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| For the Mo series: | |
| Gene (MGI) | All Alleles (MGI) |
Although a number of X-linked mutations have been reported which affect coat color, all of these, with the exception of yellow mottling ( Ym) and Pewter ( Pew) ( Section III), probably represent mutations at one locus, the so-called mottled or Mo locus. Because some of these mutations are lethal in hemizygous males, it has been difficult sometimes to demonstrate allelism directly, but all the information which is available is consistent with the notion that they all represent changes at the same locus (Falconer, 1953, 1956b, Lyon, 1960, 1972b, Grahn et al., 1971, 1972; Cattanach and Williams, 1972). Thus there is sufficient evidence to consider five of the six X-linked mutations, mottled ( Mo), blotchy ( Moblo), dappled ( Modp), brindled ( Mobr), and viable-brindled ( Movbr) as representing a multiple series of X-linked alleles and they have accordingly been so designated. Only in the case of tortoiseshell has a separate locus designation been maintained. However, there is no evidence that this mutation represents another X-linked coat-color locus ( Lane, 1960b), and much evidence to support the notion that it too is another Mo allele (Grahn et al., 1969a, 1969b). Indeed, its effects are so similar to the alleles at the Mo-locus that there is much to be said for changing its designation from To to Moto. Nevertheless, tortoiseshell will be referred to as it is currently designated.
| For the Mo allele: | ||
| Mo Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
The initial mottled ( Mo) female occurred among the progeny of a cross segregating for albinism ( c), pied ( s), brown ( b), and hairlessness ( hr) ( Fraser et al., 1953). The female was B/—;S/— and had many regions of light-colored (off white) hair scattered in an apparently patternless fashion over the entire body. The depth of color of the hairs in these regions varied between regions. All of the subsequent mottled females derived from this initial female displayed essentially the same pattern although the diffuse areas of very lightly pigmented hairs varied in extent and sometimes needed to be arranged in an irregular pattern of transverse bars ( Falconer, 1953) which, when well defined, very rarely crossed the mid-dorsal or mid-ventral line ( M.C. Green, 1966a).
Another feature of the mottled mutation is that it produces curling of the vibrissae, a characteristic which allows the condition to be recognized as early as 1 or 2 days after birth ( Falconer, 1953).
While it was immediately apparent that mottled expressed itself when heterozygous, it was also evident that it never occurred in males and that some females bearing the mutation died before 2 weeks of age ( Fraser et al., 1953). To determine the fate of the mottled males, Falconer ( 1953) killed and dissected mottled females at various stages of pregnancy. He found a significant group of dead embryos at the 11-day stage of development and by the twelfth day of gestation their frequency (23%) agreed well with the expected frequency of 25% of mottled males. It therefore appeared that although these dead embryos did not display any obvious external abnormality, they must in fact have been mottled males.
| For the dappled-2 allele: | ||
| dappled-2 Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
In 1960 Lyon described another sex-linked mutation which she provisionally called dappled-2. However, because she subsequently judged that this mutation was not clearly distinguishable from mottled, she withdrew this name and no formal designation has been given this deviant. 3 Nevertheless, this mutation deserves special consideration because some of its features, as described by Lyon ( 1960), are not mentioned either by Fraser and his colleagues ( 1953) or by Falconer ( 1953). Indeed, this raises the question as to whether Lyon's mutation is in fact a remutation to Mo or whether it represents a different allele? If it is Mo, it illustrates that different descriptions of the same mutation can often be misleading. It also indicates that there are more features associated with the Mo mutation than had previously been described.
The original mutant animal of Lyon's was a male which upon reflection must have been a mosaic with some cells, both of his soma and his gonads, carrying a normal X-chromosome and some carrying an X-chromosome bearing the mutation. Phenotypically this male resembled his female descendents which possessed, to varying degrees, a mottled coat with patches of white, light-colored and full-colored hairs, as well as intermingled hairs of different colors. 4 Females which were heterozygous for this mutation also sometimes exhibited patches with well-defined edges and when these occurred they rarely crossed the mid-dorsal or mid-ventral line of the animal ( Figure 8-2). This was especially obvious on the head, which was often divided by a line from the ears to the tip of the nose into dark and light halves. Thus, insofar as their coat colors were concerned these females were identical in every respect to the descriptions noted above for mottled. They also resembled Mo/+ in that they had curly vibrissae, although the degree of curliness was variable. In situations where the color of the hair was very different on the two sides of the snout, the whiskers were curlier on the lighter side.
