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Modern Genetic Analysis Chapter 8. Chromosome Mutations
Changes in Chromosome Number

In genetics as a whole there are few topics that impinge on human affairs quite so directly as this one. Foremost is the fact that a large proportion of genetically determined ill health in humans is caused by abnormal chromosome numbers. Additionally, manipulation of chromosome number is routinely used by breeders to improve agriculturally important species.

Changes in chromosome number are of two basic types: changes in whole chromosome sets (resulting in a condition of aberrant euploidy) and changes in parts of chromosome sets (resulting in aneuploidy). These topics are covered next.

Aberrant Euploidy

Organisms with multiples of the basic chromosome set are called euploid. We learned in earlier chapters that familiar eukaryotes such as plants, animals, and fungi carry in their cells either one chromosome set (haploid) or two sets (diploid). In these species, the haploid and diploid states are both cases of normal euploidy. Organisms that have more or less than the normal number of sets are aberrant euploids. Polyploids are individual organisms in which there are more than two chromosome sets. They can be represented by 3n (triploid), 4n (tetraploid), 5n (pentaploid), 6n (hexaploid), and so forth. (Recall that the number of sets is called the ploidy or ploidy level.) In essentially diploid taxa, an individual organism with only one chromosome set (n) is called a monoploid to distinguish it from species in which all individuals are normally haploid (also n). Examples of these conditions are shown in Table 8-1.

Monoploids.

Male bees, wasps, and ants are monoploid. In the normal life cycles of these insects, males develop parthenogenetically from unfertilized eggs. However, in most species, monoploid individuals are abnormal, arising in natural populations as rare aberrations. The germ cells of a monoploid cannot proceed through meiosis normally, because the chromosomes have no pairing partners. Thus, monoploids are characteristically sterile. (Male bees, wasps, and ants bypass meiosis; in these types, gametes are produced by mitosis.)

Polyploids.

In aberrant euploids, there is often a correlation between the number of copies of the chromosome set and the size of the organism and its component parts. For example, typically a tetraploid organism looks very similar to its diploid counterpart in its proportions, except that the tetraploid is bigger as a whole and in its component parts. The higher the ploidy level, the larger the size (Figure 8-1).

In the realm of polyploids, we must distinguish between autopolyploids, which are composed of multiple sets orignating from within one species, and allo-polyploids, which are composed of sets from two or more different species. Allopolyploids form only between closely related species; however, the different chromosome sets are only partly homologous (homeologous), not fully homologous, as they are in autopolyploids.

Autopolyploids.

Triploids are usually autopolyploids. They arise spontaneously in nature, and they can be constructed by geneticists from the cross of a 4n (tetraploid) and a 2n (diploid). The 2n and the n gametes unite to form a 3n triploid. Triploids are characteristically sterile. The problem, like that of monoploids, lies in pairing at meiosis. The molecular mechanisms for synapsis or true pairing dictate that pairing can take place only between two of the three chromosomes of each type (Figure 8-2). Paired homologs (bivalents) segregate to opposite poles, but the unpaired homologs (univalents) pass to either pole randomly. This happens for every chromosome threesome, and the result is meiotic products with chromosome numbers intermediate between the haploid and diploid number; such genomes are termed aneuploid. Aneuploid gametes generally do not give rise to viable offspring. There are a couple of reasons for this. First of all, in plants, pollen cells are very sensitive to aneuploidy, and aneuploid pollen grains will generally be inviable. Second, the zygotes that do result from fertilization by an aneuploid gamete will themselves be aneuploid, and typically these zygotes also are inviable. We will examine the underlying reason for the inviability of aneuploids when we consider gene balance later in the chapter.

MESSAGE
Polyploids with odd numbers of chromosome sets are sterile or highly infertile, because their gametes and offspring are aneuploid.

