The P Locus
The Pink-Eyed Dilution Mutation in The Mongolian Gerbil & Other Domestic Species
- Effects on coat & eye colour in gerbils
- Other effects
- Pigment synthesis
- Human analogues
- Pink-Eyed Dilution in other Species
- In Mice
- In Rats
- Linkage & Dominance modification
- Linkage In Guinea Pigs & Hamsters
- Linkage In Gerbils
- Dominance Modification
- Further research on Pink-Eyed Dilution in gerbils
- Effects on Eyesight
- Exceptions to the norm in visual acuity
The first early descriptions of the P locus and its mutations were by the maize geneticist Emerson, who analysed the inheritance of a variegating allele of the maize P locus during the early decades of the last century (1914, 1917 & 1929). In many domestic animals the Pink-eyed dilution mutation is a well known and very much established mutation, and in fancy mice its origins are ancient and are believed to have occurred first in Japanese wild mice (Mus musculus molossinus). This gene was incorporated into several common laboratory strains of mice during the early part of the last century. In Mongolian gerbils however this mutation occurred much later and the first pink-eyed dilution mutant occurred in 1977 in a North London school.
Originally when terminology was used to describe differing loci, they were named by virtue of their phenotype, however in modern nomenclature, most of their names have been replaced to reflect their protein product. So for genes such as b, c, d, s, W, and SI, they are referred to as tyrosinase-related protein 1 (Tyrp1), Tyrosinase (Tyr), myosin 5 (Myo5a), endothelin receptor B (Ednrb), c-Kit protooncogene (Kit) and mast cell growth factor (Mgf) respectively, however to this day both the Agouti and Pink-eyed dilution locus still retain their original names. The specific function of The P protein itself is currently unknown but is thought to be involved in tyrosinase processing and transport.
The gene mode of inheritance is autosomal recessive in nature.
P = Normal pigmentation
p = Pink-Eyed Dilution
Two copies of the gene must be present in the offspring for this trait to appear.
On an agouti coat this gene produces the well known Argente Golden coat colour variety. The black pigment in the coat is greatly reduced and the result is a rich golden colour. The eye pigment is also reduced and becomes a rich ruby colouring. On a non-agouti (aa) coat it produces the Lilac coat colour variety. In the hair shaft itself, eumelanin is very much reduced, but phaeomelanin remains largely unaffected. Homozygotes (pp) in many domestic animal species have pink eyes, where the pigmentation is very much reduced but not completely absent in the retina and choroid. In Mongolian gerbils, the result is a dark ruby eye and it appears that in their case there appears to be more pigment remaining. It is only when a gerbil is c(-)c(-)pp or pseudo albino, that they have eyes that are a true pink, and these are distinctly lighter than a ruby eyed individual.
Melanosomes become abnormally shaped. In particular there is an altered morphology of the black pigment granules (eumelanosomes). In studies with pp mice it was found that the pigment granules themselves are irregular and shred like in shape and packed together in masses.
The pink-eyed dilution mutation effectively creates a poor cellular environment for pigment synthesis. Pigment synthesis itself occurs in melanosomes. This is an organelle containing melanin. An organelle is a structure within an individual cell that has a specialized function. (An organelle is to a cell what an organ is to the body). Tyrosine enters the melanosomes and the enzyme tyrosinase catalyses it into dopaquinone. Tyrosine is an amino acid that is used by cells to synthesise protein, and dopaquinone is an intermediate metabolite in the production of melanin. When eumelanin is to be created, tyrosinase related proteins turn brown pigment into black eumelanin.
In experiments with tissue cultures of the eye, the amount of pigment formed can be increased by increasing the amount of tyrosine present. In this study retinal melanocytes from p-deficient mice became pigmented in the presence of very high concentrations of tyrosine. A similar study confirming this involved cultured mouse skin melanocytes. This suggests that mutations at the P locus may block the melanin synthesizing pathway by interfering with the supply of tyrosine. However in later studies it was clearly demonstrated that the P protein itself doesn't function in tyrosine transport, as the transport of tyrosine was found to be normal across the plasma membrane and the melanosome membrane of the p mutation melanocytes. It seems there is a high probability that the P protein mediates favourable conditions for tyrosinase activity. Therefore the excess tyrosine used in the above experiments can drive melanin synthesis, even in the absence of a functional P protein.
