Dominant white

All-white dominant white horse with pink skin, brown eyes, and white hooves.
This dominant white Thoroughbred stallion (W2/+) has one form of dominant white. His skin, hooves, and coat lack pigment cells, giving him a pink-skinned white coat.

Dominant white is a group of genetically related coat color conditions in the horse, best known for producing an all-white coat, but also for producing some forms of white spotting and white markings. Dominant white horses are born with unpigmented pink skin and white hair with dark eyes, although the amount of white hair or spotting can vary depending on which genetic mutation is involved. Dominant white is a rare condition, and 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.

Dominant white can occur in any breed, and has been studied in many different breeds. Two color breeds, the American White Horse and Camarillo White Horse are characterized by their dominant white coats.

There are many different forms of dominant white; in genetics, as of 2013 they are labeled W1 through W20. All known dominant white coat colors are associated with the KIT gene.[B] As the name suggests, these known white coats are inherited dominantly,[D] meaning that a horse only needs one copy of a W allele to have the white or white spotted coat.

Dominant white is genetically distinct from Sabino and both genetically and visually distinct from gray and cremello. Dominant white is not the same as lethal white syndrome, nor are dominant white horses "albinos". Albinism has never been documented in horses. Some forms of dominant white are thought to result in nonviable embryos when a zygote has two W alleles (is homozygous). However, this has not been verified for all dominant white genetic variations.

Identification

The dark skin under a white hair coat, easily seen at the muzzle and genitals, shows that this white-looking horse is actually a gray. Most horses that look "white" are actually grays.

Dominant white horses are born with pink skin and a white coat, which they retain throughout their lives.[1] 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.[2] The amount of white hair depends on which mutation of W is involved.[3] Non-white areas of skin and hair are most commonly seen along the dorsal midline of the horse, known as the topline, and are especially common in the mane and on the ears.[2] They may also have interspersed specks or spots of non-white skin and hair. In addition, the hooves are most often white, but may have striping if there is pigmented skin on the coronary band just above the hoof.[4][5] 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.[6] Dominant white spotting does not affect eye color, and most dominant white horses have brown eyes.[7] The pink skin is devoid of pigment cells (melanocytes), and appears pink from the underlying network of capillaries. White hair is rooted in unpigmented pink skin. There are many other genetic factors that produce white, near-white, and off-white coat colors in horses, some of which are visually very similar to dominant white.[8]

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,[6] American Quarter Horses,[2] Frederiksborg horses,[2] Icelandic horses,[2] Shetland ponies,[6] Franches Montagnes horses,[6] South German Draft horses,[2] and in one family of the Arabian horse.[6] The American White Horse, which is descended primarily from one dominant white stallion crossed on non-white mares, is known for its dominant white coat, as is the Camarillo White Horse.[9][10]

Inheritance

The W locus was mapped to the KIT gene in 2007.[6] The terms "Kit oncogene" and "dominant spotting" gene, symbolized by KIT and W respectively, can be used interchangeably.[11] Current research has now shown that there are multiple forms, or alleles, of the W gene.[6] 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 forms 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.[A] Thus, a dominant white horse has one KIT allele with a mutation associated with dominant white spotting, and one wild type KIT allele.

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:

This dominant white Franches Montagnes colt (W1/+) lost almost all his residual pigment by the time he was 3 years old (below)
The same foal as an adult horse. 100% unpigmented skin and hair is not necessary for a horse to be considered "dominant white." Some dominant white horses lose pigment with age, even though they do not possess the gray gene.
"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."[5]

Sturtevant and his contemporaries agreed that this colt's blue eyes were inherited separately from his white coat.[12] In 1912, Sturtevant assigned the "white" trait to the White or W locus.[5] 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.[9] 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.[13] Other factors, such as variations in expressivity and the influence of multiple genes, may have influenced the progeny ratios that Pulos and Hutt observed.[14] 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.[15] Wriedt described a range of what he considered to be homozygote phenotypes: all-white, white with pigmented flecks, or weißgraue, which transliterates to "white-gray."[16] The German term for gray horse is schimmel, not weißgraue.[17] 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.[18]

Other researchers prior to modern DNA analysis developed remarkably prescient theories. The gene itself was first proposed and named W in 1948.[3] 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.[19]

This mare comes from a family of white Thoroughbreds.