Autotetraploids arise by the doubling of a 2n complement to 4n. This doubling can occur spontaneously, but it can also be induced artificially through the application of chemical agents that disrupt microtubule polymerization. This process normally takes place in the formation of spindle fibers in cells undergoing division. A commonly used agent is colchicine, an alkaloid drug extracted from the autumn crocus. In colchicine-treated cells, an S phase of the cell cycle occurs, but not chromosome segregation or cell division. As the treated cell enters telophase, a nuclear membrane forms around the entire doubled set of chromosomes (Figure 8-3). Thus, treating diploid (2n) cells for one cell cycle leads to tetraploids (4n), with exactly four copies of each type of chromosome. Treatment for an additional cell cycle produces octaploids (8n), and so forth. This method works in both plant and animal cells, but generally plants seem to be much more tolerant of polyploidy. Note that all alleles in the genotype are doubled. Therefore, if a diploid cell of genotype A /a ;B /b is doubled, the resulting autotetraploid will be of genotype A /A /a /a ;B /B /b /b.

Because 4 is an even number, autotetraploids can have a regular meiosis, although this is by no means always the case. The crucial factor is how the four chromosomes of each set pair and segregate. There are several possibilities, as shown in Figure 8-4. In cases where pairing is by bivalents or quadrivalents, the normal meiotic segregation processes result in diploid gametes, which upon fusion regenerate the tetraploid state.

MESSAGE
Polyploid plants are often larger and have larger component parts than their diploid relatives.

Allopolyploids.

An allopolyploid is a plant that is a hybrid of two or more species, with two or more copies of each of the input genomes. The prototypic allopolyploid was an allotetraploid synthesized by G. Karpechenko in 1928. He wanted to make a fertile hybrid that would have the leaves of the cabbage (Brassica) and the roots of the radish (Raphanus), because they were the agriculturally important parts of each plant. Each of these species has 18 chromosomes and they are related closely enough to allow intercrossing. A viable hybrid progeny individual was produced from seed. However, this hybrid was functionally sterile because the 9 chromosomes from the cabbage parent were different enough from the radish chromosomes that pairs did not synapse and segregate normally:

Eventually, one part of the hybrid plant produced some seeds. On planting, these seeds produced fertile individuals with 36 chromosomes. All of these individuals were allopolyploids. They had apparently been derived from spontaneous, accidental chromosome doubling to 2n1+2n2 in one region of the sterile hybrid, presumably in tissue that eventually became germinal and underwent meiosis. Thus, in 2n1+2n2 tissue, there is a pairing partner for each chromosome, and balanced gametes of the type n1+ n2 are produced. These gametes fuse to give 2n1+2n2 allopolyploid progeny, which also are fertile. This kind of allopolyploid is sometimes called an amphidiploid, which means doubled diploid (Figure 8-5). (Unfortunately for Karpechenko, his amphidiploid had the roots of a cabbage and the leaves of a radish.)

When the allopolyploid was crossed with either parental species, sterile offspring resulted. The offspring of the cross with radish were 2n1+2n2, constituted from an n1+n2 gamete from the allopolyploid and an n1 gamete from the radish. The n2 chromosomes had no pairing partners, so sterility resulted. Consequently, Karpechenko had effectively created a new species, with no possibility of gene exchange with its parents. He called his new type Raphanobrassica.

Treating a sterile hybrid with colchicine greatly increases the chances of doubling the chromosome sets. Therefore amphidiploids can be synthesized routinely.

In nature, allopolyploidy seems to have been a major force in the speciation of plants. There are many different examples. One particularly satisfying one is shown by the genus Brassica, as illustrated in Figure 8-6. Here three different parent species have hybridized in all possible pair combinations to form new amphidiploid species.

A particularly interesting natural allopolyploid is bread wheat, Triticum aestivum(6n=42). By studying various wild relatives, geneticists have reconstructed a probable evolutionary history of bread wheat. Figure 8-7 shows that bread wheat is composed of two sets of each of three ancestral genomes. At meiosis, pairing is always between homologs within an ancestral genome. Hence, in a bread wheat meiosis, there are always 21 bivalents.

MESSAGE
Allopolyploid plants can be synthesized by crossing related species and doubling the chromosomes of the hybrid.

Agricultural applications.

Variation in chromosome number is used in several commerical applications. Some examples follow.

Monoploids.

