Tandem genetic duplications in Salmonella typhimurium: amplification of the histidine operon.

~Satmo?~ella strains harboring tandem duplications of chromosomal segments including t,he histidine operon ma] be selected from populations of his0 promoter-like mutants. The twofold increase in gene dosage of the histidine oporon caused by tandem duplication provides resistance to concentrations of the histidine analogue 3.amino1,2,4-triazole that inhibit’ the growth of haploid h.isO mutants. Several properties of ATT-resistant, mutants indicate that they harbor tandem chromosomal duplications: (i) the AT-resistant phenotype of these strains is genetically unstable. Such instability is dependent, upon a funct,ional recombinabion system. (ii) AT-resistant mutants express approximately twice the levels of his enzymes as parental strains. (iii) Genetic tests iltdicate that, AT-resistant mutants are merodiploid for large segments (up to 26O?) of their genome. (iv) For certain isolates, the merodiploid and AT-resistant nature of these strains are properties cotransducible with a dist,ant chromosomal tnarker unrelated to the his operon. We interpret these results as indicating cotransduction of the joill-point of a t,andem duplication with this distant tnarker. The spontaneous freyuenc>of tandem hix tluplications IS remarkably high (6.2 x 10e5 per cell). This frequency is more than 6000-fold reduced in recA genetic backgrounds. Two major types of tandem his duplications are repeatedly isolated, having an identical -13oj, or -22?,, of their genome duplicated, respectively. When duplication-containing strains are grown under conditions that select for resistance to increased AT concentrations, clones harboring additional t,andem copies (amplification) of the his operon are obtained. The role which such gene amplification tnay play in bacterial adaptation is discussed.