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.[20] Sabino is a type of white spotting, and the one allele now mapped, the dominantly inherited Sabino-1 (SB-1), is genetically related, though distinct. When homozygous, SB-1 can produce nearly all-white horses that resemble dominant white. Other genes responsible for all possible patterns labeled "Sabino" have not yet been identified, though some forms of the splashed white gene may be responsible for certain patterns.

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.[6] 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.[2]

Allelic series

The KIT gene contains over 2000 base pairs, and a change in any of those base pairs results in a mutant allele.[2] Over forty such alleles have been identified by sequencing the KIT genes of various horses.[2] The resultant phenotype of most of these alleles is not yet known, but 20 have been linked to dominant white.[3] To date, DNA tests can identify if a horse carries the various identified W alleles, some commercially available.[21]

A stocky Camarillo White horse, with a white coat, pink skin, and dark eyes.
The Camarillo White Horse breed has a dominant white coat owed to the W4 mutation.

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.[2] 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.[3]

Skin biopsies of non-white (left) and white horses. Blue staining identifies Kit protein activity, while melanin is visible in the non-white sample as brown granules. The sample from the white horse shows reduced Kit activity, no melanocytes, and no melanin.

Molecular genetics

Main article: CD117

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.[26]

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.[27]

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.[28] 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.[29] 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 kind of dominant white.[2]

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 have the homozygous genotype.[30] 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.[3] A 2013 study also unearthed horses that were compound W5/W20 heterozygotes, almost completely white, essentially with greater depigmentation than could be accounted for by either allele alone.[25]

The embryonic lethality hypothesis was originally supported by Pulos and Hutt's 1969 study of Mendelian progeny ratios.[1] 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 are not subject to Mendelian ratios.[31]

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.[32]

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.[33] No aborted fetuses were found, suggesting that death occurred early on in embryonic or fetal development and that the fetus was "resorbed."[34]

Prior to Pulos and Hutt's work, researchers were split on the mode of inheritance of white and whether it was deleterious (harmful).[35] 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.[14]

The white (W) locus was first recognized in mice in 1908.[36] 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.[37] 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.[38] 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.[37] 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.[39] A recent study showed that blood parameters in horses with the W1 mutation were normal.[23]

"White" horses that are not dominant white

See also: White (horse)
Pale blue eyes, rosy-pink skin and cream-colored hair identify the presence of some sort of dilution gene, most often the cream gene. This cremello is neither white nor gray.

White horses are potent symbols in many cultures.[40] 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.[41][42] Dominant white is caused by the absence of pigment cells (melanocytes), whereas albino animals have a normal distribution of melanocytes.[43] 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.[44] In other mammals, the diagnosis of albinism is based on the impairment of tyrosinase production through defects in the Color (C) gene.[45] No mutations of the tyrosinase or C gene are known in horses.[46]

Non-white colors

This "white-born" or "fewspot" Appaloosa foal is hard to distinguish from a dominant white without familiarity with the leopard complex and the animal's pedigree.

Lethal White

Main article: Lethal white syndrome

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.[57] 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.[58]

Sabino

Main article: Sabino horse

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, there are genetic differences. The term "dominant white" is reserved for known W alleles. Dominant white horses are heterozygous for any one of 11 known alleles of the KIT gene (e.g. W8/+).[C] Homozygosity for some of the 11 known alleles may not create a viable embryo. In contrast, Sabino-White horses are homozygous for the Sabino 1 allele of the KIT gene (SB1/SB1).[59][60]

The arrangement of irregular white markings on this Paso Fino is typical of Sabino-1, other sabino-like patterns, and some types of dominant white. Such ambiguous white markings are usually called "sabino" even in the absence of a positive SB1 DNA test.

