Chapter 6

Beige, Silver, Greying with Age, and Other Determinants

IV. Other Determinants

In addition to the above coat-color determinants there are a number of other coat color mutants in mice (given below) which have been described only briefly.

A. Ashen ( ash)

This recessive mutation arose in strain C3H/DiSn ( Lane and Womack, 1977). The coat color of these mice mimics that of dilute ( d) and leaden ( ln). It has been assigned to chromosome 9.

B. Buff ( bf)

This mutation occurred spontaneously in the C57BL/6J strain and was originally described by Dickie ( 1964a). The mutation is inherited as an autosomal recessive and has been assigned to chromosome 5 ( M.C. Green, 1966a). Nonagouti buff ( a/a;bf/bf) animals are khaki colored and look somewhat like misty brown ( a/a;b/b;m/m) mice. The eye color does not seem to be affected (see Chapter 4, Section IV, B).

Recently this mutation has been shown to be associated with the activities of three lysosomal glycosidases: beta-galactosidase, beta-glucuronidase, and N-acetyl-beta-hexosaminidase. Thus bf/bf mice usually have much higher activities of these enzymes in their kidney cells than bf/+ mice. The significance of this, however, remains to be determined ( Hakansson and Lundin, 1977).

C. Dark Footpads ( Dfp)

This dominant mutation, which has not as yet been mapped, was first observed in a descendent of an irradiated female ( Kelly, 1968). The mutation is lethal when homozygous; Dfp/Dfp embryos die before implantation ( Kelly, 1970). Dfp heterozygotes are distinguished by the fact that the pads at the base of the digits, as well as the more proximal pads, are either black or significantly darker than the rest of the foot. The trait is somewhat variable since occasionally one foot may be unaffected, or some pads on all feet may be unaffected. In extreme cases the pads on the distal phalanges as well as those on the feet are black ( Kelly, 1968).

D. Dilution-Peru ( dp)

This autosomal (linkage unknown) recessive arose in the descendents of a cross between a CBA/FaCam male and a wild Peru-Harland female ( Wallace, 1971) derived from specimens trapped in a Peruvian yard used to dry maize ( Wallace, 1970). When homozygous dp is fully penetrant and in combination with extreme nonagouti ( a^e/a^e) produces a phenotype which is very similar to misty (although it has no belly spot or white tail tip), but nearer black. Animals expressing this mutation are somewhat similar in color to pale ear ( ep), light ear ( le), pearl ( pe), and taupe ( tp) mice. Because their wild Peru ancestry causes segregation of agouti modifiers, dilution-Peru mice are difficult to classify in A/— animals.

E. Freckled ( Fkl)

This mutation, an autosomal dominant about 6 cM from piebald ( s) on chromosome 14 ( Lyon and Glenister, 1978), is probably an allele of Roan ( Rn) (see Section J). It arose spontaneously in a random bred stock carrying t-alleles. Heterozygotes are variegated with small white or light colored patches in the coat and whitish ear hairs ( J. Butler and Lyon, 1969). In young animals these patches are clearly discrete, but as they get older more and more unpigmented hairs appear in the coat generally so that an uneven roan effect is produced. Animals homozygous for freckled are viable and fertile and a whitish or cream color, though again uneven ( J. Butler and Lyon, 1969). A dominant modifier, which has provisionally been called fawn ( Fw), makes freckled heterozygotes considerably lighter but has no effect on normal mice ( J. Butler and Lyon, 1969).

F. Gunmetal ( gm)

Gunmetal, an autosomal recessive [chromosome 14 ( M.C. Green, 1973)], occurred spontaneously in the C57BL/6J strain ( Dickie, 1964a). Homozygotes have a diluted coat color somewhat similar to that of dilute ( d/d). Eye color does not appear to be affected. Gunmetal ( gm/gm) mice have a high mortality of unknown etiology and do not breed well ( Dickie, 1964a).