In addition to these features, however, Lyon also noted that "in some of these females the fur was slightly wavy and of a finer texture than normal." Moreover, she noted that some heterozygous females were distinguished by incoordination of the limbs which was first noticeable as a tremor when they were a few days old. This condition progressed rapidly until the affected animals lost all coordination of the limbs and died at about 2 weeks of age.
Lyon also reported that some of her heterozygous mutants when a few months old displayed calcified lumps either attached to their bones or free in their muscles or tendons. These lumps were frequently seen attached to the vertebrae or bones of the feet, but were also common in the muscles of the limbs. The frequency of these calcifications increased as the animals got older.
As in the case of mottled, males hemizygous for Lyon's mutation also fail to reach term and apparently die in utero at about the same stage of development. Thus, at 12.5 days of gestation Lyon found some recently dead, normal looking embryos. However, these embryos were white with yolk sac circulations which appeared empty. Indeed, this observation, together with the fact that at 11.5 days some living embryos were found with hemorrhages inside the yolk sac, is undoubtedly significant. Since other Mo-locus alleles are known to be associated with vascular disorders (see Table 8-1) and there is every reason to believe that these defective embryos were hemizygous for Lyon's mutation, it is very likely that they too were afflicted with some disorder of the circulatory system.
| For the Mobr allele: | ||
| Mobr Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
Brindled arose spontaneously in the C57BL strain ( Fraser et al., 1953). The phenotypes associated with this mutation have been described in detail by Grüneberg ( 1969) and most of what follows is based on his description.
The coat of Mobr males is usually almost white with sooty tips, but sometimes it is light grey in color ( Figure 8-3). The eyes are dark and the ears, tail, and scrotum all display normal levels of pigmentation. Although the color of the brindled male has been compared with Himalayan albinism ( Falconer, 1953) this resemblance is only superficial for unlike himalayan animals (see Chapter 3, Section II, B, 6), where the pigmentation of the extremities involves the hair, in brindled males only the skin of the ears, tail, and scrotum is pigmented normally. The vibrissae of Mobr males are very curly and irregular and the coat, which as a whole is short, possesses many finely curved or undulated hairs (see Figure 8-3). Whereas in the normal coat a halo of guard hairs usually projects above the rest of the fur, these hairs are almost completely absent in Mobr/Y mice. Moreover the tail hairs of these animals are reduced in number and less regularly arranged than in normal mice.
A careful examination of the coat of brindled males reveals that it includes both overhairs (awls, auchenes, and probably some guard hairs) and underfur (zigzags), but these hairs are reduced in caliber and structurally abnormal ( Figure 8-4). Most of the hairs are unpigmented, but some have a little, mostly cortical, pigment in the tip. The first few septules may also contain melanin granules.
The coat of Mobr/+ females displays a wide variation in its pigmentation ( Figure 8-5). Some females are very light, while others are phenotypically almost normal, but all display at least some irregular mottled or brindled regions in which ill-defined lighter and darker areas tend to grade imperceptibly into each other. Hair bases are much lighter than the tips and the hairs on the tail are reduced and less regular in arrangement than in normal animals.
In addition to mottling some Mobr/+ females display more regular patterns. Thus, as pointed out by Falconer ( 1953) and Grüneberg ( 1969), the light hairs sometimes form an irregular pattern of transverse stripes which is most conspicuous in the juvenile coat and tends to decrease with age. This banding pattern resembles those found in allophenics whose components differ with respect to a hair follicle marker, and like some allophenic patterns is occasionally characterized by a "midline effect" in which dark and light areas meet sharply along the midline. There is no color mottling on the ears or tail of brindled females and, as in mottled ( Mo/+) and dappled ( Modp/+) females, there seems to be a correlation between the color and curliness of the whiskers: they are straight in the dark, but a little curled in light individuals.
Females heterozygous for Mobr sometimes change in color with age and when this occurs they tend to get darker.