Another type of sabino patterning, called simply "sabino," "minimal sabino" if slight, or if particularly dramatic, "maximum sabino," refers to horses that test negative for any of the Dominant White alleles, negative for Sabino 1, and also negative for Tobiano and Frame overo.[61] 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 hair and skin.[2] 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."[2][6]

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.[62] However, not all KIT alleles currently identified as "dominant white" have been proven lethal.[22]

The similarities between Dominant White, Sabino 1, and other forms of sabino may reflect their common molecular origin: The W1-W11 series and SB1 have been mapped to KIT. The researchers who mapped Sabino 1 suggested that other sabino-like patterns might also map to KIT.[63] Similarly, major alleles for white leg and facial markings have also been mapped to or near to the KIT gene.[64]

Mosaicism

Mosaicism in horses is thought to account for some spontaneous occurrences of white, near-white, spotted, and roan horses.[65] Mosaicism refers to mutations that occur after the single-cell stage, and therefore affect only a portion of the adult cells.[66] Mosaicism may be one possible cause for the rare occurrence of brindle coloring in horses.[67] 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.[68] Though this is not always the case, genetic mutations can occur spontaneously in one sex cell of a parent during gametogenesis.[69] 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.[65]

Homologous conditions

Some spotted patterns on pigs, such as this one, are caused by polymorphisms of the porcine KIT gene.

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.[70] In pigs, the "patch," "belted," and commercial "white" colors are caused by mutations on the KIT gene.[71] 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.[72] To date, no such pleiotropic effects have been described in horses with KIT mutations.

Notes

  1. ^ Use of the term "wild type" is subjective, as genes undergo changes, called mutation, at statistically regular intervals called mutation rates.
  2. ^ A gene is a unit of heredity which encodes the instructions to make molecules.[73] An allele is a specific version of a gene.[74] Geneticists often discuss only two alleles at a time: the "wildtype" or normal allele which encodes the correct molecule, and the mutant allele. When more than two alleles are known, they form an allelic series. A locus is the physical location of a gene on a chromosome.[74]
  3. ^ For any particular gene, when an individual inherits two identical alleles, one from each parent, it is homozygous, or a homozygote. When an individual inherits two different alleles, one from each parent, it is heterozygous or a heterozygote.[74]
  4. ^ Mendelian traits are characteristics of an organism that are controlled by a single gene. Mendelian traits can be described as dominant if the characteristic is found in heterozygotes, or recessive if not. Dominance and recessiveness are properties of traits, not genes. Defining a trait as dominant (the word dominate is a verb) or recessive depends on how the trait is defined.[75]

