Interest in coat color genetics is almost as old as the science of genetics itself, for it was only shortly after the rebirth of Mendelism, at the beginning of the century, that W.E. Castle and his students, as well as others, initiated studies on the inheritance of specific coat colors in guinea pigs, rats, rabbits, and mice. Although these investigators were completely unaware of the anatomical basis of pigmentation, not to mention its biochemistry, their studies clearly established that the production of coat-color patterns involved a local interaction of specific gene products which was relatively unaffected by systemic or environmental factors.
It remained for subsequent investigators to produce the evidence that melanogenesis is the sole prerogative of specialized branched or dendritic cells, now known as melanocytes, of neural crest origin (Rawles, 1940, 1947, 1948), and that these cells function as unicellular melanin-secreting glands in the epidermis (see Billingham and Silvers, 1960). This elucidation of the cellular basis of pigment formation set the stage for extensive studies on the physiological genetics of pigmentation. These studies are directed toward answering the important question of how genes which influence pigmentation produce their effects, and it is precisely this question which forms the principal subject matter of this book.
Since the influence or influences of a specific genetic locus can be established only on the basis of variations (alleles) from the "wild type" that have been produced by mutations, it is obvious that the subject matter which follows initially depended upon the occurrence, recognition, and description of mutations, along with their preservation. Mutations give rise to alleles which not only identify the locus but which, on the basis of their effects, tell us something about the kind of activity with which the locus is involved.
In the house mouse (Mus musculus L.) more genes have been identified which affect coat color than any other trait. Moreover, this number has increased enormously over the past 25 years. During this period the number of coat-color determinants has risen from 32 to more than 130 and the number of loci involved has increased from approximately 20 to more than 50. While there have been a number of reviews concerned either entirely or in part with these genes ( Little 1958; Billingham and Silvers, 1960, Silvers, 1961; Deol, 1963, 1970a; Foster, 1965; Wolfe and Coleman, 1966; Searle 1968a; Quevedo, 1969a, 1969b, 1971) none approaches, either in scope or detail, the masterful treatment which Grüneberg gave this subject in Chapters 4 and 5 of the 1952 edition of his book The Genetics of the Mouse. Indeed, one of the reasons this book was initiated was because it was believed the time had come to bring these chapters up to date. 1
The subject has been attacked in a fashion similar to Grüneberg's. Thus, for the most part, each locus is considered separately. While this seemed to be the most logical approach, it has the disadvantage of often failing to emphasize the fact that each phenotype results from the cumulative effect of a multiplicity of determinants. For this reason I would like to call the reader's attention to the classic studies of E.S. Russell ( 1946, 1948, 1949a, 1949b); as far as I am aware these are the only ones which attempt to define each phenotype in terms of the actions and interactions of all the participating factors.
Many coat-color determinants have pleiotropic effects which cannot, at least at present, be related to their influence on pigmentation; these too are considered, if only briefly, in the hope that they may provide important clues for future investigations. Much of the information relating to these other effects, and indeed much of the detailed information concerning the pigmentary influences of specific alleles, are to be found in the notes at the end of each chapter. This format was adopted not to deemphasize the information presented in these notes but only to enhance the continuity of the text.
Any consideration of coat color requires some appreciation of the intimate relationship that exists between the melanocyte and the hair in which its product, the melanin granule (or mature melanosome), is deposited. Therefore, before embarking on the main theme of this effort, it is necessary to comment briefly on the coat of the mouse and its development (for more extensive treatments see Dry, 1926, Chase et al., 1951; Chase, 1954, 1958; Chase and Silver, 1969).
The coat of the mouse consists of two kinds of hairs, the overhairs and the underhairs. There are three types of overhairs (which together make up about 20% of the total number of hairs), the guard hairs (or monotrichs) and the awls, which have no constrictions, and the auchenes which have a single constriction. 2 The underhairs or zigzags constitute the remaining and predominant hair population. These fibers are shorter than the other hair types and usually have three flat constrictions, the segments following each being angulated against each other (and hence zigzagged). Because of their small size these underhairs play only a minor role in determining the overall color of the animal ( Deol, 1970a).
In fine structure all hairs are essentially similar, consisting of a wide central medulla surrounded by a narrow cortex which, in turn, is surrounded by a thin cuticle. the tips and bases of all the hairs are solid and deficient in medullary cells, and these cells may also be absent at the constrictions. Other than in these regions, the medullary cells are arranged transversely, separated from one another by areas devoid of melanin granules. In the overhairs these medullary cells may form rows of three, four, or even five septules, whereas in zigzags there is only a single row of septa. Although pigment granules are normally present both in the cortex and in the medulla of the shaft, most of the pigment occurs in the medulla. The four main hair types and some of their characteristics are shown in Figure 1-1.
The hair itself is formed in the hair follicle which begins as an epidermal invagination in the dermis. The dermis forms a thickening immediately beneath, and the blind end of the invagination comes to surround it partly. The dermal thickening develops into the hair papilla, and the surrounding part of the invagination forms the hair bulb (see Figure 1-2).
The melanocytes of the mature hair follicle are highly dendritic cells found in the hair bulb which their embryonic precursors (melanoblasts) enter as each follicle is formed ( Figure 1-2). 3 These cells, which are derived from the neural crest, 4 secrete pigment granules (mature melanosomes) into the hair cortex and medullas as they develop. 5 This deposition of granules continues during the entire growing phase of the hair (about 17 days). This phase is known as anagen and has been further divided into six substages (see Chase et al., 1951). When matrix cell proliferation in the bulb (the stage known as catagen ceases, the pigment cells also cease producing pigment and generally no further cells enter the shaft as medulla. This stage is followed by the resting or telogen stage. In young animals this phase may last 10 days or less, whereas in older mice it may persist for months before a new wave of hair growth begins. Nevertheless, new cycles can be initiated by plucking telogen hairs.