Journal articles: 'Slipped strand mispairing'

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Sanabria-Valentín, Edgardo, Marie-Teresa C. Colbert, and Martin J. Blaser. "Role of futC slipped strand mispairing in Helicobacter pylori Lewisy phase variation." Microbes and Infection 9, no. 14-15 (November 2007): 1553–60. http://dx.doi.org/10.1016/j.micinf.2007.08.011.

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Karlyshev, Andrey V., Dennis Linton, Norman A. Gregson, and Brendan W. Wren. "A novel paralogous gene family involved in phase-variable flagella-mediated motility in Campylobacter jejuni." Microbiology 148, no. 2 (February 1, 2002): 473–80. http://dx.doi.org/10.1099/00221287-148-2-473.

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Flagella-mediated motility is recognized to be one of the major factors contributing to virulence in Campylobacter jejuni. Motility of this bacterium is known to be phase variable, although the mechanism of such variation remains unknown. C. jejuni genome sequencing revealed a number of genes prone to phase variation via a slipped-strand mispairing mechanism. Many of these genes are hypothetical and are clustered in the regions involved in formation of three major cell surface structures: capsular polysaccharide, lipooligosaccharide and flagella. Among the genes of unknown function, the flagellar biosynthesis and modification region contains seven hypothetical paralogous genes designated as the motility accessory factor (maf) family. Remarkably, two of these genes (maf1 and maf4) were found to be identical and both contain homopolymeric G tracts. Using insertional mutagenesis it was demonstrated that one of the genes, maf5, is involved in formation of flagella. Phase variation of the maf1 gene via slipped-strand mispairing partially restored motility of the maf5 mutant. The maffamily represents a new class of bacterial genes related to flagellar biosynthesis and phase variation. Reversible expression of flagella may be advantageous for the adaptation of C. jejunito the varied in vivo and ex vivo environments encountered during its life cycle, as well in evasion of the host immune response.

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Torres-Cruz, Joshua, and Marjan W. van der Woude. "Slipped-Strand Mispairing Can Function as a Phase Variation Mechanism in Escherichia coli." Journal of Bacteriology 185, no. 23 (December 1, 2003): 6990–94. http://dx.doi.org/10.1128/jb.185.23.6990-6994.2003.

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ABSTRACT Slipped-strand mispairing (SSM) has not been identified as a mechanism of phase variation in Escherichia coli. Using a reporter gene, we show that sequences that cause phase variation by SSM in Haemophilus influenzae also lead to phase variation when introduced onto the chromosome of E. coli, and the frequencies of switching are in the biologically relevant range. Thus, the absence of SSM-mediated phase variation in E. coli does not appear to be due to a mechanistic constraint.

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Taylor, John S., and Felix Breden. "Slipped-Strand Mispairing at Noncontiguous Repeats in Poecilia reticulata: A Model for Minisatellite Birth." Genetics 155, no. 3 (July 1, 2000): 1313–20. http://dx.doi.org/10.1093/genetics/155.3.1313.

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Abstract The standard slipped-strand mispairing (SSM) model for the formation of variable number tandem repeats (VNTRs) proposes that a few tandem repeats, produced by chance mutations, provide the “raw material” for VNTR expansion. However, this model is unlikely to explain the formation of VNTRs with long motifs (e.g., minisatellites), because the likelihood of a tandem repeat forming by chance decreases rapidly as the length of the repeat motif increases. Phylogenetic reconstruction of the birth of a mitochondrial (mt) DNA minisatellite in guppies suggests that VNTRs with long motifs can form as a consequence of SSM at noncontiguous repeats. VNTRs formed in this manner have motifs longer than the noncontiguous repeat originally formed by chance and are flanked by one unit of the original, noncontiguous repeat. SSM at noncontiguous repeats can therefore explain the birth of VNTRs with long motifs and the “imperfect” or “short direct” repeats frequently observed adjacent to both mtDNA and nuclear VNTRs.

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Pettigrew, Melinda M., Christian P. Ahearn, Janneane F. Gent, Yong Kong, Mary C. Gallo, James B. Munro, Adonis D’Mello, Sanjay Sethi, Hervé Tettelin, and Timothy F. Murphy. "Haemophilus influenzaegenome evolution during persistence in the human airways in chronic obstructive pulmonary disease." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): E3256—E3265. http://dx.doi.org/10.1073/pnas.1719654115.

