Autosomes have been numbered on the basis of their sizes from 1—22 in the human genome in contrast to the letters X and Y used for the allosomes. Genes located on these autosomes affect males and females in the same way Ohno Another striking property of autosomes is that they are homomorphic, i. This is a preview of subscription content, log in to check access.
Alberts, B. Molecular biology of the cell 4th ed. London: Garland Science, Taylor and Francis. Google Scholar. Craig, J. Genes and genomes: Chromosome bands—flavours to savour. Bioessays, 15 , — Niebuhr, E. Tumor suppressor genes are located on autosomal chromosomes. Therefore, an understanding of how cancer-related mutations occur in somatic cells requires a detailed understanding of spontaneous and induced autosomal mutagenesis.
This review will present recent advances in the study of how autosomal mutations form in somatic cells by focusing on the mouse Aprt and Tk model systems that have been developed to examine the formation of autosomal mutations in vivo.
By starting with mice heterozygous for Aprt or Tk it has been possible to examine second step mutations. At the present time spontaneous mutants have been isolated from three cell types: T cells from the spleen Van Sloun et al.
Aprt mutant cells from these three cell types have been reported, whereas Tk mutants have only been reported for T cells. An analysis of spontaneous mutant frequencies has revealed several interesting observations. One is that significant animal-to-animal and tissue-to-tissue variation exists for autosomal mutant frequencies with as much as fold differences observed in a given study Van Sloun et al.
Lower Hprt mutant frequencies have also been reported for the kidney Horn et al. Taken together, these observations are consistent with the broader spectrum of mutational events for autosomal loci Table I and they suggest that this broader spectrum leads to higher autosomal mutant frequencies and a greater degree of variation.
A third interesting observation is that average Aprt mutant frequencies for the solid tissues i. A similar elevation for Hprt mutant frequencies in solid tissues can be discerned when comparing T cell Hprt mutant frequencies Dobrovolsky et al. Reduced mutant frequencies for the T cells could be due to a selective disadvantage resulting from loss of purine salvage enzymes, as has been shown for Hprt -deficient T cells in the mouse Deubel et al.
Alternatively, it is possible that mutant cells can accumulate in the solid tissues because they do not turn over as rapidly as blood cells. Although rapid turnover will lead to more cell divisions and, therefore, potentially more mutant cells, this turnover will also lead to continuous loss of the mutant cells.
The ability to expand mutant Aprt and Tk clones has allowed analyses of the spectrum of spontaneous autosomal mutations. The predominant observation for both loci is that second step loss of gene expression is often accompanied by large mutational events that cause loss of the entire wild-type gene Van Sloun et al. As shown in Table I , there are four distinct mutational mechanisms that can remove an entire copy of an autosomal gene: mitotic recombination, chromosome loss, gene conversion and interstitial deletion.
However, to detect these events by molecular analysis it is necessary to examine multiple syntenic i. This can be accomplished by breeding mouse strains that are heterozygous for a microsatellite sequence on a given chromosome Shao et al. Several reports of Aprt mutation in vivo have suggested unexpected complexity in mutational pathways.
Spontaneous mutations occurring in kidney and ear epithelial cells revealed tissue-specific differences Ponomareva et al. The discordant results for the prevalence of mitotic recombination in the ear cells observed by different groups is potentially explained by a separate observation showing that the frequency of mitotic recombination is significantly influenced by the degree of homology between homologous chromosomes Shao et al.
When the degree of homology falls too low, as will happen when homologs from different mouse species are present in the same cell, mitotic recombination is essentially eliminated.
Tissue-specific differences were also observed in this study because in certain hybrid strains mitotic recombination was eliminated in ear cells, but still occurred commonly in T cells. The presence of more than one mutant cell in a given solid tissue can have two potential sources. One is that all mutant cells are derived from a progenitor cell in which the mutational event occurred. The prediction for this possibility is that all mutant cells isolated from a given tissue will exhibit the same mutational event.
Alternatively, multiple mutational events can occur within a given tissue leading to the observation of mutant cells from a given tissue exhibiting different types of mutations. Studies with Aprt have suggested that both possibilities can occur, sometimes in the same tissue Shao et al. An additional observation that has been made regarding spontaneous loss of gene expression in vivo is that many small events are not actually mutations, but instead appear to be caused by epigenetic silencing.