References

  1. 1 2 Pulos WL, Hutt FB (1969). "Lethal dominant white in horses". The Journal of Heredity 60 (2): 59–63. PMID 5816567.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Haase B, Brooks SA, Tozaki T; et al. (October 2009). "Seven novel KIT mutations in horses with white coat colour phenotypes". Animal Genetics 40 (5): 623–9. doi:10.1111/j.1365-2052.2009.01893.x. PMID 19456317.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Bailey, Ernest; Brooks, Samantha A. (2013). Horse genetics (2. ed.). Wallingford: CABI. pp. 56–59. ISBN 9781780643298.
  4. ↑ Pulos, WL; FB Hutt. "Lethal Dominant White in Horses". Journal of Heredity.
  5. 1 2 3 Sturtevant, AH (1912). "A critical examination of recent studies on coat colour inheritance in horses" (PDF). Journal of Genetics 2 (1): 41–51. doi:10.1007/BF02981546. "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 eyes." [WP Newell] The term "glass eye" means a white eye. Therefore the colt described above is almost an albino in appearance. However, his sire is one of the dark-eyed somewhat spotted whites, his dam being a brown Trotter. Since "glass" eyes occur not infrequently in pigmented horses it seems probable that this white-eyed albino (?) is really an extreme case of spotting, plus an entirely independent "glass" eye. Mr Newell writes that white mated to white gives about 50% white to 50% pigmented. He reports only three matings of white to white. The results of these were, one white, one roan, and one gray.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Haase B, Brooks SA, Schlumbaum A; et al. (November 2007). "Allelic heterogeneity at the equine KIT locus in dominant white (W) horses". PLoS Genetics 3 (11): e195. doi:10.1371/journal.pgen.0030195. PMC 2065884. PMID 17997609.
  7. 1 2 Haase B, Brooks SA, Schlumbaum A; et al. (November 2007). "Allelic heterogeneity at the equine KIT locus in dominant white (W) horses". PLoS Genetics 3 (11): e195. doi:10.1371/journal.pgen.0030195. PMC 2065884. PMID 17997609. Eyes are normally pigmented in dominant white horses, probably due to the different origin of the retinal melanocytes, which develop from local neuroectoderm and not from the neural crest, as do the skin melanocytes.
  8. ↑ Haase B, Brooks SA, Schlumbaum A; et al. (November 2007). "Allelic heterogeneity at the equine KIT locus in dominant white (W) horses". PLoS Genetics 3 (11): e195. doi:10.1371/journal.pgen.0030195. PMC 2065884. PMID 17997609. The dominant white coat colour is phenotypically very similar to the coat colour in homozygous sabino horses
  9. 1 2 "American Creme and White". Breeds of Livestock. Oklahoma State University. 1999-05-03. Retrieved 2009-06-20.
  10. ↑ "Camarillo White Horse Association (CWHA)". Camarillo White Horse Association. 2009-03-17. Retrieved 2009-07-03.
  11. ↑ "Nomenclature History, Kit". Mouse Genome Informatics. The Jackson Laboratory. Retrieved 2009-06-30.
  12. ↑ Sturtevant, AH (1912). "Since "glass" eyes occur not infrequently in pigmented horses it seems probable that this white-eyed albino [sic] is really an extreme case of spotting, plus an entirely independent "glass" eye."
  13. ↑ Pulos, WL; FB Hutt (1969). "Lethal Dominant White in Horses". Journal of Heredity.
  14. 1 2 Haase, B. et al (2007). "However, this report on the embryonic lethality was derived from the analysis of offspring phenotype ratios in a single herd segregating one or more unknown mutations."
  15. ↑ Wriedt, C (1924). "Vererbungsfaktoren bei weissen Pferden im Gestut Fredriksborg". Zeitschrift für Tierzuchtung und Zuchtungsbiologie 1: 231–242. doi:10.1111/j.1439-0388.1924.tb00195.x.
  16. ↑ WL Pulos & FB Hutt (1969). "Although Wriedt referred to Sturtevant's report in his genetic analysis of records of the Frederiksborg white horses, he considered the latter to be recessive whites, with homozygotes white, white with gray spots, or gray white ("weissgraue"). Heterozygotes were believed to vary all the way from dilute gray to full color."
  17. ↑ Beth Mead (2005-09-09). "International Horse & Pony Colour Term Dictionary Online (Part 2)". Retrieved 2009-07-08.
  18. ↑ WL Pulos & FB Hutt (1969). "In the light of more recent evidence, these conclusions now seem to have been erroneous ..."