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NontypeableHaemophilus influenzae(NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

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Salvatori, Roberto, Serban Radian, Yoan Diekmann, Donato Iacovazzo, Alessia David, Plamena Gabrovska, Giorgia Grassi, et al. "In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism." European Journal of Endocrinology 177, no. 3 (September 2017): 257–66. http://dx.doi.org/10.1530/eje-17-0293.

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Objective Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Design and methods Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Results Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. Conclusions The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability.

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Lopez, Genghis H., Robyn M. Turner, Eunike C. McGowan, Elizna M. Schoeman, Stacy A. Scott, Helen O'Brien, Glenda M. Millard, et al. "A DEL phenotype attributed toRHDExon 9 sequence deletion: slipped-strand mispairing and blood group polymorphisms." Transfusion 58, no. 3 (December 6, 2017): 685–91. http://dx.doi.org/10.1111/trf.14439.

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Bzymek, Malgorzata, and Susan T. Lovett. "Evidence for Two Mechanisms of Palindrome-Stimulated Deletion in Escherichia coli: Single-Strand Annealing and Replication Slipped Mispairing." Genetics 158, no. 2 (June 1, 2001): 527–40. http://dx.doi.org/10.1093/genetics/158.2.527.

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Abstract Spontaneous deletion mutations often occur at short direct repeats that flank inverted repeat sequences. Inverted repeats may initiate genetic rearrangements by formation of hairpin secondary structures that block DNA polymerases or are processed by structure-specific endonucleases. We have investigated the ability of inverted repeat sequences to stimulate deletion of flanking direct repeats in Escherichia coli. Propensity for cruciform extrusion in duplex DNA correlated with stimulation of flanking deletion, which was partially sbcD dependent. We propose two mechanisms for palindrome-stimulated deletion, SbcCD dependent and SbcCD independent. The SbcCD-dependent mechanism is initiated by SbcCD cleavage of cruciforms in duplex DNA followed by RecA-independent single-strand annealing at the flanking direct repeats, generating a deletion. Analysis of deletion endpoints is consistent with this model. We propose that the SbcCD-independent pathway involves replication slipped mispairing, evoked from stalling at hairpin structures formed on the single-stranded lagging-strand template. The skew of SbcCD-independent deletion endpoints with respect to the direction of replication supports this hypothesis. Surprisingly, even in the absence of palindromes, SbcD affected the location of deletion endpoints, suggesting that SbcCD-mediated strand processing may also accompany deletion unassociated with secondary structures.

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Thomas, Mark G., Charles E. Cook, Kevin W. P. Miller, Michael J. Warin, and Erika Hagelberg. "Molecular instability in the COII–tRNA Lys intergenic region of the human mitochondrial genome: multiple origins of the 9–bp deletion and heteroplasmy for expanded repeats." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 353, no. 1371 (June 29, 1998): 955–65. http://dx.doi.org/10.1098/rstb.1998.0260.

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We have identified two individuals from Glasgow in Scotland who have a deletion of one of two copies of the cytochrome oxidise II (COII) intergenic 9–bp sequence motif CCCCCTCTA, located between the COII and tRNA Lys genes of the human mitochondrial genome. Although this polymorphism is common in Africa and Asia, it has not been reported in Northern Europe. Analysis of the mitochondrial DNA control region sequences of these two individuals suggests that they belong to a lineage that originated independently of the previously characterized African and Asian 9–bp deleted lineages. Among the Scottish population we have also identified a maternal lineage of three generations exhibiting heteroplasmy for two, three and four copies of the CCCCCTCTA motif. Polymerase chain reaction amplification across the COII – tRNA Lys intergenic region of these individuals gives different ratios of the three product lengths that are dependent on the concentration of the DNA–binding dye crystal violet. To investigate whether changes in repeat number were generated de novo , we constructed clones containing known numbers of the CCCCCTCTA motif. In the presence of high concentrations of crystal violet we obtained two, three and four copies of this motif when the amplification template contained only four copies. Various DNA–binding drugs are known to stabilize bulged structures in DNA and contribute to the process of slipped–strand–mispairing during DNA replication. These results suggest that the COII – tRNA Lys intergenic region is unstable owing to slipped–strand mispairing. Although sequences containing four copies of the CCCCCTCTA motif are less stable in vitro , we observed an increase in the proportion of mitochondrial genomes with four repeats between a mother and a daughter in the heteroplasmic lineage. From this we conclude that drift in the germ–line lineage is a main factor in the maintenance or loss of heteroplasmy.