According to Grüneberg the juvenile coat of Mobr/+ females includes some morphologically normal hairs which are pigmented completely, and some of which are abnormal and contain as little pigment as the hairs of brindled males (Figure 8-4 and 8-6). However, these latter hairs are usually not nearly as structurally abnormal as those of brindled hemizygotes. Most of the hairs are intermediate between these extremes. They usually start normal both with regard to stucture and pigmentation, but the pigmentation decreases and eventually ceases altogether, and their structure becomes increasingly abnormal. Although the same polarization of pigment occurs in Mobr/+ females as in brindled males, a greater portion of the hair shaft contains pigment and the level of pigmentation is significantly heavier. In the morphologically abnormal hairs the deterioration in hair morphology may begin early or late in the hair cycle. While in some instances only a middle portion of the hair may appear abnormal, there are no hairs which start abnormal and gradually become normal.
In the adult coat of heterozygous brindled females hairs as extreme as those found in the juvenile coat are all but absent, and changes in the degree of mottling are evidently largely the result of differences in the amount of pigment deposited in different hair generations.
The exact relationship between the structure and pigmentation of the hair in brindled mice is not clear. While it is conceivable that the effect of hair structure is primary, and that melanocytes cannot function properly in follicles which give rise to abnormal hairs, it is also possible that Mobr acts via the melanocyte and that these cells can somehow alter the morphology of the hair. This latter possibility, however, seems highly unlikely because the pigmentation of the skin is unaffected, and because it is inconsistent with the fact that some of the pigment patterns of Mobr/+ females simulate the hair banding pattern of allophenics. Indeed, the most likely possibility, and one to which we will return, is that while the major effect of Mobr is on the hair follicle ( Grüneberg, 1969) it also is able to influence directly, albeit in a relatively minor way, the melanocyte.
Brindled is usually lethal in males. As originally described all Mobr males died between 10 and 14 days of age ( Fraser et al., 1953). However, Grüneberg ( 1969) reported that they sometimes live up to 3 weeks and occasionally longer and a few have lived and been fertile ( Falconer, 1956b; M.C. Green, 1966a). In fact the survival of such males enabled Falconer ( 1956b) to produce homozygous brindled females which were in every way indistinguishable from hemizygous males. He also was able to produce females which carried both mottled and brindled. These were indistinguishable from Mobr/Mobr females or Mobr/Y males. One of these brindled males was also crossed with one of Lyon's "mottled" females, producing one litter in which there was one black-eyed white female which died at 11 days of age ( Lyon, 1960). These findings, along with the phenotypic resemblances of Mo and Mobr, and their similar linkage relationships to tabby ( Ta), 5 make it reasonable to assume that they are alleles.
Brindled males suffer from a neurological impairment ( Sidman et al., 1965; D. Hunt and D. Johnson, 1972a, 1972b) characterized by "slight tremor, uncoordinated gait, and characteristic reflex of the hind legs when the animal is held up by the tail, the feet clasping each other instead of being spread out" ( Falconer, 1956b). 6
Because there is a great deal of variation in the variegated patterns of Mobr/+ females, Falconer and Isaacson ( 1969, 1972) attempted to determine whether these patterns could be selected for. They reasoned that since this variegation is due to X-chromosome inactivation, if it could be modified by selection this would show that the inactivation process, or some property of the derived cell populations, is under genetic control. Mobr/+ females were accordingly selected for on the basis of the amount of mutant color they displayed. They found that although selection based on individual phenotypes was ineffective in influencing the amount of variegation, four cycles of reciprocal recurrent selection based on progeny-means did produce a "High" line with 64% mutant area and a "Low" line with 30% mutant area, from a base population with 53% mutant area ( Falconer and Isaacson, 1972). They went on to demonstrate that the difference between the selected lines was not due to autosomal modifiers but was due entirely to properties of the X-chromosomes bearing the Mobr allele, i.e., apparently there are X-linked modifiers of X-linked loci which operate only upon the allele located on the same chromosome. They also showed that the altered properties of X chromosomes were not restricted to the Mo-locus but extended at least as far as tabby ( Tab). Although there was no evidence that the chromosomes carrying the + allele of brindled were altered by the selection procedure, normal X-chromosomes from other strains did influence the degree of variation. Falconer and Isaacson ( 1972) concluded from their experiments "that the difference between the selected lines was due either to non-random inactivation or to somatic cell selection." Their protocol did not allow them to distinguish between these possible mechanisms.