  19. ↑ WL Pulos & FB Hutt (1969). "Odriozola added no new data on dominant white, but ... suggested that different forms of W arranged linearly in the chromosome might be responsible for the differing degrees of white ... and that the expression of white is also influenced by modifying genes."
  20. ↑ "Sabino". Equine Color. Archived from the original on 2008-12-25. Retrieved 2011-12-09. The problem with this theory was that many horses who were "Dominant White" didn't have the necessary "Dominant White" parent, the rule of dominant genes being that at least one parent must have it for the foal to have it. Research has shown that these "Dominant White" horses who are usually born from non-white parents are really Sabinos with the maximum expression of the pattern. The theory of the "Dominant White" gene has been left in the past, especially since there has never been any scientific evidence to support that it exists
  21. 1 2 3 Dominant White - Horse Coat Pattern Genetic Testing
  22. 1 2 3 Haase, B. et al (2007) "While [homozygous lethality] is certainly likely for the two nonsense mutations found in Franches-Montagnes Horses and Arabians, it should not necessarily be assumed for the two reported missense mutations or for any of the other as-yet unknown W mutations."
  23. 1 2 Haase, B; Obexer-Ruff G; Dolf G; Rieder S; Burger D; Poncet PA; Gerber V; Howard J; Leeb T (9 April 2009). "Haematological parameters are normal in dominant white Franches-Montagnes horses carrying a KIT mutation.". Veterinary Journal 184 (3): 315–7. doi:10.1016/j.tvjl.2009.02.017. PMID 19362501.
  24. 1 2 3 4 Castle, Nancy (2009-05-19). "Equine KIT Gene Mutations" (PDF). Retrieved 2009-06-18.
  25. 1 2 3 4 5 Hauswirth, Regula; Jude, Rony; Haase, Bianca; Bellone, Rebecca R.; Archer, Sheila; Holl, Heather; Brooks, Samantha A.; Tozaki, Teruaki; Penedo, Maria Cecilia T.; Rieder, Stefan; Leeb, Tosso (December 2013). "Novel variants in the KIT and PAX3 genes in horses with white-spotted coat colour phenotypes" (PDF). Animal Genetics 44 (6): 763–765. doi:10.1111/age.12057. Retrieved 30 June 2015.
  26. ↑ Thiruvenkadan, AK; N Kandasamy; S Panneerselvam (2008). "Review: Coat colour inheritance in horses". Livestock Science (Elsevier) 117 (2-3): 109–129. doi:10.1016/j.livsci.2008.05.008. During embryogenesis the pigment cells (melanocytes) migrate to specific sites on either side of the body as well as the backline. There are three such sites on the head (near the eye, ear, and top of the head), and six sites along each side of the body, and several along the tail. A few pigment cellsmigrate to each of these sites, there they proliferate and migrate outwards, joining up to form larger patches, spreading down the legs and down the head until they meet up under the chin, and down the body until they meet up on the belly (Cattanach, 1999).
  27. ↑ Rieder S, Hagger C, Obexer-Ruff G, Leeb T, Poncet PA (2008). "Genetic analysis of white facial and leg markings in the Swiss Franches-Montagnes Horse Breed". The Journal of Heredity 99 (2): 130–6. doi:10.1093/jhered/esm115. PMID 18296388. Phenotypes may vary from tiny depigmentated body spots to white head and leg markings, further on to large white spotting and finally nearly complete depigmentation in white-born horses ... White markings result from the lack of melanocytes in the hair follicles and the skin ... A completely pigmented head or leg depends on the complete migration and clonal proliferation of the melanoblasts in the mesoderm of the developing fetus, thus ensuring that limbs and the head acquire a full complement of melanocytes
  28. ↑ Kurakin A (January 2005). "Self-organization vs Watchmaker: stochastic gene expression and cell differentiation". Development Genes and Evolution 215 (1): 46–52. doi:10.1007/s00427-004-0448-7. PMID 15645318.
  29. ↑ Woolf CM (1995). "Influence of stochastic events on the phenotypic variation of common white leg markings in the Arabian horse: implications for various genetic disorders in humans". The Journal of Heredity 86 (2): 129–35. PMID 7751597.
  30. ↑ Haase, B. et al. (2007) "In one study, white horses were shown to be obligate heterozygous (W/+), as the W/W genotype was hypothesized to cause early embryonal lethality [4]."