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Lindbäck, Toril, Indira Secic, and Liv Marit Rørvik. "A Contingency Locus inprfAin a Listeria monocytogenes Subgroup Allows Reactivation of the PrfA Virulence Regulator during Infection in Mice." Applied and Environmental Microbiology 77, no. 10 (April 1, 2011): 3478–83. http://dx.doi.org/10.1128/aem.02708-10.

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ABSTRACTA nonhemolyticListeria monocytogenesstrain isolated from a fish processing plant was avirulent in a plaque-forming assay and in a subcutaneous mouse virulence assay. However, it showed 60% lethality (9/15 mice) when 109CFU were intraperitoneally injected into mice. HemolyticL. monocytogenesbacteria were recovered from liver and spleen of the deceased mice, and the pulsed-field gel electrophoresis patterns were indistinguishable for the nonhemolytic and the hemolytic isolates. Sequencing ofprfAfrom the nonhemolytic strain revealed a duplication of 7 bp in the helix-turn-helix region, resulting in a truncated PrfA protein. We propose that the direct repeat of 7 bp causes a reversible inactivation ofprfAand that slipped-strand mispairing regulates the phase variation in hemolytic activity and virulence. NonhemolyticL. monocytogenesstrains with identical duplications inprfAwere isolated from several sources in France, as well as in Norway, suggesting that the reversible inactivation described in this study is not an isolated event.

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Simpson, Paul R. "Variation among the dispersed (GATA)n sequences in Drosophila melanogaster." Genome 33, no. 5 (October 1, 1990): 750–54. http://dx.doi.org/10.1139/g90-113.

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Five nonallelic copies of the dispersed (GATA)n repeated sequence of Drosophila melanogaster (referred to as GATA elements) have been sequenced and analysed. The GATA elements range in size from 111 to 444 bp, consisting predominantly of tandemly repeated GATAs, interspersed with variants of the subunit. The types and distributions of these variants are consistent with the hypothesis that they have arisen by a random accumulation of point mutations (substitutions, deletions, and insertions) in pure (GATA)n sequences. Duplications or deletions of the GATA subunit, and of GATA variants, have also probably occurred, as a result of either unequal crossing-over or slipped-strand mispairing. Evidence for duplication (deletion) has been obtained from a comparison of two allelic GATA elements isolated from different populations. GATA elements, in common with other dispersed, simple repeats, are probably highly variable in length.Key words: simple sequences, GATA element, Drosophila.

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Belland, R. J., S. G. Morrison, P. Ley, and J. Swanson. "Expression and phase variation of gonococcal P.11 genes in Escherichia coli involves ribosomal frameshifting and slipped-strand mispairing." Molecular Microbiology 3, no. 6 (June 1989): 777–86. http://dx.doi.org/10.1111/j.1365-2958.1989.tb00226.x.

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Murphy, George L., Terry D. Connell, Diana S. Barritt, Michael Koomey, and Janne G. Cannon. "Phase variation of gonococcal protein II: Regulation of gene expression by slipped-strand mispairing of a repetitive DNA sequence." Cell 56, no. 4 (February 1989): 539–47. http://dx.doi.org/10.1016/0092-8674(89)90577-1.

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Alcalá, Josefina, Leonard M. Pike, and James J. Giovannoni. "Identification of Plastome Variants useful for Cytoplasmic Selection and Cultivar Identification in Onion." Journal of the American Society for Horticultural Science 124, no. 2 (March 1999): 122–27. http://dx.doi.org/10.21273/jashs.124.2.122.

