Hartl, Jones - Genetics. Principlers and analysis - 1998 (522927), страница 90
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With continued proliferation, many cells within such clones develop chromosomalabnormalities, such as extra chromosomes, missing chromosomes, deletions, duplications, or translocations. Thechromosomal abnormalities found in cancer cells are diverse, and they may differ among cancer cells in the sameperson or among people with the same type of cancer. The accumulation of chromosome abnormalities is evidentlyone accompaniment of unregulated cell division.Amid the large number of apparently random chromosome abnormalities found in cancer cells, a small number ofaberrations are found consistently in certain types of cancer, particularly in blood diseases such as the leukemias.For example, chronic myelogenous leukemia is frequently associated with an apparent deletion of part of the longarm of chromosome 22.
The abnormal chromosome 22 in thisPage 298disease is called the Philadelphia chromosome; this chromosome is actually one part of a reciprocal translocationin which the missing segment of chromosome 22 is attached to either chromosome 8 or chromosome 9.
Similarly, adeletion of part of the short arm of chromosome 11 is frequently associated with a kidney tumor called Wilmstumor, which is usually found in children.For many of these characteristic chromosome abnormalities, the breakpoint in the chromosome is near thechromosomal location of a cellular oncogene. An oncogene is a gene associated with cancer. Cellular oncogenes,also called protooncogenes, are the cellular homologs of viral oncogenes contained in certain cancer-causingviruses.
The distinction is one of location: Cellular oncogenes are part of the normal genome; viral oncogenes arederived from cellular oncogenes through some rare mechanism in which they become incorporated into virusparticles. More than 50 different cellular oncogenes are known. They are apparently normal developmental genesthat predispose cells to unregulated division when mutated or abnormally expressed.
Many of the genes function innormal cells as growth factors that promote and regulate cell division. When a chromosome rearrangement happensnear a cellular oncogene (or when the gene is incorporated into a virus), the gene may become expressedabnormally and result in unrestrained proliferation of the cell that contains it. However, abnormal expression byitself is usually not sufficient to produce cancerous growth.
One or more additional mutations in the same cell arealso required.A sample of characteristic chromosome abnormalities found in certain cancers is given in Figure 7.37, along withthe locations of known cellular oncogenes on the same chromosomes. The symbols are again p for the short armand q for the long arm. The + and - signs are new designations:• A + or - preceding a chromosome number indicates an extra (or missing) copy of the entire chromosome.• A + or - following a chromosome designation means extra material (or missing material) corresponding to part ofthe designated chromosome or arm; for example, 11p- refers to a deletion of part of the short arm of chromosome11.The symbol t means reciprocal translocation; hence t(9;22) refers to a reciprocal translocation betweenchromosome 9 and chromosome 22.In Figure 7.37, the location of the cellular oncogene, when known, is indicated by a red arrow at the left, and thechromosomal breakpoint is indicated by a black arrow at the right.
In most cases for which sufficient information isavailable, the correspondence between the breakpoint and the cellular oncogene location is very close, and in somecases, the breakpoint is within the cellular oncogene itself. The significance of this correspondence is that thechromosomal rearrangement disturbs normal cellular oncogene regulation and ultimately leads to the onset ofcancer.Retinoblastoma and Tumor-Suppressor GenesA second class of genes associated with inherited cancers consists of the tumor-suppressor genes. These aregenes whose presence is necessary to suppress tumor formation. Absence of both normal alleles, through eithermutational inactivation or deletion, results in tumor formation.
An example of a tumor-suppressor gene is thehuman gene Rb-1, located in chromosome 13 in band 13q14. When the normal Rb-1 gene product is absent,malignant tumors form in the retinas, and surgical removal of the eyes becomes necessary. The disease is known asretinoblastoma.Retinoblastoma is unusual in that the predisposition to retinal tumors is dominant in pedigrees but the Rb-1mutation is recessive at the cell level; that is, a person who inherits one copy of the Rb-1 mutation through thegerm line is heterozygous, and the penetrance of retinoblastoma in this person is 100 percent.
However, the retinalcells that become malignant have the genotype Rb-1 Rb-1. The explanation for this apparent paradox is illustratedin Figure 7.38. Part A of Figure 7.38 shows the genotype of an Rb-1 heterozygote, along with a few other genes inthe same chromosome. Parts B through E show four possible ways in which a second genetic event can resultPage 299Figure 7.37Correlation between oncogene positions (red arrows) and chromosome breaks (black arrows) in aberrant humanchromosomes frequently found in cancer cells. A number of break-points near myb result in a cancer-associated t(6;14).in Rb-1Rb-1 cells in the retina.
