a genome for $40,000 in one week, already a millionfold reduction in price.

As of August 2021, the estimated cost to sequence a human genome was below $600, according to data from the NIH National Human Genome Research Institute.

Dr. Ashley wrote later in his book that, today, “a physician can order a genome for a rare-disease patient almost as easily as ordering a cholesterol test.”

“Health insurance companies increasingly list it as a covered benefit, acknowledging that transformative insights can emerge,” he wrote. “Some health systems are even starting to offer genetic sequencing as part of preventive care—a way to reveal disease risks in advance of the disease arising.”

Adam Boyko, PhD, is an associate professor and researcher of canine genetics at Cornell University as well as one of the cofounders of the dog DNA testing company Embark. He said he hears thanks from pet owners about once every other week for health information that was revealed in company testing that helps guide care.

For example, in 2019, genetic testing from his company identified hemophilia in a dog, Wolfy, and that diagnosis may have saved the dog’s life. Another dog attacked Wolfy and punctured his neck a month later, and the genetic results helped guide the treatment by his regular veterinarian and the veterinarians who cared for him over four days at an emergency and specialty hospital, Dr. Boyko said.

I would expect that whole genome sequencing will be a routine box you can check as part of the management of the health care of our companion animals, including horses, cats, and dogs.

Leslie A. Lyons, PhD, director of the Feline Genetics and Comparative Medicine Laboratory at the University of Missouri College of Veterinary Medicine and a professor of comparative medicine

Dr. Doug Antczak, who is a veterinary scientist and professor of equine medicine at Cornell, said the Human Genome Project helped develop a large workforce with expertise in sequencing genomes and a wealth of scientific instruments for that purpose.

“The human genome project generated an enormous capacity for deciphering genomes,” he said.

Comparative genetics lets researchers find which genes are conserved across mammals, vertebrates, and even fruit flies, information helpful in improving health.

Dr. Antczak was part of a global group of scientists who began focused work on the horse genome in 1995, with hopes they might someday create a crude genome map.

“More and more technology kept coming online, and the cost kept getting lower and lower, so we were able to expand our aspirations and set our sights higher so that we, eventually, got in line for having the whole horse genome sequenced,” Dr. Antczak said.

Sequencing the first horse genome took six months of continuous sequencing by 100 machines, he said. Now, it can be done in a few days on one machine.

“It’s unimaginable how efficient this process has become,” he said. “It really has outstripped our ability to understand and process the information that we’re getting.”

Genetic testing now is also being used to eliminate genetic diseases, which Dr. Antczak said is a form of preventive medicine. Owners of Arabian horses, for example, now have access to a $50 test that finds whether their horses are carriers of the gene for severe combined immunodeficiency disease, which causes horses to be born without functioning immune systems.

Applications may become routine

Within the next decade, Dr. Lyons wants to see genetic testing panels become common, maybe when animals are born, so owners know about deficiencies and health risks. She also wants whole genome sequencing to become part of routine health care, just as she expects it will become part of state-of-the-art health care for humans.

“I would expect that whole genome sequencing will be a routine box you can check as part of the management of the health care of our companion animals, including horses, cats, and dogs,” she said.

The price of sequencing will continue to drop, she said, and health insurers may see benefits in paying for genomic tests that can be used for preventive medicine that would make overall health care more efficient.

Dr. Ashley, of Stanford, predicts in his book that genomes will become cheaper and faster to produce. More importantly, genome data will become more accurate, and “we will start to shine a much more powerful light into the dark corners of the genome.”

Some of those advancements will include custom medicine using genetic data for disease risk prediction and prevention, real-time health monitoring, pathogen detection and identification, and studies that show how pathogens have spread. For example, he described genomics as the heavy artillery in the fight against SARS-CoV-2, with rapid availability of the virus sequence used to create genetic tests for infections, reveal the story of how the virus spread across the globe, and develop vaccine candidates with unprecedented speed.

Dr. Antczak noted that genomics researchers are now identifying the control mechanisms in non–gene coding areas of the genome and working to understand how genes are controlled at different stages of animal development, health, and disease.

Dr. Boyko expects that, within the next 10 years, more veterinarians will embrace genetic testing as part of their practice. Genetic markers for drug sensitivities could be taken into account when a veterinarian treats a dog for cancer, and DNA tests for puppies could drastically change other clinical outcomes for many dogs, he said.

Dr. Bellone cited work underway at UC-Davis, led by Dr. Carrie Finno, director of the Center for Equine Health, to identify genetic causes of disease in horses under controlled conditions, a project that Dr. Bellone sees as paving the way for precision medicine.

Any veterinarian can participate in precision medicine, Dr. Lyons said.

“All your private practice veterinarian needs to do is be able to collect a good blood sample and have the right interest,” she said.