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The relatively low evolution rate of the chloroplast DNA has made it an ideal tool to study evolutionary processes in plants above the species levels. However, recent studies have demonstrated that intraspecific variation in the chloroplast DNA is also common. This variation has provided useful insights into population level evolutionary processes. The polymerase chain reaction and sequencing of a noncoding chloroplast region used to classify onion lines for cytoplasmic type facilitated the identification of one sterile and two normal plastome variants in onion (Allium cepa L.). Sequence comparison revealed that differences between plastome variants included the presence of single-nucleotide polymorphisms associated with cytoplasmic type and variable numbers of tandem repeats, possibly resulting from slipped-strand mispairing. Our observations support the use of chloroplast-specific markers to assist in the selection of specific cytoplasmic types, suggest the potential to facilitate genotype determination, and demonstrate the presence of additional variation within cytoplasm type which gives insight into plastome evolution and may facilitate more accurate genotyping and selection.

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Wang, Jun, Xin-Yi Dai, Xiao-Dong Xu, Zi-Yi Zhang, Dan-Na Yu, Kenneth B. Storey, and Jia-Yong Zhang. "The complete mitochondrial genomes of five longicorn beetles (Coleoptera: Cerambycidae) and phylogenetic relationships within Cerambycidae." PeerJ 7 (September 5, 2019): e7633. http://dx.doi.org/10.7717/peerj.7633.

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Cerambycidae is one of the most diversified groups within Coleoptera and includes nearly 35,000 known species. The relationships at the subfamily level within Cerambycidae have not been convincingly demonstrated and the gene rearrangement of mitochondrial genomes in Cerambycidae remains unclear due to the low numbers of sequenced mitogenomes. In the present study, we determined five complete mitogenomes of Cerambycidae and investigated the phylogenetic relationship among the subfamilies of Cerambycidae based on mitogenomes. The mitogenomic arrangement of all five species was identical to the ancestral Cerambycidae type without gene rearrangement. Remarkably, however, two large intergenic spacers were detected in the mitogenome of Pterolophia sp. ZJY-2019. The origins of these intergenic spacers could be explained by the slipped-strand mispairing and duplication/random loss models. A conserved motif was found between trnS2 and nad1 gene, which was proposed to be a binding site of a transcription termination peptide. Also, tandem repeat units were identified in the A + T-rich region of all five mitogenomes. The monophyly of Lamiinae and Prioninae was strongly supported by both MrBayes and RAxML analyses based on nucleotide datasets, whereas the Cerambycinae and Lepturinae were recovered as non-monophyletic.

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Simmons, Warren L., Jeffrey R. Bolland, James M. Daubenspeck, and Kevin Dybvig. "A Stochastic Mechanism for Biofilm Formation by Mycoplasma pulmonis." Journal of Bacteriology 189, no. 5 (December 1, 2006): 1905–13. http://dx.doi.org/10.1128/jb.01512-06.

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ABSTRACT Bacterial biofilms are communities of bacteria that are enclosed in an extracellular matrix. Within a biofilm the bacteria are protected from antimicrobials, environmental stresses, and immune responses from the host. Biofilms are often believed to have a highly developed organization that is derived from differential regulation of the genes that direct the synthesis of the extracellular matrix and the attachment to surfaces. The mycoplasmas have the smallest of the prokaryotic genomes and apparently lack complex gene-regulatory systems. We examined biofilm formation by Mycoplasma pulmonis and found it to be dependent on the length of the tandem repeat region of the variable surface antigen (Vsa) protein. Mycoplasmas that produced a short Vsa protein with few tandem repeats formed biofilms that attached to polystyrene and glass. Mycoplasmas that produced a long Vsa protein with many tandem repeats formed microcolonies that floated freely in the medium. The biofilms and the microcolonies contained an extracellular matrix which contained Vsa protein, lipid, DNA, and saccharide. As variation in the number of Vsa tandem repeats occurs by slipped-strand mispairing, the ability of the mycoplasmas to form a biofilm switches stochastically.

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Vaughan, Thomas E., Catherine B. Pratt, Katie Sealey, Andrew Preston, Norman K. Fry, and Andrew R. Gorringe. "Plasticity of fimbrial genotype and serotype within populations of Bordetella pertussis: analysis by paired flow cytometry and genome sequencing." Microbiology 160, no. 9 (September 1, 2014): 2030–44. http://dx.doi.org/10.1099/mic.0.079251-0.

