New Genetic Disorder Affecting Cows

A scientist stumbles onto a new bovine genetic disorder.

By Larry Husten|Friday, May 01, 1992
RELATED TAGS: GENES & HEALTH
Marcus Kehrli, an immunologist and veterinarian with the U.S. Department of Agriculture in Iowa, was flying to Marco Island, Florida, but he wasn’t thinking about sun and surf. Nor was he thinking about the meeting he was traveling to, an important conference on leukocytes (the white blood cells of our immune system). What he was thinking about during that flight in October 1989 was a dead calf.

Kehrli has thought about cows most of his life. He grew up on an Iowa farm and has milked cows since he was three, and whenever he talks about them, an evangelical tone creeps into his voice. Since we are mammals, Kehrli says, milk is nature’s most perfect food. One look at his honest midwestern face and you know it’s no use even arguing the point. Kehrli loves cows.

On the plane, Kehrli was working on an article about his troublesome calf, which had died the previous spring. Kehrli had come across the young Holstein in the course of his lab’s immunological research. The calf had an abnormally high white blood cell count, often a sign that the immune system is fighting an infection; it developed intractable diarrhea and was dead within a week.

I suspected it wasn’t just an infectious problem, recalls Kehrli. We went to incredible efforts, but we were never able to isolate any one virus or bacterium that could cause this. All Kehrli knew was that the calf had way too many neutrophils--the white cells that act as the immune system’s first line of defense against bacteria--and that they weren’t doing their job. But he was at a complete loss to explain why.

Grasping for clues, Kehrli pored over the record of the calf’s pedigree. That’s when I realized the animal was inbred a little bit, and I began to suspect a genetic disorder. He remembered reading two obscure articles a few years earlier about a similar disorder in Holsteins. When I traced the pedigrees of the other sick calves, I found that the calf in the first report was very closely related to a bull that appeared three times in the genealogy of our calf, too. (The bull, a prodigious stud named Osborne Dale Ivanhoe, was active in the late 1950s and 1960s.) It was then that Kehrli realized he might have stumbled onto a new bovine genetic disorder.

A genetic disorder could spell disaster for Holsteins, which are the mainstay of the $18 billion U.S. dairy industry. Holsteins were first brought to this country from the Netherlands, 140 years ago. About 10,000 of the cows arrived before imports ceased in 1905, after hoof-and-mouth disease broke out in Europe.

So the breed had to be developed from a rather limited number of animals, explains Kehrli, considering that we’re dealing with a population of over ten million animals in America today. Breeders made great efforts to preserve genetic diversity, but from the start they used selective breeding and occasionally inbreeding to produce animals with particularly valuable traits, such as hardiness and the ability to produce more or creamier milk. A prize bull would be mated with several cows. Of course, back then they just walked the bull down the road to the neighboring farm to let him mate with Flossie.

By the late 1950s, however, two developments had changed the dairy industry drastically. Artificial insemination (AI) and the new practice of storing semen in liquid nitrogen greatly increased breeders’ ability to spread the genetic legacy of prize bulls, with the result that just a few top bulls like Ivanhoe could be used to inseminate tens of thousands of cows.

Farmers, says Kehrli, soon responded to the business pressures. They had to use AI bulls because they were clearly the most genetically desirable sires in the world, the ones that continually gave the most productive results. In fact, because of current AI methods, milk production is still increasing by a staggering thirty-three gallons per cow with each successive generation. So obviously AI is a very powerful method to improve the ability of dairy farmers to feed the world using fewer animals.

Yet AI can also sow the seeds of trouble. Along with all its desirable traits, a popular bull may harbor a disease-causing gene and pass it along to his innumerable offspring. Such genes are usually recessive, meaning that the offspring develop the disease only if they inherit a double dose of the gene, one copy from each parent. You can help prevent recessive diseases from showing up, then, by continually adding new genetic material to the pool. But in the U.S. Holstein population the genetic pool is fixed. The frequency of a faulty gene can thus rapidly increase in the breed, with disease becoming a serious threat after several generations. And unfortunately, the problem can become quite widespread before veterinarians pick it up. The economic pressures on farmers are such that a sick calf is simply allowed to die if it can’t easily be cured. Kehrli knew that his dead calf might represent just the tip of a very large iceberg.