G. Light (Li)

This mutation, not to be confused with B^lt, has provisionally been given the symbol Li. The mutation occurred at Oak Ridge in the offspring of an irradiated female. The coat of heterozygotes is slightly but definitely diluted and homozygotes are lighter than chinchilla ( c^ch/c^ch). Both eumelanin and phaeomelanin are affected by this mutation which has been shown to be inherited independently, and probably assorts independently, of the c-locus. This mutation has an additive effect with c^ch/c^ch ( Bangham, 1968).

H. Ochre ( Och)

Ochre is a semidominant which was found in the progeny of an irradiated male. According to R.J.S. Phillips and her colleagues ( 1973) who first reported this mutation " Och/+ mice look very light at weaning age (similar to Mi^wh/+ except that their ears are not lightened) but darken with age, becoming more d/d like in color." Animals homozygous for Och are yellower and smaller than heterozygotes and many die before or soon after weaning. From about 8 days of age homozygotes also display an abnormal landing reaction; when held by the tail and lowered fairly quickly toward a table they tend to tip their heads ventrally. Moreover, when handled similarly as adults their whole body gives a compulsive jerk ( R.J.S. Phillips, 1975). Although this behavior is somewhat reminiscent of the behavior of pallid ( pa) mice, the gross structure of the ear and the otoliths of ochre homozygotes are normal ( Lyon, 1975).

Ochre interacts with white ( Mi^wh) producing a cream-colored animal. It also interacts with viable dominant spotting ( W^v) but not obviously with steel ( Sl^d ) or light ( B^lt) ( R.J.S. Phillips et al., 1973). Ochre is on chromosome 4 ( R.J.S. Phillips and Hawker, 1973), about 3 cM from brown ( b) ( R.J.S. Phillips, 1974).

I. Pale Ear ( ep) and Light Ear ( le)

There are two autosomal recessive color mutations in the mouse, pale ear ( ep) and light ear ( le), which mimic each other but which have been shown to be inherited independently. Light ear is on chromosome 5, about 10 cM from viable dominant spotting ( W^v) and pale ear is about 1.5 cM from ruby eye ( ru) on chromosome 19. Both mutations occurred within a year of each other at the Jackson Laboratory, le in C3H/HeJ and ep in C3HeB/FeJ ( Lane and E. Green, 1967).

Neonatal le/le and ep/ep mice can be distinguished from wild type animals by a lack of eye pigment. The pigment is not completely absent from the eye but it is reduced considerably for the first day or two after birth. At 3 to 4 days of age, light ear and pale ear mice display less skin pigment than normal. This becomes most striking in the pinna of the ear and on the tail and feet. The coat of juvenile ep/ep and le/le mice is also lighter than normal and this combined with the light ears and tail makes each mutant clearly recognizable ( Lane and E. Green, 1967).

When combined with nonagouti ( a), brown ( b), and dilute ( d), ep/ep (and presumably le/le) mice retain their lighter colored ears, tail, and coat. a/a;b/b;D/D;ep/ep mice have dark red or ruby eyes in contrast to the light red or pink eyes of a/a;b/b;d/d;ep/ep animals. According to Lane and E. Green it may be possible to differentiate B/B from B/b and D/D from D/d in ep/ep animals.

When cleared hairs from the juvenile coats of nonagouti light ear and pale ear mice were examined microscopically, and compared with the corresponding normal genotypes, no gross differences in the amount of pigment were apparent. However, the eumelanin granules of the le/le and ep/ep hairs were smaller, particularly near the tip of the hair. Slices of skin from 5-day-old pale ear and normal mice did not differ in their ability to incorporate ¹⁴C-labeled tyrosine into melanin ( Lane and E. Green, 1967). ¹⁷

J. Roan ( Rn)

Roan is another autosomal (chromosome 14) semidominant characterized in the heterozygote by white hairs distributed throughout the coat (M.C. Green, 1966b, 1971). Other hairs may have both pigmented and nonpigmented areas with no regular pattern in their distribution. In Rn/+ animals the expression of the mutation is variable, some heterozygotes possessing only a very few white hairs. This variability is in part genetically determined. Roan homozygotes appear as very light grey, with a much higher proportion of white hairs than heterozygotes. In spite of the fact that the roan phenotype is characterized by the occurrence of white hairs, in neither heterozygotes nor homozygotes have discrete areas of white spotting been observed ( M.C. Green, 1966b).

