REVIEW OF THE MOLECULAR CHARACTERISTICS OF GENE-MUTATIONS OF THE GERMLINE AND SOMATIC-CELLS OF THE HUMAN

Molecular analyses of the limited number of de novo germinal mutations identified in humans indicate that an array of alterations in gene structure can be generated. Similar conclusions are derived from the large data set obtained from molecular analyses of alleles that segregate in the human population and cause genetic diseases. The molecular alterations include nucleotide substitutions as well as insertions, deletions and other rearrangemets of the DNA. The lesions may be located in the coding or the noncoding regions of genes or may involve the flanking sequences. The insertions and deletions involve fragments ranging from single nucleotides to many kilobases, and involve both unique sequences and repetive elements. The nature of the lesions observed to date as either de novo mutations or segregating variants suggests there are locus-specific characteristics of the alterations in DNA structure that are recovered as genetic diseases. Differences in mutation spectra among genetic loci appear to reflect both the structure of the target sequences and the relationship between gene structure and gene function. No induced germinal mutations have been identified, thus no data are available that reveal the relationships between mutagenic exposures and the molecular fingerprints of the lesion induced in the human germ cell and transmitted to the subsequent generations. In contrast, the prospects for analyzinng the roles of genetic target, exposure history and individual responsiveness to exposure in creating particular molecular lesions in somatic cells are excellent, both for alterations of single nucleotides and for major alterations of gene structure. By analysis of mutations at specific loci, it is possible to optimize recovery and subsequent detailed analysis of particular types of molecular events. The number of loci currently under study is small, but as more data are accumulated on the molecular nature of somatic mutation and exposure history, and more genetic targets come under study, it may be possible to identify molecular fingerprints of mutagen exposure. Somatic cells then will not only provide insight into the relationship between exposure to mutagens and somatic events such as cancer, but also serve as surrogate dosimeters for induction of heritable mutation. © 1990.