Abstract
Genetic information should be accurately transmitted from cell to cell; conversely, the adaptation in evolution and disease is fueled by mutations. In the case of cancer development, multiple genetic changes happen in somatic diploid cells. Most classic studies of the molecular mechanisms of mutagenesis have been performed in haploids. We demonstrate that the parameters of the mutation process are different in diploid cell populations. The genomes of drug-resistant mutants induced in yeast diploids by base analog 6-hydroxylaminopurine (HAP) or AID/APOBEC cytosine deaminase PmCDA1 from lamprey carried a stunning load of thousands of unselected mutations. Haploid mutants contained almost an order of magnitude fewer mutations. To explain this, we propose that the distribution of induced mutation rates in the cell population is uneven. The mutants in diploids with coincidental mutations in the two copies of the reporter gene arise from a fraction of cells that are transiently hypersensitive to the mutagenic action of a given mutagen. The progeny of such cells were never recovered in haploids due to the lethality caused by the inactivation of single-copy essential genes in cells with too many induced mutations. In diploid cells, the progeny of hypersensitive cells survived, but their genomes were saturated by heterozygous mutations. The reason for the hypermutability of cells could be transient faults of the mutation prevention pathways, like sanitization of nucleotide pools for HAP or an elevated expression of the PmCDA1 gene or the temporary inability of the destruction of the deaminase. The hypothesis on spikes of mutability may explain the sudden acquisition of multiple mutational changes during evolution and carcinogenesis.
Highlights
The precise balance between genome stability and mutagenesis is vital for the survival of a species [1,2,3]
HAP is an adenine base analog that has an ambiguous basepairing capacity. In imine form it can pair with thymine, whereas in its rarer amine form it pairs with cytosine
PmCDA1 is involved in the diversification of genes encoding immunoglobulin analogs in sea lamprey and is closely related to other APOBEC enzymes [31]
Summary
The precise balance between genome stability and mutagenesis is vital for the survival of a species [1,2,3]. It ensures the maintenance of the optimal combinations and frequencies of alleles with high fitness and, simultaneously, the introduction of new mutations that are the raw material for the natural selection that drives adaptation in a changing environment. The accumulated mutation load cannot be explained by normal mutation rates and requires highly mutable cells ([10,11]; reviewed in [12]). A stable mutator phenotype would inexorably reduce tumor fitness due to the accumulation of mutations in regulatory and essential genes. Spikes of hypermutability can be caused by epigenetic changes and/or the defective regulation of DNA repair and replication [6], abnormally high expression of DNA editing deaminases [15,16] and other processes
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