Dominant white

Dominant white or white spotting is a group of genetically related coat color conditions in the horse, best known for producing an all-white coat, but also able to produce various forms of white spotting and white markings, several of which are sometimes referred to as sabino.
There are many different forms of dominant white or white spotting; they are labeled "W1" through "W27" and are associated with the "KIT" gene, along with Sabino 1. The white spotting produced can range from flashy white markings like those made by "W20", to patterns similar to Sabino 1, to a fully white or almost fully white horse. White horses are born with unpigmented pink skin and white hair, usually with dark eyes. Under normal conditions, at least one parent must be dominant white to produce dominant white offspring. However, most of the currently-known alleles of dominant white can be linked to a documented spontaneous mutation in a single ancestor. For many of the "W" alleles, the white coats are, as the name suggests, inherited dominantly, meaning that a horse only needs one copy of the allele to have a white or white spotted coat. Others, such as "W20", are incompletely dominant, with horses with two copies having more white than horses with only one. In addition, different alleles which on their own give a white spotted but not completely white horse, such as "W5" and "W10", can combine to make a horse completely white.
White can occur in any breed, and has been studied in many different breeds. Camarillo White Horses are characterized by their white coats.
White is both genetically and visually distinct from gray and cremello. Dominant white is not the same as lethal white syndrome, nor are white horses "albinos". Tyrosinase negative albinism has never been documented in horses. Some forms of white are thought to result in nonviable embryos when a zygote has two "W" alleles (is homozygous). However, others, such as "W20", are perfectly viable in their homozygous form.
Description.
Although the term "dominant white" is typically associated with a pure white coat, such horses may be all-white, near-white, partially white, or exhibit an irregular spotting pattern similar to that of sabino horses. To add to the confusion, at least some horses in each of those groups might be referred to as "dominant white", "white spotted", or "sabino". The amount of white hair depends on which KIT alleles are involved. At birth, most of the white hair is rooted in unpigmented pink skin. The pink skin lacks melanocytes, and appears pink from the underlying network of capillaries. White spotting is not known to affect eye color, and most white horses have brown eyes.
White or near-white.
White horses are born with pink skin and a white coat, which they retain throughout their lives. The genetic factors that produce an all-white horse are often also capable of producing a near-white horse, which is mostly white but has some areas that are pigmented normally. Near-white horses most commonly have color in the hair and skin along the topline (dorsal midline) of the horse, in the mane, and on the ears. The color is often interspersed as specks or spots on a white background. In addition, the hooves are usually white, but may have striping if there is pigmented skin on the coronary band just above the hoof. In some cases, foals born with residual non-white hair may lose some or all of this pigment with age, without the help of the gray factor.
White spotting.
White spotting from a "W" allele is difficult to identify visually, as it can range from small white markings in the case of a heterozygous "W20" horse all the way to an obvious pinto pattern. In addition, even completely white horses can have genes which by themselves would only give white spotting, such as "W20" combined with "W22" or "W5" combined with "W10". As such, the only reliable way to find out whether a horse has one of the known white spotting patterns from an allele on KIT is to have it genetically tested.
Prevalence.
Dominant white is one of several potential genetic causes for horses with near-white or completely white coats; it may occur through spontaneous mutation, and thus may be found unexpectedly in any breed, even those that discourage excessive white markings. To date, dominant white has been identified in multiple families of Thoroughbreds, American Quarter Horses, Frederiksborg horses, Icelandic horses, Shetland ponies, Franches Montagnes horses, South German Draft horses, and in one family of the Arabian horse. The American White Horse, which is descended primarily from one white stallion crossed on non-white mares, is known for its white coat, as is the Camarillo White Horse.
Inheritance.
The "W" locus was mapped to the "KIT" gene in 2007. KIT is short for "KIT proto-oncogene receptor tyrosine kinase". White spotting is caused by multiple forms, or alleles, of the "KIT" gene. All horses possess the "KIT" gene, as it is necessary for survival even at the earliest stages of development. The presence or absence of dominant white is based on the presence of certain altered variants of "KIT". Each unique form is called an allele, and for every trait, all animals inherit one allele from each parent. The original or "normal" form of "KIT", which is expected in horses without dominant white spotting, is called the "wild type" allele. Thus, a dominant white horse has at least one "KIT" allele with a mutation associated with dominant white spotting, and either the wild type "KIT" allele or a second allele on KIT associated with white spotting, which could be one of the ones in the "W" series or could be "Sabino 1".
Allelic series.
The "KIT" gene contains over 2000 base pairs, and a change in any of those base pairs results in a mutant allele. Over forty seven such alleles have been identified by sequencing the "KIT" genes of various horses. The resultant phenotype of many of these alleles is not yet known, but 29 have been linked to white spotting. To date, DNA tests can identify if a horse carries the various identified "W" alleles, some commercially available.