  31. ↑ Strachan, Tom & Read, Andrew (1999) [1996]. "Genes in pedigrees: 3.4 Nonmendelian characters". In Kingston, Fran. Human Molecular Genetics. BIOS Scientific Publishers (2 ed.). New York: John Wiley & Sons. p. 333. ISBN 1-85996-202-5. Retrieved 2009-07-10.
  32. ↑ Pulos & Hutt (1969). "Each of the five white stallions used in the stud sired one or more colored foals. Similarly, all of the eight white mares that were adequately tested produced at least one colored foal. The fact that these 13 white horses were all proven to be heterozygotes agrees with previous reports that white horses with colored eyes did not breed true to type, but always produced some colored progeny. This, in turn, suggests that the genoytpe WW is not viable."
  33. ↑ Pulos & Hutt (1969). "Among six white foals (from parents both white) that died soon after birth, one had been unable to stand and nurse; death of another was attributed to exposure, one was strangled and another killed by the mare. The possibility that any of these might have been homozygotes is refuted by the fact that similar conditions caused death of several foals from the colored pony mares. Some of those foals were white, and some colored, but none could have been WW."
  34. ↑ Pulos & Hutt (1969). "As aborted foetuses were not found although a constant watch was maintained for them, it is possible that the homozygotes die early in gestation and are resorbed."
  35. ↑ Pulos & Hutt (1969). "... in his genetic analysis of records of the Frederiksborg white horses, [Wriedt] considered [them] to be recessive whites, with homozygotes white, white with gray spots, or gray white ("weissgraue") ... He considered that the gene for white could not itself be lethal because four fertile white mares produced from 46 matings a total of 37 foals, none of which was dead or weak, and that good record (80 percent fertility) was better than could have been expected if the gene for white color were lethal. Subsequently von Lehmann-Mathildenhoh reported evidence of a dominant white in the Bellschwitz and Ruschof studs ... He did not consider the possibility that it might be associated with any lethal action ... [Salisbury] made no reference to effects of the gene in homozygotes ... Berge lists dominant white horses as heterozygotes, and follows Castle in suggesting that homozygosity for W is lethal."
  36. ↑ Durham, F.M. A preliminary account of the inheritance of coat colour in mice. Reports to the Evolution Committee IV: 41-53, 1908.
  37. 1 2 Silvers, Willys K. (1979). "10: Dominant Spotting, Patch, and Rump-White". The Coat Colors of Mice: A Model for Mammalian Gene Action and Interaction. Springer Verlag. ISBN 0-387-90367-4. Retrieved 2009-07-03.
  38. ↑ Chabot, Benoit; Dennis A. Stephenson; Verne M. Chapman; Peter Besmer; Alan Bernstein (1988-09-01). "The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus". Nature 335 (6185): 88–9. doi:10.1038/335088a0. PMID 2457811.
  39. ↑ Haase, B. et al (2009). "Currently, there is little known about possible pleiotropic effects of KIT mutations in horses."
  40. ↑ Cooper, JC (1978). "Horse". An Illustrated Encyclopedia of Traditional Symbols. London: Thames & Hudson. pp. 85–6. ISBN 0-500-27125-9. ... [T]he white horse ... represents pure intellect; the unblemished; innocence; life and light, and is ridden by heroes.
  41. ↑ Castle, William E (1948). "The ABC of Color Inheritance in Horses". Genetics 33 (1): 22–35. PMC 1209395. PMID 17247268. No true albino mutation of the color gene is known among horses, though several varieties of white horse are popularly known as albinos.
  42. ↑ O'Hara, Mary (1941). My Friend Flicka. Lippincott. ISBN 0-06-080902-7.
  43. ↑ Silvers, Willys K. (1979). "3: The b-Locus and c (Albino) Series of Alleles". [http://www.informatics.jax.org/wksilvers/ The Coat Colors of Mice: A Model for Mammalian Gene Action and Interaction]. Springer Verlag. p. 59. Retrieved 2009-07-07. ... the inability of albino animals to produce pigment stems not from an absence of melanocytes External link in |title= (help)
  44. ↑ "What is Albinism?". The National Organization for Albinism and Hypopigmentation. Retrieved 2009-07-07.
