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January 16, 2019 – Dr. Kelly Diehl discusses equine eye diseases and genetic testing issues with Dr. Rebecca Bellone, the Director of the Veterinary Genetics Laboratory at UC, Davis, and an adjunct professor in the Department of Population Health and Reproduction at that university. Dr. Bellone covers some of the most common ocular diseases in horses, genetic testing to detect those diseases and her Morris Animal Foundation-funded work.

00:18 Dr. Kelly Diehl: Welcome to Fresh Scoop, episode four: Equine Eye Diseases and Genetic Testing. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation's Interim vice president of scientific programs. And today we'll be talking with Dr. Rebecca Bellone who's both the director of the Veterinary Genetics Laboratory at the University of California Davis, and an adjunct professor in the Department of Population Health and Reproduction at the same university. She is also a long-standing Morris Animal Foundation funded researcher. For those of you who may be new to Fresh Scoop, this is the monthly podcast of Morris Animal Foundation, the largest non-profit foundation in the world, dedicated to funding studies that finds solutions to serious health threats in animals. Founded in 1948 by Dr. Mark Morris Senior, a veterinarian, we've invested more than $126 million in more than 2,600 studies that have improved and protected the health of companion animals like cats, dogs, and horses, as well as wildlife.

01:24 DD: In each episode, we feature one of our researchers we fund or one of our staff members, discussing their work in advancing animal health. Whether you're a practicing veterinarian, technician or student, or just an animal-loving science geek, Fresh Scoop is the podcast for you. You can learn more about us at Okay, onto today's show.

01:47 DD: Today, we welcome Dr. Rebecca Bellone, director of the Veterinary Genetics Laboratory at the University of California Davis. She earned her PhD from the University of Kentucky in 2001, when she was just a child and was on faculty at the University of Tampa for 12 years prior to moving to Davis. Dr. Bellone has been awarded several grants from Morris Animal Foundation, and we are so pleased to have her with us today, as we discuss a little bit about her research on genetic testing, particularly of equine ocular disease.

02:22 DD: So hello Rebecca, and thanks for joining us today.

02:25 Dr. Rebecca Bellone: Oh, thank you for having me.

02:27 DD: Before we jump into some of the questions I have for you today, can you tell us a little bit about... More about your background, particularly as it relates to your research?

02:37 DB: Yes, so as an undergraduate student at the University of Florida, I took a course called Genetic Improvement of Domesticated Animals, and it was during that course really that my passion for equine genetics was ignited. My professor was really passionate about education and about teaching students, and he was teaching about cochlear genetics, ironically, and I just became really, really fascinated by all the things that he had to say and to teach and to tell. And it was actually during that course that I decided I wanted to pursue a PhD and studied the genetics of Appaloosa spotting, and then from there, that kind of morphed into studying ocular disorders. And so it's been an exciting journey.

03:24 DD: That's really interesting, and I wanted to ask you because I know you did also your PhD at University of Kentucky, where I believe they have a few horses in that state.

03:36 DB: Yeah.


03:38 DD: And how do eye diseases for... The folks who are listening out there, who may not own a horse or know a lot about horses, how do eye diseases impact horses?

03:51 DB: So there are several common eye diseases in horses, including corneal ulcers, uveitis, glaucoma, cataract, and squamous cell carcinoma, and they impact horses in the same way as other species, including humans and small animals, in that they can cause pain, they can cause vision loss. But horses, for many horses the pain and the vision loss can also impact their ability to do the work that they do and perform in their disciplines. And so ocular diseases in horses can be very challenging from that perspective.

04:30 DD: Right, and so let's talk a little bit about your Morris Animal Foundation funded studies, and I know they're fairly broad. So in a nutshell, what made you decide on the particular diseases you elected to look at genetically?

04:48 DB: So oftentimes, I like to say there's serendipity in science. So, when I was studying Appaloosa spotting, I was able to collaborate with Dr. Lynne Sandmeyer and Dr. Bruce Grahn from the University of Saskatchewan, and we started looking at Appaloosa horses. Well, it turns out horses that have two copies of the Appaloosa mutation are night blind. And the serendipitous part comes in, I was asked to present that work at an equine ophthalmology meeting, and Dr. Mary Lassaline was there at that meeting. And so several months later after my talk, she reached out and said, "I'm seeing Haflinger horses are commonly presenting with ocular squamous cell carcinoma. And I think there might be a genetic basis there, would you be willing to collaborate with me on this project?"

05:37 DB: So I went from night blindness to squamous cell, very luckily, I guess you could say, but we then decided to work together and wrote a Morris Animal Foundation proposal that was funded for a pilot study, and because of that work, we were able to identify a genetic risk factor that explains about 80% of Haflinger horses that get ocular squamous cell carcinoma.