Diploidy is an inherent nuisance when breeders want to induce and select new gene mutations that are favorable and to find new combinations of favorable alleles at different loci. New recessive mutations cannot be detected unless they are homozygous. Furthermore, favorable allelic combinations in heterozygotes can be broken up by meiosis. Monoploids provide a way around some of these problems. In some plant species, monoploids can be artificially derived from the products of meiosis in the plant's anthers. A cell destined to become a pollen grain can instead be induced by cold treatment to grow into an embryoid, a small dividing mass of monoploid cells. The embryoid can be grown on agar to form a monoploid plantlet, which can then be potted in soil and allowed to mature (Figure 8-8).

Plant monoploids can be exploited in several ways. In one approach, they are first examined for favorable allelic combinations that have arisen from heterozygosity either already present in the diploid parent or induced in the parent by mutagens. Hence from a parent that is A / a ; B / b might come a favorable monoploid combination a ; b. The monoploid can then be subjected to chromosome doubling, through application of microtubule inhibitors such as colchicine, to produce cells that are homozygous diploid, a / a ; b / b, and capable of normal reproduction.

Another approach is to treat monoploid cells basically as a population of haploid organisms in a mutagenesis-and-selection procedure. A population of monoploid cells is isolated, their walls are removed by enzymatic treatment, and they are treated with mutagen. They are then plated on a medium that selects for some desirable phenotype. This approach has been used to select for resistance to toxic compounds produced by one of the plant's parasites, as well as to select for resistance to herbicides being used by farmers to kill weeds. Resistant plantlets eventually grow into haploid plants, which can then be doubled (by using colchicine) into a pure-breeding, diploid, resistant type.

These powerful techniques can circumvent the normally slow process of meiosis-based plant breeding. They have been successfully applied to several important crop plants, such as soybeans and tobacco.

MESSAGE
To create new plant lines, geneticists produce monoploids with favorable genotypes and then double the chromosomes to form fertile, homozygous diploids.

Autotriploids.

The bananas that are widely available commercially are sterile triploids with 11 chromosomes in each set The most obvious expression of the sterility of bananas is that there are no seeds in the fruit that we eat. Another example of the commercial exploitation of triploidy in plants is the production of triploid watermelons, which also are seedless, a phenotype favored by some for its convenience.

Autotetraploids.

Many autotetraploid plants have been developed as commercial crops because of their increased size (Figure 8-9). Large fruits and flowers are particularly favored.

Allopolyploids.

Allopolyploids can be used in plant breeding to combine the useful features of parental species into one type. Only one synthetic amphidiploid has ever been widely used commerciallyTriticale, an amphidiploid between wheat (Triticum, and rye (Secale, Hence, for Triticale, This novel plant combines the high yields of wheat with the ruggedness of rye.

Polyploid animals.

Polyploidy is more common in plants than in animals, but there are cases of naturally occurring polyploid animals. Examples are found in flatworms, leeches, and brine shrimps. In these animals, reproduction is by parthenogenesis, the development of a special type of unfertilized egg into an embryo, without the need for fertilization. Triploid and tetraploid Drosophila have been synthesized experimentally. However, examples are not limited to these so-called lower forms. Polyploid amphibians and reptiles are surprisingly common. They have several modes of reproduction. Polyploid male and female frogs and toads participate in a sexual cycle, whereas polyploid salamanders and lizards are parthenogenetic. The Salmonidae family of fishes (including salmon and trout) is a familiar example of a group that appears to have originated through ancestral polyploidy.

The sterility of triploids has been commercially exploited in animals as well as plants. Triploid oysters have been developed, and such oysters have a commercial advantage over their diploid relatives. The diploids go through a spawning season, when they are unpalatable, but triploids, because of their sterility, do not spawn and are palatable all year round.