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The fimbriae of Bordetella pertussis are required for colonization of the human respiratory tract. Two serologically distinct fimbrial subunits, Fim2 and Fim3, considered important vaccine components for many years, are included in the Sanofi Pasteur 5-component acellular pertussis vaccine, and the World Health Organization recommends the inclusion of strains expressing both fimbrial serotypes in whole-cell pertussis vaccines. Each of the fimbrial major subunit genes, fim2, fim3, and fimX, has a promoter poly(C) tract upstream of its −10 box. Such monotonic DNA elements are susceptible to changes in length via slipped-strand mispairing in vitro and in vivo, which potentially causes on/off switching of genes at every cell division. Here, we have described intra-culture variability in poly(C) tract lengths and the resulting fimbrial phenotypes in 22 recent UK B. pertussis isolates. Owing to the highly plastic nature of fimbrial promoters, we used the same cultures for both genome sequencing and flow cytometry. Individual cultures of B. pertussis contained multiple fimbrial serotypes and multiple different fimbrial promoter poly(C) tract lengths, which supports earlier serological evidence that B. pertussis expresses both serotypes during infection.

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Highlander, S. K., and V. T. Hang. "A putative leucine zipper activator of Pasteurella haemolytica leukotoxin transcription and the potential for modulation of its synthesis by slipped-strand mispairing." Infection and immunity 65, no. 9 (1997): 3970–75. http://dx.doi.org/10.1128/iai.65.9.3970-3975.1997.

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Khamri, Wafa, Anthony P. Moran, Mulugeta L. Worku, Q. Najma Karim, Marjorie M. Walker, Heidi Annuk, John A. Ferris, et al. "Variations in Helicobacter pylori Lipopolysaccharide To Evade the Innate Immune Component Surfactant Protein D." Infection and Immunity 73, no. 11 (November 2005): 7677–86. http://dx.doi.org/10.1128/iai.73.11.7677-7686.2005.

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ABSTRACT Helicobacter pylori is a common and persistent human pathogen of the gastric mucosa. Surfactant protein D (SP-D), a component of innate immunity, is expressed in the human gastric mucosa and is capable of aggregating H. pylori. Wide variation in the SP-D binding affinity to H. pylori has been observed in clinical isolates and laboratory-adapted strains. The aim of this study was to reveal potential mechanisms responsible for evading SP-D binding and establishing persistent infection. An escape variant, J178V, was generated in vitro, and the lipopolysaccharide (LPS) structure of the variant was compared to that of the parental strain, J178. The genetic basis for structural variation was explored by sequencing LPS biosynthesis genes. SP-D binding to clinical isolates was demonstrated by fluorescence-activated cell sorter analyses. Here, we show that H. pylori evades SP-D binding through phase variation in lipopolysaccharide. This phenomenon is linked to changes in the fucosylation of the O chain, which was concomitant with slipped-strand mispairing in a poly(C) tract of the fucosyltransferase A (fucT1) gene. SP-D binding organisms are predominant in mucus in vivo (P = 0.02), suggesting that SP-D facilitates physical elimination. Phase variation to evade SP-D contributes to the persistence of this common gastric pathogen.

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Shaw, Brandon M., Warren L. Simmons, and Kevin Dybvig. "The Vsa Shield of Mycoplasma pulmonis Is Antiphagocytic." Infection and Immunity 80, no. 2 (November 14, 2011): 704–9. http://dx.doi.org/10.1128/iai.06009-11.

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ABSTRACTThe infection of mice withMycoplasma pulmonisis a model for studying chronic mycoplasmal respiratory disease. Manyin vivoandin vitrostudies have used the organism to gain a better understanding of host-pathogen interactions in chronic respiratory infection. The organism's Vsa proteins contain an extensive tandem repeat region. The length of the tandem repeat unit varies from as few as 11 amino acids to as many as 19. The number of tandem repeats can be as high as 60. The number of repeats varies at a high frequency due to slipped-strand mispairing events that occur during DNA replication. When the number of repeats is high, e.g., 40, the mycoplasma is resistant to lysis by complement but does not form a robust biofilm. When the number of repeats is low, e.g., 5, the mycoplasma is killed by complement when the cells are dispersed but has the capacity to form a biofilm that resists complement. Here, we examine the role of the Vsa proteins in the avoidance of phagocytosis and find that cells producing a protein with many tandem repeats are relatively resistant to killing by macrophages. These results may be pertinent to understanding the functions of similar proteins that have extensive repeat regions in other microbes.