06:09 DD: And that was a great study and publications, and we're very proud to be part of that. Can you tell us, I know this is tough, but start simple, and you can get more complicated, about the methodology you use when you start looking at a horse for a particular genetic abnormality. Where do you start when you think, "Okay, we're seeing this in a particular breed of horse." Where do you start with that kind of question?

06:47 DB: That's a great question. I think the first place to start is to say, "Do you have evidence that what you're looking at might have an inherited component?" So in that particular example, Dr. Lassaline was seeing Haflingers more frequently with squamous cell carcinoma, and Haflingers didn't really present to her clinic for anything else. And so you start to think, "Is there something going on with this breed of horse that is inherited?" And then also when it comes to eyes, oftentimes if it's something that is bilateral, you think, "Okay, if it's happening to both eyes, there is also an increased likelihood that there is some inherited component."

07:33 DB: And so one of the very first things that we did is we looked at the records of the horses that from her clinic that were presenting with squamous cell, and we said, "Let's see if we can identify a common ancestor and potentially investigate the pedigrees to see if we can determine a mode of inheritance." And that was really important, because it started to help us understand, "Okay, it looks like it could be recessive," meaning that horses that were at risk for cancer inherited two copies of the risk version of the gene. And so by starting to understand that it could potentially be recessive, we then could figure out how many animals do we need in order to map this risk factor.

08:22 DB: And what I mean when I say map, is determine what chromosome the gene may be on that influences risk. And so, we decided, "Okay, if it's recessive, and if it might be that it's a single gene, we could use a small number of horses." And so we started the study with 24 horses, and we had about half of them were affected and half of them were unaffected. And we try to carefully pick horses that were affected, that were as closely related to each other as they were to the unaffected, so that any associations we identified, we were hoping that that was an association with disease and not just because the affected horses were more closely related.

09:11 DB: So from there we mapped the trait, and then we looked at that region in the genome and said, "What genes here could explain cancer risk?" And there was obvious what we call functional candidate gene. That gene, variance of that gene, have been shown to cause human skin cancer. So we started to sequence that gene, and we found a variance in our affected horses. And by doing computational work, we were able to predict that that variant actually changed the protein's function. So horses that have two copies of that variant, what we think is happening, is that the protein is not able to do its normal job. And this particular protein, what it does, is it basically surveys the DNA and looks for damages in the DNA that's caused by ultraviolet light. And so horses with this mutation, we proposed, are not able to repair the damage that's caused by UV light, and that is what leads to changes in the DNA that lead to cancer.

10:21 DD: Okay, and we're talking a little bit about genetic testing, and it seems obvious, you see one particular breed, and that could be a dog or a cat or a horse, that you see a particular disease more commonly, and, but once you get... For example, your Haflinger, you've identified that mutation, can it be applied maybe to other breeds of horses? Would you look at it in other breeds, or is it not that easy?

10:57 DB: That's an excellent question. So one of the things that that study showed was we also decided to screen other breeds of horses that were reported in a literature to have a high incidence of squamous cell carcinoma, and we found that mutation in other breeds, for example, the Belgian breed. And it was at a similar allele frequency in Belgian horses as it was in Haflingers, and so we decided, "Okay, this would be the next direction that we should go, and we should collect samples from both affected and unaffected Belgians, and see if this mutation also explains risk in that breed." And it turns out that it explains about the same level or the same number of affected horses in the Belgian breed as well.

11:47 DD: Okay, and to back up a second, just to explain better for me and for the audience, when you talk about the percentage that the mutation explains, can you explain what that means as far as genetic testing?

12:05 DB: Oh, that's a great question. Thank you for highlighting that. So in our sample set of horses, when I say it explains 80% of them, what that means is that 80% of our affected cases are homozygous for that mutation. And so to a geneticist, that potentially could mean one of two things: That that mutation itself is tagging on something else nearby that is the causal variant, or it means that it is more complicated than a single gene contributing. And so some of our current studies we're looking to see, can we identify additional risk factors within the breeds, the Haflingers and Belgians, that explain the other 20% that are affected but are not homozygous for that mutation.

13:03 DD: Okay, and so the higher the percentage, theoretically, the better the test, or the more that you could say if your horse has this mutation, you can feel more confident about their risk. Oh, how am I trying to say... The higher the percentage, the more likely that that is a significant player.

13:26 DB: Contributor.

13:27 DD: Right, okay, whereas if it was only it only accounts for 20% of the risk, that would be implied that 80% is due to something completely different.

13:39 DB: Correct.

