title: The tandem repeats enabling reversible switching between the two phases of β-lactamase substrate spectrum.
abstract: Expansion or shrinkage of existing tandem repeats (TRs) associated with various biological processes has been actively studied in both prokaryotic and eukaryotic genomes, while their origin and biological implications remain mostly unknown. Here we describe various duplications (de novo TRs) that occurred in the coding region of a β-lactamase gene, where a conserved structure called the omega loop is encoded. These duplications that occurred under selection using ceftazidime conferred substrate spectrum extension to include the antibiotic. Under selective pressure with one of the original substrates (amoxicillin), a high level of reversion occurred in the mutant β-lactamase genes completing a cycle back to the original substrate spectrum. The de novo TRs coupled with reversion makes a genetic toggling mechanism enabling reversible switching between the two phases of the substrate spectrum of β-lactamases. This toggle exemplifies the effective adaptation of de novo TRs for enhanced bacterial survival. We found pairs of direct repeats that mediated the DNA duplication (TR formation). In addition, we found different duos of sequences that mediated the DNA duplication. These novel elements-that we named SCSs (same-strand complementary sequences)-were also found associated with β-lactamase TR mutations from clinical isolates. Both direct repeats and SCSs had a high correlation with TRs in diverse bacterial genomes throughout the major phylogenetic lineages, suggesting that they comprise a fundamental mechanism shaping the bacterial evolution.
authors.affiliation: Department of Biosystems and Biotechnology, Korea University, Seoul, Korea; Department of Biomedical Sciences, Korea University, Seoul, Korea.
authors.forename: Hyojeong
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Biomedical Sciences, Korea University, Seoul, Korea.
authors.forename: Han
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Biomedical Sciences, Korea University, Seoul, Korea.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Sciences, Korea University, Seoul, Korea.
authors.forename: Karan
authors.initials: K
authors.lastname: Kim
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Nierman
authors.affiliation: Department of Biosystems and Biotechnology, Korea University, Seoul, Korea; Department of Biomedical Sciences, Korea University, Seoul, Korea.
authors.forename: Heenam Stanley
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000483:Alleles; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D005075:Biological Evolution; D002442:Ceftazidime / Q000378:metabolism / Q000494:pharmacology; D020440:Gene Duplication; D016680:Genome, Bacterial; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008969:Molecular Sequence Data; D010802:Phylogeny; D017354:Point Mutation; D013379:Substrate Specificity / Q000235:genetics; D020080:Tandem Repeat Sequences / Q000235:genetics*; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D001618:beta-Lactamases