Comparative studies have not played a central role in the development of mammalian genetics until quite recently. The reason for this is clear: There was little to compare with ease and certainty until spectacular advances in molecular biology revealed details of the genetic structure of many mammalian species. Coat color was the one major exception before the advent of molecular technologies. In the early decades of the century, much information accumulated on the genetics of coat colors in a wide array of mammalian species, and a few pioneers in genetics, including some of the outstanding figures in the history of the discipline, used this knowledge to speculate on the comparative aspects of mammalian genomes.

J. B. S. Haldane emerged as the dominant figure in this endeavor. In 1927, he published a famous paper in which he discussed the fundamentals of homology and how these could be demonstrated by examining the coat color genetics of six species of rodents and nine species of carnivores (Haldane 1927). His criteria for homology are presented, together with those of Lalley and McKusick (1985), in Table 1. Although the language and details understandably differ, the agreement on the fundamentals necessary for making a decision is impressive. Despite advances that have made the assignment of homology much more reliable, the uncertainty inherent in Haldane's criteria persists.

Haldane and others, notably Little (1958) and Searle (1961, 1968, 1969), recognized that the closer the phenotypes were to the primary action of the genes in question, the stronger any decision on homology would be.

Because I am concerned with comparative aspects of the X chromosome, I have tried to create a companion volume to McKusick's catalog of X-linked phenotypes in man, Mendelian Inheritance in Man (MIM), and the format is patterned on it. I have used the same numbering system and have attempted to integrate the entries into McKusick's system: Apparently true homologies are given the number assigned in McKusick's catalog (with a few exceptions noted below); probable or possible homologies are given different numbers, but attention is drawn to the fact that a homologous relation with a human locus or phenotype might exist. To minimize any conflict or potential confusion, loci that are apparently unknown in man have been given numbers that are, as yet, unassigned in MIM. These general statements cover most entries; separate comment is required for a few others.

In attempting to comply with the recommendations of Lalley and McKusick (1985) noted in the Introduction, I have fitted homologous loci known in the mouse and other species into the human nomenclature system where appropriate; for example, the mottled series in the mouse and the mutation at the homologous locus in the Syrian hamster appear under MENKES SYNDROME. In one instance, although the same number (30150) is used, the entry is named after the normal product of the locus (Alpha-galactosidase A) not the mutant phenotype (Angiokeratoma, diffuse). Finally, in several instances, where I believe the MIM entry heading gives an inadequate notion of the nature of the locus, I have changed it.

30006 ABSENT PINNAE [NK]

Black rhinoceros

Absence of pinnae in the black rhinoceros has been recorded in at least 7 discrete populations in eastern and southern Africa (Goddard 1969). Of the 15 affected animals whose sex was known, 13 were males; 1 of the females may have been sired by an affected male, and the other was affected only unilaterally. Although relevant breeding data are virtually nonexistent, Goddard (1969) suggests that the trait may be X-linked de Vos (1978) reported a unilaterally affected bull.

de Vos V: 1978. Congenital unilateral aotus in a black rhinoceros Diceros bicornis bicornis (Linn. 1758). J S Afr Vet Assoc 47: 71 only.

Goddard J: 1969. A note on the absence of pinnae in the black rhinoceros. E Afr Wildl 7: 178–181.

*30030 AGAMMAGLOBULINEMIA (BRUTON-TYPE AGAMMAGLOBULINEMIA; IMDI)

Cattle

Perk and Lobl (1962) studied a 3-month-old bull calf with agammaglobulinemia; the animal had repeated respiratory tract infections and several attacks of severe diarrhea, and died before additional immunologic studies could be carried out.

Horse

This disorder has been observed in Thoroughbred, Standardbred, and quarter horses. Four cases (all colts) were diagnosed among 2,516 horses evaluated for immunologic disorders (Perryman et al. 1983). Two of these have been described in detail (Banks et al. 1976; McGuire et al. 1976; Deem et al. 1979); both died at approximately 11/2 years. Pneumonia, enteritis, dermatitis, arthritis, and laminitis were noted at 2–6 months of age after the maternally derived immunoglobulins disappeared. B lymphocytes were absent, IgM and IgA could not be detected, and IgG and IgG(T) occurred in very low concentrations.

