By Knud Christensen
The Royal Veterinary and Agricultural University, Copenhagen
Department of Animal Science and Animal Health
Division of Genetics and Breeding
Bülowsvej 13, 1870 Frederiksberg C, Denmark. Phone +45 3528 3060, Fax +45 3528 3042
Link to chapter on color genetics in mammal here
Colour genetics has always been of interest to man. Up through history there has especially been paid much attention to the colour of horse. As not to long ago horses were the means of transport. In many periods horses with a particular colour were among people of high order used to show their status. In newer time fur animals have been bred with the most fancy colours and each period have hat its most favorite colour type which for the fur farmer could fetch most money. All the effort to get special colour have been based on natural genetic variants which has aroused through breeding of natural occurring mutations.
Colour genes and melanin production.
For some time it has been known that the same colour gene occur in different mammal species and a common nomenclature has been developed for colour genes, cf. Searle (1968). The species with most studied colour genes until today are the dog (Little 1957), the rabbit and the laboratory mice. In the latter more than 50 colour genes are known. The colour producing grains in the hair and skin are made up of melanin which again is made up through many biochemical steps from the amino acid tyrosine. The colour variants are either due to differences in distribution in the skin of the melanin producing cells (melanocyte) or to the melanocytes ability to produce melanin grains. The shape and lumping of the grains also play an important role for the final colour. There exist two basic type of melanin eu- and pheo- melanin. The former giving rise to the colours black and brown and the latter giving rise to the colours yellow and red. The phaeo melanin is dissolved in hydrochloric acid which is not the case for eu- melanin. How the colour genes has been functioning has for most of them been a mystery except for the Albino gene. Since the sixties it has been known that the albino variant arise due to failure in the first step of converting tyrosine into melanin. This step is the change tyrosine to DOPA-quinone and the albino phenotype is caused by an inactive variant of the enzyme tyrosinase. With the development of a complete genetic map in the mice, together with the use of the new DNA technological methods it has been possible to identify both the location and the genetic code of more than 20 colour genes and thereby also find some clues to how they function.
Her would be dealt with,only superficial, the mice colour genes agouti (a), brown (b) albino (c), dilution (d), extension (e), steel (sl) and white spotting (w) as they show the principles how colour genes function. Attention would also be paid to how to transfer the knowledge gained from the mice to other species of domestic animals.
Cellular action of colour genes.
In Table 1 is given a list of 7 colour genes and their chromosome location in the mice. The Table also contains a collum for the mode of action for each gene. Table 1. Location of the colour genes in mice given by chromosome number and centi Morgan from the centromere. The symbol for the DNA clone (action) is given as well as the site of action is indicated.
Gene Symbol Chromosome cMorgan Site of action --------------------------------------------------------------------------------------------------- agouti a 2 88 MSH* receptor blocker brown b (Tyrp1) 4 40 Inside melanocyte albino c (Tyr) 7 44 Inside melanocyte dilution d (Myo5a) 9 42 Melanocyte dendrite size extension e (Mc1r) 8 68 MSH receptor steel sl (Mgf) 10 55 Mgf* white spotting w (Kit) 5 45 Mgf receptor ----------
*) MSH = Melanocyte stimulating hormone, Mgf = Mast cell growth factor, this factor affect cell growth in many tissues and thereby the number and distribution of melanocytes.
The information given in Table 1 can be found at the World Wide Web server (as seen in the Figure to the left) with the address http://www.jax.org. The address refers to the Jackson Laboratory in USA which is the world center for research with mice. All the colour genes also have other names as the DNA clone (gene) in many cases has had been identified by an other function, and first latter the relationship to the colour gene has been recognized, as example see allele symbols in Figure.
Some of the colour genes works in pairs. This is often the case when one of them is a signal receptor located in the cell membrane. Such a pair of genes are found in the extension gene which is the melanocyte stimulating hormone (MSH) receptor and the product from the agouti gene which is a small protein being able the interfere with the function of MSH. The function of the agouti and extension genes are limited to only one cell type which is the melanocyte. These two genes work in determining how much and which type of melanin should be produced, cf. Jackson (1993).
An other pair of genes which work together is the steel and the white spotting genes, cf. Bedell et al. (1996). The white spotting gene is a receptor for the mast cell growth factor (Mgf) which is produced by the steel gene. This system is not limited to the melanocyte, only, but it works also in many other cell types. This system is operating during the development of an individual through the distribution over the body and number of melanocyte there later in life will be available for melamine production.
The product of the dilution gene has also effect on the growth of the melanocyte but it is on their form. The size of the dendrites of the melanocyte are determined by the product from the dilution gene. This gene is also affecting the dendrites of the nerve cells.
The gene product from the brown and the albino locus works within the melanocyte. The albino locus give rise to the enzyme tyrosinase, and the product from the brown locus give rise to a tyrosinase like protein with yet unknown function.
