APHA.Com - Lethal Whites

Several experts clarify what we now know, and what we hope
to know soon about this devastating syndrome

Lethal White: a foal of overo lineage, born all white or mostly white. The foal may seem normal at birth, but usually begins showing signs of colic within 12 hours because of a non-functioning colon. Because the syndrome is always fatal, lethal white foals are often euthanized.

Since the origin of the American Paint Stock Horse Association in 1962, lethal white syndrome has been a plaguing presence, lurking in the shadows of the breed's success. For lack of a scientific explanation, or perhaps to downplay the one negative aspect of the breed, Paint breeders and the association itself adopted a "sweep it under the rug" policy for many years.

But now, as the APHA watches its registration and membership numbers climb ever skyward, and breeders see their black and white overos bringing premium prices across the country, each is uncomfortably aware of a matching increase in the incidence of lethal whites.

After 30 years of questions, everyone seems to agree it is time to get some answers.

The closest thing to an explanation of the lethal white foal syndrome thus far has been an article written by Dr. Ann Bowling of the University of California at Davis, which was published in the August 1993 issue of the Paint Horse Journal. In her article, Bowling proposed that the three classes of horses that resulted from overo-to-overo matings (overo, solid and lethal white) fit a model of overo as a dominant gene with lethal effects in the homozygous state. This model predicted that 25 percent of foals from two overo parents would be lethal whites.

Bowling went on to say that the studbook definition of overo may include more than one genetic entity, which complicates the application of her model for understanding overo inheritance and predicting lethal whites.

In a recent interview, Bowling stood by her proposition, pointing out that there has been no successful homozygous overo stallion to date, leading her to believe that whatever causes homozygosity in overos is linked to lethal white syndrome.

At the same time Bowling was formulating her theory, the APHA and Portland State University in Portland, Oregon, were doing pedigree studies of their own. For the past 10 years, the APHA has collected surveys on lethal white foals from its members and submitted them to a team at the university for analysis.

In the first half of this article, Dr. Debbie Duffield, a researcher at Portland State University who has been working on the project since its inception, shares her team's conclusions on how to predict the occurrence of lethal white foals.

Recently, lethal white syndrome has also been examined from a genetic standpoint. In July of 1996, a team of researchers at the University of Minnesota sent the APHA a comprehensive proposal for a grant to describe the inheritance of lethal white syndrome and to locate the gene responsible. In November, the APHA Executive Committee approved the $7,650 grant, and the project is now under way.

The project is headed by three researchers at the university--Dr. James Mickelson, Dr. Stephanie Valberg, and Dr. Elizabeth Santschi. In the second part of this article, Dr. Santschi tells us what they know now, what theories they plan to test, and what they hope to accomplish during the next six months.

A: When we looked at the surveys, we felt that the biases that were built in on people reporting lethal whites overwhelmed the interpretation. We tried to get rid of that bias by sending a random poll to breeders asking only for the first foal born that year, and its sire and dam.

The question we were asking ourselves was, if we look at all overo-to-overo breedings, do we get one-quarter solid foals, one-half overos, and one-quarter lethal whites?

A: The numbers were right on. We feel that the poll strongly supported that the overo Paint gene is acting predominantly as a lethal dominant as Dr. Bowling predicted. By that, I mean that a horse that is overo is a heterozygous horse. It has one overo gene and one non-overo gene. A solid Paint is one that has two non-overo genes, and a lethal white is one that has two overo genes.

That doesn't rule out modifiers that impact how much color, or how high or low color extends. It just says that most of the time it is going to operate that way, and people can pretty safely base their breeding programs on that.

Q: If the overo gene is dominant, how would you explain cropouts (when two Quarter Horses, two Thoroughbreds, or a Quarter Horse and a Thoroughbred, produce an overo foal)?

A: There are two things that could be going on. There could be modifiers that do indeed hide an overo periodically. However, we think it is more likely that the actual overo pattern isn't fully described yet--that sometimes horses that are considered, say, Quarter Horses, are actually overos. They are just not identified as such.

What we did was go back to every example we had in our files where there was a cropout. And there was always an instance where we would suspect that at least one of the horses in their background had been an overo, by looking at its picture.

