Figure 1. Mechanisms of loss of heterozygosity. A cell containing two copies of chromosome 13, one with the normal or wild-type RB1 allele (+) and one with the mutant RB1 allele (m) is shown at the top (the remaining 44 chromosomes are not shown for clarity). Independent mutation of the wild-type allele (i) is possible but relatively rare. Aberrant cell division in which segregation of chromosomes into daughter cells does not occur faithfully can lead to loss of the whole chromosome carrying the wild-type allele (ii), and this may be combined with duplication of its homolog carrying the mutant allele (iii, iv). Alternatively, after DNA replication (v) exchange of material between chromatid arms can occur by mitotic recombination (vi). As the two copies of the mutant allele are now on different copies of the chromosome, they will segregate independently at the following cell division (vii), and some daughter cells will acquire two copies of the mutant allele and no wild-type allele. These pathways lead to four possible genotypes (1–4), all of which have no remaining wild-type allele. Not all of these pathways are important for all tumor suppressor genes; in particular, for some chromosomes genotype 2 may be inconsistent with cell survival because essential gene products are not produced in sufficient amounts.