The mammalian Y chromosome, which had received little detailed attention previously, became the focus of vigorous research activity during the 1980s: Goodfellow et al. (1985) reviewed the Y chromsome, and Davies et al. (1987) presented the report of the Committee on the Genetic Constitution of the X and Y Chromosomes to the Ninth Human Gene Mapping Conference. Various forms of maps have been published (Vergnaud et al. 1986; Ferguson-Smith et al. 1987). The chromsome has merited a monograph (Sandberg 1985) and has become the subject of intense study (Goodfellow et al. 1987). However, few genes are known to be Y-linked in man, and there is little published information on the Y chromosome of other mammals, aside from the mouse. The existing data are presented below. An asterisk indicates that a probably homologous gene or region is known in man (Davies et al. 1987; McKusick 1986).

Molecular studies of the mouse Y chromosome

Eicher et al. (1983) and Eicher and Washburn (1986) described cytogenetic and molecular studies that resulted in partitioning of the normal Y chromosome into 6 functionally distinct regions containing the centromere; the Tdy and Hya loci, and Bkm-related sequences; sequences involved with sperm motility and with Xmmv; an X-pairing-and-recombinant segment; Sts; and the telomere. Bishop et al. (1985) used a Y-specific genomic DNA probe (pY353/B) to examine the RFLPs in 10 newly established mouse lines of the European semispecies, Mus musculus domesticus and Mus musculus musculus, and identified 2 variant forms of the Y chromosome, each characteristic of 1 of the semispecies.

No attempt to deal with the facts of meiosis would be complete without some consideration of the evolution of the various modes and mechanisms to which the greater part of this monograph has been devoted.

The data summarized in Chapter 6 indicate that all the component parts of the meiotic mechanism are under genetic control and show heritable variation in the form of mutations. Since selection will operate on any set of entities with the properties of heredity, variation and a capacity for multiplication,it has commonly been assumed, as the quote which introduces this chapter also initially assumes, that changes in the character of meiosis stemming from mutation will necessarily reflect adjustments relating to selection for enhanced fitness. Inherent in this assumption is the belief that different meiotic systems have different consequences which allow them to respond to differentselection pressures.

It is certainly possible to demonstrate a response to artificial selection for a number of aspects of meiotic behaviour. Shaw (1971b), for example, was able to alter the mean cell chiasma frequency of male meiocytes by selecting grasshoppers with high and low mean cell chiasma frequencies and using these as parents in experimental crosses.

Every aspect of meiosis that we have considered is evidently beset with both controversial and unresolved issues. Far from having solved longstanding problems, the new information now available to us has simply served to put them into a different context. It is for this reason that we still lack a complete theory of meiosis.

Over and above individual issues there are two rather more fundamental features of meiosis which are also in need of a solution. The first of these is a developmental matter. The meiocyte is simply a specialized cell with a distinctive pattern of cytodifferentiation though, unlike most other categories of cytodifferentiation, that of the meiocyte principally involves changes in the chromosomes themselves rather than chromosome-induced changes in the cell cytoplasm (Stern & Hotta, 1984). In S. pombe, cell-type determination is controlled by a class of master regulatory, mat, genes, whereas cell differentiation is regulated by protein kinases (see Section 4A). These two systems are associated through the mei-3+ gene which is transcriptionally regulated by the mat genes and whose product, in turn, inhibits the ran-1+ protein kinase (McLeod & Beach, 1988). Precisely how the differentiated state of the meiocyte is initiated in other eukaryotes remains unsolved, though the molecular events associated with it are now tolerably well known. Some of them involve the activity of genes, enzymes and proteins available to, and used by, mitotic cells. This includes those genes responsible for such ubiquitous cell products as actins, tubulins and kinetochores, as well as some of the enzymes involved in the replication and recombination of DNA. Meiocyte differentiation also involves novel gene products.

THE SWITCH TO MEIOSIS

The precise factors responsible for the transition from mitosis to meiosis are still largely unknown. In mammals, as we saw earlier, while differentiation of the gonad into a recognizable testis occurs in the embryo, male germ cells do not enter meiotic prophase before early puberty. Fetal mouse testes and ovaries,together with their urinogenital connections, can be cultured either singly, or in pairs, on nucleopore filters. When a fetal testis is cultured in combination with older ovaries containing germ cells at prophase-1 of meiosis, the primordial male germ cells are triggered to enter meiosis(Byskov & Saxen, 1976). The female gonad thus appears to secrete a meiosis-inducing substance which can trigger indifferent male germ cells to enter meiosis. In keeping with this, XY cells in fetal mouse chimaeras also embark on meiosis and McLaren (1984) has proposed that they are stimulated to do so by the surrounding XX cells.

