Some new research into blue eyes and KIT mutations

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.

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.

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

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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3 Responses to Some new research into blue eyes and KIT mutations

  1. Henriette August 25, 2014 at 1:14 pm #

    Read “Do KIT Gene Mutations Cause Blue Eyes?” The proposed answer is no, but the reasoning faulty. The retinal pigment epithelium is an important agent in eye development and function. It generates its own pigmentation. An extension of the RPE is found at the back of the iris (iridial retina, or better posterior epithelium of the iris), but the iris stroma is served by the melanoblasts from the neural crest, just like skin and hair. In the iris, however, eumelanin predominates over phaeomelanin; chestnut horses have the same colour eyes as bays and blacks. MITF mutations may affect RPE (usually bad news for vision), but in classic splashed white it is the spotting that hinders pigmentation of iris stroma, not of RPE. KIT spotting mutations in the horse likewise may affect pigmentation of iris stroma only, resulting in pigmentless = blue, or parti-blue eyes. When pigmentation is extremely diluted, in RPE and iris stroma, in complete albinos, then the eyes will be red (and vision impaired).
    In “The colors of mice” differences between mouse and human eyes are remarked on. Has anyone actually seen pictures of blue-eyed mice? Fascinating subject…. Eenriette

    • equinetapestry November 28, 2014 at 4:08 pm #

      Thank you for that clarification, Henriette. What I thought I was reading, going through various papers that touched upon eye color, was that the RPE was only part of the story. That was the answer I received when I inquired about the BEW (KIT) mutations in other species.

      So I am curious. The extreme dilutions that can alter both – is that what is responsible for the “leaky” coloration you see in photographs of human albino eyes? From a distance, those eyes look almost lavender, but close-up they look more striated blue and pink/red. That ties into some of the same questions I have had about the possibility of a blue-eyed mouse. I have seen blue-eyed rabbits, but they don’t seem to have the true crystal blue that you see in horses or dogs. They look more lavender. At first I wondered if “colorless” and “reduced color” just might not look different depending on the eye structure. In some animals the range seems to be black>brown>amber>blue, while in others it seems to go black>ruby>pink, but those blue/lavender-eyed bunnies messed up that tidy theory! :D

  2. Sabrina October 1, 2014 at 11:26 pm #

    Awesome read. I have had quite a few HZ tobianos with blue eyes. I’ve tested them all for LWO, Splash, & Sabino genes and they have all been NN so far, and TT. Most have had little to no white on thier faces. So far all I have been told is that they must carry splash that you can’t test for yet, and that true tobianos can’t have blue eyes. Wonder if that could change some day. :)