Aneuploidy

Aneuploidy is the second major category of chromosome aberrations in which chromosome number is abnormal. An aneuploid is a individual organism whose chromosome number differs from the wild type by part of a chromosome set. Generally, the aneuploid chromosome set differs from wild type by only one chromosome or by a small number of chromosomes. An aneuploid can have a chromosome number either greater or smaller than that of the wild type. Aneuploid nomenclature (see Table 8-1) is based on the number of copies of the specific chromosome in the aneuploid state. For example, the aneuploid condition 2n1 is called monosomic (meaning "one chromosome") because there is only one copy of some specific chromosome present instead of the usual two found in its diploid progenitor. For autosomes in diploid organisms, the aneuploid 2n+1 is called trisomic,2n1 is monosomic, and 2n2 (where the 2 represents homologs) is nullisomic. In haploids, n+1 is di-somic. Special symbolism has to be used to describe sex-chromosome aneuploids, because we are dealing with two different chromosomes (X and Y) and the homogametic and heterogametic sexes have different sex-chromosome compositions even in euploid individuals. The symbolism merely lists the copies of each sex chromosome, such as XXY, XYY, XXX, or XO (the "O" stands for absence of a chromosome and is included to show that the symbol is not a typographical error).

Nondisjunction.

The cause of most aneuploid conditions is nondisjunction in the course of meiosis or mitosis. Disjunction is another word for the normal segregation of homologous chromosomes or chromatids to opposite poles at meiotic or mitotic divisions. Nondisjunction is a failure of this process, and two chromosomes or chromatids go to one pole and none to the other. In meiotic nondisjunction, the chromosomes may fail to disjoin at either the first or the second division (Figure 8-10). Either way, n+1 and n1 gametes are produced. If an n1 gamete is fertilized by an n gamete, a monosomic (2n1 zygote is produced. The fusion of an n+1 and an n gamete yields a trisomic 2n+1

MESSAGE
Aneuploid organisms are produced mainly by nondisjunction at meiosis.

Nondisjunction occurs spontaneously; it is another example of a chance failure of a basic cellular process. The precise molecular processes that fail are not known, but, in experimental systems, the frequency of nondisjunction can be increased by interference with microtubule action. It appears that disjunction is more likely to go awry in meiosis I. This likelihood may not be surprising, because normal anaphase I disjunction requires that proper homologous associations be maintained during prophase I and metaphase I. In contrast, proper disjunction at anaphase II or at mitosis requires that the centromere splits properly but does not require nearly as elaborate a process during prophase and metaphase.

Meiosis I nondisjunction can be viewed as the failure to form or maintain a tetrad until anaphase I. Crossovers are implicit in this process normally. In most organisms, the amount of crossing-over is sufficient to ensure that all tetrads will have at least one exchange per meiosis. In Drosophila, many of the nondisjunctional chromosomes in newly arising disomic gametes are nonrecombinant, with one nondisjunctional homolog carrying the markers of one input chromosome and the other homolog carrying the markers of the other chromosome. Similar observations have been made in human trisomies. In addition, in several different experimental organisms, mutations that interfere with recombination have the effect of massively increasing the frequency of meiosis I nondisjunction. This effect points to an important role of crossing-over in maintaining chromosomal associations in the tetrad; in the absence of these associations, chromosomes are vulnerable to anaphase I nondisjunction.

MESSAGE
Nondisjunction at meiosis I is more frequent than that at meiosis II, indicating the necessity of crossovers in the maintenance of the intact tetrad until anaphase I.

Monosomics (2 - 1).

Monosomic chromosome complements are generally deleterious. Monosomics for all human autosomes die in utero.

In humans, a sex-chromosome monosomic complement of 44 +1 X produces a phenotype known as Turner syndrome (XO). Affected people have a characteristic phenotype: they are sterile females, short in stature, and often have a web of skin extending between the neck and shoulders (Figure 8-11). Although their intelligence is near normal, some of their specific cognitive functions are defective. About 1 in 5000 female births show Turner syndrome.

Geneticists have used viable plant monosomics to identify the chromosomes that carry the loci of newly found recessive mutant alleles. For example, a geneticist may obtain different monosomic lines, each of which lacks a different chromosome. Homozygotes for the new mutant allele are crossed with each monosomic line, and the progeny of each cross are inspected. The mutant phenotype appears only in the progeny of the parent monosomic for the locus-bearing chromosome and thus identifies it. The test works because half the gametes of a fertile monosomic will be n1 and, when such an n1 gamete is fertilized by a gamete bearing a new mutation on the homologous chromosome, the mutation will be hemizygous and hence will be expressed.

Trisomics (2n + 1).