Employing an X-linked gene, mosaic ( Ms) (see Section J), which produces a variegated phenotype very much like that of brindled, Krzanowska and Wabik ( 1971, 1973) also attempted to select for high and low proportions of mutant areas. In contrast to Falconer and Isaacson, these investigators were successful in establishing such lines on the basis of individual selection. Thus they obtained lines with 73 and 35% mutant areas after four generations of within family selection. To account for this success Falconer and Isaacson ( 1972) suggest that it was due to variations in the properties of the X-chromosome arising by recombination. This variation was presumably either not present in their strain, or at least no suitable crossovers occurred. 7
| For the Movbr allele: | ||
| Movbr Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
This mutation has been described only briefly ( Cattanach, et al., 1969) but from all indications the range of coat-color phenotypes it produces when heterozygous, as well as the coat color of hemizygous males, is indistinguishable from those produced by brindled. As in the case of Mobr/+ females, the banding patterns of Movbr/+ mice more closely resemble those associated with hair follicle phenoclones than with melanoblast phenoclones, the bands being composed of whitish hairs like those which comprise the coat of the hemizygous Movbr male. Like Mobr, Movbr also causes a rippling of the coat and a curling of the whiskers which is more pronounced in hemizygous males. This influence on the texture of the coat suggests that the primary effect of the allele is on hair structure. Nevertheless, it seems likely that this allele has a direct effect on melanoblasts as well since the banding in Movbr/+ heterozygotes is broader than the banding in tabby heterozygotes ( Ta/+) ( Cattanach et al., 1969) which, as already noted see note 5) is believed to be produced solely by hair follicle phenoclones.
Movbr/+ females are not good mothers and about 50% of their offspring, regardless of genotype, do not survive until weaning. This together with the additional loss of 50% of Movbr/Y males before they are a month old, results in an overall early mortality of about 75% for these males. Although the Movbr/Y males which succumb early in life have a mean survival of 22.7 days, and most die between days 20 and 30, an appreciable number die at 12-14 days of age (Grahn, personal communication).
Viable brindled, like brindled, males suffer from a neurological disturbance ( D. Hunt and D. Johnson, 1972a). Many Movbr males which survive into adulthood also display aortic aneurysms, which are not observed in Mobr males ( Rowe et al., 1974). Indeed, many viable-brindled males succumb to blood vessel rupture between 50 and 100 days of age ( Rowe et al., 1974).
| For the Modp allele: | ||
| Modp Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
Dappled ( Modp) occurred in an F1 male from a low-dosage gamma-irradiation experiment ( Carter et al., 1958). The only affected male sired 10 dappled females which phenotypically resembled himself, as well as 278 normal females and 290 normal males ( R.J.S. Phillips, 1961b). Inasmuch as dappled has proved to be lethal in the hemizygous condition, it is apparent that the original male who displayed the mutation, like the male who originally manifested the "mottled" mutation described by Lyon ( 1960), carried a sectorial mutation with at least the coat and part of the testes being affected.
The supposition that dappled is a member of the Mo series is supported both by linkage tests and by the fact that dappled females mated to a brindled ( Mobr) male produced six females which resembled brindled males. These females, which died before weaning, presumably carried both dappled and brindled, i.e., were Modp/Modp ( R.J.S. Phillips, 1961b).
Most dappled females can be identified at birth by a curling of the vibrissae, but the degree of curling is very variable and some animals' whiskers are nearly straight ( R.J.S. Phillips, 1961b). The adult coat has a variegated pattern similar to that of mottled. 8 Although the hairs have not been studied in the same detail as brindled, and dappled males die prenatally and hence cannot be studied, some dappled hairs possess abnormalities which resemble those found in Mobr/+ females ( Cattanach et al., 1972). Medullary cells appear to be fused, perhaps as a result of the presence of liquid (absence of air) as suggested by Grüneberg ( 1969), and a flattening of the hair is also apparent Cattannach et al., 1972). In addition to the structural abnormalities, the hairs also tend to be deficient in pigment. However, there is not a complete correlation between the structural abnormalities of the hair and lack of pigmentation ( Cattanach et al., 1972).
Although the variegated phenotypes of heterozygous dappled females appear to resemble more closely those produced by melanoblast phenoclones than those which result from hair follicle phenoclones, it seems apparent from the structural abnormalities of the hair, as well as from a close examination of the pelage of an Modp/+ <--> Ta/Ta allophenic female ( Cattanach et al., 1972), that this allele too most likely acts both in the melanocyte and in the hair follicle.