In research it has also been shown that for normal tyrosinase function, an acid environment within the cell is needed. When melanosomes are in an acidic environment they produce more pigment, with a greater increase in the dark coloured eumelanins. When the melanosome is in a pH neutral environment they behave differently and produce less eumelanin, but leave phaeomelanin largely unaffected. So we know that these chemical reactions within the cell that produce pigment can be either enhanced or impaired by changes of pH within the melanosome.
The P locus has been shown to code for a protein that is located on the membrane of a eumelanosome. This is a like a biological gate, known as a transporter protein that effectively lets molecules into the cell. The gate regulates the pH by letting in anions. A similar gate lets in H+. The P locus mutation alters how this gate behaves and changes the normal acidic pH into a more neutral environment. This effectively decreases the production of dark pigments. These P proteins aren't found on phaeomelanosomes, so red/yellow pigments are not affected by this mutation at the P locus. So the net result is that the p allele dilutes coat and eye colour, by reducing black-brown pigments and leaving the red-yellow pigments alone.
As our understanding of genetics is furthered, and an increasing number of genomes are sequenced in different mammals, it has become increasingly clear that there is little variation in gene content or gene identity between species. It has been shown that many of the gene mutations that cause coat colour variations in mice and other species have also been found in humans. Variations in human pigmentation genes can be classified into rare genetic syndromes such as albinism or piebaldism, or common variation in eye, hair, and skin colour that may distinguish individuals of differing ancestries.
In medical genetics, albinism refers to a condition where there is a loss of pigmentation or dilution. These variants of albinism are placed into two broad groupings, these are conditions that effect eyes, skin, and hair (oculocutaineous albinism) or just the eyes (ocular albinism) In both of these groups, defects in retinal pigmentation leads to various degrees of visual impairment. In humans there are roughly ten different genes that when mutation occurs on them cause albinism. These include some involved in vacuolar sorting or transport, i.e., Hermansky-Pudlak or Chediak-Higashi syndrome, and some involved in melanin biosynthesis such as Tyrosinase, Tyrosinase-related protein and Pink-eyed dilution.
It is the human P locus that is responsible for variations in skin colouring amongst ethnic groups, and deletions on this locus are associated with hypopigmentation. The pink-eyed dilution mutation's human analogue is known to cause oculocutaneous albinism type 2 or (OCA2), and is the commonest form of albinism in humans; and this is most noticeable amongst African Americans, some Native American groups, and people from sub-Saharan Africa. Similar to animal species, the effects of the mutation can be very variable and can range from moderate to very minimal pigmentation of hair, skin and the iris. People affected with OCA2 tend to have yellow, blonde or light brown hair, creamy white skin with various amounts of localized pigmentation, and their irises are either partially or completely pigmented with a tan coloured melanin.
The P gene in human's maps to chromosome 15 which is close to the Prader-Willi syndrome locus and because of this, the p mutation has been proposed to provide a mouse model for Prader-Willi syndrome, Angelman syndrome, for one form of hypomelanosis of Ito, and for type 2 oculocutaneous albinism. There exists a small nuclear ribonucleoprotein particle gene or Snrpn gene which maps very close to p and its human ortholog (A gene with similar function to a gene in an evolutionarily related species) in the similar Prader-Willi region of the human chromosome 15, and this appears to be a better candidate for the Prader-Willi syndrome ortholog. P is deleted in human type 2 oculocutaneous albinism, making p a model for this disease.
- Oculocutaneous Albinism Information
- Prader-Willi Syndrome
- Angelman Syndrome
- Hypomelanosis of Ito
- Mutations associated with OCA2 can be found in the Albinism Database
The majority of knowledge regarding coat colour genes and their function has come from mice; however studies in other mammals have often confirmed or refined the principles of coat colour inheritance. In the mouse, spontaneous coat colour mutations account for more than a hundred different coat colour genes, where as in other mammals only a small number of loci (usually fewer than ten) have been recognized as coat colour mutations. While only a few of these mutations have been studied and characterized at a molecular level, in many cases it has been possible to assign homologies among different species despite the absence of information at the molecular level. For example, a temperature sensitive loss-of-function mutation in Tyrosinase produces a distinct phenotype known as the Himalayan mutation in mice, however this mutation also produces a similar phenotype in rabbits, guinea pigs and many other species, and it is also responsible for the lightly pigmented Dark tailed white in gerbils.
In mice the first mutation found at the P locus was the recessive allele designated p, and it is referred to in literature on the subject as the original p mutation. Research has found that this particular mutation was derived from Mus musculus and most likely from the Japanese/Manchurian sub-species M.m molossinus. In contrast to this, the wild type and many other mutant p alleles found in laboratory mice strains today appear to have been derived from Mus domesticus. This has been confirmed by molecular genetic analysis.
