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Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.

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An Introduction to Genetic Analysis. 7th edition.

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Translocations

When two nonhomologous chromosomes mutate by exchanging parts, the resulting chromosomal rearrangements are translocations. Here we consider reciprocal translocations, the most common type. A segment from one chromosome is exchanged with a segment from another nonhomologous one, so two translocation chromosomes are generated simultaneously.

The exchange of chromosome parts between nonhomologs establishes new linkage relations. These new linkages are revealed if the translocated chromosomes are homozygous and, as we shall see, even when they are heterozygous. Furthermore, translocations may drastically alter the size of a chromosome as well as the position of its centromere. For example,

Image ch17fu11.jpg

Here a large metacentric chromosome is shortened by half its length to an acrocentric one, and the small chromosome becomes a large one. Examples from natural populations are known in which chromosome numbers have been changed by translocation between acrocentric chromosomes and the subsequent loss of the resulting small chromosome elements (Figure 17-22).

Figure 17-22. Genome restructuring by translocations.

Figure 17-22

Genome restructuring by translocations. Short arrows indicate breakpoints in one homolog of each of two pairs of acrocentric chromosomes. The resulting fusion of the breaks yields one short and one long metacentric chromosome. If, as in plants, self-fertilization (more...)

In heterozygotes having two translocated chromosomes and their normal counterparts, there are important genetic and cytological effects. Again, the pairing affinities of homologous regions dictate a characteristic configuration for chromosomes synapsed in meiosis. Figure 17-23, which illustrates meiosis in a reciprocally translocated heterozygote, shows that the configuration is that of a cross.

Figure 17-23. The meiotic products resulting from the two most commonly encountered chromosome-segregation patterns in a reciprocal translocation heterozygote.

Figure 17-23

The meiotic products resulting from the two most commonly encountered chromosome-segregation patterns in a reciprocal translocation heterozygote.

Note that the configuration presented in Figure 17-23 lies on the equatorial plate of the cell at metaphase, with the spindle fibers perpendicular to the page. Thus, the centromeres would migrate upward above the page or downward under it. Homologous paired centromeres disjoin, whether or not a translocation is present. Because Mendel’s second law still applies to different paired centromeres, there are two common patterns of disjunction. The segregation of each of the structurally normal chromosomes with one of the translocated ones (T1 + N2 and T2 + N1) is called adjacent-1 segregation. Both meiotic products are duplicated and deficient for different regions. These products are inviable. On the other hand, the two normal chromosomes may segregate together, as do the reciprocal parts of the translocated ones, to produce N1 + N2 and T1 + T2 products. This type is called alternate segregation. These products are viable. Because the adjacent-1 and alternate segregation patterns are equally frequent. There is another event, called adjacent-2 segregation, in which homologous centromeres migrate to the same pole, but in general this event is rare.

As a result of the equality of adjacent and alternate segregations, half the gametes will be incapable of contributing to the next generation, a condition known as semisterility. The condition of semisterility, or “half sterility,” is an important diagnostic for translocation heterozygotes. However, semisterility is defined differently for plants and animals. In plants, the 50 percent unbalanced meiotic products from the adjacent-1 segregation generally abort at the gametic stage (Figure 17-24). In animals, however, the duplicationdeletion products are viable as gametes but lethal to the zygote.

Figure 17-24. Photomicrograph of normal and aborted pollen of a semisterile corn plant.

Figure 17-24

Photomicrograph of normal and aborted pollen of a semisterile corn plant. The clear pollen grains contain chromosomally unbalanced meiotic products of a reciprocal translocation heterozygote. The opaque pollen grains, which contain either the complete (more...)

Remember that heterozygotes for the other rearrangements such as deletions and inversions may show some reduction of fertility, but the precise 50 percent reduction in viable gametes or zygotes is usually a reliable diagnostic clue for a translocation.

Translocations are economically important. In agriculture, translocations in certain crop strains can reduce yields considerably owing to the number of unbalanced zygotes that form. On the other hand, translocations are potentially useful: it has been proposed that insect pests could be controlled by introducing translocations into their wild populations. According to the proposal, 50 percent of the offspring of crosses between insects carrying the translocation and wild types would die, and 10/16 of the progeny of crosses between translocation-bearing insects would die.

MESSAGE

Translocations, inversions, and deletions produce partial sterility by generating unbalanced meiotic products that may themselves die or that may cause zygotes to die.

Genetically, markers on nonhomologous chromosomes appear to be linked if these chromosomes take part in a translocation and the loci are close to the translocation breakpoint. Figure 17-25 shows a situation in which a translocation heterozygote has been established by crossing an a/a ; b/b individual with a translocation homozygote bearing the wild-type alleles. We shall assume that a and b are close to the translocation breakpoint. On testcrossing the heterozygote, the only viable progeny are those bearing the parental genotypes, so linkage is seen between loci that were originally on different chromosomes. In fact, if all four arms of the meiotic pairing structure are genetically marked, recombination studies should result in a cross-shaped linkage map. Apparent linkage of genes known to be on separate nonhomologous chromosomes is a genetic giveaway for the presence of a translocation.

