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Some new research into blue eyes and KIT mutations

BlueNAmber1
A tobiano pony with partially blue and partially gold eyes (cause unknown)

A year ago I posted expressing my doubts about the theory that blue-eyed horses with KIT mutations (tobiano, sabino and the white spotting patterns) must carry an additional mutation to account for their eye color. At the time, I did not think that there was enough evidence to merit the absolute terms that were often used regarding this theory. It is also true that, having tracked so many instances of blue eyes in the patterns in question, I thought the weight of probability favored the theory that the blue eyes were part of at least some of these patterns and not always a separate mutation. At the time I wrote:

The common theory in horses is that these W-series horses must have a splash mutation as well. And they may. Certainly there are far more mutations for white patterning than previous expected. I have long thought that the numbers of blue eyes on the dominant whites, particularly among the founder horses (ie., the horse that carried the initial mutation) were just too high for them all to happen to have a splash mutation as well. I did not have an exact number, though – just a sense that it was high. But the new sort gave me a number – six of twenty.

The argument that KIT mutations are “incapable” of producing blue eyes is based on information about how pigment is formed in the eyes of mice. I found the theory difficult to evaluate because the passages referenced by its supporters do not deal directly with eye color in horses, and I simply do not have the deep level of understanding of eye structure necessary to extrapolate beyond the specific subject, which was not the absence of blue eyes but the presence of dark eyes in a particular mouse color.

But perhaps more importantly, I just wasn’t sure that mice and horses were the same in this regard. In fact, I just wasn’t sure that eye color in various mammals might not be different in significant ways, just as other aspects of coloration vary between species. In that same post, I included a picture of what was then a newly-identified KIT mutation in dogs – the panda pattern in German Shepherds. I found the blue eyes on the founding dog particularly compelling because in dogs blue eyes are not generally associated with the common forms of white patterning, despite the fact that the mutations for most of those patterns have been found on MITF, which those of us more familiar with horses think of as the “splashed white” gene.

It seemed to me that these blue-eyed (KIT) German Shepherds, and the more common dark-eyed “irish marked” (MITF) dogs were a pretty good argument that when it came to eye color, there was probably some variation from the mouse model.

BlueNAmber4
The same pony, with one predominantly blue and one
predominantly gold eye (and an occluding spot over his blaze)

Some time after that post was made, I ran across a paper on Blue-Eyed White (BEW) alpacas. In that paper, the blue-eyed white phenotype was linked to the presence of two mutations to KIT. The alpacas, which were uniformly blue-eyed, were compound heterozygotes for two different white patterns (bew1 and bew2), both located at KIT. Since that time I have been able to confirm with one of the researchers that there were no mutations at the sites associated with splashed white in horses that could be correlated with the blue eyes on these alpacas.

Then just this month a paper was published linking the blue-eyed white phenotype in cats – called Dominant White (W) – to a mutation on KIT. In that study, the authors were quite clear about the connection between KIT and blue eyes.

In the population sample, we were also able to examine the correlation between genotype at the W locus and iris color. An individual that is homozygous W is much more likely to have blue iris, exhibiting odds 77.25 times larger than the odds of having blue irises of a genotype other than W/W (p < 0.0001).  An individual that is heterozygous (W/w+) also demonstrates increased odds of having blue iris (OR=4.667), four times larger than the odds of having blue irises of a genotype other than W/w+ (p=0.046) The odds of having blue irises of a wild type individual is 0.

With those two studies seeming to cast considerable doubt on the “Never From KIT” theory, I decided to contact one of the corresponding authors with some questions in hopes of getting a better understanding of this topic and of eye color in general. What I was told was that eye color is most likely a polygenic trait, and that it really does depend on the species, as well as the specifics of each particular mutation to KIT. That could explain why some KIT mutations are more prone blue eyes than others, as well as why there appears to be a higher incidence of blue eyes in homozygotes of some patterns.