A: Actually, we thought the problem would be bigger than it is. We have heard stories for years that often Quarter Horse people hid those little bits of white when they registered the animals. So, we thought that the problem was going to be extensive among Quarter Horses. But when we did the poll there were very few real cropouts.

Q: How do you explain lethal whites that have occurred from overo-to-solid or overo-to-tobiano crosses?

A: If you asked me, could I get a lethal white from an overo and a tobiano, I would say no. However, we do occasionally see that. The reason that we see it is because there is actually overo there, it just isn't called that. In fact, the true cross is probably overo-to-tovero.

A lethal white should not occur from an overo-to-solid cross, either. However, some of the "solids" may actually be overos that are not classified as overos.

The only true combinations that should produce lethal whites are overo-to-overo and overo-to-tovero.

A: We want to alert tobiano and overo breeders to some conditions that we see coming up a lot. More and more, people are mixing the two lines. We're seeing a lot of it in our tobiano testing. What is going to happen is that after awhile, horses which kind of look tobiano, but have overo in them, are going to start throwing lethal whites.

If someone stepped into that picture down the line when those horses were doing that, they might think lethal white syndrome was linked to the tobiano gene.

Q: Did you find that lethal white foals occurred more frequently among certain families of horses?

A: We never really saw that certain lines of overo horses produced lethal whites more than any others.

What we did was to go back through all the polls and pull out lineages and check to see if there were any that tended to come up again and again.

We did have certain horses whose names came up more, but it was because people were breeding to them more often. If you took into account the total number of breedings to that horse, the proportion of lethal whites still fell into the normal ratio.

More likely than not, although we don't feel that we've proven it, it was not that certain lines had a higher possibility of lethal whites, it was merely a reflection of breeding preference.

Q: Is the likelihood of a lethal white foal related to the amount of white on the parents?

A: We saw no indication that the amount of color on the parents gave any statistical leaning to the probability of getting a lethal white foal.

Like with the lineages, what we did see was that although a lot of lethal whites seemed to be coming out of O3- and O4-type horses (color types shown on the registration form), when we looked at how many breedings occurred between horses of different color types, most of the breedings were between O3s and O4s. So, again, the trend was probably related to what people were choosing to breed.

A: According to this theory, all overos would carry the lethal white gene, meaning it's the overo gene itself, and if you get two copies of it, you get lethal white syndrome. We haven't seen any evidence that there is an overo gene that doesn't carry it. However, there may be other types of spotting, like sabino, that might not carry it because they might be different from overo.

However, we didn't have a good way to separate, say, sabinos, from frame overos in our study, so we can't really address this point.

Q: Could this explain why the incidence of lethal white foals from overo-to-overo crosses isn't as high as 25 percent? Or is there another explanation?

A: I suspect some of them are aborted. There were some cases in our studies where mares had aborted, so it's possible. That might also be one reason why the lethal white number isn't right at 25 percent in some studies.

Q: If the researchers at the University of Minnesota are able to identify the markers for the overo gene, how will that affect breeders?

A: You've still got a problem on your hands. It's important to find a marker, but until you can do amniocentesis (analysis of the mare's amniotic fluid) on horses, you still won't know before the baby is born whether it is lethal. So the technology of being able to test a fetus has to be developed, too, for the marker to be useful.

Right now the question is, did my foal get two copies of the gene, or not? When the markers are identified, you still have to find a way to get in and get a blood sample from the baby. (They can't use the blood of the mare.) From what I understand of horse reproduction, that's a problem. You can't easily do an amniocentesis on a horse.

As the technology changes, and as they start to do in-vitro fertilization with horses, then breeders can capitalize on using the markers when they are developed. With in-vitro fertilization, embryos that are going to be lethal whites can be weeded out, and those that are normal, or overo, can be implanted.

Cattle breeders are using this technology right now with in-vitro fertilization. They can test embryo cells after they have begun to divide to see whether the embryo is carrying a particular marker. Then they save the embryos that aren't, and get rid of the embryos that are.

Therefore, use of a marker for lethal white also requires the acceptability of in-vitro fertilization. But I think that's all coming. Everything is changing so fast.

A: For the individual breeder, if they breed overo to truly solid, then they will not get lethal whites. They can also breed to a true tobiano.

With any overo-to-overo cross, they have a 25 percent chance of getting a lethal white.