The trisomic condition also is one of chromosomal imbalance and can result in abnormality or death. However, there are many examples of viable trisomics. Furthermore, trisomics can be fertile. When cells from some trisomic organisms are observed under the microscope at the time of meiotic chromosome pairing, the trisomic chromosomes are seen to form an associated group of three, whereas the other chromosomes form regular pairs. What genetic ratios might we expect for genes on the trisomic chromosome? Let us consider a gene A that is close to the centromere on that chromosome, and let us assume that the genotype is A / a / a. Furthermore, if we postulate that the two paired chromosomes pass to opposite poles and that the other chromosome passes randomly to either pole, then we can predict the three equally frequent segregations shown in Figure 8-12. These segregations result in an overall gametic ratio of 1A:2A / a:2a:1a / a. This ratio and the one corresponding to a trisomic of genotype A / A / a are observed in practice. If a trisomic tester set is available then a new mutation can be located to a chromosome by determining which of the testers gives the special ratio.

There are several examples of viable human trisomics. Several sex-chromosome trisomics can live to adulthood. (In considering human sex-chromosome trisomies, recall that mammalian sex is determined by the presence or absence of the Y chromosome.) Each of these types is found in the frequency range of about 1 in 1000 births of the relevant sex. The combination XXY results in Klinefelter syndrome, males with lanky builds who are mentally retarded and sterile (Figure 8-13). Another abnormal combination, XYY, has a controversial history. Attempts have been made to link the XYY condition with a predisposition toward violence. This linkage is still hotly debated, although it is now clear that an XYY condition in no way guarantees such behavior. The XYY males are usually fertile. Their meioses are of the XY type; the extra Y is not transmitted, and their gametes contain either X or Y, never YY or XY. Triplo-X trisomies (XXX) are phenotypically normal and fertile females; meiosis is of the XX type, producing eggs bearing only one X.

Of human trisomies, the most familiar type is Down syndrome (Figure 8-14), occurring at a frequency of about 0.15 percent of all live births. Most cases of Down syndrome are trisomy 21 caused by nondisjunction of chromosome 21 in a parent who is chromosomally normal. In this sporadic type of Down syndrome, there is no family history of aneuploidy. Some rare types of Down syndrome arise from translocations (a rearrangement discussed later in the chapter), and, in these cases, there is recurrence in the pedigree because of the transmission of the translocation.

The combined phenotypes that make up Down syndrome include mental retardation (with an IQ in the 20-to-50 range), broad flat face, eyes with an epicanthic fold, short stature, short hands with a crease across the middle, and a large wrinkled tongue. Females may be fertile and may produce normal or trisomic progeny, but males do not reproduce. Mean life expectancy is about 17 years, and only 8 percent survive past age 40.

The only other human autosomal trisomics to survive to birth are trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome). Both show severe physical and mental abnormalities. The phenotypic syndrome of trisomy 13 includes a harelip, a small malformed head, "rockerbottom" feet, and a mean life expectancy of 130 days. That of trisomy 18 includes "faunlike" ears, a small jaw, a narrow pelvis, and rockerbottom feet; almost all babies with trisomy 18 die within the first few weeks after birth. All other trisomies die in utero.

Down syndrome is related to maternal age; older mothers run a greatly elevated risk of having Down-syndrome children (Figure 8-15). For this reason, fetal chromosome analysis (by amniocentesis or by chorionic villus sampling) is now recommended for older mothers. A less-pronounced paternal-age effect also has been demonstrated.

Even though the maternal-age effect has been known for many years, the cause of it is still not known. Nonetheless, there are some interesting biological correlations. It is possible that one aspect of the strong maternal-age effect on nondisjunction is an age-dependent decrease in the probability of keeping the chromosomal tetrad together during prophase I of meiosis. Meiotic arrest of oocytes (female meiocytes) in late prophase I is a common phenomenon in many animals. In female humans, all oocytes are arrested at diplotene before birth. Meiosis continues only upon menstruation, which means that proper chromosome associations in the tetrad must be maintained for decades. If we speculate that, by accident over time, these associations have an increasing probability of breaking down, we can envision a mechanism contributing to increased maternal nondisjunction with age. Consistent with this speculation, most nondisjunction related to the maternal-age effect is due to nondisjunction at anaphase I, not anaphase II.