These alleles do not account for all dominantly inherited white spotting in horses. More "KIT" alleles are expected to be found with roles in white spotting. Most "W" alleles each occur within a specific breed or family and arise as spontaneous mutations. The "KIT" gene itself seems prone to mutation, and so new alleles of W could occur in virtually any breed.
Relation to sabino.
Sabino can refer either specifically to "Sabino 1" ("SB1") or to a variety of visually similar spotting patterns. SB1 creates a nearly pure white horse when homozygous, which is not true for other sabino patterns. To add to the confusion, white spotting created by several "W" alleles, such as "W5", "W15", and "W19" creates patterns that historically were called sabino. For that reason, the use of the word "sabino" is evolving. Genetically, "Sabino 1" is basically another allele on "KIT", and thus is probably able to be classified as a form of dominant white.
In its homozygous form, "Sabino 1" can be confused with dominant white alleles such as "W1", "W2", "W3", or "W4" that create a white or near-white horse with only one copy. Both dominant white and "Sabino-White" horses are identified by all-white or near-white coats with underlying pink skin and dark eyes, often with residual pigment along the dorsal midline. However, it takes two copies of "Sabino 1" to produce a Sabino-white horse, and "Sabino 1" is not homozygous lethal. 
Initially, dominant white was separated from sabino on the grounds that the former had to be entirely white, while the latter could possess some pigment. However, the 2007 and 2009 studies of dominant white showed that many dominant white alleles produce a range of white phenotypes that include horses with pigmented spots in their hair and skin. Each of the larger families of dominant white studied included pure-white horses, horses described as having "sabino-like" white markings, as well as white horses described as "maximal sabino".
More recently, dominant white and sabino were distinguished from one another on the grounds that dominant white alleles produce nonviable embryos in the homozygous state, while "Sabino 1" was viable when homozygous. However, not all "KIT" alleles currently identified as "dominant white" have been proven lethal, and in fact "W20" is known to be viable in the homozygous form.
The similarities between Dominant White, "Sabino 1", and other forms of sabino may reflect their common molecular origin: The "W" series and "SB1" have both been mapped to "KIT". The researchers who mapped "Sabino 1" suggested that other sabino-like patterns might also map to "KIT". Similarly, major alleles for white leg and facial markings have also been mapped to or near to the "KIT" gene.
Molecular genetics.
The "KIT" gene encodes a protein called steel factor receptor, which is critical to the differentiation of stem cells into blood cells, sperm cells, and pigment cells. A process called alternative splicing, which uses the information encoded in the "KIT" gene to make slightly different proteins (isoforms) for use in different circumstances, may impact whether a mutation on "KIT" affects blood cells, sperm cells, or pigment cells. Steel factor receptor interacts chemically with steel factor or stem cell factor to relay chemical messages. These messages are used during embryonic development to signal the migration of early melanocytes (pigment cells) from the neural crest tissue to their eventual destinations in the dermal layer. The neural crest is a transient tissue in the embryo that lies along the dorsal line. Melanocytes migrate along the dorsal line to a number of specific sites: near the eye, near the ear, and the top of the head; six sites along each side of the body, and a few along the tail. At these sites, the cells undergo a few rounds of replication and differentiation, and then migrate down and around the body from the dorsal aspect towards the ventral aspect and the limb buds.
The timing of this migration is critical; all white markings, from a small star to a pure white coat, are caused by the failed migration of melanocytes.
A certain degree of the eventual amount of white, and its "design", is completely random. The development of an organism from single-celled to fully formed is a process with many, many steps. Even beginning with identical genomes, as in clones and identical twins, the process is unlikely to occur the same way twice. A process with this element of randomness is called a stochastic process, and cell differentiation is, in part, a stochastic process. The stochastic element of development is partly responsible for the eventual appearance of white on a horse, potentially accounting for nearly a quarter of the phenotype. The research team that studied dominant white cited "subtle variations in the amount of residual KIT protein" as a potential cause for the variability in phenotype of horses with the same allele. They also speculated that variability in the phenotype of horses with "W1" might be caused by "different efficacies of [nonsense-mediated decay] in different individuals and in different body regions." That is, some horses destroy more of the mutant KIT protein than others.
Lethality.
Early embryonal lethality, also known as early embryonic death or a non-viable embryo, may occur when the embryo possesses two dominant white alleles, or has the homozygous genotype. The reason for this is that many mutations for "W" are caused by nonsense mutations, frameshift mutations or DNA deletions, which, if homozygous, would make it impossible to produce a functional KIT protein. However, it is possible that homozygous embryos from alleles of missense and splice site mutations might be viable because they have less effect on gene function. For instance, "W1" is a nonsense mutation and it is thought that horses with the genotype "W1/W1" would die in utero, while "W20" is a missense mutation and living horses with the "W20/W20" genotype have been found. A 2013 study also located horses that were compound W5/W20 heterozygotes, almost completely white, essentially with greater depigmentation than could be accounted for by either allele alone.