A most fascinating effect on the pigmentation of dappled females occurs in the presence of either piebald ( s) ( Chapter 9, Section II, A) or belted ( bt) ( Chapter 9, Section IV) spotting. In Modp/+;s/s and Modp/+;bt/bt mice the two hair colors which constitute the "normal" variegated pattern are separated out to give and overall tricolored animal possessing normally (+) pigmented, lightly ( Modp) pigmented, and nonpigmented ( s/s or bt/bt) areas ( Cattanach et al., 1972). This effect, which undoubtedly is associated with the fact that the major influence of Modp is on the melanoblast, 9 is of interest not only in its own right but because a similar situation occurs in guinea pigs, rabbits, tortoiseshell cats, and other animals as well ( Searle, 1968a). For example, the extension series in the guinea pig (see Chase, 1939), which is autosomal, includes E (self black) which is dominant over ep (tortoiseshell) and e (self yellow). In the absence of white spotting, ep/ep guinea pigs display a brindling pattern of yellow hairs on a black background. However, in the presence of white spotting ( s/s) the black and yellow areas become segregated from each other and a tricolored yellow, black, and white phenotype is produced. Indeed, the two inbred strains of guinea pigs which are currently most utilized, strains 2 and 13, are ep/ep;s/s and represent such tricolored phenotypes. How white spotting produces this effect and whether the mechanism is the same in mice, guinea pigs, cats, and rabbits is not known, although it probably is. 10
In addition to its influence on pigmentation, Modp sometimes influences the morphology of the feet. Some Modp/+ females show clubbing of one or both fore feet at birth, or, at weaning, have a tendency to walk on the dorsal surface of the hind feet. Moreover, the occurrence of abnormal feet seems to be associated with a greater degree of curling of the whiskers ( R.J.S. Phillips, 1961b). The amount of curling of the vibrissae is likewise associated with the degree of lightness of the coat at weaning: the lighter the coat, the more pronounced the curling ( R.J.S. Phillips, 1961b).
Another condition associated with some Modp/+ females is the development, with age, of calcified lumps in the region of the periosteum especially on the vertebral column, the lumbar and thoracic regions of which are principally affected. Whether these bodies are outgrowth from the bone is not clear. None has been observed in mice under 8 week of age ( R.J.S. Phillips, 1961b). This anomaly also occurred in Lyon's ( 1960) "mottled" mutation.
Finally, about 10% of Modp/+ females have been reported to have aortic lesions ( Rowe et al., 1974) (see Table 8-1).
When the offspring of the dappled daughters of the original dappled male were sexed at birth, there were about half as many males as females. This of course suggested that, as in the case of mottled, males hemizygous for dappled die before birth. R.J.S. Phillips ( 1961b) found that among embryos 15 days old or more some had ribs which were very white, thickened, and bent and some also displayed distortion of the pelvic and pectoral girdles and the limb bones. She also observed that most of these abnormal embryos either were dead already or were moribund at 17-18 days of gestation. 11 These defective embryos were assumed to be the hemizygous males and this was supported by the data which showed that half the males and none of the females were affected. Males with abnormal ribs have occasionally been found dead at birth. The specific cause of death is not known.
| For the Moblo allele: | ||
| Moblo Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
Blotchy (
Moblo) arose spontaneously at Oak Ridge (
L. Russell, 1960).
12 As in the case of the other
Mo-alleles, females heterozygous for this mutation also display irregular patches of light colored fur. Its expression is occasionally poor at weaning (heterozygous
females are sometimes misclassified as wild type) but it is complete by adulthood (
L. Russell, 1960). The pigment patterns which occur in
Moblo/+ females resemble those produced by melanoblast phenoclones (
Mintz, 1971a). However, inasmuch as
Mo
Blotchy when hemizygous in either males or females (X/0), and when homozygous in females ( Moblo/Moblo), produces a light phenotype (with no blotching) somewhat resembling cch/c in intensity. These genotypes usually also are of small size, and occasionally have deformed hind legs. Their whiskers are kinked at birth but straighten out by the time they are weaned. Whereas the viability and fertility of heterozygotes is normal, and Grahn and his colleagues ( 1969b) note that Moblo/Moblo females also are of normal viability, L. Russell ( 1960) reports that hemizygous and homozygous blotchy mice have reduced viability and many are infertile.
