The Pigment Parade

by Lorraine Shelton, TICA Provisional Allbreed Judge and Genetics Instructor

Of all the genetics questions I get asked, no other genetic phenomenon seems to inspire curiosity quite like our cats that have white on them. Some are totally white, some have patches of white, some have cute little white mittens and boots, and some have no more than a few little hairs of white on their chests or tummies (lockets). Strangely enough, although all of these cats may be very different genetically, they exhibit the results of the same physiological phenomenon.

To understand this, we have to not only know some basics of genetics, but some concepts of embryology as well. Most of us are familiar with the terms “dominant” and “recessive”. The common white spotting gene, responsible for our bicolor, van, and harlequin (a term used by some associations when the amount of white spotting is between that of a bicolor and a van) colored cats is dominant. If a cat has white spotting, you know that at least one parent had white on him. The same is true of the epistatic white gene. When we see a beautiful shimmering white Persian we know that at least one of his parents was white. The term “epistasis” refers to the fact that the cat’s “whiteness” covers up whatever color he may be underneath. For all you know, that white Persian is genetically a shaded tortoiseshell, or a blue lynx point, or a dilute calico.

All of our genes are inherited in sets of two, one from each parent. Each gene may come in only one or in many varieties that are called “alleles”. The KIT gene has multiple alleles, including W (epistatic white), caused by an ancient viral infection in a cat that lived many centuries ago. By convention, recessive alleles are given lower case letters and dominant alleles upper case letters. If one parent in a breeding is white, then a kitten could receive a white allele (W) from that parent. If the other parent is non-white, the kitten must receive a “non-white” allele (w) from the other parent. Since W is dominant over w, the kitten will be white. Such a kitten is called “heterozygous”. “Hetero” means “different”, and in this case the kitten would have the genotype Ww. Either a W or a w would be passed to each of that kitten’s future offspring. If both of the parents were white, the kitten COULD (but not always) get a W allele from each parent. This creates what is referred to as a “homozygous” white cat. “Homo” means “same”. This kitten would have the genotype WW and all future offspring from this kitten would be white, as every offspring would receive a W even if the other parent contributed a w. When a Ww cat is bred to a Ww cat, the odds are that 25% of the kittens will be WW, 50% will be Ww, and 25% will be ww (non-white). The WW cat will look just like a Ww cat; in this case, two cats with different genotypes (genetic make-up) will share an identical phenotype (appearance).

This is NOT the case with the white spotting gene, another variant of the KIT gene which gives the cat fancy its lovely bicolors, tricolors, and mitted cats. In this case, the dominant allele (Ws) is extremely variable in its expression. A cat with only one copy of the dominant allele (genotype Wsw) may only have a small amount of white or could have a large amount of white. Cats with two copies of the dominant allele (genotype WsWs) frequently have very large amounts of white and may be referred to as “vans”. Carried to the extreme, a homozygous (WsWs) cat may even be completely white. This very rarely happens, however.

The extent to which the amount of white is expressed can be somewhat controlled by selective breeding. By breeding only the cats with a lot of white on them you can decrease your chances of getting cats with very little white. This is because for every major gene we know about, like KIT, there are many other genes (“polygenes”) and other heritable factors (“epigenetics”) that can influence what our cats look like. For instance, ear size, coat texture, and temperament are not controlled by identified major genes, but can be influenced by selective breeding and the accumulation of desired heritable factors. On a historic note, older articles on bicolor breeding in Persians warned against getting “too much white”, as 1/3 white was considered optimal. With time, preferences changed and the majority of breeders now appear to believe that you can never have too much white!

The opposite direction is taken by Birman breeders. They have selectively bred their cats for many generations to influence the way that the KIT allele unique to their breed (wg) is expressed. Through careful selection of breeding stock, they can produce cats with white limited only to the four paws with a level of consistency that is quite amazing and indicative of being cause by an allele unique to this breed. The hybridization of Birmans with other breeds (both intentional and accidental) has demonstrated that the trait of white spotting is caused by a dominant mutation in this breed, although penetrance of the trait can be incomplete (not all cats with the wg allele will exhibit white spotting). However, this “gloving” allele has also been described as a recessive mutation, since the specific pattern of the show quality Birman requires the cats to be homozygous for this allele. The correct pattern can be lost very easily, reintroducing a whole spectrum of distribution of white, once a group of cats becomes heterozygous at this gene or if the allele is combined with the Ws allele. When Birmans were bred to a flame point Himalayan to introduce the red factor into some lines, the gloving was reinstated within a few generations by recreating cats homozygous for the gloving pattern mutation.