The specific somatic cell system that appears to be essential for the differentiation of the mammalian fetal ovary is the rete ovarii. Both the onset of female meiosis and follicle formation seem to depend on this urinogenital connection, of mesonephric origin, in the early gonadal anlage. When fetal testes with developed testicular cords are cultured in combination with ovaries of the same age, but which contain germ cells already in meiosis, the oocytes are prevented from reaching diplotene. This implies that the male gonads are producing some kind of meiosis-inhibiting substance. Unfortunately no diffusible inducing or inhibiting substances have yet been isolated.

Every living eukaryote either is, or at some time has been, a single cell. New cells arise only by the division of existing cells and this involves the division of both nucleus and cytoplasm. In eukaryotes nuclei divide in only two ways, by mitosis or by meiosis. Meiosis represents a unique form of cellular differentiation and, unlike mitosis, is most usually initiated only once in the life cycle of a eukaryote. Moreover, while mitosis is associated with uniparental, asexual, systems, it is meiosis that has made sex and biparental inheritance possible. It is then a unique and distinctive event in the life of an organism.

It is also a meticulously exact event normally involving both an accurate quantitative reduction in chromosome number, on the one hand, and aprecise partitioning of genetic material, on the other hand. Meiosis thus fulfills two interrelated functions both of which are connected with the process of sexual reproduction. It ensure the production of a haploidphase in the life cycle of an organism (reduction) and, in one form or another, provides for the production of genetically distinct offspring (recombination). Deviations from this strict schedule of behaviour are, with few exceptions, eventually either lethal or sublethal since a precisely structured chromosome complement is an essential prerequisite for basic cell function during development.

Because meiosis is such a highly ordered process, the essential genes and proteins that control it can be reasonably anticipated to show considerable conservation throughout eukaryotes.

LIFE CYCLES AND SEXUAL CYCLES

All eukaryotes are constructed out of cells or their products. The simplest forms of life are single cells which are capable of performing all lifeactivities. More complex organisms are composed of collections of cells which individually perform only specific functions. Each eukaryotic cell has a defined and compartmentalized structure in which a specialized,internal and double membrane creates a distinctive environment, thenucleus. Within this organelle the major DNA component of the cell is associated with basic histone proteins to form a molecular complex referred to as chromatin. This chromatin is organized into a series ofsubunits, termed nucleosomes, each of which contains a combination of 200 base pairs (bp) of DNA together with nine histone molecules consisting of two each of H2A, 2B, 3 and 4 plus one HI molecule. The four pairs of histone molecules are bound together as a core which is closely associated with c. 140 bp of DNA, with the remaining 60 bp forming a linker unit to which HI is bound (reviewed in Matthews, 1981).Collectively the nucleosomes are organized around a protein scaffold to form a system of two or more individual threads, the chromosomes, which are highly diffused within the nuclear area.

The nuclear membrane also serves to separate the machinery of RNA transcription, carried out at the chromosome level, from the machinery of RNA translation, carried out at the ribosome level within the cell cytoplasm. Consequently, while the synthesis of proteins is a function of cell cytoplasm, the instructions for this synthesis emanate from the nucleus.

DIFFERENTIATION OF THE GERM LINE

In the late 1800s it was widely accepted that the germ cell line of animals was continuous from one generation to the next. Weismann(1892), however, proposed that the true continuity was provided not by the germ cells as such but by a nuclear substance handed down from parent germ cells to those of the offspring. He termed this substance germ plasm. In the early 1900s Hegner succeeded in tracing cytoplasmic granules from the pole plasm of insect oocytes of one generation to the germ cells of the next generation (Hegner, 1914). He referred to these granules as germ line determinants and argued that they were the visible expression of a specialized differentiation in the cytoplasm which controlled the production of the primordial germ cells.In Hegner's terms, therefore, the germ plasm was cytoplasmic in character and not nuclear, as Weismann had assumed. Time has confirmed the essential accuracy of Hegner's ideasand it is now clear that there is no difference in principle between the differentiation of the germ line and the differentiation of the various categories of somatic cells.Germ cells are simply cells specialized for meiosis and sexual heredity.

