The spectra of large second-step mutations are similar for two different mouse autosomes

Abstract

Loss of tumor suppressor gene expression via mutations plays a critical role in cancer development, particularly when occurring in heterozygous cells. These so-called "second-step" mutational events are often large in size and arise most often from chromosome loss, mitotic recombination, or interstitial deletion. An open question in cancer research is whether different chromosomes are equally susceptible to formation of large mutations, or alternatively if the unique sequence of each chromosome will lead to chromosome-specific mutational spectra. To address this question, the spectra of second-step mutations were determined for chromosomes 8 and 11 in Aprt and Tk mutants, respectively, isolated from primary kidney clones heterozygous for both loci. The results showed that the spectra of large mutational events were essentially the same. This observation suggests that internal and external cellular environments provide the driving force for large autosomal mutational events, and that chromosome structure per se is the substrate upon which these forces act.

Figure 1. Polymorphic loci examined to determine mutational spectra

A. Chromosome 8 mutations were analyzed in DAP or FA selected mutants by examining loss or retention of heterozygosity for 7 polymorphic loci, which are represented on the left hand side of the figure by relative cM mappings (see Table 2). Black circles represent loci inherited from the C57BL/6 parent, including the Aprt knockout allele (KO) and white circles represent loci inherited from the DBA/2 parent including the expressed Aprt allele. Heterozygosity for a given locus is represented in a mutational pattern with a mottled black and white (grey) pattern. LOH is represented by a black circle, which represents loss of the DBA/2 allele and retention of the C57BL/6 allele. Representative patterns for intragenic events (IE), mitotic recombination, (MR), intragenic deletion (DEL), and chromosome loss (CL) are shown. B. Chromosome 11 mutations were analyzed in TFT selected mutants by examining loss or retention of heterozygosity for 6 polymorphic loci on chromosome 11, which are represented on the left hand side of the figure by relative cM mappings (see Table 2). The same analysis as part was followed as part A of this figure. The only difference in the results obtained is that two forms of chromosome loss were observed; CL1, in which all DBA/2 loci were lost including the wild type Tk allele, and CL2, in which all C57BL/6 loci were lost including the knockout Tk allele. See text for more details.

Figure 1. Polymorphic loci examined to determine mutational spectra

A. Chromosome 8 mutations were analyzed in DAP or FA selected mutants by examining loss or retention of heterozygosity for 7 polymorphic loci, which are represented on the left hand side of the figure by relative cM mappings (see Table 2). Black circles represent loci inherited from the C57BL/6 parent, including the Aprt knockout allele (KO) and white circles represent loci inherited from the DBA/2 parent including the expressed Aprt allele. Heterozygosity for a given locus is represented in a mutational pattern with a mottled black and white (grey) pattern. LOH is represented by a black circle, which represents loss of the DBA/2 allele and retention of the C57BL/6 allele. Representative patterns for intragenic events (IE), mitotic recombination, (MR), intragenic deletion (DEL), and chromosome loss (CL) are shown. B. Chromosome 11 mutations were analyzed in TFT selected mutants by examining loss or retention of heterozygosity for 6 polymorphic loci on chromosome 11, which are represented on the left hand side of the figure by relative cM mappings (see Table 2). The same analysis as part was followed as part A of this figure. The only difference in the results obtained is that two forms of chromosome loss were observed; CL1, in which all DBA/2 loci were lost including the wild type Tk allele, and CL2, in which all C57BL/6 loci were lost including the knockout Tk allele. See text for more details.