In Ragdoll cats, the presence of another mutation, possibly yet another KIT allele, has been hypothesized to explain the predictable heritability of the mitted and bicolor patterns in cats that cannot be explained by their genotypes for the currently identified KIT variants.

Another example in our spectrum of white is the case of “lockets” seen in some cats. These are genetically solid cats with no bicolored or white cats in their background that have a small patch of white hair somewhere on them. This does not appear to be influenced by any yet identified major genes, although a predisposition for lockets appears to “run in lines”. Removing cats that throw locketed kittens from breeding programs can lower the incidence. Using bicolored or white cats in a breeding program will not cause lockets. However, keep in mind that if a cattery was having a problem with lockets in solid colored cats, shifting their focus to breeding white or bicolored cats would easily “cover up” the problem.

When these lockets occur, they are almost always seen on the underside of a cat. Spots at the groin or chest are the most common. Now picture the typical bicolored cat. These cats always have white chests and tummies. You never see a bicolor that is black on the bottom and white on top, do you? White kittens when they are born frequently have a patch of color on them. Where is it? On the topmost region of the cat: between its ears. Are you getting the picture? White on bottom, color on top.

When an egg is first fertilized, all the cells are the same. This is followed by a process known as differentiation, where individual cells start to take on their specific duties in the complete animal. In this process, some cells start to move from the part of the embryo called the neural crest (at the top of what will develop into the kitten), down over the sides of the embryo towards the bottom. These cells will later further differentiate into cells responsible for many functions, including the melanocyte cells that give color to a cat’s skin and fur. If these cells contain the genotype ww and no alleles for white spotting, the population of cells will travel all the way to the bottom of the embryo. If they contain one or two copies of the white spotting gene, the cells will reproduce less effectively and the spread of the population will stop before they complete the full journey. If they have one or more copies of the epistatic white gene, this journey will be interfered with even more strongly, and the reproduction of these cells will stop very early in embryonic development. Not only will the cells never leave their point of origin at the tip of the neural crest, but the cells that do remain may not survive. This is why the “kitten cap” fades as the cat matures.

Other factors appear to influence this “pigment parade”. Some bicolors have perfectly symmetrical markings, some have their white “askew”. Some have one, well defined, unfragmented area of white, others have color that seems to scatter across an area. This could be due to other heritable factors or even possibly what is surrounding the embryo as it develops. In a study of the effects of ultrasound on developing human fetuses, no ill effects were found. However, they did find that more babies were lefthanded if they received ultrasound scanning prior to about 12 weeks. Science still has a lot to explore in the field of embryology and the effect of environment on developing cells.

Can there be bad effects from stopping the parade of pigment forming cells prematurely? Yes, and this is what causes deafness in some white cats and (very rarely) in bicolors as well. As I stated earlier, these marching neural crest cells have more than one function to perform. Another type of cell, located in the inner ear, is formed from these neural crest cells and is essential for sound hearing. That is why deafness is most common in blue eyed white cats and when it occurs in vans, only in those with VERY little color.

The pigment producing cells are responsible for giving our cats colored eyes as well as colored skin and fur. An eye without these cells is blue. If the cells have marched down from the neural crest far enough to give the eyes color, chances are they have progressed far enough to provide sound hearing as well. But remember how some bicolors are assymetrical? The same thing can happen in whites, causing odd eyed cats or deafness in only one ear. I have seen bicolored cats with eyes that are blue on the side towards the middle of the face and copper on the side towards the outside of the face. Now THAT is an odd-eyed cat! As breeding programs consistently produce bicolored and van cats with more and more white on them, blue and odd eyes have increased in frequency in these programs. However, any cat with white spotting, no matter how little, could have blue or odd eyes and could theoretically, although rarely, be deaf in one or both ears. Breeders have observed that if a white kitten has a “kitten cap” that the kitten is most likely sound of hearing. The kitten cap shows us how far the melanoblast cells have traveled. Most of these cats are not blue-eyed. When I initially started researching this subject, I was under the misunderstanding that all blue-eyed cats were homozygous and copper, gold, or green eyed cats were heterozygous for mutations of the KIT gene. This is not true. A kitten with only one white parent can still have blue eyes and/or be deaf, however the incidence is lower compared to cats that have the genotype WW or WWs. The expression of the white gene is highly variable, however the tendency towards blue eyes (and deafness) can run in certain lines. The more blue eyed cats in the pedigree, the greater your chances of experiencing blue eyed and/or deaf kittens. Homozygous whites (WW) or whites carrying the allele for white spotting (WWs) tend to have blue or odd eyes more frequently than heterozygous cats, indicating a possible “additive” effect influencing the migration of pigment cells.