"White" horses that are not dominant white.
White horses are potent symbols in many cultures. An array of horse coat colors may be identified as "white", often inaccurately, and many are genetically distinct from "dominant white".
"Albino" horses have never been documented, despite references to so-called "albino" horses. Dominant white is caused by the absence of pigment cells (melanocytes), whereas albino animals have a normal distribution of melanocytes. Also, a diagnosis of albinism in humans is based on visual impairment, which has not been described in horses with dominant white nor similar coat colors. In other mammals, the diagnosis of albinism is based on the impairment of tyrosinase production. No mutations of the tyrosinase gene are known in horses, however, cream and pearl colors result from mutations to a protein involved in tyrosinase transport.
Lethal white overo.
Foals with lethal white syndrome (LWS) have two copies of the frame overo gene and are born with white or nearly white coats and pink skin. However, unlike dominant white horses, foals with LWS are born with an underdeveloped colon that is untreatable, and if not euthanized, invariably die of colic within a few days of birth. Horses that carry only one allele of the LWS gene are healthy and typically exhibit the "frame overo" spotting pattern. In cases of "solid" horses with frame overo ancestry, uncertain "overo" (non-tobiano) phenotype, or horses with multiple patterns, the LWS allele can be detected by DNA test.
Mosaicism.
Mosaicism in horses is thought to account for some spontaneous occurrences of white, near-white, spotted, and roan horses. Mosaicism refers to mutations that occur after the single-cell stage, and therefore affect only a portion of the adult cells. Mosaicism may be one possible cause for the rare occurrence of brindle coloring in horses. Mosaic-white horses would be visually indistinguishable from dominant whites. Mosaicism could produce white or partially white foals if a stem cell in the developing foal underwent a mutation, or change to the DNA, that resulted in unpigmented skin and hair. The cells that descend from the affected stem cell will exhibit the mutation, while the rest of the cells are unaffected.
A mosaic mutation may or may not be inheritable, depending on the cell populations affected. Though this is not always the case, genetic mutations can occur spontaneously in one sex cell of a parent during gametogenesis. In these cases, called germline mutations, the mutation will be present in the single-celled zygote conceived from the affected sperm or egg cell, and the condition can be inherited by the next generation.
History of dominant white research.
Dominant white horses were first described in scientific literature in 1912. Horse breeder William P. Newell described his family of white and near-white horses to researcher A. P. Sturtevant of Columbia University:
"The colour of skin is white or so-called pink, usually with a few small dark specks in skin. Some have a great many dark spots in skin. These latter usually have a few dark stripes in hoofs; otherwise the hoofs are almost invariably white. Those that do not have dark specks in skin usually have glass or watch eyes, otherwise dark eyes ... I have one colt coming one year old that is pure white, not a coloured speck on him, not a coloured hair on him, and with glass [blue] eyes."
Sturtevant and his contemporaries agreed that this colt's blue eyes were inherited separately from his white coat. In 1912, Sturtevant assigned the "white" trait to the "White" or "W" locus. At the time there was no means of assigning "W" to a position on the chromosome, or to a gene.
This family of white horses produced Old King in 1908, a dark-eyed white stallion that was purchased by Caleb R. and Hudson B. Thompson. Old King was bred to Morgan mares to produce a breed of horse known today as the American White Horse. A grandson of Old King, Snow King, was at the center of the first major study of the dominant white coat color in horses, conducted in 1969 by Dr. William L. Pulos of Alfred University and Dr. Frederick B. Hutt of Cornell. They concluded, based on test matings and progeny phenotype ratios, that the white coat was dominantly inherited and embryonic lethal in the homozygous state. Other factors, such as variations in expressivity and the influence of multiple genes, may have influenced the progeny ratios that Pulos and Hutt observed. The white coat of the American White Horse has not yet been mapped.
A 1924 study by C. Wriedt identified a heritable white coat color in the Frederiksborg horse. Wriedt described a range of what he considered to be homozygote phenotypes: all-white, white with pigmented flecks, or ', which transliterates to "white-gray." The German term for gray horse is ', not "weißgraue". Heterozygotes, according to Wriedt, ranged from roaned or diluted to more or less solid white horses. Reviewers, such as Miguel Odriozola, reinterpreted Wriedt's data in successive years, while Pulos and Hutt felt that his work had been "erroneous" because Wriedt never concluded that white was lethal when homozygous.