The way I look at it for the industry is that it's just the cost of breeding overos. Certainly, individual breeders may have difficulty with that because they only have one mare and if they get a lethal white foal, that takes them out for the whole season.

But at this point, with just the current technology, they are not going to be able to get away from this problem.

Q: From what point does your study begin? You say you have a candidate gene for lethal white syndrome?

A: There are a couple of genes that have been identified in people and in mice that have been found to cause conditions that are very similar to lethal white syndrome. What we're doing is looking at these candidate genes and sequencing them--determining what their base pairs actually code for in normal horses and in lethal whites--to see if there is a difference.

The copy of the gene that is in the lethal whites will hopefully be very different from those in normal horses. What that will mean is that there is a high likelihood that that gene is responsible for the condition.

It could be that it's not these two genes and we have to go somewhere else. But if we're successful, and find that a mutation in one of these genes is responsible for this condition, then we go on and start looking for that gene in various horses that had some lethal whites in their pedigree and make sure it is not present in those that did not. Then we can say more conclusively that this gene is responsible for lethal white.

What we have to do is test a bunch of mares--those who have produced lethal whites, and, for instance, Arabian mares, who never produce lethal whites. We have to make sure the mutation is never found in horses that never produce lethal whites, is found in a certain percentage of mares that have produced lethal whites, and is always found in foals that are lethal whites.

A: Within about six months we should know whether or not the genes we are most interested in are the culprits. But even if this particular gene is not responsible for lethal whites, it is the first time these genes have been sequenced in horses, and that is valuable in itself.

Q: The current theory based on pedigree research strongly shows that overo-to-overo crosses will produce solids, overos, and lethal whites in a 1:2:1 ratio, meaning lethal whites will occur in 25 percent of all matings. Does this theory contradict your study?

A: It could turn out to be something that is simple Mendelian genetics, which is where the homozygous state of the gene is lethal. Then, if you have a heterozygous mare, you certainly don't want to breed her to a heterozygous stallion, because 25 percent of the time you are going to get a lethal white foal.

If you were to assume that every overo was a heterozygote—if it was simple one-gene inheritance—then all overo stallions should sire the same percentage of lethal whites.

But we know that's not true, right? Nobody talks about any one horse siring 25 percent lethal whites. People talk about it being around the 8 to 10 percent level.

Q: Is it possible that the percentage of lethal whites appears less than 25 percent because of early embryonic death?

A: Some people talk about early embryonic death, which is what they think happens with a lot of homozygous HYPP horses.

However, talking to Paint breeders, they don't seem to think that they have any higher incidence of mares resorbing or being in foal and coming up empty than anybody else. But of course that hasn't withstood scientific scrutiny.

Q: How else can you explain the observation that lethal whites occur significantly less than 25 percent of the time in all overo-to-overo matings?

A: It is hard to know for sure, but I do talk to Paint breeders a lot. Many say, "You know, I just don't have that many lethal whites," whereas other breeders either admit it, or people who have bred to their horse say it sires lethal whites all the time.

I think we may find out that there are genetic differences between splashed whites, sabinos and frames, just like there is more than one gene that controls spotting in mice. With this, it is possible that not all combinations will produce a lethal white foal in the homozygous state. How that all sorts out is going to be very interesting.

It would seem that frame horses tend to be the ones that are most likely to produce a lethal white. But we have seen lethal whites out of sabino stallions. And splashed whites are so uncommon that I'm not really sure how they fit in. We are going to try and stick with the frames in our study for now, because that will make it simple. But then we'll branch out into the other types of overo.

Something else that I think is a bit of a problem is, what is an overo? Dr. Phillip Sponenburg says that overo has come to mean anything that is not tobiano.

I think we have to be very specific about what we are calling an overo. That's why the registration papers that have the pictures on them are so valuable to us.

A: There has been some research done in England with twin horses. Some guy took an embryo, split it in half, and put the halves into two different mares. The foals that were born were very similar, but they didn't have the same white markings.

According to the old nature vs. nurture argument, any trait is a combination of genetics and environment. What is the intra-uterine environment that can affect the melanocytes—the cells that contain color? They migrate from the neural crest, which is where the nervous system develops, out to the body to give it color. What they do is stop at a certain point of the body or leg, and no color develops past that point.

We don't know what message these cells get in order to move. In lethal white foals, we know they don't get the message at all, because neither the melanocytes nor the nerves that innervate the gut move. Some gene doesn't get turned on to make the protein that tells these cells to move.