The concept of gene balance.

In considering aberrant euploidy, we noted that an increase in the number of full chromosome sets correlates with increased organism size but that the general shape and proportions of the organism remain very much the same. In contrast, autosomal aneuploidy typically alters the shape and proportions in characteristic ways. Plants tend to be somewhat more tolerant of aneuploidy than are animals. Studies in the jimsonweed, Datura stramonium, provide a classical example of the effects of aneuploidy and polyploidy. In the jimsonweed, the haploid chromosome number is 12. As is expected, the polyploid jimsonweed is proportioned like the normal diploids, only larger. In contrast, each of the 12 possible trisomics is disproportionate, but in ways different from one another, as exemplified by changes in the shape of the seed capsule (see Figure 2-11). The 12 different trisomies lead to 12 different and characteristic shape changes in the capsule. Indeed, these and other characteristics of the individual trisomies are so reliable that the phenotypic syndrome can be used to identify plants carrying a particular trisomy. Similarly, the 12 monosomies are themselves different from one another and from each of the trisomies. In general, a monosomic for a particular chromosome is more severely abnormal than is the corresponding trisomic.

We see similar trends in aneuploids of animals as well. In the fruit fly, Drosophila, the only autosomal aneuploids that survive to adulthood are trisomics and monosomics for chromosome 4, which is the smallest Drosophila chromosome, representing from only about 1 to 2 percent of the genome. Trisomics for chromosome 4 are only very mildly affected and are much less severely abnormal than are monosomic-4 flys. In humans, no autosomal monosomic survives to birth, whereas three autosomal trisomies survive. As is true with aneuploid jimsonweed, the three surviving trisomies produce unique phenotypic syndromes, owing to the special effects of altered dosages of each of these chromosomes.

Why are aneuploids so much more abnormal than polyploids? Why do aneuploids for different chromosomes each have their own characteristic phenotypic effects? And why are monosomics typically more severely affected than the corresponding trisomics? The answers seem certain to be a matter of gene balance. In a euploid, the ratio of genes on any one chromosome to genes on other chromosomes is 1:1 (that is, 100 percent), regardless of whether we are considering a monoploid, diploid, triploid, or tetraploid. In contrast, in an aneuploid, the ratio of genes on the aneuploid chromosome to genes on the other chromosomes differs from wild type by 50 percent (50 percent for monosomics; 150 percent for trisomics). Thus, we can see that the aneuploid genes are out of balance. How does this help us to answer the questions raised?

A key fact is that, in general, the amount of transcript produced by a gene is directly proportional to the number of copies of that gene in a cell. That is, for a given gene, the rate of transcription is directly related to the number of DNA templates. Thus, the more copies of that gene, the more transcripts are produced. Because of this gene-dosage relation, segmental aneuploids, in which pieces of individual chromosomes are trisomic or monosomic, have proved to be very useful in locating the positions of genes encoding various cellular enzymes. The approach is to look for segments of the genome that change the amount of an enzyme proportionally to the dosage of that genomic segment. This approach has been exploited extensively in Drosophila, where there has been about a 90 percent success rate in identifying enzyme-coding genes by this method.

We can infer that normal physiology in a cell depends upon the proper ratio of gene products in the euploid cell. This is the normal gene balance. If the relative dosage of certain genes changesfor example, owing to the removal of one of the two copies of a chromosome or a segment thereofphysiological imbalances in cellular pathways can arise.

In some cases, the imbalances of aneuploidy are due to a few "major" genes. Such genes can be viewed as haplo-abnormal or triplo-abnormal or both and contribute significantly to the aneuploid phenotypic syndrome. For example, the study of persons trisomic for only part of human chromosome 21 has made it possible to localize determinants specific to Down syndrome to various regions of chromosome 21, hinting that some aspects of the phenotype might be due to trisomy for single major genes in these chromosomal regions. In addition to these major gene effects, other aspects of aneuploid syndromes are likely to be due to cumulative effects of aneuploidy for numerous genes whose products are all out of balance. Undoubtedly, the entire aneuploid phenotype is a synthesis of the imbalance effects of a few major genes, together with a cumulative imbalance for many minor genes.