Evidence that blotchy is a member of the Mo-series of alleles (and hence that its designation should be changed from Blo to Moblo) was provided by the fact that it displays the same crossover frequency with tabby ( ~ 4%) as the other members of the series ( L. Russell, 1960; L. Russell and Saylors, 1962). Moreover, no crossovers between Moblo and Movbr have been observed ( Cattanach and Williams, 1972) and both Moblo/Mobr and Moblo/Movbr females are lightly pigmented. Animals of the former genotype are of a uniform light coat color ( Lyon, 1972b) and those of the latter are described as tending to show a white ( Movbr)-brownish white ( Moblo) variegated coat although the two types of pigmentation are not readily distinguishable ( Cattanach and Williams, 1972). 13
In addition to these originally described features of blotchy the mutation is also associated with spontaneous aortic and abdominal aneurysms ( Grahn et al., 1969b; Rowe et al., 1974; Andrews et al., 1975). According to Rowe and his colleagues about 95% of hemizygous blotchy males, 85% of Moblo/Moblo females, and 35% of Moblo/+ females have aortic aneurysms (see Table 8-1). Indeed, many blotchy males succumb to blood vessel rupture when more than 150 days of age ( Rowe et al., 1974). Their median age at death is about 200 days and over 90% are dead by 1 year of age ( Grahn et al., 1971). Blotchy males also have recently been reported to develop osteoarthritis at a much earlier age than "normal" animals. Silberberg ( 1977) found that from the age of 3.5 months on such males develop this condition in their knee joints and by the time they die 88% have it. Emphysema-like changes have also been noted in the lungs of these males ( Silberberg, 1977).
| For the To allele: | ||
| To Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
This mutation arose spontaneously in an obese stock at the Jackson Laboratory ( Dickie, 1954). Heterozygous tortoiseshell ( To/+) females ( Plate 3-C) are variegated and resemble Mo/+ females in color. They also, as expected, display a wide range of phenotypes so that a large number of individuals must be examined to determine the general pattern trend. Such an examination indicates that the basic To/+ pattern is composed of both melanoblast and hair follicle phenoclones, one superimposed upon the other ( Mintz, 1971a). Indeed, it is because of this that Mintz ( 1970) suggests that the To locus may be a complex one, with one portion controlling and being expressed in melanoblasts, and another in hair follicle clones. Further support for this contention is provided by the fact that To affects the texture of the hair which is silkier than normal. The vibrissae are also slightly waved ( Dickie, 1954).
Unlike the situation in dappled females, piebald ( s/s) spotting has no effect on the tortoiseshell pattern ( Dickie, 1954).
Some tortoiseshell females also suffer from skeletal abnormalities in the fore and hind limbs ( Dickie, 1954) and an appreciable number of them have aortic lesions, including aneurysms (see Table 8-1) ( Fry et al., 1967; Grahn et al., 1969a, 1969b; Rowe et al., 1974).
Although a few To/Y males are stillborn, many of them die in utero with blood vessel aneurysms (Grahn et al., 1969a, 1969b; Rowe et al., 1974) (see Table 8-1). 14 A presumed mosaic male carrying To (see Grahn and Craggs, 1967) was utilized to produce Moblo/To, Mobr/To, Modp/To, and To/To females and it was found that whereas animals of the first two genotypes reach term but usually die by 15 days, 15 the latter two genotypes are presumably prenatal lethals (Grahn et al., 1969a, 1969b). Such information provides further evidence that To is a member of the Mo-series of alleles.
The phenotypic effects of Mo-locus alleles are summarized in Table 8-2 and the relative viability of various Mo-locus genotypes is given in Table 8-3. While it is evident that all of these determinants produce banded patterns when heterozygous with the wild type allele, these patterns seem to vary from those which are similar to the melanoblast bands of allophenics to those which bear a much closer resemblance to the hair follicle clonal strips of these mice. Whereas the coat-color patterns of Mo/+, Moblo/+, and Modp/+ females resemble those of allophenics whose components differ with regard to melanocyte pigment, the patterns found in Mobr/+ and Movbr/+ heterozygotes more closely resemble the striped patterns produced by hair follicle clones. Nevertheless, evidence has been presented which indicates that all of these alleles may act both in the melanocyte and the hair follicle but to quite different degrees. This evidence includes the following: (1) all these genes appear to be associated with curly whiskers; (2) although the Moblo/+ pattern appears to resemble that produced by melanoblast phenoclones ( Mintz, 1971a), Moblo causes no lightening of the skin pigment in the ears and tail, and therefore its hair-lightening effect could be attributed to some effect on hair structure ( Lyon, 1970); (3) Movbr is known to affect the structure of the hair and yet the banding in Movbr heterozygotes is broader than in tabby ( Ta/+) heterozygotes ( Cattanach et al., 1969); (4) the variegated phenotypes of Modp/+ females appear to resemble those produced by melanoblast phenoclones and yet the hairs of these mice are structurally abnormal; and (5) in tortoiseshell females ( To/+) both melanoblast and hair follicle clonal patterns are clearly visible ( Mintz, 1971a).