The original p mutation itself is ancient, and this is reflected by early accounts of this gene along with c and w genes in literature. In Chinese and Japanese tradition a white mouse is considered a symbol of good luck, and when they were found in the wild these mice were highly treasured. They were often given as gifts to religious and political leaders. It is quite probable that one of the progenitors of the original p mutation strains available today was initially captured from the wild so long ago.
This mutation, in addition to being one of the first mutations described in mice, was used to define the first gene linkage group in the mouse (original p mutation and a mutation at the C locus) This linkage shows us that they are located on the same chromosome. Scientific research at the molecular level has mapped the P locus to position 28 in chromosome 7 in mice. The gene is divided into 25 exons (24 coding exons) which encode an integral melanosome membrane protein.
To date there has been more than a hundred mutant p alleles discovered and identified in mice, some of which were spontaneous in origin, where as many others have been induced by either X-rays or chemical mutagens. When present in the homozygous state, these mutant alleles cause hypopigmentation of the coat and eye which results in dilution ranging from moderate to severe. In addition to affecting pigmentation, several of these mutant alleles are associated with other abnormalities including neurological disorders, cleft palate, male sterility and female semi-fertility, genetic instability and prenatal lethality. The P gene itself is expressed predominantly in melanocytes, but P gene transcripts are also found in the brain (cerebellum), testes, and ovaries. The significance of expression in cells other than melanocytes is unknown at this time, and mice (and humans) lacking all P gene-encoding sequences exhibit normal behavior and fertility. The type of p mutations that cause the pleiotropic effects mentioned above are nearly all radiation -induced, and it seems that pleiotropism in their case is due to multi-locus deletions, that in addition to altering the gene required for normal pigmentation (P), also go on to alter adjacent genes that control distinct functions.
An interesting point noticed in research on black and tan a(t)a(t) mice is that the P transcript is well expressed in the black dorsal skin, but is absent in the yellow ventral skin, which corroborates earlier research that P mutations affect eumelanin and not phaeomelanin biosynthesis.
The p mutation in Agouti mice gives rise to a yellow/golden coat with a silvery blue base, known as the Argente coat colour variety. On a non-Agouti background it gives rise to the Dove coat colour.
In lab populations the p mutation is carried by several rats strains including RCS (Royal College of Surgeons) and BDV (Borna Disease Virus) strains. In addition to these strains, several albino strains including KHR (kaken hairless rat), KMI (Komeda miniature rat Ishikawa) and WNA (albino Developed at Nagoya University) all of which are descendants of Wistar stock are homozygous for the p allele. It has been shown by molecular analysis that all these strains share a common ancestor for the p allele. This historical relationship suggests that the p mutation had been carried in stock heterogenous for the C and P loci, and was consequently inherited independently by the ancestor of the Wistar albino stock and the ancestor of the pink-eyed Agouti rats in Europe. The p mutation in rats is an intragenic deletion mutation including exons 17 and 18.
The p mutation in Agouti rats dilutes the dark banding on the hairshaft to a pale colour which produces the coat colour variety known as Amber. In non-Agouti rats the black coat colouring is diluted to a pale yellow which produces the coat colour variety known as Champagne.
Both the albino and Pink-eyed dilution genes are considered common mutations in mammal coat colour genetics and are assumed to be similar loci in a range of species. This evidence for this is supported by research conducted proving linkage between these two loci in five species of rodents. This linkage shows us that they are both located on the same chromosome. Presumably during the evolution of these rodent species, the presence of the two loci on the same chromosome has been conserved. However this conservation has undergone modification as the data in breeding tests in several species shows that the varying crossover values also suggests a variation of genetic distances between the two loci . In the mouse, rat and deermouse the crossover values are approximately 17% where as in the Mongolian gerbil and the Syrian hamster they are approximately 30%. The difference on crossover values between these two groups of rodent species could be due to the actual distances apart where the two loci are located on the same chromosome, or the nature of the distribution of chiasmata (regions where paired homologous chromosomes exchange genetic material during meiosis) between the two loci.