BlueNAmber2
On this eye, the blue and gold portions are interspersed in such a way that the colors appear softly blended

BlueNAmber3
On this eye, there are fewer flecks of blue, as well as irregular patches of dark brown

So why does it matter if KIT mutations can produce blue eyes alone, or if they need a splashed white mutation? What purpose does this kind of information serve? The fact is that knowing the cause can help breeders more reliably get the outcome they desire, whether they wish to breed for or select against blue eyes. Likewise, breeders seeking to produce – or avoid – the splashed white phenotype need to know if blue eyes are always significant. If it is possible for some of the other patterns to produce blue eyes independent of a splashed white patterns, then assembling a herd of blue-eyed tobianos in hopes of developing a line of splashed whites is going to ultimately prove frustrating.

It is also true that quite a few blue-eyed horses have come back negative for the known splashed white patterns. It is likely that some of them have as-yet-unidentified splashed patterns. However, if some have blue eyes that are just a less common aspect of a pattern that is already identified, then knowing this could spare their owners time and money spent looking for something that is not really there. So while the subject is quite technical, it really does have a very practical aspect.

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Names, categories and descriptive terms

TobiTypical

FrameTypical

I believe that often a seemingly illogical system makes sense when its history is considered. Because revelations are often gradual, systems build on what came before. In this way you often end up with something that is less ideal than what could have been devised had a more accurate picture been known from the start. I believe that knowing this is essential to understanding where things stand today with the terminology for pinto patterns.

When I first took an interest in horse color, most American horsemen accepted that there were two kinds of pinto patterns: tobiano and overo. Those were the terms used by the American Paint Horse Association, which was the largest registry for pinto-patterned horses. If you read enough horse magazines, eventually you would run across a list of rules for determining whether or not a horse was a tobiano or an overo. Did the white cross the topline? Tobiano. Was one or more legs dark? Overo. Did the horse not follow either set of rules? Then he was a combination of the two – a tovero. The rules were useful if you had a typical tobiano or a pure frame overo like the one pictured above.

They were slightly less useful for minimal tobianos like this one.

MiniTob

But the real limitation came when dealing with any of the other pinto patterns. Splashed white, for instance, actually followed the tobiano rules more closely than those for overo. The truth was that the rules for “overo” could be more accurately said to be the rules for frame overo. The rules described that very specific pattern, but in actual practice the term overo was being used to mean anything not tobiano.

In the 1970s and early-1980s, a number of writers began to include additional pinto categories. Among these were splashed white (which had been described in still earlier literature) and sabino. In the United States, Paint Horses with these patterns were registered as overos, so the convention became that, aside from tobiano, the “new” patterns were different forms found under the general category of overo. Thus there was a frame overo, sabino overo, and splashed white overo. Later, when it was identified and named, there was manchado overo. This convention can be a source of frustration for breeders in other countries where overo has been used pretty exclusively for frame overo. (The fact that frame overo is one of the better-known lethal genes probably adds to the desire not to see the same word tacked on to the back of other pattern names.) It makes more sense if it is understood that this was a way of integrating new information into a widespread, existing naming system. It was easier to tell the many breeders of Paint Horses that they needed to be more specific about which type of overo they had, rather than tell them that they had been wrong for calling all those non-tobiano horses overo in the first place.

Categories of Patterns

That process has repeated itself a few times in the years since. We start out with patterns that have names, and then find out we have unwittingly placed genetically different things together under one name. So the name becomes a category, rather than one specific pattern. This has meant it was necessary to search for a way to distinguish between the patterns within the new category. With the advent of genetic tests, the most common approach has been to number the different variations. So when it became clear that Splashed White was a category of patterns, and not one specific pattern, the variations were given numbers in the order in which they were discovered: Splashed White-1, Splashed White-2, and so on through to (at the time of this writing) Splashed White-5.

Although the speed of new discoveries made it difficult for many to adjust, the system has worked reasonably well, with one big exception. That exception is Sabino.