In most metazoans there is a clear division of labour between the cells responsible for sexual reproduction, the germ line cells, and the somatic lineages of the organism. The mode of origin of the germ cells is, however, varied and the differentiation between soma and germ line is not always abrupt.

TWO-TRACK HEREDITY

That differences exist between the two sexes within a given species in respect of sex chromosome behaviour has long been recognized. This is most obvious in XO, or ZO, systems. Here, genes carried by the X- or Z-chromosome pass unrecombined through the heterogametic sex because of the lack of a homologous partner. The same is also true for many, in some cases probably all, of the genes in the X- or Z-chromosomes of XY, or ZW, systems, respectively, since here too the X or Z is paired with a Y or W with which at best it has only partial homology (see Chapter 4C.6).

Differences of this kind are, of course, expected and easily explained. What is surprising, however, is that the autosomes may also behave differentially in the two sexes in respect of their meiotic behaviour.

Sex differences in recombination

In a majority of species, meiosis is without doubt chiasmate in both sexes. In most of these, no detailed analysis has been undertaken of either chiasma frequency or chiasma distribution. In a growing number of cases where both sexes within a given species have been analysed meiotically there are significant differences between them in respect of the occurrence,the frequency or else the distribution of chiasmata within the autosomal sets (Table 7.1). The most overt examples concern species where meiosis is achiasmate in one sex but chiasmate in the other. No less impressive are those cases, like the grasshopper Stethophyma grossum (Perry & Jones, 1974), where chiasmata are proximally localized in one sex and distally localized in the other.

The essential requirement of meiosis is the regular segregation of homologous chromosomes or chromosome regions. Only in this way is it possible to produce the genetically balanced gametes necessary to sustain development. There are three principal means of achieving such a segregation and these define three rather distinctive modes of meiosis: chiasmate meiosis, achiasmate meiosis and inverted meiosis.

CHIASMATE MEIOSIS

This is the most common category of meiosis and it occurs, and recurs, in a reasonably conserved form, in by far the vast majority of diploid eukaryotes. It thus has high evolutionary stability. Even so, the precise details may differ in diploids and polyploids and between diploids with a structurally homozygous set of chromosomes compared to diploids which are heterozygous for structural chromosome changes.

Meiosis in diploids

As in the mitotic cycle, the replication of the greater part of the genome occurs before the onset of meiosis though, as will become apparent later (see Chapter 4D.2.2), a small amount of replication also occurs during prophase of the first meiotic division.Each chromosome entering meiosis thus consists of two sister chromatids. Unlike the situation in mitosis, however, these are not readily resolvable by light microscopy and it is for this reason that the first substage of prophase-1 is named leptotene.Added to this, individual chromosomes are not distinguishable since they are long and tangled (Fig. 2.1a). The one exception involves the sex chromosomes of many male animals, and especially the single X-chromosome of male orthopterans which is compact and heteropycnotic.

MOVEMENT AND ORIENTATION

The controlled distribution of chromosomes during meiosis, as in mitosis, depends on the orderly behaviour of chromosomes on the division spindles. This is achieved principally by two series of coupled movements which lead to the development of first metaphase orientation.

Prophase movements

Chromosome movements in the first prophase nucleus are dominated by an interaction between the chromosomes and the centrosome or, in cases where there is no centrosome, by an equivalent spindle-forming centre. At the onset of meiosis the centromeres are often gathered close to that centre, in Rabl orientation. This is a passive form of orientation, indicating that little movement has occurred since the preceding pre-meiotic telophase. Bouquet formation, which commonly replaces Rabl orientation, involves an active movement of chromosome ends in relation to the centrosome or its equivalent.The centrosome itself separates into two daughter centres during first prophase and these take up positions on opposite sides of the nucleus. It is this movement which, in effect, first establishes bipolarity within the cell.

In some species the bouquet forms during leptotene. Here all chromosome ends become associated with the side of the nucleus close to the undivided centrosome with the remainder adopting a looped arrangement within the body of the nucleus. This involves an interaction between chromosome ends and the centrosome, with all ends moving along the inner surface of the nuclear membrane relative to the extranuclear polarizing centre represented by the centrosome or its equivalent.