Once in Florida, Kehrli dutifully attended the scientific presentations at the meeting, including one by Donald Anderson, a pediatrician at the Baylor College of Medicine in Houston, Texas. Anderson’s talk was on a rare disease called LAD, or leukocyte adhesion deficiency, that he’d discovered seven years earlier in children. These children have a defect in a gene coding for an adhesion molecule, which is the protein that lets leukocytes stick to other cells. (Neutrophils, for example, need to latch onto cells lining the blood vessels in order to enter the cells and ferret out bacteria invading the body’s tissues.) Without this ability, neutrophils and other leukocytes are useless, and a large part of the immune system becomes dysfunctional.
Kehrli listened with growing excitement as Anderson described the disease’s symptoms. LAD children have an abnormally high number of white cells in their blood. Because these leukocytes can’t stick to other cells, they’re doomed to wander endlessly and ineffectively through the bloodstream. Meanwhile the body, thinking it doesn’t have enough leukocytes, produces more and more of them to counter everyday low-grade infections.

I realized that the syndrome he was describing in the children was almost identical to what we had seen in our calf, recalls Kehrli, and I could hardly wait for the end of the session to run up to Don. I was afraid his initial reaction would be, ‘Get this vet away from me!’ But because I was writing my report on the way to the meeting, I had all my data showing the functional aberrations in our calf and in the other published cases. The neutrophil function tests in the children and in the cattle were similar.

Anderson, realizing that Kehrli was no flake, agreed to help him find out if his calf had a bovine type of LAD. Before the calf died, Kehrli had stashed a tube of its neutrophils in the freezer. After returning to Iowa, Kehrli mailed a sample of the frozen cells to Anderson’s lab, along with fresh cells drawn from the calf’s parents. There tests were done to detect the presence of the sticky adhesion molecules normally found on leukocytes. The results proved Kehrli was right on track. The sticky protein was completely missing in the dead calf, strongly suggesting that the animal had had the disease. Moreover, each of its parents had diminished levels of the protein--exactly what you’d expect if they were carriers of a single copy of a recessive LAD-type gene. Subsequent tests of 32 relatives of Ivanhoe, the progenitor bull, found that roughly half the animals were carriers.

As the summer of 1990 approached, Kehrli and his postdoc Dale Schuster moved into high gear. They isolated and cloned a normal copy of the target gene from a healthy animal and sequenced its DNA--that is, they deciphered the order of its nucleotide building blocks. Then they did the same thing with the gene from a defective animal. Comparing the two sequences, Kehrli discovered a tiny difference, called a point mutation, caused by the substitution of one nucleotide for another. The change in the gene altered a vital portion of the adhesion molecule it produced, and that in turn rendered the neutrophils useless. Kehrli had found the source of bovine LAD.

After pinpointing the problem, Kehrli’s lab was able to develop a rapid test for the disorder. All bulls active in the United States are now being screened, says Kehrli, and we’re finding out the exact incidence of the trait. To eliminate the disease, no two carriers of the defective gene will be mated with each other; and in the future, carrier bulls may not be mated at all. So in a matter of ten years the gene will pretty much wash out, says Kehrli.

These days no one is a bigger fan of Kehrli’s than Anderson. Mark Kehrli may have made one of the most important contributions in the history of veterinary science, he says, with only a hint of exaggeration in his voice. The fact is that we’re dealing with an economic issue of monumental proportions. We have an inbred trait that is now calculated to be carried by almost fifteen percent of all Holstein bulls. Just to put that in perspective: that’s about three to four times higher than the frequency of any human disease-causing gene. And the real impact was just about to occur, because it takes four or five generations of moderate inbreeding before actual disease starts to show up. (Indeed, the dead animals that vets were beginning to see were fourth- or fifth-generation descendants of Ivanhoe.)

Virtually every major bull sperm bank in the world was poised to perpetuate this problem, adds Anderson. Now, with a test, they’re going to be able to eliminate this disease instead of having hundreds of thousands of dairy cattle in the world dropping dead in the next few years.

It isn’t just that he happened to be in the right place at the right time, says Anderson of Kehrli. Most people would simply have ignored the issue and never even saved leukocytes from the calf in the first place. It takes a doggedness, an investigative curiosity. I mean, to save blood from a cow that died and have it available for study later because it might yield something--oh, that’s what you look for in a scientist.
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