Other researchers prior to modern DNA analysis developed remarkably prescient theories. The gene itself was first proposed and named "W" in 1948. In a 1969 work on horse coat colors, "A los colores del caballo", Miguel Odriozola suggested that various forms of dominantly inherited white spotting might be arranged sequentially along one chromosome, thus allowing for the varied expression of dominant white. He also proposed that other, distant genes might also influence the amount of white present.
The embryonic lethality hypothesis was originally supported by Pulos and Hutt's 1969 study of Mendelian progeny ratios. Conclusions about Mendelian traits that are controlled by a single gene can be drawn from test breedings with large sample sizes. However, traits that are controlled by allelic series or multiple loci are not Mendelian characters, and may not be subject to Mendelian ratios.
Pulos and Hutt knew that if the allele that created a white coat was recessive, then white horses would have to be homozygous for the condition and therefore breeding white horses together would always result in a white foal. However, this did not occur in their study and they concluded that white was not recessive. Conversely, if a white coat was a simple autosomal dominant, "ww" horses would be non-white, while both "Ww" and "WW" horses would be white, and the latter would always produce white offspring. But Pulos and Hutt did not observe any white horses that always produced white offspring, suggesting that homozygous dominant ("WW") white horses did not exist. As a result, Pulos and Hutt concluded that white was semidominant and lethal in the homozygous state: "ww" horses were non-white, "Ww" were white, and "WW" died.
Pulos and Hutt reported that neonatal death rates in white foals were similar to those in non-white foals, and concluded that homozygous white fetuses died during gestation. No aborted fetuses were found, suggesting that death occurred early on in embryonic or fetal development and that the fetus was "resorbed."
Prior to Pulos and Hutt's work, researchers were split on the mode of inheritance of white and whether it was deleterious (harmful). Recent research has discovered several possible genetic pathways to a white coat, so disparities in these historical findings may reflect the action of different genes. It is also possible that the varied origins of Pulos and Hutt's white horses might be responsible for the lack of homozygotes. Therefore, it remains to be proven whether all equine dominant white mutations cause embryonic lethality in the homozygous state.
The "white" ("W") locus was first recognized in mice in 1908. The mutation of the same name produces a belly spot and interspersed white hairs on the dorsal aspect of the coat in the heterozygote ("W/+") and black-eyed white in the homozygote ("W/W"). While heterozygotes are healthy, homozygous "W" mice have severe macrocytic anemia and die within days. A mutation which affects multiple systems is "pleiotropic." Following the mapping of the "KIT" gene to the "W" locus in 1988, researchers began identifying other mutations as part of an allelic series of "W". There are over 90 known "W" alleles, each representing a unique mutation on the "KIT" gene, which primarily produce white spotting from tiny head spots to fully white coats, macrocytic anemia from mild to lethal, and sterility. Some alleles, such as "sash" produce white spotting alone, while others affect the health of the animal even in the heterozygous state. Alleles encoding small amounts of white are no more likely to be linked with anemia and sterility than those encoding conspicuous white. Presently, no anecdotal or research evidence has suggested that equine "KIT" mutations affect health or fertility. A recent study showed that blood parameters in horses with the "W1" mutation were normal.
Between the time of Pulos and Hutt's study in 1969 and the beginning of molecular-level research into dominant white in the 21st century, a pattern known as "Sabino" became regarded by some as a more likely cause of white phenotypes. Sabino is a type of white spotting, and the one allele now named, the incompletely dominant "Sabino-1" ("SB-1"), is found on the same locus as other "W" alleles. When homozygous, "SB-1" can produce nearly all-white horses.
In 2007, researchers from Switzerland and the United States published a paper identifying the genetic cause of dominant white spotting in horses from the Franches Montagnes horse, Camarillo White Horse, Arabian horse and Thoroughbred breeds. Each of these dominant white conditions had occurred separately and spontaneously in the past 75 years, and each represents a different allele (variation or form) of the same gene. These same researchers identified a further seven unique causes of dominant white in 2009: three in distinct families of Thoroughbreds, one Icelandic horse, one Holsteiner, a large family of American Quarter Horses and a family of South German Draft horses.
Homologous conditions.
In humans, a skin condition called piebaldism is caused by more than a dozen distinct mutations in the "KIT" gene. Piebaldism in humans is characterized by a white forelock, and pigmentless patches of skin on the forehead, brow, face, ventral trunk and extremities. Outside of pigmentation, piebaldism is an otherwise benign condition. In pigs, the "patch," "belted," and commercial "white" colors are caused by mutations on the "KIT" gene. The best-known model for "KIT" gene function is the mouse, in which over 90 alleles have been described. The various alleles produce everything from white toes and blazes to black-eyed white mice, "panda-white" to "sashed" and "belted". Many of these alleles are lethal in the homozygous state, lethal when combined, or sublethal due to anemia. Male mice with "KIT" mutations are often sterile. To date, no such pleiotropic effects have been described in horses with "KIT" mutations.