I have written before about my own involvement in researching sabino patterns. In the 1990s, an article I wrote speculating that many white-born horses were in fact “maximum” sabinos was widely circulated on the internet. While I came to that conclusion primarily using research on the Tennessee Walking Horse, I really was just rediscovering what the Dutch researcher J. K. Wiersema already knew in the 1960s. The pattern we both were studying is now known as Sabino-1. With that specific pattern, heterozygous Sabino-1 horses have flashy white markings with roaning, and homozygous Sabino-1 horses are white. We both also observed, however, that there seemed to be other kinds of sabinos that did not look quite like this. What’s more, those patterns did not seem to have a connection to white horses. We both also noted that there were white-born horses that did not quite fit the profile. In hindsight, it is clear that this should have been a big clue that too many different patterns were being lumped into this one category.

This problem is quiet obvious if you group images of horses with patterns that have been called sabino in the past. Here is a slide I used in a recent presentation that makes this point in a very visual way. All the horses in this image have patterns that would, at one time, have been referred to as sabino.

SabinoSlide

Given the broad range of white patterning in that image, it would not be surprising that many began to consider sabino a pattern category. Within that category, or group, one might expect to find quite a lot of separate patterns. And that was what many expected, after the first sabino pattern (Sabino-1) was identified. The assumption was that researchers had found the first of what was likely quite a large number of them. Certainly it was clear that what was arguably the most common form of sabino – what many breeders refer to as “flashy white” – was not the one that had been identified. Although Sabino-1 was later found to be quite an ancient pattern, in modern times it is found in a rather limited range of breeds. It was expected that some of the more common types of sabinos would soon follow.

FlashySab
Horses like this one, with flashy white stockings, a blaze, and maybe a bit of white on the belly or girth, have long been thought of as the most common form of sabino

That expectation did not come to pass. The next set of patterns that were formally identified were classified as Dominant Whites and given the names White-1 through White-4. Each of these particular mutations resulted in horses that were, in terms of phenotype, either completely white or nearly all-white. Because the idea that white-born horses were “maximum sabinos” had gained a lot of traction in the years prior, there were some that felt those first four patterns should have been part of the sabino category, picking up the numerical sequence at Sabino-2. The truth was that those first patterns did fit the original definition of Dominant White in that they produced their own color 50% of the time, and the mutations appeared to be homozygous lethal. The fact that some of the individuals with those mutations were not entirely white would not have actually come as a complete surprise to earlier authors who wrote about Dominant White. Almost every account of the color mentioned the tendency to throw “pied” foals along with white ones. It did make sense to classify those mutations as White rather than Sabino.

When more patterns were added to the White category, the difficulty with the terminology increased. That was especially true with some of the later patterns that looked far more like what had traditionally been called Sabino. Some breeders working with the bloodlines where the more patchy expression was common referred to their horses as Sabinos in advertising. This stallion, Sato, from the Puchilingui line (W-5) of Thoroughbreds, is a good example.

Sato1

For someone interested in producing pinto-patterned sport horses, advertising a horse as Sabino makes good sense, because most pinto breeders do not actually want a white horse. Indeed, some registries for colored horses will not issue regular papers for white horses; they are considered “solids”. Did breeders know that a horse like Sato was technically White? Yes. And the line did produce all-white horses on occasion. But most were loudly patterned in a way that would, at least at one time, be called Sabino.

Officially, however, these horses were White, popularly known as Dominant White. For the sixteen patterns of this type that were discovered after those initial four, each was named as part of the W series of mutations. It was assumed that any other mutations found in that same region were likely to continue in this fashion, while nothing else would be added to the Sabino series. In this way, Sabino could be said to have gone from a named pattern, to a category of patterns, to an informal term used to describe a specific pattern on a specific horse (much like the way roaning is used). Put another way, sabino became the official name for one specific pattern (Sabino-1), and an unofficial descriptive term for some individual horses with patterns of some other official name.

That was roughly where things have stood until very recently, as reflected in the chart below.

NameChart

That seemed to be the system that would continue, until researchers got to W-20. That is where the naming system became a bit harder to explain, because there have been unexpected twists in the most recent discoveries. Because things get a bit more complicated from here, I am going to break this across to a second post. This one has already run quite long (even for a blog that routinely breaks the “keep it brief” rule of blogging!) and there is a lot to digest. I also want to pull the next part out because a study is currently being organized that touches on these new developments, and I want to give that the space it deserves. With luck, I will get the next part out in a more timely manner than this one!

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