13:40 DD: Okay, Oh, go ahead.

13:42 DB: One of the things that we hope in doing this work, is that if there is other genetic risk variants, that we're able to identify those as well, because then we can use genetic testing to make even more informed mating decisions.

14:00 DD: Right, right, which is the... Was sort of your goal with that particular study. Do you want to talk a little bit about some of the other diseases that at least Morris Animal Foundation has funded, but feel free to talk about some of the other genetic abnormalities, eye problems in horses you've looked at.

14:21 DB: Yeah, so I think a good sort of next topic to talk about would be equine recurrent uveitis which is the leading cause of blindness in horses. And so, because of my initial interest in studying Appaloosas and night blindness, we began to establish a large collaborative group to study equine recurrent uveitis in Appaloosas, because Appaloosas are more likely to get recurrent uveitis than any other horse breed and more likely to go blind from it. And so in contrast to squamous cell carcinoma, and what we know in Haflingers, where it looks like there's a single gene that is explaining a lot of the risk of disease. I think equine recurrent uveitis is going to be or is more complicated than that. So when we were talking a little bit earlier about there's this risk locus that explains 80% and then another one that might explain 20%, that 20% is still as important, particularly if you're dealing with particular lines of horses where that allele or that form of the gene is more at a higher frequency, so better understanding all of the genetic components is really, really important to better understanding the disease.

15:47 DD: How has genetics and what you've been doing, Rebecca, really changed diagnosis of these diseases and understanding of them in horses?

16:01 DB: I think that really the importance of it is that genetics can be used as a tool, both in making clinical diagnoses, but also in making management decisions and breeding decisions. So if we go back to the Appaloosa story, I have a 28-year-old Appaloosa who happens to be night blind, and because I know that he's homozygous for the Appaloosa variant, wherever I have him housed, I always make sure that he has a night light on at his stall. So that's a management decision that I choose to make for him to keep him safer. In terms of genetic testing for squamous cell carcinoma, if you have a barn full of Haflingers, and you have them tested for this genetic mutation, you're going to know which ones are the ones that you want to keep, for lack of a better pun, keep an eye on and have them screened more frequently by a veterinary ophthalmologist, because those are the ones that are at higher risk of developing cancer. And so the work with uveitis is we hope to get to that place where we can have a genetic risk model so that it can help inform both clinical management and breeding decisions.

17:27 DD: Okay, and when you were doing a lot of your work over these last few years, did any of the results surprise you when you set out to look at some of these diseases?

17:39 DB: I would say the one thing that probably surprised me about the squamous cell carcinoma is that when we discovered the risk variant, it didn't explain all of the cases. And it's not so surprising when you think about what we know about cancer in other species, and that it is a complex disease that involves both environment and genetics, but given how animals are bred, I guess that would be the one thing that I would say that I was surprised with.

18:17 DD: So a quick question, are your some of the tests you developed, are they now commercially available or available through your lab or the university?

18:27 DB: Yeah, so both the test for night blindness, the test for squamous cell carcinoma, and others are available commercially through the Veterinary Genetics Laboratory.

18:41 DD: Awesome, and I just, I know there's been just an explosion in genetic testing. What do you see as the pros and cons of just genetic testing in general? Whether it's a horse or a dog or a cat or 23andMe, and we're sending out our spitting in a cup. What do you see as you've watched this mature in your career?

19:12 DB: I think the pros are that it really is a valuable tool that can be used... If used properly, it can be used really to advance the health of animals and people. I think the cons is that there's so much that goes into genetic testing, and in order to utilize it as a tool, there has to be an effort to educate so that the information can be used appropriately.

19:46 DD: Where do you see, as far as... Do you have any experience in where something really made you cringe as far as the use of people touting genetic tests for whatever, and it could be any breed, where you went, "Well, that's not maybe quite how you should use your genetic testing."

20:08 DB: I think what's important is that if people are going to be using genetic testing to make decisions about their animals, that they should know what genetic tests are relevant to their particular breed.

20:26 DD: That sounds logical. I know it's easy to get kind of swayed by what we're seeing, and I think there's a lot of direct-to-consumer advertising, at least in the human genetic world. So on that note, what do you envision the future of genetic testing for, at least our veterinary patients, where do you see it going?

20:54 DB: I do see it going... Moving towards the direction of individualized medicine. I see it going towards genetic testing being able to assist in clinical diagnoses, and sort of like I've mentioned with the squamous cell test, it will help owners know which are the animals that I should pay more attention to in terms of screening for eye exams or screening for different things. And what I'm hopeful is that with the proper education and the proper use of genetic testing, that we will be able to create healthier animals.