However, the gene-balance idea does not tell us why having too few gene products (monosomy) is much worse for an organism than having too many gene products (trisomy). Along the same lines, in well-studied organisms, there are many more haploabnormal genes than triplo-abnormal ones. An important factor in explaining the abnormality of monosomics is that any deleterious recessives present on the autosome will be automatically expressed. This same effect is relevant to deletion mutations (see the next section).

How do we apply the idea of gene balance to cases of sex-chromosome aneuploidy? Gene balance holds for sex chromosomes as well, but we also have to take into account the special properties of the sex chromosomes. In organisms with X-Y sex determination, the Y chromosome seems to be a degenerate X chromosome in which there are very few functional genes other than some involved in sex determination itself or in sperm production or both. On the other hand, the X chromosome contains many genes involved in basic cellular processes ("housekeeping genes") that just happen to reside on the chromosome that eventually evolved into the X chromosome. X-Y sex-determination mechanisms have probably evolved independently from 10 to 20 times in different taxonomic groups. Thus, there appears to be one sexdetermination mechanism for all mammals, but it is completely different from the mechanism governing X-Y sex determination in fruit flies.

In a sense, X chromosomes are naturally aneuploid. Females have two of them, whereas males have only one. Nonetheless, it has been found that the X chromosome's housekeeping genes are expressed to equal extents per cell in both females and males. How is this accomplished? The answer depends on the organism. In fruit flies, the male's X chromosome appears to be hyperactivated, allowing it to be transcribed at twice the rate as either X chromosome in the female. In mammals, in contrast, the rule is that no matter how many X chromosomes are present, there is only one transcriptionally active X chromosome in each somatic cell. This dosage compensation is achieved by random X-chromosome inactivation. (A person with two or more X chromosomes is a mosaic of two cell types in which one or the other X is active.) Thus, XY and XX individuals produce the same amount of X-chromosome housekeeping gene products. X-chromosome inactivation also explains why triplo-X humans are phenotypically normal, inasmuch as only one of the three X chromosomes is transcriptionally active in a given cell. Similarly, an XXY male is only moderately affected because only one of his two X chromosomes is active in each cell.

Why are XXY individuals abnormal at all, given that triplo-X individuals are phenotypically normal? It turns out that a small part of the X chromosome near one telomerethe pseudoautosomal regionis not inactivated by the mechanism of dosage compensation. In XXY males, this region is active at twice the level of the pseudoautosomal region in XY males. This level appears to have the consequence of slightly feminizing the phenotype of XXY males, although exactly which pseudoautosomal genes contribute to this effect is currently unknown. In XXX females, on the other hand, the pseudoautosomal region is active at only 1.5 times the level that it is in XX females. This lower level of functional aneuploidy in XXX than that in XXY, plus the fact that the pseudoautosomal genes appear to lead to feminization, may explain the feminized phenotype of XXY individuals. The severity of XO, Turner syndrome, can be interpreted as being due to the considerable deleterious effects of monosomy for the pseudoautosomal region of the X. As is usually observed for aneuploids, monosomy for this segment of the X chromosome produces a more abnormal phenotype than does having an extra copy of the same region (triplo-X females or XXY males).

Human polyploid zygotes do arise through various kinds of mistakes in cell division. Most die in utero. Occasionally, triploid babies are born, but none survive. This fact seems to violate the principle discussed earlier in this sectionnamely, that polyploids are more normal than aneuploids. The explanation for this violation seems to lie with X-chromosome dosage compensation. Part of the rule for the single active X seems to be that there is one active X for every two copies of the autosomal chromosome complement. Thus, some cells in triploid mammals are found to have one active X, whereas others have two. Neither situation is in balance with autosomal genes. Presumably this functional underactivation of housekeeping genes (in 3n cells with one active X) or functional overactivation (in 3n cells with two active X's) leads to substantial functional aneuploidy and the inviability of triploid individuals.

MESSAGE
Aneuploidy is nearly always deleterious because of genetic imbalancethe ratio of genes is different from that in euploids and this difference interferes with the normal function of the genome.

© 1999 by W. H. Freeman and Company. All rights reserved.