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Indra, Alexander, Marion Blaschitz, Silvia Kernbichler, Udo Reischl, Guenther Wewalka, and Franz Allerberger. "Mechanisms behind variation in the Clostridium difficile 16S–23S rRNA intergenic spacer region." Journal of Medical Microbiology 59, no. 11 (November 1, 2010): 1317–23. http://dx.doi.org/10.1099/jmm.0.020792-0.

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Clostridium difficile infection is an increasing problem in hospitals worldwide, mainly due to the recent emergence of a hypervirulent C. difficile strain. C. difficile PCR ribotyping, based on size variation of the 16S–23S rRNA intergenic spacer region (16S–23S ISR), is widely used in Europe for molecular epidemiological investigation. The mechanism underlying the 16S–23S ISR size variations in the genome of C. difficile is currently not completely understood. To elucidate this mechanism, isolates of six different PCR ribotypes were analysed by cloning and sequencing the 16S–23S ISR. A direct repeat, IB, of 9 bp was detected up to five times in the 16S–23S ISR in all 47 clones investigated. Thirty-five clones displayed differences either by ribotype or by nucleotide sequence. The sequences of the 16S–23S ISR of C. difficile showed a uniformly organized structure, composed of a tRNAAla gene and spacers of 33 and 53 bp separated by the 9 bp direct repeat IB. The results of the study support the hypothesis that this composition is responsible for the length variations seen in the 16S–23S ISR, and indicate that these length variations result from slipped-strand mispairing and intra- and possibly interchromosomal homologous recombination.

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Huang, Shuyan, Josephine Kang, and Martin J. Blaser. "Antimutator Role of the DNA Glycosylase mutY Gene in Helicobacter pylori." Journal of Bacteriology 188, no. 17 (September 1, 2006): 6224–34. http://dx.doi.org/10.1128/jb.00477-06.

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ABSTRACT Helicobacter pylori has a highly variable genome with ongoing diversification via inter- and intragenomic recombination and spontaneous mutation. DNA repair genes modulating mutation and recombination rates that influence diversification have not been well characterized for H. pylori. To examine the role of putative base excision repair ung and mutY glycosylase and xthA apurinic/apyrimidinic endonuclease genes in H. pylori, mutants of each were constructed in strain JP26 by allelic exchange. Spontaneous mutation frequencies of JP26 mutY mutants, assessed by rifampin resistance, were consistently higher (26-fold) than that of the wild type, whereas the ung and xthA mutants showed smaller increases. In trans complementation of the JP26 mutY mutant restored spontaneous mutation frequencies to wild-type levels. In cross-species studies, H. pylori mutY complemented an Escherichia coli mutY mutant and vice versa. In contrast, the ung and mutY mutants did not show higher frequencies of intergenomic recombination or greater sensitivity to UV-induced DNA damage than the wild type. The H. pylori mutY open reading frame contains an eight-adenine homonucleotide tract; we provide evidence that this is subject to slipped-strand mispairing, leading to frameshifts that eliminate gene function. Our findings indicate that H. pylori possesses phase-variable base excision repair, consistent with a tension between repair and mutation.

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Saveson, Catherine J., and Susan T. Lovett. "Enhanced Deletion Formation by Aberrant DNA Replication in Escherichia coli." Genetics 146, no. 2 (June 1, 1997): 457–70. http://dx.doi.org/10.1093/genetics/146.2.457.

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Repeated genes and sequences are prone to genetic rearrangements including deletions. We have investigated deletion formation in Escherichia coli strains mutant for various replication functions. Deletion was selected between 787 base pair tandem repeats carried either on a ColE1-derived plasmid or on the E. coli chromosome. Only mutations in functions associated with DNA Polymerase III elevated deletion rates in our assays. Especially large increases were observed in strains mutant in dnaQ the ϵ editing subunit of Pol III, and dnuB, the replication fork helicase. Mutations in several other functions also altered deletion formation: the α polymerase (dnaE), the γ clamp loader complex (holC, dnaX), and the β clamp (dnaN) subunits of Pol III and the primosomal proteins, dnaC and priA. Aberrant replication stimulated deletions through several pathways. Whereas the elevation in dnaB strains was mostly recA- and lexA-dependent, that in dnaQ strains was mostly recA- and lexA-independent. Deletion product analysis suggested that slipped mispairing, producing monomeric replicon products, may be preferentially increased in a dnaQ mutant and sister-strand exchange, producing dimeric replicon products, may be elevated in dnaE mutants. We conclude that aberrant Polymerase III replication can stimulate deletion events through several mechanisms of deletion and via both recA-dependent and independent pathways.