The simplest (part B) is mutation of the wildtype allele in the homolog. Thewildtype allele could also be deleted (part C). Part D illustrates a situation in which the normal homolog of the Rb1 chromosome is lost and replaced by nondisjunction of the Rb-1-bearing chromosome. Mitotic recombination(part E) is yet another possibility for making Rb-1 homozygous. Although each of these events takes place at a verylow rate per cell division, there are so many cells in the retina (approximately 108) that the Rb-1 allele usuallybecomes homozygous in at least one cell.
(In fact, the average number of tumors per retina is three.)Figure 7.38Mechanisms by which (A) a single copy of Rb-1 inherited through the germ line can become homozygous in cells of the retina:(B) new mutation; (C) deletion; (D) loss of the normal homologous chromosome and replacement by nondisjunction ofthe Rb-1-bearing chromosome; (E) mitotic recombination.
Each of these events is rare, but there are so many cells in theretina that on average, there are three such events per eye.Page 300Chapter SummaryA typical chromosome contains a single centromere, the position of which determines the shape of thechromosome as it is pulled to the poles of the cell during anaphase. Rare chromosomes with no centromere, andthose with two or more centromeres, are usually lost within a few cell generations because of aberrant separationduring anaphase. Ring chromosomes are genetically relatively stable but are very rare.Polyploid organisms contain more than two complete sets of chromosomes.
Polyploidy is widespread amonghigher plants and uncommon otherwise. Between 30 and 35 percent of all species of flowering plants are thought tohave originated as some form of polyploid. An autopolyploid organism contains multiple sets of chromosomesfrom a single ancestral species; allopolyploid organisms contain complete sets of chromosomes from two or moreancestral species. Organisms occasionally arise in which an individual chromosome either is missing or is presentin excess; in either case, the number of copies of genes in such a chromosome is incorrect.
Departures from normalgene dosage (aneuploidy) often result in reduced viability of the zygote in animals or of the gametophyte in plants.In general, too many copies of genes or chromosomes have less severe effects than too few copies.The normal human chromosome complement consists of 22 pairs of autosomes, which are assigned numbers 1through 22 from longest to shortest, and one pair of sex chromosomes (XX in females and XY in males). Fetusesthat contain an abnormal number of autosomes usually fail to complete normal embryonic development or dieshortly after birth, though people with Down syndrome (trisomy 21) sometimes survive for several decades.Persons with excess sex chromosomes survive, because the Y chromosome contains relatively few genes other thanthe master sex-controller SRY, and because only one X chromosome is genetically active in the cells of females(dosage compensation through the single-active-X principle). The mosaic orange and black pattern of the female"calico" cat results from X inactivation, because these alternative coat color alleles are X-linked in cats.Most structural abnormalities in chromosomes are duplications, deletions, inversions, or translocations.
In aduplication, there are two copies of a chromosomal segment. In a deletion, a chromosomal segment is missing. Anorganism can often tolerate an imbalance of gene dosage resulting from small duplications or deletions, but largeduplications or deletions are almost always harmful. Chromosome rearrangements may affect gene expressionthrough position effects.
Although most genes can be expressed whatever their location in the genome, the level ofexpression may vary substantially according to position. A major effect of gene location on expression is observedin position-effect variegation (PEV), in which a wildtype allele repositioned in or near heterochromatin is unable tobe expressed in a fraction of the cell lineages.A chromosome that contains an inversion has a group of adjacent genes in reverse of the normal order.
Expressionof the genes is usually unaltered, so inversions rarely affect viability. However, crossing-over between an invertedchromosome and its noninverted homolog in meiosis yields abnormal chromatids. Crossing-over within aheterozygous paracentric inversion yields an acentric chromosome and a dicentric chromosome, both of which alsohave a duplication and a deficiency. Crossing-over within a heterozygous pericentric inversion yields monocentricchromosomes, but both have a duplication and a deficiency.Two nonhomologous chromosomes that have undergone an exchange of parts constitute a reciprocal translocation.Organisms that contain a reciprocal translocation, as well as the normal homologous chromosomes of thetranslocation, produce fewer offspring (this is called semisterility) because of abnormal segregation of thechromosomes in meiosis.
The semisterility is caused by the aneuploid gametes produced in adjacent-1 andadjacent-2 segregation. Alternate segregation yields equal numbers of normal and translocation-bearing gametes.In genetic crosses, the semisterility of a heterozygous translocation behaves like a dominant genetic marker thatcan be mapped like any other gene; however, what is actually mapped is the breakpoint of the translocation.A translocation may also be nonreciprocal. A Robertsonian translocation is a type of nonreciprocal translocation inwhich the long arms of two acrocentric chromosomes are attached to a common centromere. In human beings,Robertsonian translocations that include chromosome 21 account for about 3 percent of all cases of Downsyndrome, and the parents have a high risk of recurrence of Down syndrome in a subsequent child.Malignant cells in many types of cancer contain specific types of chromosome abnormalities. Frequently, thebreak-points in the chromosomes coincide with the chromosomal location of one of a group of cellular oncogenescoding for cell growth factors.
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