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Chromosomal Aberrations and Human Disorders

In addition to mutations that alter the information content of a single gene, chromosomes may be subjected to more extensive alterations that occur most commonly during cell division. Pieces of a chromosome may be lost or segments may be exchanged between different chromosomes. Because these chromosomal aberrations follow chromosomal breakage, their incidence is increased by exposure to agents that damage DNA, such as viral infection, X‐rays, or reactive chemicals. In addition, the chromosomes of some individuals contain “fragile” sites that are particularly susceptible to breakage. Persons with certain rare inherited conditions, such as Bloom syndrome, Fanconi anemia, and ataxia‐telangiectasia, have unstable chromosomes that exhibit a greatly increased tendency toward breakage.

The consequences of a chromosomal aberration depend on the genes that are affected and the type of cell in which it occurs. If the aberration occurs in a somatic (nonreproductive) cell, the consequences are generally minimal because only a few cells of the body are usually affected. On rare occasions, however, a somatic cell carrying an aberration may be trans- formed into a malignant cell, which can grow into a cancerous tumor. Chromosomal aberrations that occur during meiosis— particularly as a result of abnormal crossing over—can be trans- mitted to the next generation. When an aberrant chromosome is inherited through a gamete, all cells of the embryo will have the aberration, which generally proves lethal during development. There are several types of chromosomal aberrations, including the following:

● Inversions. Sometimes a chromosome breaks in two places, and the segment between the breaks becomes resealed into the chromosome in reverse orientation. This aberration is called an inversion. More than 1 percent of humans carry an inversion that can be detected during chromosome karyotyp- ing (see Figure 10.30b). A chromosome bearing an inversion usually contains all the genes of a normal chromosome, and therefore, the individual is not adversely affected. However, if a cell with a chromosome inversion enters meiosis, the aberrant chromosome cannot pair properly with its normal homologue because of differences in the order of their genes. In such cases, chromosome pairing is usually accompanied by a loop (FIGURE 1). If crossing over occurs within the loop, as shown in the figure, the gametes generated by meiosis either pos- sess an additional copy of certain genes (a duplication) or are missing those genes (a deletion). When a gamete containing an altered chromosome fuses with a normal gamete at fertiliza- tion, the resulting zygote has a chromosome imbalance and is often nonviable. ranslocations. When all or a piece of one chromosome becomes attached to another chromosome, the aberration is called a translocation (FIGURE 2). Like inversions, a translocation that occurs in a somatic cell generally has little effect on the functions of that cell or its progeny. However, certain trans- locations increase the likelihood that the cell will become malignant. The best studied example is the Philadelphia chromosome, which is found in the malignant cells (but not the normal cells) of individuals with certain forms of leukemia. The Philadelphia chromosome, which is named for the city in which it was discovered in 1960, is a shortened version of human chromosome number 22. For years, it was thought that the missing segment represented a simple deletion, but with improved techniques for observing chromosomes, the missing genetic piece was found translocated to another chromosome (number 9). Chromosome number 9 contains a gene (ABL) that encodes a protein kinase that plays a role in cell proliferation. As a result of translocation, one small end of this protein is replaced by about 600 extra amino acids encoded by a gene (BCR) carried on the translocated piece of chromosome num- ber 22. This novel “fusion protein” retains the catalytic activity of the original ABL but is no longer subject to the cell’s normal regulatory mechanisms. As a result, the affected cell becomes malignant and causes chronic myelogenous leukemia (CML). It has generally been assumed that translocations occur following the random breakage of chromosomal DNA. Recent studies, however, suggest that such breaks in the DNA may occur at sites during the normal process of transcription, an activity that may make the DNA more susceptible for breakage. Prostate cancer, for example, is characterized by translocations affecting a number of genes that are transcribed in normal prostate cells in response to male hormones (androgens). Like inversions, translocations cause problems during meiosis. A chromosome altered by translocation has a different genetic content from its homologue. As a result, the gametes formed by meiosis will either contain extra copies of genes or be missing genes. Translocations have been shown to play an important role in evolution, generating large‐scale changes that may be pivotal in the branching of separate evolutionary lines from a common ancestor. Such a genetic incident prob- ably happened during our own recent evolutionary history. A comparison of the 23 pairs of chromosomes in human cells with the 24 pairs of chromosomes in the cells of chimpanzees, gorillas, and orangutans reveals a striking similarity. Close exam- ination of the two ape chromosomes that have no counterpart in humans reveals that together they are equivalent, band for band, to human chromosome number 2 (FIGURE 3). At some point during the evolution of humans, an entire chromosome was apparently translocated to another, creating a single fused chromosome and reducing the haploid number from 24 to 23.

● Deletions. A deletion occurs when a portion of a chromosome is missing. As noted above, zygotes containing a chromosomal deletion are produced when one of the gametes is the product of an abnormal meiosis. Forfeiting a portion of a chromosome often results in a loss of critical genes, producing severe con- sequences, even if the individual’s homologous chromosome is normal. Most human embryos that carry a significant deletion do not develop to term, and those that do exhibit a variety of malformations. The first correlation between a human disor- der and a chromosomal deletion was made in 1963 by Jerome Lejeune, a French geneticist who had earlier discovered the chromosomal basis of Down syndrome. Lejeune discovered that a baby born with a variety of facial malformations was missing a portion of chromosome 5. A defect in the larynx (voice box) caused the infant’s cry to resemble the sound of a suffering cat. Consequently, the scientists named the disorder cri‐du‐chat syndrome, meaning cry‐of‐the‐cat syndrome. ● Duplications. A duplication occurs when a portion of a chromosome is repeated. The role of duplications in the formation of multigene families was discussed on page 390. More substantial chromosome duplications create a condition in which a number of genes are present in three copies rather than the two copies normally present (a condition called partial trisomy). Cellular activities are very sensitive to the number of copies of genes, and thus extra copies of genes can have serious deleterious effects.

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