21:39 DD: And do you... Have you seen people... I know that your test, you just said are commercially available, do you see people, and that includes yourself, sort of building on what you've found already?

21:52 DB: Yes, I think one of the things that I think is potentially exciting for me... So when I started in this field 20 years ago... And I remember being a shy, timid graduate student thinking, "Where do I even get started to look for the gene that causes Appaloosa spotting?" And you think back, and at that time, in terms of the horse genome, there were maybe, maybe 100 genes that had been mapped to horse chromosomes. And here we are, all these years later, and the entire horse genome has been sequenced. And our ability to find variants that cause disease is so much better than it was. And so the information continues to build on itself, and now there's an effort to better understand regions in the genome that control gene expression so that we can better understand the physiology of disease.

22:56 DD: Right, because I think... And maybe you can speak to this really quickly about people that just because a gene is there, it doesn't mean that it's actually expressed.

23:07 DB: Right, so some of what we know about genetic variance or some of the earliest studies in trying to identify variance that cause different phenotypes or disease, we're focused on looking at the regions of the gene that code for the proteins. But we're now learning more about other regions in the genome that basically will turn a gene on or turn a gene off, and I think it's part of what makes genetics so complicated, but also what makes being a geneticist so exciting, because we keep learning more and more about how everything interplays together.

23:48 DD: To wrap-up a bit, what diseases or problems are piquing your interest right now? Where are you headed next, do you think? Doesn't have to be in horses, but what's really of interest to you now?

24:05 DB: So we talked a little bit about the equine recurrent uveitis study that we're doing in Appaloosas, and we have expanded that to include several different breeds of horses that are also Appaloosa spotted or have the same spotting pattern, to try and understand what is the connection between the spotting pattern and the risk for uveitis, but also try and understand what are all of the other genes involved. But because it's the leading cause of blindness in horses, we've really expanded that study to really include any breed of horse to try and really better understand the genetics across breeds. I'm also really interested in continuing with understanding the genetics of ocular squamous cell carcinoma and across different breeds of horses as well.

25:01 DB: And we have several studies looking at, we didn't talk about this, but one of the studies... Another study that was funded by Morris Animal Foundation, is a study looking at bilateral corneal stromal loss in Friesian horses. And through that study, we were able to map the locus of where we think there might be a genetic variant contributing to that disease, so we're continuing on with that as well. Friesian horses also get distichiasis, or they get aberrant lashes that grow inward to the eye, which can also cause corneal ulcers, so we're studying that as well. So I'm really interested in studying anything that is genetic-related and anything that influences the eye and/or pigmentation.

25:56 DD: Do you do any research on any other species, or is it all horses?

26:02 DB: That's a great question. So mostly horses, but recently through collaborative efforts, again, with Dr. Sandmeyer at the University of Saskatchewan, we are starting to look at ocular disorders in dogs to study the genetic basis of those as well.

26:20 DD: Very cool. Probably not a whole lot of overlap, or is there between horses and dogs?

26:29 DB: Well, you know, there's some overlap. There are things that both horses and dogs will serve as a model for humans, and sometimes a mutation in the same gene will cause a similar phenotype in different species, but the tools that you would use to study genetic disorders would be the same, no matter what species you're looking at.

26:51 DD: Well, that is really cool. Well, we are definitely going to be looking forward to reading and finding out about those results in the future. I think they'll make a big difference. I think people are very... Our clients, not just our patients, are really sensitive to things that happen to the eyes of their animals. It can really impact the quality of life, as you alluded to with horses. It's particularly not a great thing to have a blind horse. That is really difficult for them, so we are... We'll be excited to see what you find. And Rebecca, thanks so much for joining us today to talk about horse eye disease and especially genetics and genetic testing, which is a great new technology that I think we're going to hear more about, and we really appreciate it and hope we can talk to you again.

27:48 DB: Thank you so much, thanks for the opportunity.

27:50 DD: Alright, well, take care Rebecca, and again, thanks for joining us. That does it for this episode of Fresh Scoop. Once again, thanks to Dr. Rebecca Bellone of University of California Davis for joining us and talking about equine eye issues, particularly as they relate to genetic testing. We'll be back with another episode next month that we hope you'll find just as informative. The science of animal health is ever-changing, and veterinarians need cutting-edge research information to give their patients the best possible care, and that's why we're here. You can find us on iTunesSpotify, Google Podcasts, and Stitcher. To learn more about Morris Animal Foundation's work, visit There you'll see how we bridge science and resources to advance the health of animals. You can also follow us on FacebookTwitter, and Instagram. I'm Dr. Kelly Diehl, and we'll talk soon.