Chapter 8

X-Linked Determinants

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I. X-Chromosome Inactivation and the Allophenic Model

One of the most fundamental discoveries in mammalian genetics stems from the pigment patterns of female mice heterozygous for an X-linked coat-color determinant. Thus, the single-active-X hypothesis was originally suggested to explain the variegated or banded coat-color patterns of such females ( Lyon, 1961; L. Russell, 1961). it was proposed that in the early embryo one X-chromosome, chosen at random, was inactivated in each mammalian somatic cell and that the affected chromosome remained inactive. Thus, in the adult all the cells descended from any particular embryonic cell after the time of decision constituted a clone characterized by the presence of the same active X-chromosome (with the exception of the germ cells in which both X-chromosomes remained active). The wild type colored patches of the coat of heterozygous females were therefore attributed to the activity of cells in which the X-chromosome bearing the mutant allele had been inactivated, whereas the mutant colored patches were attributed to cells in which the X-chromosome carrying the gene for wild type color was inert ( Figure 8-1). This inactivation hypothesis, which is now accepted as dogma (see Lyon, 1970, 1971, 1972a, 1974), 1 is of particular interest because, like the allophenic patterns described in the previous chapter, it too can result in a situation in which melanocytes and/or hair follicle cells are derived from clonal-initiator cells bearing different markers. Consequently, a careful comparison of the patterns produced by X-linked coat-color determinants with those of the appropriate allophenics provides a means of assessing whether Mintz's interpretation of the latter also applies to these naturally occurring phenotypes. Such a comparison has been made ( Cattanach et al., 1972) and it clearly indicates that all of the phenotypic features of X-linked heterozygotes can be found in their allophenic counterparts. 2 Indeed, the pigment patterns displayed by females heterozygous for an X-linked coat-color factor are so similar to those of certain allophenics that all the postulates which Mintz has formulated to explain the latter almost certainly apply to the activity of these genes.

What is most surprising however is that some of the pigment patterns of females heterozygous for X-linked color genes stem from both melanoblast and hair follicle phenoclones ( Mintz, 1970; Cattanach et al., 1972). This observation is unexpected because it implies that some X-linked coat-color determinants are complex genetic units, of which different parts are expressed in different cells that give rise to different clones ( Mintz, 1970). Indeed, Mintz ( 1970) raises the possibility that "perhaps many (or even all) other genes once thought of as acting only in melanoblasts, or only in hair follicles, may be complex or highly polycistronic loci."

Finally, before focusing our attention on the effects of specific X-linked coat-color factors, it should be noted that because the patterns produced by these factors are replicas of those found in allophenic mice, they must be determined at a similar development stage. Thus the same line of reasoning that led to the conclusion that the melanoblast and hair follicle patterns of allophenics were established sometime between the fifth and seventh day of gestation, undoubtedly applies to these X-linked heterozygotes as well ( Mintz, 1974). In accord with this supposition are the results of injecting blastocysts with single cells from embryo donors heterozygous for an X-linked coat-color marker. The phenotypes which result from this procedure show that at 4.5 days of gestation X-chromosome inactivation has not yet occurred ( Gardner and Lyon, 1971; Lyon, 1972a).

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