Evidence for epigenetic events includes a lack of detectable point mutations when many Aprt alleles Shao et al.
Reversibility of inactivation for cultured Aprt -deficient cells derived from the kidney Rose et al. It is important to describe the types of mutations induced by various carcinogens to better assess how these agents can trigger cancer.
This information will also provide signature mutations that can allow carcinogenic exposures to be determined after they have occurred. These mutations are commonly found in mutant p53 and Patched genes in human skin cancers providing molecular confirmation of the link between some types of skin cancer and exposure to the sun Dumaz et al. The majority of studies describing the types of mutations induced by various genotoxins in vivo have focused on small events such as base pair substitutions because bacterial transgenes are most often used as the mutational target Gossen et al.
However, large events that trigger LOH for chromosomal segments are more common in cancers Lasko and Cavenee, ; Wijnhoven et al. Therefore, a great deal of information is still needed to understand how carcinogens induce large mutational events in mammalian cells. Ionizing radiation has been shown to cause large mutational events, including interstitial deletions, in cultured cells Grosovsky et al.
Therefore, it should provide an ideal genotoxin to induce large mutational events in vivo. However, studies with single exposures to 1—4 Gy X-rays for Aprt Wijnhoven et al. In contrast, a single exposure to 7. Statistical power was increased for this study by only irradiating one side of each animal and then comparing results from the exposed and non-exposed sides on an animal-by-animal basis. Moreover, the induction of apparent deletions by ionizing radiation was observed in kidney cells.
A second molecular observation from this study was that discontinuous LOH Figure 1 on chromosome 8 was induced by ionizing radiation in both ear and kidney cells. Discontinuous LOH represents mutational patterns in which LOH events are observed on a chromosome that is apparently unlinked to the mutational event causing loss of gene expression.
This result suggested a delayed mutagenic effect in vivo. Consistent with this possibility, discontinuous LOH on chromosome 8 was observed as a delayed effect of ionizing radiation in cultured kidney cells Ponomareva et al.
A comparison of two carcinogens known to produce base pair substitutions in bacterial transgenes and at the Hprt locus in mice Gorelick et al. This difference is reflected in the predominant types of autosomal mutations that these carcinogens induced at the Tk and Aprt loci Wijnhoven et al.
ENU induced predominantly small events consistent with base pair substitution events, which was demonstrated directly at the sequence level for Tk mutants. DMBA also induced intragenic events at Aprt ; however, its predominant mutagenic effect was to induce large mutational events that were shown with a cytogenetic analysis for Aprt to be the result of mitotic recombination or chromosome loss. These observations suggest that replication blocks occurring as a result of bulky adduct formation caused by DMBA, but not the smaller lesions caused by ENU, can trigger large mutational events.
Etoposide, a topoisomerase II inhibitor that is used to treat a variety of human cancers da Rocha et al. Most of the mutant cells examined exhibited loss of the wild-type Aprt allele, again consistent with the induction of large events.
At the same dose, a 2-fold increase was observed for Tk , but this number was not statistically significant for the number of animals tested. Interestingly, when a fold higher dose of etoposide was tested the mutant frequencies decreased in both systems. These results were most likely due to increased T cell killing by etoposide at this higher dose.
When tested singly, a 2- to 3-fold increase in the Tk mutant frequency was observed for AZT, but no increase was observed for 3TC.
However, a synergistic interaction was observed when the drugs were used in combination, with a 4- to 6-fold induction of Tk mutant cells. Although AZT and 3TC are base analogs, most of the induced mutations were large events that resulted in loss of the wild-type Tk locus.
AZT induced deletional events at the Hprt locus in a cultured lymphoblastoid cell line Sussman et al. The cross-linking agent mitomycin C was also shown to induce large mutational events causing loss of Tk expression in T cells Dobrovolsky et al. A significant advantage of using in vivo systems is that it is possible to breed mice with DNA repair deficiencies to those with Aprt or Tk deficiencies to examine spontaneous and induced mutagenesis in different DNA repair-deficient backgrounds.
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