Exceptions to linkage between the albino and pink-eyed dilution locus occur in the Guinea pig and the dwarf hamster Phodopus campbelli. In Guinea pigs the C and P loci show independent inheritance. This absence of linkage could be due to the fact that the Guinea pig has an exceptionally large number of chromosomes (32) when compared to the more typical number of 20-24 in other rodent species. However this cannot be fully explained for the dwarf hamster. The dwarf hamster has been described by Pogosiantz and Bruyako (1967) to have 28 chromosomes, and a majority of these chromosomes are described as being metacentric, so it maybe possible that centric fusion hasn't occurred on one of the metacentric arms to create a c & p combination. Of course there are other possible explanations, such as they are still on the same chromosome but are very loosely linked, but it maybe more likely that the p mutation in dwarf hamsters is a phenotype mimicking loci, similar to the grey gene in gerbils.
Breeding data conducted with c(h) and p in gerbils confirmed linkage of these two genes and results were published by Leiper & Robinson in1986. Although in the published paper regarding a second acromenalistic allele at the C locus (F.Petrij, K.Van Veen, M. Mettler,V. Bruckman) breeding tests to prove linkage wasn't undertaken with the mutant c(chm) gene, however it is very likely that this is the case.
At present there are two mutations that have been discovered on the C locus, both are recessive and both are acromelanistic (a temperature-dependent pigmentation pattern, with full expression only occurring on legs, ears, tail and face) c(h) (himalayan) is the more extreme of the two mutations, the other mutation being c(chm) or chinchilla medium.
We know through breeding that a type of dominance modification occurs when either c(chm) or c(h) is combined with pp. The normal dominance hierarchies of alleles at the C locus are modified when there are two recessive alleles at the P locus (pp). Rather than the expression of the wild type full colour gene C being completely dominant over the lesser alleles, it becomes incomplete, allowing the c(h) and c(chm) alleles to be expressed. This creates lighter forms of the A- CCpp (Argente Golden) coat colour. These coat colours being A-Cc(h)pp (Argente Cream) and A-Cc(chm)pp (Argente fawn or Topaz). The same coat colour effect occurs on a non-agouti (black) background, where Lilac (aaCCpp) then becomes the Dove coat colour (aaCc(h)pp) and with c(chm) present (aaCc(chm)pp it becomes the Sapphire coat colour variety. The Sapphire coat colour shade is in between Lilac and Dove in colouring. Both these coat colour varieties have dark ruby eyes.
A gerbil that carries two copies of either c(h) or c(chm) on a pink-eyed dilution background, will always be white all over with pink eyes, regardless of the other genes carried, they are known as pseudo albinos. However if a gerbil is c(h)c(h)PP or c(h)c(h)Pp, the presence of at least one dominant P gene stops one c(h) gene having any effect, and two copies of the c(h) gene creates the Dark tailed white (Himalayan) coat colour variety. The presence of the dominant dark eyed genes doesn't produce a dark eyed gerbil as we might expect but then again the pair of c(h) genes doesn't produce a completely white gerbil either. On an agouti background A-c(h)c(h) produces a pink eyed white gerbil with a light brown tail, or a Sepia-Tailed White, but on a non-agouti background the tail becomes a much darker brown colour known as the Dark-Tailed White coat colour variety.
Studies on whether coat colours can influence seizures were studied by Penelope Gray-Allen & Roderick Wong at the dept, of psychology at the University of British Columbia in Canada. This involved experiments with three coat colour varieties, Agouti (A*) Black (aa) and Argente golden (A*pp) where seizures were induced by stroking then placing the gerbils in novel cage environments. The results of which were measured in terms of latency, duration and severity. The results of these tests showed that A*pp type gerbils exhibited shorter and less severe seizures where as Black (aa) type gerbils showed a shorter latency to manifest seizures. This work undertaken suggests there are some links between the genetic mechanisms that determine coat colours and the influence that these colours may have on the susceptibility to seizures that arise from novel stimulation.
The same authors also studied the same coat colours in relation to differing behaviours. Tests involved placing the animals in three different types of cage conditions, warm (35-40°C), neutral (20°C), and cold (0-5°C) and observing differing behaviour frequencies. These behaviours were scratching, face and body grooming, belly/side rubs and shaking activities. They noted that although sex differences were not observed, the coat colour, age and temperature affected belly/side rubs and shaking activities. The experiment showed that these coat colour variants can manifest dissimilar patterns of COBS (care of body surface) behaviours in various thermal environments.
Further experiments in behaviour with the same three coat colour variants illustrated the social preferences of females when encountering males of the different coat colours. The experiment involved females of the same three coat colours who were subjected to a test involving encounters with male gerbils of the three different coat colours. The experiment involved a Y-maze whose arms led to compartments containing unfamiliar male gerbils who were separated from the females by a plexi glass door. The trials lasted two minutes and each female was exposed to the following combinations: Two males of the same colour as the female. One male of the same colour and one male of a different colour from the female, and both males of a different colour than the female. The number of crossings from the left to the right arm of the Y-maze was relayed by photocells to a computer and the results analysed. The results showed that the Agouti female preferred visiting the arm where the Agouti males were located, while the females of the mutant coat colours (Black and Argente) preferred to visit those of non-wild type males.
