Mutagenesis and human genetic disease: Dominant mutation frequencies and a characterization of mutational events in mice and humans

Abstract

Dominant deleterious traits are generally regarded to be the most relevant genetic endpoints when the expected increased mutational load of genetic diseases associated with exposure to mutagenic agents is considered in humans. At present, human risk estimation procedures rely on results from laboratory mammal germ-cell mutagenicity experiments as well as on data from human epidemiology and medical genetics. A comparison of the mouse and human data indicates that a small subset of loci, which when mutated result in a dominant phenotype, is contributing disproportionately to the observed mutation frequency. This is likely due to the fact that those loci with an observed high mutation frequency are inherently unstable, the function of such loci is critical, and/or the wild-type phenotype requires two copies of the normal gene (haploinsufficiency). The locus specificity of the observed spontaneous and induced mutation frequencies implies that efforts must be made to closely match those genetic endpoints screened in the mouse with the human genetic endpoints considered relevant in estimating the genetic risk after exposure to mutagenic agents. The contributions to our understanding of the organization, function, and stability of the mouse and human genomes provided by molecular biological techniques should make compliance with this restriction feasible.