A: Even if overo is dominant, if there are genes that regulate its expression, it can be hidden. For instance, if there is a second gene that is modifying the expression of white, and the horse does not get white over its knees or hocks, a horse that is genetically an overo could be classified as a Quarter Horse.

I can look at some of my lethal white pedigrees, and a stallion that I know has sired a lethal white will sometimes be seven-eighths Quarter Horse. That confuses me, because Quarter Horses are supposedly not overos. But maybe what they are is minimally-marked overos.

If we can find this gene, then perhaps we can go back and look within different phenotypes, and determine whether those horses carry this gene.

Q: What is the long-term goal of this study, as far as helping breeders avoid producing lethal white foals?

A: What we're hoping to do is develop a genetic (blood) test that may be somewhat crude, but which may provide breeders with some information about a better way to avoid lethal whites. Will we stumble upon something that will help them breed for color? Maybe so, although I sure wouldn't guarantee it.

Lethal whites may be the price we pay for breeding for color, but it may be that it is only carried in some horses with overo color. What I'm hoping to be able to find are some overo horses who still produce color, yet don't carry the lethal white trait.

That's kind of way out in the future, but that's what we'd really like—to get rid of lethal whites but still be able to have color.

This illustration represents the model put forth by Dr. Ann Bowling of the University of California-Davis, and Dr. Debbie Duffield of Portland State University. According to this model, in every overo-to-overo cross, solids, overos, and lethal whites should occur in a 1:2:1 ratio. This means that there is a 25 percent chance of producing a lethal white foal each time two overos are crossed.


Overo 03	Overo 04
In their studies, researchers at Portland State University found that many lethal white foals came from crosses of O3 and O4 horses, the two overo color types shown above. However, Duffield attributed this trend to the fact that these were the most common color types people were choosing to breed to.

This is the classic coat pattern of a frame overo, which is what the researchers at the University of Minnesota are focusing on in their study. Dr. Elizabeth Santschi said it seems that this type of overo tends to produce more lethal white foals than, say, sabinos (calicos) or splashed white overos.

There are three issues that may account for the fact that we do not see 25 percent of all overo-to-overo crosses producing lethal whites:

1. Not all lethal white foals survive to birth. Some are resorbed or aborted by the mare.

3. Not all patterns that are currently classified as overo, such as sabino or splashed white, are lethal when homozygous.

In clarifying what we do know about lethal white syndrome, it is necessary to dispel some myths that have developed over the years.

Lethal whites can occur from any cross involving two overos or two horses that have overo in their backgrounds.

Based on the forms that crossed her desk, APHA Field Services Director Barbara Scheffler said that most lethal whites arise from two overos.

"Probably 99 percent of them are overo-to-overo crosses," Scheffler said. "But we have had incidents from an overo parent and a Quarter Horse parent, an overo parent and a tobiano parent, and an overo parent and a Solid parent."

While Paint foals that are born all white should be highly suspect of having lethal white syndrome, there are some white foals that are completely normal. While both might appear normal at birth, a lethal white foal will soon (usually within 24 hours) demonstrate several definite symptoms that indicate its condition.

The most characteristic trait of lethal white syndrome is a lack of gut activity, so a lethal white foal will probably fail to pass its meconium and will also begin to show signs of colic. Its condition will deteriorate quickly, with or without treatment.

Myth #3—A mare will not produce a lethal white foal in two consecutive years.

If you are lucky, she will not. But if she carries the lethal trait, and the stallion she is crossed with also carries it, she has a one-in-four chance of producing a lethal white foal every time she is bred to him.

Myth #4—If the stallion has never produced a lethal white, he is a safe bet to breed your mare to.

There are several reasons why this statement is untrue. First, if the stallion is young and has only a limited number of breedings, the fact that he has not yet produced a lethal white does not mean he will not in the future.

Second, it is necessary to look at the color of the mares the stallion was bred to who contributed to these statistics. If the stallion is a tovero, but was crossed on only tobiano mares, the likelihood of a lethal white would be much less than if he were crossed on all overo mares.

Third, it is possible that the stallion has conceived lethal whites, but that the embryos were resorbed or aborted by the mares. However, there is not yet any kind of blood test to confirm this notion.

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