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Ashgar, Sami S. A., Neil J. Oldfield, Karl G. Wooldridge, Michael A. Jones, Greg J. Irving, David P. J. Turner, and Dlawer A. A. Ala'Aldeen. "CapA, an Autotransporter Protein of Campylobacter jejuni, Mediates Association with Human Epithelial Cells and Colonization of the Chicken Gut." Journal of Bacteriology 189, no. 5 (December 15, 2006): 1856–65. http://dx.doi.org/10.1128/jb.01427-06.

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ABSTRACT Two putative autotransporter proteins, CapA and CapB, were identified in silico from the genome sequence of Campylobacter jejuni NCTC11168. The genes encoding each protein contain homopolymeric tracts, suggestive of phase variation mediated by a slipped-strand mispairing mechanism; in each case the gene sequence contained frameshifts at these positions. The C-terminal two-thirds of the two genes, as well as a portion of the predicted signal peptides, were identical; the remaining N-terminal portions were gene specific. Both genes were cloned and expressed; recombinant polypeptides were purified and used to raise rabbit polyclonal monospecific antisera. Using immunoblotting, expression of the ca.116-kDa CapA protein was demonstrated for in vitro-grown cells of strain NCTC11168, for 4 out of 11 recent human fecal isolates, and for 2 out of 8 sequence-typed strains examined. Expression of CapB was not detected for any of the strains tested. Surface localization of CapA was demonstrated by subcellular fractionation and immunogold electron microscopy. Export of CapA was inhibited by globomycin, reinforcing the bioinformatic prediction that the protein is a lipoprotein. A capA insertion mutant had a significantly reduced capacity for association with and invasion of Caco-2 cells and failed to colonize and persist in chickens, indicating that CapA plays a role in host association and colonization by Campylobacter. In view of this demonstrated role, we propose that CapA stands for Campylobacter adhesion protein A.

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Janulczyk, Robert, Vega Masignani, Domenico Maione, Hervé Tettelin, Guido Grandi, and John L. Telford. "Simple Sequence Repeats and Genome Plasticity in Streptococcus agalactiae." Journal of Bacteriology 192, no. 15 (May 21, 2010): 3990–4000. http://dx.doi.org/10.1128/jb.01465-09.

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ABSTRACT Simple sequence repeats (SSRs) and their role in phase variation have been extensively studied in Gram-negative organisms, where they have been associated with antigenic variation and other adaptation strategies. In this study, we apply comparative genomics in order to find evidence of slipped-strand mispairing in the human Gram-positive pathogen Streptococcus agalactiae. In two consecutive screenings, 2,233 (650 + 1,583) SSRs were identified in our reference genome 2603V/R, and these loci were examined in seven other S. agalactiae genomes. A total of 56 SSR loci were found to exhibit variation, where gain or loss of repeat units was observed in at least one other genome, resulting in aberrant genotypes. Homopolymeric adenine tracts predominated among the repeats that varied. Positional analysis revealed that long polyadenine tracts were overrepresented in the 5′ ends of open reading frames (ORFs) and underrepresented in the 3′ ends. Repeat clustering in ORFs was also examined, and the highest degree of clustering was observed for a capsule biosynthesis gene and a pilus sortase. A statistical analysis of observed over expected ratios suggested a selective pressure against long homopolymeric tracts. Altered phenotypes were verified for three genes encoding surface-attached proteins, in which frameshifts or fusions led to truncation of proteins and/or affected surface localization through loss or gain of the cell wall sorting signal. The data suggest that SSRs contributes to genome plasticity in S. agalactiae but that the bet-hedging strategy is different from Gram-negative organisms.

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Shak, Joshua R., Jonathan J. Dick, Richard J. Meinersmann, Guillermo I. Perez-Perez, and Martin J. Blaser. "Repeat-Associated Plasticity in the Helicobacter pylori RD Gene Family." Journal of Bacteriology 191, no. 22 (September 11, 2009): 6900–6910. http://dx.doi.org/10.1128/jb.00706-09.