  45. ↑ Cheville, Norman F (August 2006). Introduction to veterinary pathology (3 ed.). Wiley-Blackwell. ISBN 978-0-8138-2495-6. Albinism results from a structural gene mutation at the locus that codes for tyrosinase; that is, albino animals have a genetically determined failure of tyrosine synthesis.
  46. ↑ Castle, William E. (1948). "The ABC of Color Inheritance in Horses". Genetics 33 (1): 22. No true albino mutation of the color gene is known among horses, though several varieties of white horse are popularly known as albinos.
  47. ↑ "Facts and Myths". Cream Gene Information. Cremello and Perlino Education Association. Retrieved 2009-07-08.
  48. ↑ Mariat, Denis; Sead Taourit; Gérard Guérin (2003). "A mutation in the MATP gene causes the cream coat colour in the horse.". Genet. Sel. Evol. (INRA, EDP Sciences) 35 (1): 119–133. doi:10.1051/gse:2002039. PMC 2732686. PMID 12605854.
  49. ↑ "Champagne-Cream Combinations". International Champagne Horse Registry. Retrieved 2009-06-04.
  50. ↑ Rosengren Pielberg G, Golovko A, Sundström E; et al. (August 2008). "A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse". Nature Genetics 40 (8): 1004–9. doi:10.1038/ng.185. PMID 18641652.
  51. ↑ Bellone, Rebecca R; Samantha A Brookers; Lynne Sandmeyer; Barbara A Murphy; George Forsyth; Sheila Archer; Ernest Bailey; Bruce Grahn (August 2008). "Differential Gene Expression of TRPM1, the Potential Cause of Congenital Stationary Night Blindness and Coat Spotting Patterns (LP) in the Appaloosa Horse (Equus caballus)". Genetics (Genetics Society of America) 179 (4): 1861–1870. doi:10.1534/genetics.108.088807. PMC 2516064. PMID 18660533. A single autosomal dominant gene, leopard complex (LP), is thought to be responsible for the inheritance of these patterns and associated traits, while modifier genes are thought to play a role in determining the amount of white patterning that is inherited (Miller 1965; Sponenberg et al. 1990; S. Archer and R. R. Bellone, unpublished data)
  52. ↑ "Rules & Knabstrupper Breed Standard of the German ZfDP Registry". UK Knabstrupper Association. Archived from the original on 2009-05-29. Retrieved 2009-06-20.
  53. ↑ "Die Farbmerkmale" (in German). Knabstrupper.de. Retrieved 2009-06-20.
  54. ↑ Sponenberg, Dan Phillip (2003). "5. Patterns Characterized by Patches of White". Equine color genetics (2 ed.). Wiley-Blackwell. p. 94. ISBN 0-8138-0759-X. ... most Appaloosas have a blanket or varnish roan phenotype ... In the Noriker breed most horses with LpLp are leopard, and the few varnish roans or blanketed horses in the breed tend to produce leopards more than their own blanket or varnish roan pattern
  55. ↑ Vrotsos, Paul D.; Elizabeth M. Santschi; James R. Mickelson (2001). "The Impact of the Mutation Causing Overo Lethal White Syndrome on White Patterning in Horses". Proceedings of the Annual Convention of the AAEP (American Association of Equine Practitioners) 47: 385–391. This is a rare color pattern in which the coat is almost entirely white (Fig. 6). Pigmented areas are found primarily on the ears and poll, but may also appear on the thorax, flank, dorsal midline, and tail head. Medicine hat horses can arise from overo or tovero bloodlines; when of overo bloodlines, medicine hat horses may have pigment that is quite faint on the dorsal midline.
  56. ↑ Janet Piercy (2001). "Breed Close Up Part II". The Colorful World of Paints & Pintos. International Registry of Colored Horses. Retrieved 2009-07-03. The perfectly marked medicine hat is usually a tovero, but these horses can be overos and tobianos too
  57. ↑ Metallinos, DL; Bowling AT; Rine J (June 1998). "A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung Disease". Mammalian Genome (New York: Springer New York) 9 (6): 426–31. doi:10.1007/s003359900790. PMID 9585428. Retrieved 2008-09-04.
  58. ↑ "Equine Coat Color Tests". Veterinary Genetics Laboratory. UC Davis. Retrieved 2009-07-08.
  59. ↑ Brooks, Samantha; Ernest Bailey (2005). "Exon skipping in the KIT gene causes a Sabino spotting pattern in horses". Mammalian Genome (PDF) 16 (11): 893–902. doi:10.1007/s00335-005-2472-y. PMID 16284805. Chapter 3