That the gene product of the albino locus is working locally within the melanocyte is shown by one of the classical experiments using the Himalaya allele of the albino locus in rabbits. The Himalaya allele give a white animal except for the extremities, that is ears snout, tail and legs which are black. If such an individual is clipped on the body and kept at low temperature then the black colour also develop in the new growing hairs at the clipped spot. The conclusion is that the Himalaya allele is a temperature sensitive mutant which works at temperatures below the normal body temperature.
Gene homology between mammal species.
The information from the mice can be utilized in farm animal species. The reason why it can be done is by means of homology between the DNA in the different mammal species. Pure DNA from each of the human chromosome is produced in large quantities and is commercially available. Identity between mice and human chromosomes is published by Lyon et al. (1996). The human chromosomes are used as intermediate as this is the specie form which pure DNA is available, cf. Hayes (1995) Rettenberger et al. (1995), Rettenberger et al. (1995a) identifying the chromosome homology between human and - cattle, - swine and - cat, respectively. The same type of work is under way in mink and foxes, preliminary results for mink can be seen at world wide web site http://www.ihh.kvl.dk/htm/kc/mink.htm.This makes it possible to identify the chromosome in mink that correspond to a given mouse gene. Some of the colour genes are also identified in human. For instance, it is known that mutants in the e locus (the MSH receptor) are the cause or red hair in man, cf. Valverde et al. (1995). The MSH receptor gene is also identified in cattle (Klungland et al. 1995) and in red foxes a mutant in this system cause the Alaskan silver phenotype (V†ge, 1996)
Perspectives.
Until now it has been difficult to utilize the genetic information obtained from one specie to an other. The DNA technological methods, by using the DNA homologies between species, has now made it foreseeable that all genetic knowledge obtained can be used in our fur animals. As it is well known the mink colour gene symbols has not yet in any way been related to the other mammals. The gene mapping project in mink (Brusgaard & Malencho 1996) will in the near future make the basis for this transfer of knowledge by means of a crude genetic map in the mink. There has in this report mostly been stressed the quick information gained in the mice on the colour genes. This information has mainly been acquired through using mutagenes of different types, as well as producing transgenic animals. This way with artificially made mutations and transgenes will still be followed in many biological laboratories. - - But the quickest progress in the years to come will be made in the Human Gene Mapping Project. In the next five years this project is being completed and a complete sequence of the human genome will be available. To utilize all this information it is important, that some basic work is done in our farm animals. This should be planned so as to make maximum use of the information made available in man and mice. The colour genes has been chosen for this contribution other important genes in the leather or the cuticula of the hairs could also have been chosen. The new technologies will give a better understanding of the biological basis on the characters which we might want to utilize in our farm animals
References.
Bedell, M.A., Copeland, N.G. & Jenkins, N.A. 1996. Multiple pathways for Steel regulation suggested by genomic and sequence analysis of the murine Steel gene. Genetics 142, 927-934.
Brusgaard, K. And Malencho, S.N. 1996. Fur properties analyzed by molecular biological methods. xxx
Hayes, H. 1995. Chromosome painting with human chromosome-specific DNA libraries reveals the extent and distribution of conserved segments in bovine chromosomes. Cytogenet. Cell Genet. 71, 168-174.
Jackson, I.J. 1993. Colour coded switches. Nature 362, 587-589.
Little, C.C. 1957. The Inheritance of Coat Color in Dogs. Comstock Publishing Associates, New York. xiii+192pp.
Klungland, H., V†ge, I.D., Gomez-Raya, L., Adelsteinsson, S. & Lien, S. 1995. The role of melanocyte stimulating hormone (MSH) receptor in bovine coat color determination. Mammalian Genome 6, 636-639.
Lyon, M.F., Cocking, Y. And Gao, X. 1996. Mouse chromosome atlas. Mouse Genome 94, 29-74.
Rettenberger, G., Klett, C., Zechner, U., Bruch, J., Just, W., Vogel, W. & Hamister, H. 1995. ZOO-FISH analyses: cat and human Karyotypes closely resemble the putative ancestral mammalian karyotype. Chrom. Res. 3, 479-486.
Rettenberger, G., Klett, C., Zechner, U., Kunz, J., Vogel, W. & Hameister, H. 1995a. Visualization of the conservation of synteny between humans and pigs by heterologous chromosomal painting. Genomics 26, 372-378.
Searle, A.G. 1968. Comparative Genetics of Coat Colour in Mammals. Logos Press. 308pp.
Valverde, P., Healy, E., Jackson, I., Rees, J.L. & Thody, A.J. 1995. Variants of the melanocyte stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Gen. 11, 328-330.
Våge, I.D, 1996. Development of a DNA test for the Alaska gene. Scientifur 20, 131.