Roan strongly resembles freckled (Fkl) ( Section E) with which it is very closely linked ( M.C. Green, 1971). Indeed, Green suggests they may be alleles (see Lyon and Glenister, 1978). Nevertheless, it is clear that these mutations are not identical. When crossed on to strain 101/H, Fkl produces a very light-colored coat with almost no wild type patches, whereas Rn gives a near wild type coat with a few small light-colored spots. " Rn/+;Fkl/+ double heterozygotes are very variable, and not certainly distinguishable from single heterozygotes, but among segregating litters from Rn/+;Fkl/+, Rn and Fkl young can be distinguished" ( Lyon and Glenister, 1973). No evidence of crossing-over between Rn and Fkl has yet been observed, but because of the normal overlapping of Rn and variability of Rn/+;Fkl/+ this evidence would be difficult to obtain. It thus remains uncertain whether Rn and Fkl are alleles or part of a gene cluster (Lyon and Glenister, 1973, 1978).

K. Sepia ( sea)

Sepia (chromosome 1) is another recessive mutation which has only very recently been described ( H. Sweet and Lane, 1977). It occurred in the C57BL/6J strain and closely resembles beige ( bg) but the coat, ears, and tail are not quite as light as in bg/bg mice, and the eyes are not light enough to recognize this mutant at birth.

L. Slaty ( slt)

This recessive autosomal [chromosome 14; about 5 cM from piebald ( s)] mutation occurred in a heterogeneous stock carrying limb-deformity ( ld^J) and mahogany ( mg). On a nonagouti background slaty homozygotes have a slightly diluted coat and slightly yellowish ears ( M.C. Green, 1972).

M. Taupe ( tp)

Taupe, an autosomal recessive about 2 cM from albinism ( c) on chromosome 7, arose spontaneously in the C57BL/10 strain ( M.C. Green, 1966a). Nonagouti taupe ( a/a;tp/tp) animals have a diluted (slate grey) coat color which resembles the coat of nonagouti ruby-eye ( a/a;ru/ru) mice except that the underfur is lighter, with distinct yellow at its margins. Besides, unlike ruby eye, the color of the eye is not affected ( Fielder, 1952).

The viability of taupe homozygotes is normal and the fertility of taupe males also is normal, but taupe females may have difficulty gestating their young ( M.C. Green, 1966a). Thus while many taupe females become pregnant, litter members often either die in utero and are resorbed, are born dead, or die soon after birth. Furthermore, a number of young, of both those born alive and those born dead, are unusually small, though other animals in the same litters are of normal size ( Fielder, 1952). Taupe females sometimes have such great difficulty in delivering their young that they may die within several days afterwards. Moreover, even when they successfully deliver a viable litter and survive they are unable to nurse it. Although the ducts and alveoli of their mammary glands are normal, most or all of their nipples are so underdeveloped that they are difficult to detect ( Fielder, 1952). The primary lesion(s) responsible for the diverse effects of this mutation is not known.

N. Underwhite ( uw)

Underwhite is an autosomal (chromosome 15) recessive mutation which arose spontaneously in the C57BL/6J strain ( Dickie, 1964a). The dorsum of the uw homozygotes is a light buff color whereas the ventrum is white. The eyes of uw/uw mice are unpigmented at birth but darken to a dark reddish color at maturity ( M.C. Green, 1966a). According to Dickie mice carrying underwhite and agouti ( A), black and tan ( a^t), or such spotting genes as viable dominant spotting ( W^v) and white ( Mi^wh) are almost impossible to classify because their coat color is so dilute.

O. White Underfur (Provisional Symbol; wuf)

This recessive mutation (linkage unknown) occurred in a stock carrying rosette ( rst). It is impenetrant on brown ( b) and makes extreme nonagouti ( a^e) difficult to classify. wuf/wuf is not completely penetrant and, unlike underwhite ( uw), does not affect the eyes ( Ferguson and Wallace, 1977). ¹⁸