It is apparent from the above that the alleles at the Mo-locus not only affect pigmentation and hair texture but are associated with a number of other more serious conditions including neurological disturbances, aortic aneurysm, and skeletal abnormalities. To account for these seemingly unrelated effects D. Hunt ( 1974a) has suggested that the mottled syndrome is caused by a primary defect in copper transport. His arguments include the following:
To further support the thesis of copper involvement D. Hunt and Skinner ( 1976) have recently reported that the activity of the copper-dependent enzymes cytochrome c oxidase and superoxide dismutase are reduced in Mobr/- brain tissue. They have also found that the lethality and to some extent the pigment deficiency of brindled males can be overcome by administering copper chloride (see note 18).
On the other hand Rowe and his associates ( 1977) note that there are a number of inconsistencies with the assumption that the primary effect of all Mo-alleles is on the transport of copper. These include the fact that:
Because of these inconsistencies, Rowe et al. ( 1977) suggest that "a possible explanation for the multiple defects of the mottled alleles are overlapping deletions and a common defect in pigmentation." Thus, according to this scheme there are genes adjacent to the "mottled locus" which code for an enzyme necessary for copper transport, for lysyl oxidase and for dopamine-beta-hydroxylase, and these are affected to varying degrees.
| For the Ms allele: | ||
| Ms Allele (MGI) | Gene (MGI) | All Alleles (MGI) |
This X-linked mutation, which we have already referred to (Section C, 4, notes 7 and 18), has been described and studied by Krzanowska ( 1966, 1968), Radochonnska ( 1970), Wabik ( 1971), and Styrna ( 1976, 1977a, 1977b). It arose spontaneously in an outbred strain maintained in the Department of Animal Genetics, Jagellonian University, in Krakow.
Males hemizygous for this mutation display a notably lighter coat. According to Radochonska, agouti males carrying the mutation are a light shade of silvery-grey, whereas black mosaic males are brownish black with hair that is cream-colored at the base and darker at the tip. The head and the midline of the trunk of hemizygous males are darker than the other parts of the body. When combined with pink-eyed dilution ( p/p), agouti mosaic males ( A/A;p/p;Ms/Y) are ivory and nonagouti mosaic males ( a/a;p/p;Ms/Y) are completely white ( Krzanowska, 1966). Heterozygous females frequently display pigmented patches arranged in an irregular pattern of transverse bars. This effect is most conspicuous in p/p females when white and wild stripes occur ( Krzanowska, 1966).
The coat of males and females bearing the mutation also is silkier than normal and grows thinner. The specific changes in the hairs have been described by Radochonska. One interesting feature is that the zigzag hairs of hemizygous males usually have two instead of three constrictions. The structure of the awls also is abnormal. The vibrissae of Ms mice are curly. The greatest degree of curliness occurs in hemizygous males and homozygous females. In heterozygous females there appears to be a significant correlation between the lightness of the coat and the curliness of the whiskers. In the more darkly pigmented females the vibrissae are curly at birth but gradually straighten and often appear nearly normal by the third week of life. Very light females, however, display twisted vibrissae even when mature. The lightness of the coat of heterozygous females also is associated with reduced body weight and lowered viability ( Radochonska, 1970).
Hemizygous Ms males grow normally up to about 10 days of age but then suddenly stop growing, develop a progressive paresis of the hind limbs ( Radochonska, 1970), and die when about 12-20 days old. 19 However, a few males, about 4%, survive this crisis, resume growing, and eventually are of near normal size. Some have been fertile and have sired litters containing Ms/Ms females. Such females are identical phenotypically with hemizygous males and also die when about 15 days old ( Krzanowska, 1968).
Although this mutation undoubtedly belongs to the Mo locus series of alleles (and accordingly might be noted as Moms), to my knowledge no tests have been undertaken to determine its relationship to this locus. From its description it appears most similar to brindled and, indeed, could represent a remutation to this allele.
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