In humans, individuals with OCA2 apart from having pigmentary deficiency have a number of differences in their visual systems when compared to normally pigmented individuals. This ranges from variable visual acuity, abnormal crossings of the temporal fibres in the optic chiasm, nystagmus, photophobia, strabismus and foveal hypoplasia (in many rodent species they do not possess a fovea so this really isn't an issue). In gerbils as we mentioned earlier a mutation at the P locus results in eyes with much less pigmentation, and when this mutation is combined with further mutations at the C locus it results in the gerbil having pink eyes. Quite simply these pseudo albinos have very little or no pigment left at all in their eyes. This is why the iris looks red as the only colour left comes from the blood in the capillaries. In research conducted on albino rats it is shown that they also lack pigment deeper in the eye. This pigment is used to absorb light and when it is absent the light inside the eye scatters because of the inability of the eye to control the incoming levels and thus floods the eye with light. Over time this condition causes retinal degeneration.
If we look at a normally functioning eye, the pigmented iris that surrounds the pupil effectively controls how much light shines on the retina. When pigment is lacking in the iris, light passes through and dazzles the retina. So in very bright light, eyes with no pigmentation will see very little because the light levels overwhelm the retina.
If we look even closer into how gerbils use their eyes we can see that they have a far greater proportion of rods than cones (87% rods, 12-14% cones) and this is expected in rodents that are largely at their most active at dawn and dusk. Now rods themselves need a melanin precursor to develop called dopa or Dihydroxyphenylalanine, which is a natural chemical that the body makes as a step in the process of making the pigment melanin. This production is severely impaired in our pseudo albino gerbils so many of these rods will fail to develop. In studies on albino rats it has been shown that 30% of the rods fail to develop, and of these rods it does possess they also have less rod photoreceptors than normally pigmented rats. It is these photoreceptors that are used for detecting low light levels, and this indicates that these animals may have problems seeing in low light conditions.
Rods themselves because they are so sensitive to light, degenerate very easily when compared to cones. In studies with albino rats it has been shown that ambient light, even at low intensities is capable of causing irreversible retinal degeneration. A single day of ambient light is enough to cause some degeneration, and a few weeks are enough to completely degenerate the outer retina by causing a loss of photoreceptors and cell bodies.
Another problem with a lack of melanin in the eye is the fact that this causes a reduced level of calcium binding sites within the eye, and calcium itself plays a large role in the retinas ability to adapt to low light conditions. In rat studies it has been shown that it takes albino rats around three hours to adapt to the dark compared to around thirty minutes for normally pigmented rats.
One of the major abnormalities in various forms of albinism involves the development of the nerves which connect the retina to the brain. These nerve connections from the eye to the vision areas of the brain are "wired up" differently than normal, and nerve signals from the eye to the brain is sent in an unusual manner. This prevents the eyes from working well together and in particular causes a reduced depth perception. In human forms of albinism this can result in a condition that is known as Strabismus, which means that the eyes do not fixate and track together, due to the altered development of the optic nerves. Despite this condition people with albinism do have some depth perception, although it is not as acute as when both eyes are working together in co-ordination. Albino rats also have a similar problem with depth perception and so do not rely on visual cues as much as pigmented rats to perceive depth. In their case vision becomes their fallback sensory system. Many owners of Pink-Eyed White gerbils notice their pet swaying and bobbing their heads. This swaying and bobbing is the gerbils attempt to increase it's perception of depth using its greatly impaired vision.
In virtually all albino animals the central retina remains underdeveloped and there exists a deficit in rods. However in some species such as birds and squirrels (Sciurus carolinensis leucotis) that have cone dominated retinas research has shown that this isn't always the case. Central ganglion cell densities in albino squirrels are only about 5% lower than pigmented squirrels, which when compared to mammals that have rod dominated vision, research shows cell densities are usually around 25% below normally pigmented animals. This may indicate as to why the squirrel is one of the very few mammals studied where albino populations thrive successfully in the wild. The research conducted on squirrels retinas shows how different patterns of cell production in cone dominated eyes lends to a relative immunity in their albino counterparts from the deficits normally associated with unpigmented eyes.
Article by Eddie Cope
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