  60. ↑ UC Davis. "Horse Coat Color Tests". Veterinary Genetics Laboratory. University of California - Davis. Retrieved 2009-07-08. Horses with 2 copies of the Sabino1 gene, are at least 90% white and are referred to as Sabino-white.
  61. ↑ Castle, Nancy (2009). "It has been the belief of horse enthusiasts that true “white” horses were always completely white with no retained pigment, and that if a horse retained some pigment of the skin and/or hair, it was genetically some form of sabino if it were not the result of other known white spotting patterns (tobiano, frame overo, splash white, etc.)"
  62. ↑ Castle, Nancy (2009). "KIT mutations that cause depigmentation generally ranging from approximately 50% depigmented to all white phenotypes, and are also predicted to be embryonic lethal when homozygous, are classified as Dominant White. Mutations that are viable in the homozygous state are categorized as Sabino."
  63. ↑ Brooks, Samantha (2005). "Presumably variation at other genetic sites within KIT, or another gene, is responsible for those sabino phenotypes."
  64. ↑ Rieder, Stefan et al (2008). "Our association analysis indicated that the putative major gene for white markings is located at or near the KIT locus."
  65. 1 2 Haase, B. et al (2009). "Whenever a white foal is born out of solid-coloured parents, the most likely explanation is a KIT mutation in the germline of one of its parents or alternatively a mutation in the early developing embryo itself, which might lead to mosaic foals."
  66. ↑ Strachan, Tom & Read, Andrew (1999) [1996]. "Genes in pedigrees: 3.2 Complications to the basic pedigree patterns". In Kingston, Fran. Human Molecular Genetics. BIOS Scientific Publishers (2 ed.). New York: John Wiley & Sons. p. 297. ISBN 1-85996-202-5. Retrieved 2009-07-08. Post-zygotic mutations produce mosaics with two (or more) genetically distinct cell lines. [...] Mutations occurring in a parent's germ line can cause de novo inherited disease in a child. When an early germ-line mutation has produced a person who harbors a large clone of mutant germ-line cells (germinal, or gonadal, mosaicism), a normal couple with no previous family history may produce more than one child with the same serious dominant disease
  67. ↑ Kay L. Isaac. "Brindle Information". American Brindle Equine Association. Retrieved 2009-07-08. One only outwardly appearing brindle that is likely the result of a mosaic or chimeric equine ...
  68. ↑ Haase, B. et al (2009) "our study included several founder animals where mosaicism cannot be excluded. One example for such a scenario is the W8 allele observed in a single "mottled" Icelandic horse, which represents the founder animal for this mutation (Fig. 1g). This horse might be a mosaic, and it remains to be determined whether it will consistently produce offspring with the mottled phenotype."
  69. ↑ Strachan, Tom & Andrew Read (1999) "A common assumption is that an entirely normal person produces a single mutant gamete. However, this is not necessarily what happens. Unless there is something special about the mutational process, such that it can happen only during gametogenesis, mutations may arise at any time during post-zygotic life."
  70. ↑ Michael D. Fox; Camila K. Janniger (2009-01-30). "Piebaldism". eMedicine. WebMD. Retrieved 2009-06-20.
  71. ↑ Pielberg G, Olsson C, Syvänen AC, Andersson L (January 2002). "Unexpectedly high allelic diversity at the KIT locus causing dominant white color in the domestic pig". Genetics 160 (1): 305–11. PMC 1461930. PMID 11805065.
  72. ↑ Silvers, Willys K. (1979). The Coat Colors of Mice. Springer Verlag. ISBN 0-387-90367-4.
  73. ↑ "Handbook: Cells and DNA: What is a gene?". Genetics Home Reference. U.S. National Library of Medicine. 2009-06-26. Retrieved 2009-07-11.
  74. 1 2 3 In: GeneTests: Medical Genetics Information Resource (database online). Educational Materials: Glossary. Copyright, University of Washington, Seattle. 1993-2009. Available at http://www.genetests.org. Accessed 2009-07-11.
  75. ↑ Strachan, Tom & Read, Andrew (1999) [1996]. "Genes in pedigrees: 3.1. Mendelian pedigree patterns". In Kingston, Fran. Human Molecular Genetics. BIOS Scientific Publishers (2 ed.). New York: John Wiley & Sons. p. 297. ISBN 1-85996-202-5. Retrieved 2009-07-08.

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