In my opinion, kittens with blue eyes AND sound hearing cannot be selectively bred for with any degree of consistency. The epistatic white allele is pleiotropic, meaning that this one gene variant can cause multiple traits, including white coat color, blue eyes, and deafness. If you are selectively breeding for the pigment parade to stop as early as possible to get those lovely blue eyes, you cannot avoid running into deafness at some point. Breeding two “sound hearing” blue eyed cats (established through a neurological exam called a BAER test) to one another in an attempt to avoid deafness is a misguided approach, as it will create homozygous kittens (WW), a genotype which has been associated with a near 100% likelihood of at least partial hearing impairment. To obtain the lowest incidence of deafness, only copper, gold, amber, hazel, or green eyed white cats should be bred and they should be mated only to cats that are neither white nor white-spotted.

Do not fall into the trap of believing that there is a “deaf gene” or a “blue eyed” gene with a simple mode of inheritance. There is no such thing as a “blue-eye carrier”, only a cat with a family history of blue eyes. Remember those Birmans? The pigment parade CAN be controlled, and in these cats to an amazing degree, but it would require many, many generations and very careful control of breeding stock, selecting only for degree of pigment progression. If you want to get an idea of how difficult this will be to do in a white program, visit a bicolor breeder and observe the diversity of pattern of white spotting in the kittens. The fun of working with bicolors is the incredible variety in expression of this gene. But it also shows how difficult it is for us to “paint” our cats with pigment just where we want it.

Blue eyes can be produced through another mechanism. Himalayan programs using white Persians or white Oriental Shorthair (“foreign white”) programs can breed sound hearing, blue eyed white cats by incorporating pointed cats into their white breeding programs. If a physiologically non blue eyed white kitten is produced, where the pigment cells have migrated to the iris and inner ears, but the kitten possesses two copies of the recessive pointed gene (a form of albinism) a metabolic phenomenon can turn the kitten’s eyes blue by suppressing pigment production in those pigment cells. However, keep in mind that the white gene is variable in its expression and a blue eyed deaf kitten can also be produced by the “traditional” effects of the white gene. My suggestion to avoid deafness in such a program? Use copper, gold, amber, hazel, or green eyed white cats for breeding that had large kitten caps when they were born. Some white cats even maintain a “kitten cap” in adulthood. These cats may have the least likelihood of producing deaf kittens.

For completeness, I would like to say that in some Himalayan and Siamese/Oriental lines there is an albinism gene that has travelled through the generations from early Siamese ancestors. This is the one case where a cat can be white without having one white parent. This variant of the tyrosinase gene (ca) is recessive to the much more common pointed allele (cs), which is a more mild form of albinism. I have only seen one albino Himalayan and one albino Siamese, both with very pale blue eyes with a distinct red cast from the lack of pigment in the retina. Most of these cats have vision problems, such as nystagmus (eye tremors) and photosensitivity. In the case of an albino, the pigment parade is not affected at all — the pigment cells just don’t do their job once they get to their destination.

So now that we know that there is no “blue eyed” gene and no “deafness” gene, what about those annoying lockets? This occurs when the pigment cells get “lazy” and stop just short of the completion of their normal journey. There may be yet unidentified variants of the KIT gene (or other genes) responsible for other forms of white spotting. Use a cat for breeding that had a “locketed” littermate and you may run into the problem again. Keeping good records of ALL kittens born to a breeding program can be a valuable aid in controlling the incidence of such undesirable traits such as lockets. In some cases, new forms of pigment parade disruption may be desirable, such as with blue-eyed cats with very little (or no) white spotting that have been seen in various breeds or have even been developed as new breeds. Be aware, however, that these mutations are effecting neurological tissue and mutations may have unwanted consequences. In the now extinct Ojos Azules breed, the mutation for blue eyes caused severe problems in homozygous form, similar to those seen in “double merle” dogs. Breeders working with new blue eyed or white spotting mutations need to proceed carefully.

I had stated that using bicolors or whites in a breeding program would not cause lockets. I would like to backstep a bit on that position. If a breeding program is selectively breeding for large amounts of white on their bicolors, they may also be selectively breeding for factors that can contribute to a slow migration and reduced reproduction of those marching melanoblast cells. This is also true of a program selectively breeding for blue eyed whites. This is purely speculation, and I would be interested in hearing from white breeders producing large percentages of blue eyed white kittens. Have you seen an increased incidence of locketed solids? Especially from lines that throw blue eyed whites bred to non-white cats? This may be the root of the “old wives tale” that using whites will improve the amount of white on a bicolor. Using blue eyed whites to increase the amount of white on a bicolor, however, would be far less effective than using a bicolor cat selectively bred for a lot of white. It is my feeling that any influence that a white cat could have on the markings of a bicolor would be very minor at best.