Figure 17-25. When a translocated fragment carries a marker gene, this marker can show linkage to genes on the other chromosome because the recombinant genotypes (in this case, a+ ; b and a ; b+) tend to be in duplication–deletion gametes and do not survive.

Figure 17-25

When a translocated fragment carries a marker gene, this marker can show linkage to genes on the other chromosome because the recombinant genotypes (in this case, a+ ; b and a ; b+) tend to be in duplication–deletion gametes and do not survive. (more...)

MESSAGE

Reciprocal translocations are diagnosed genetically by semisterility and by the apparent linkage of genes known to be on separate chromosomes.

Translocations in humans are always carried in the heterozygous state. An example between chromosomes 5 and 11 is shown in Figure 17-26. The offspring of the person with this particular translocation had a duplication of 11q and a deletion of 5p. These children showed symptoms of both cri du chat syndrome, which is caused by the deletion of 5p, and the syndrome associated with the duplication of 11q. The reciprocal duplication-deficiency chromosome was not observed.

Figure 17-26. A human translocation heterozygote with reciprocal exchange of 5p and 11q (5p15; 11q23).

Figure 17-26

A human translocation heterozygote with reciprocal exchange of 5p and 11q (5p15; 11q23).

Down syndrome is a constellation of human disorders usually caused by the presence of an extra chromosome 21 that failed to segregate from its homolog at meiosis (see Chapter 18). This common type of Down syndrome (approximately 95% of all cases) is sporadic and shows no recurrence in the family. However, there is a less common type of Down syndrome caused by a special type of translocation called a Robertsonian translocation, and this form can recur in a family. A Robertsonian translocation is one that combines the long arms of two acrocentric chromosomes, as shown in Figure 17-27. Initially, a small chromosome composed of the two short arms also forms; however, this small chromosome is generally not present. The material in the short arms must be nonessential because their loss has no effect on phenotype. Translocation Down syndrome is caused by a Robertsonian fusion between chromosomes 21 and 14. The translocated chromosome passes down through the generations in unaffected carriers. However, meiotic segregation in the translocation carriers can result in offspring that carry three copies of most of chromosome 21, as shown in Figure 17-27, and these offspring have Down syndrome. The factors responsible for numerous other hereditary disorders have been traced to translocation heterozygosity in the parents.

Figure 17-27. How Down syndrome arises in the children of an unaffected carrier of a special type of translocation, called a Robertsonian translocation, in which the long arms of two acrocentric chromosomes have fused.

Figure 17-27

How Down syndrome arises in the children of an unaffected carrier of a special type of translocation, called a Robertsonian translocation, in which the long arms of two acrocentric chromosomes have fused. The specific Robertsonian translocation in translocation (more...)

Translocations also appear in cancer cells, and some examples are shown for solid tumors in Figure 17-28. In solid tumors, translocations are not as common as deletions. As with other rearrangements in cancer cells, the involvement with the cancer phenotype is generally not clear. However, in a later section we shall study an example in which the relocation of a specific proto-oncogene seems to be causally connected to cancer.

Figure 17-28. Translocations found consistently in several different types of solid tumors in humans.

Figure 17-28

Translocations found consistently in several different types of solid tumors in humans. Band numbers indicate breakpoints. (After Jorge Yunis.)

As is true for other rearrangements, the translocation breakpoints can sometimes disrupt an essential gene, and the gene is thereby inactivated and behaves as a point mutation. Molecular geneticists can use this effect to find the exact location of a human gene and can then proceed to isolate the gene. For example, information from translocations helped in the isolation of the gene for the X-linked recessive disease Duchenne muscular dystrophy. Some rare female cases of Duchenne muscular dystrophy were also heterozygous for translocations between the X chromosome and a variety of different autosomes. The X chromosome breakpoint was always in the band Xp21, so the gene for muscular dystrophy, already known to be X-linked, was evidently in this band and had been disrupted by the break. The hunt for the gene could begin by focusing on that area. In passing, note that the expression of the mutant phenotype in a female must have been because the normal X chromosome was inactivated (Figure 17-29).

Figure 17-29. Diagram of the chromosomes of a woman with Duchenne muscular dystrophy and heterozygous for a reciprocal translocation between the X chromosome and chromosome 21.

Figure 17-29

Diagram of the chromosomes of a woman with Duchenne muscular dystrophy and heterozygous for a reciprocal translocation between the X chromosome and chromosome 21. The translocation breakpoint disrupted one DMD+ allele, rendering it nonfunctional, and (more...)

One specific autosomal breakpoint proved to be useful in providing a molecular “tag” for the Duchenne gene. The particular breakpoint that advanced the research was in the ribosomal RNA locus on chromosome 21. (Do not confuse X chromosome band 21 with chromosome 21.) A DNA probe was already available for the ribosomal locus. It was reasoned that, in the X–21 translocation, the Duchenne gene must be disrupted and attached next to the ribosomal RNA gene. The geneticists therefore used the ribosomal probe to isolate a DNA segment that had part of the Duchenne gene on it.

