https://www.cell.com/cell/pdf/0092-8674(93)90546-3.pdf

The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.

Elevated recombination rates in transcriptionally active DNA.

Elective enrichment is an indispensable technique in bacterial physiology and genetics (van Niel, 1949). Specific biotypes are most readily isolated by the establishment of cultural conditions that favor their growth or survival. It has been repeatedly questioned, however, whether a selective environment may not only select but also direct adaptive heritable changes. In accord with similar discussions in evolutionary biology (Huxley, 1942), we may denote the concepts of spontaneous mutation and natural selection in contrast to specific induction as \"preadaptation\" and \"directed mutation\", respectively. Many lines of evidence have been adduced in support of preadaptation in a variety of systems (Luria and Delbruick, 1943; Lea and Coulson, 1949; Burnet, 1929; Newcombe, 1949; Lewis, 1934; Kristensen, 1944; Novick and Szilard, 1950; Ryan and Schneider, 1949; Demerec, 1948; Welsch, 1950; also reviewed: Braun, 1047; Luria, 1947; Lederberg, 1948, 1949). This paper concerns an approach to this problem that makes use of a replica plating technique which facilitates the handling of large numbers of bacterial clones for classification on a variety of media.

Replica plating and indirect selection of bacterial mutants

The genomes of all eukaryotes contain tracts of DNA in which a single base or a small number of bases is repeated. Expansions of such tracts have been associated with several human disorders including the fragile X syndrome. In addition, simple repeats are unstable in certain forms of colorectal cancer, suggesting a defect in DNA replication or repair. We show here that mutations in any three yeast genes involved in DNA mismatch repair (PMS1, MLH1 and MSH2) lead to 100- to 700-fold increases in tract instability, whereas mutations that eliminate the proof-reading function of DNA polymerases have little effect. The meiotic stability of the tracts is similar to the mitotic stability. These results suggest that tract instability is associated with DNA polymerases slipping during replication, and that some types of colorectal cancer may reflect mutations in genes involved in DNA mismatch repair.

Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair

Nucleic acids are replicated with conspicuous fidelity. Infrequently, however, they undergo changes in sequence, and this process of change (mutation) generates the variability that allows evolution. As the result of studies of bacterial variation, it is now widely believed that mutations arise continuously and without any consideration for their utility. In this paper, we briefly review the source of this idea and then describe some experiments suggesting that cells may have mechanisms for choosing which mutations will occur.

The origin of mutants

Statistical calculations are made of the distribution numbers of mutants in a culture of bacteria in which the number of mutants increases on account both of new mutations and of division of old mutants. In this way the largely qualitative conclusions of Luria and Delbruck are extended and placed on a firm quantitative basis. The results of these calculations, which enable the mutation rate to be inferred from experiments with parallel cultures, are presented in the form of tables. Statistically efficient methods of using these tables are discussed.

C. A. Coulson

Papers

The distribution of the numbers of mutants in bacterial populations.