Taking advantage of the polygenes influencing other programs can also benefit someone wishing to increase the incidence of odd eyed whites in their lines. Some breeders have observed that adding bicolors to a white program will increase the incidence of odd eyes. In addition to the additive effect of the two KIT mutations, I think that increasing the incidence odd-eyes (over blue eyes) may be possible if ASSYMETRICAL bicolors are used. Bicoloreds with perfectly even V blazes may even DECREASE the odds of getting odd eyes over blue eyes, in my opinion, because these cats may reinforce the trait of symmetry.

Because the white spotting allele and the epistatic white allele are variants of the same gene, a white cat carrying white spotting bred to a non-white/non-white spotted cat will produce only white or white spotted kittens. The white cat’s genotype would be WWs, the solid parent would be ww, and all the kittens would therefore be WWs (white carrying white spotting) or Wsw (white spotted). A ww kitten (non-white, non-bicolor) could not be produced. It also means that a white cat can never be masking “van”, only bicolor. Luckily, commercial genetic testing is now available to determine a cat’s genotype at the KIT locus for those wishing to control this factor.

I hope that this gives you some insight as to how our cats get white on them. Amount and placement of white on bicolors can be selectively bred for. Non blue vs. blue eyes on a white can also be selectively bred for, although keep in mind that deafness and blue eyes go hand in hand. The absence of lockets can be selectively bred for. I hope that by understanding the mechanism behind why our white and “with white” cats look like they do, you can make better decisions for your own breeding program.

I’d like to thank my usual references, Book of the Cat, Roy Robinson, and Dr. Pedersen’s Feline Husbandry, as well as those embryology texts from college. I’d like to thank Laura Lewellen for answering my initial questions on this phenomenon. Thanks to Dr. Leslie Lyons and the other geneticists around the world working on identifying genetic variants in our cats. Please donate to Winn Feline Foundation to support continuing research into feline genetics.

References:

Bergsma D. R., Brown K. S., 1971. White fur, blue eyes, and deafness in the domestic cat. J. Hered. 62: 171-185

Victor A. David, Marilyn Menotti-Raymond, Andrea Coots Wallace, Melody Roelke, James Kehler, Robert Leighty, Eduardo Eizirik, Steven S. Hannah, George Nelson, Alejandro A. Schäffer, Catherine J. Connelly, Stephen J. O’Brien, David K. Ryugo. 2014. Endogenous Retrovirus Insertion in the KIT Oncogene Determines White and White spotting in Domestic Cats. G3 Aug 1;4(10):1881-91

Aoki H., Yamada Y., Hara A., Kunisada T., 2009. Two distinct types of mouse melanocyte: differential signaling requirement for the maintenance of non-cutaneous and dermal vs. epidermal melanocytes. Development 136: 2511-2521

Geigy C. A., Heid S., Steffen F., Danielson K., Jaggy A., et al. , 2006. Does a pleiotropic gene explain deafness and blue irises in white cats? Vet. J. 173: 548-553

Cable J., Jackson I. J., Steel K. P., 1995. Mutations at the W locus affect survival of neural crest-derived melanocytes in the mouse. Mech. Dev. 50: 139-150 Vella C. M., Shelton L. M., McGonagle J. J., Stanglein T. W., 1999. Robinson’s Genetics for Cat Breeders and Veterinarians, Butterworth-Heinemann, Oxford, Boston

Ragdoll Fanciers Worldwide website, Mindy Ferreira, Ragdoll Fanciers Club International website, Isabelle Bellavance

Ryugo D. K., Cahill H. B., Rose L. S., Rosenbaum B. T., Schroeder M. E., et al. , 2003. Separate forms of pathology in the cochlea of congenitally deaf white cats. Hear. Res. 181: 73-84 Lyons L. A., 2010. Feline genetics: clinical applications and genetic testing. Top. Companion Anim. Med. 25: 203-212

Cooper MP1, Fretwell N, Bailey SJ, Lyons LA. White spotting in the domestic cat (Felis catus) maps near KIT on feline chromosome B1. Anim Genet. 2006 Apr;37(2):163-5.

Frischknecht M, Jagannathan V, Leeb T, Whole genome sequencing confirms KIT insertions in a white cat. Anim Genet. 2015 Feb;46(1):98.

David VA, Menotti-Raymond M, Wallace AC, Roelke M, Kehler J, Leighty R, Eizirik E, Hannah SS, Nelson G, Schäffer AA, Connelly CJ, O’Brien SJ, Ryugo DK. Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats. G3 (Bethesda). 2014 Aug 1;4(10):1881-91.