Translocations were also used to isolate the human gene for neurofibromatosis. Once again, the critical chromosomal material came from people who not only had the disease, but also carried chromosomal translocations. The translocations all had one of their breakpoints in chromosome 17, in a band close to the centromere. Hence it appeared that this band must be the locus of the neurofibromatosis gene, which had been disrupted by the translocation breakage. Subsequent analysis showed that the chromosome 17 breakpoints were not identical, and their positions helped to map the region occupied by the neurofibromatosis gene. Isolation of DNA fragments from this region eventually led to the recovery of the gene itself.

Use of translocations in producing duplications and deletions

Geneticists regularly need to make specific duplications or deletions to answer specific experimental questions. We have seen that they use inversions to do so, and now we shall see how translocations also can be used for the same purpose. Let’s take Drosophila as an example. For reasons that are still unclear, the densely staining chromosomal regions near the centromere—regions called heterochromatin —are physically extensive but contain few genes. In fact, for a long time, heterochromatin was considered useless and inert material. In any case, for our purposes, Drosophila can tolerate a loss or an excess of heterochromatin with little effect on viability or fertility.

Now let’s select two different reciprocal translocations of the same two chromosomes. Each translocation has a breakpoint somewhere in heterochromatin, and each has another breakpoint in euchromatin (nonheterochromatin) on opposite sides of the region we want to duplicate or delete (Figure 17-30). It can be seen that, if we have a large collection of translocations having one heterochromatic break and euchromatic breaks at many different sites, then duplications and deletions for many parts of the genome can be produced at will for a variety of experimental purposes. More generally, if one breakpoint of a translocation is near a dispensable tip, then duplication or deletion of this tip can be ignored, and the translocation can be used as a way of generating duplications or deficiencies for the other translocated segment.

Figure 17-30. Using translocations with one breakpoint in heterochromatin to produce a duplication and a deletion.

Figure 17-30

Using translocations with one breakpoint in heterochromatin to produce a duplication and a deletion. If the upper product of translocation 1 is combined with the upper product of translocation 2 by means of an appropriate mating, a deletion of b results. (more...)

Position-effect variegation

In preceding chapters, we considered several mechanisms of generating variegation in the somatic cells of a multicellular organism. These mechanisms were somatic segregation, somatic crossover, and somatic mutation. Another cause of variegation is associated with translocations and is called position-effect variegation.

The locus for white eye color in Drosophila is near the tip of the X chromosome. Consider a translocation in which the tip of an X chromosome carrying w+ is relocated next to the heterochromatic region of, say, chromosome 4. Position-effect variegation is observed in flies that are heterozygotes for such a translocation and that have the normal X chromosome carrying the recessive allele w. The expected eye phenotype is red because the wild-type allele is dominant to w. However, in such cases, the observed phenotype is a variegated mixture of red and white eye facets. How can we explain the white areas? We could suppose that, when the chromosomes broke and rejoined in the translocation, the w+ allele was somehow changed to a state that made it more mutable in somatic cells; so the white eye tissue is due to cells in which w+ has mutated to w.

In 1972, Burke Judd tested this hypothesis by recombining the w+ allele out of the translocation and onto a normal X chromosome and by recombining a w allele from the normal X chromosome onto the translocation (Figure 17-31). Judd found that, when the w+ allele on the translocation was crossed onto a normal X chromosome and w was then inserted into the translocation, the eye color was red; so obviously the w+ allele was not defective. When he crossed the w+ allele back onto the translocation, the phenotype was again variegated. Thus, we can conclude that, for some reason, the w+ allele in the translocation is not expressed in some cells, thereby allowing the expression of w. This kind of variegation is called position-effect variegation because the unstable expression of a gene is due to its position in a rearrangement.

Figure 17-31. Position-effect variegation.

Figure 17-31

Position-effect variegation. (a) The translocation of w+ to a position next to heterochromatin causes the w+ function to fail in some cells, producing position-effect variegation. (b) A Drosophila eye showing the position-effect variegation. (Part b from (more...)

Such position effects can affect the genes that cause cancer. For example, most cases of Burkitt’s lymphoma, a cancer of certain human antibody-producing cells called B cells, are caused by the relocation of a proto-oncogene to a position next to a region that normally enhances the production of antibodies (Figure 17-32). The oncogene is then activated, resulting in cancer.

Figure 17-32. Reciprocal translocations between chromosomes 8 and 14 cause most cases of Burkitt’s lymphoma.

Figure 17-32

Reciprocal translocations between chromosomes 8 and 14 cause most cases of Burkitt’s lymphoma. An oncogene on the tip of chromosome 8 becomes relocated next to an antibody gene enhancer region on chromosome 14.

MESSAGE

The expression of a gene can be affected by its position in the genome.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK21947

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