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ABSTRACT The bacterium Helicobacter pylori is remarkable for its ability to persist in the human stomach for decades without provoking sterilizing immunity. Since repetitive DNA can facilitate adaptive genomic flexibility via increased recombination, insertion, and deletion, we searched the genomes of two H. pylori strains for nucleotide repeats. We discovered a family of genes with extensive repetitive DNA that we have termed the H. pylori RD gene family. Each gene of this family is composed of a conserved 3′ region, a variable mid-region encoding 7 and 11 amino acid repeats, and a 5′ region containing one of two possible alleles. Analysis of five complete genome sequences and PCR genotyping of 42 H. pylori strains revealed extensive variation between strains in the number, location, and arrangement of RD genes. Furthermore, examination of multiple strains isolated from a single subject's stomach revealed intrahost variation in repeat number and composition. Despite prior evidence that the protein products of this gene family are expressed at the bacterial cell surface, enzyme-linked immunosorbent assay and immunoblot studies revealed no consistent seroreactivity to a recombinant RD protein by H. pylori-positive hosts. The pattern of repeats uncovered in the RD gene family appears to reflect slipped-strand mispairing or domain duplication, allowing for redundancy and subsequent diversity in genotype and phenotype. This novel family of hypervariable genes with conserved, repetitive, and allelic domains may represent an important locus for understanding H. pylori persistence in its natural host.

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Holtzman, E. J., L. F. Kolakowski, O. Geifman-Holtzman, D. G. O'Brien, M. Rasoulpour, A. P. Guillot, and D. A. Ausiello. "Mutations in the vasopressin V2 receptor gene in two families with nephrogenic diabetes insipidus." Journal of the American Society of Nephrology 5, no. 2 (August 1994): 169–76. http://dx.doi.org/10.1681/asn.v52169.

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Congenital nephrogenic diabetes insipidus (CNDI) is a rare X-linked disorder in which the renal collecting duct is unresponsive to arginine vasopressin, and thus, the urine is consistently hypotonic to plasma. As a result, affected individuals are unable to concentrate urine and suffer from episodes of severe dehydration and hypernatremia. Recently, the association between arginine vasopressin V2 receptor gene mutations and CNDI has been demonstrated. In this report, two additional novel molecular defects of the arginine vasopressin V2 receptor gene in CNDI families are described. In one family, the affected individual demonstrated a G-->T transversion causing a nonsense mutation in codon 231. This mutation results in a glutamic acid becoming a termination codon, causing premature termination and truncation of the encoded receptor protein. This mutation causes a NciI site within the gene to be abolished and a BsaWI site to be created. In the second family, affected individuals showed a 28-basepair duplicating insertion in the very beginning of exon 2 down-stream of the splice acceptor site. It was hypothesized that an insertion mutagenesis mechanism involves the formation of a stem-loop structure within the newly synthesized DNA strand, followed by a slipped mispairing. This may be a general mechanism for the deletion or insertion of repeated sequences within the genome. Recent data show that G-protein-coupled receptors are susceptible to many different mutations that often result in the loss of function, causing a similar clinical phenotype.

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Hammerschmidt, Sven, Astrid Müller, Hanna Sillmann, Martina Miihlenhoff, Raymond Borrow, Andrew Fox, Jos Putten, Wendell D. Zollinger, Rita Gerardy-Schahn, and Matthias Frosch. "Capsule phase variation in Neisseria meningitidis serogroup B by slipped-strand mispairing in the polysialyltransferase gene (siaD): correlation with bacterial invasion and the outbreak of meningococcal disease." Molecular Microbiology 20, no. 6 (June 1996): 1211–20. http://dx.doi.org/10.1111/j.1365-2958.1996.tb02641.x.

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Josenhans, Christine, Kathryn A. Eaton, Tracy Thevenot, and Sebastian Suerbaum. "Switching of Flagellar Motility in Helicobacter pyloriby Reversible Length Variation of a Short Homopolymeric Sequence Repeat in fliP, a Gene Encoding a Basal Body Protein." Infection and Immunity 68, no. 8 (August 1, 2000): 4598–603. http://dx.doi.org/10.1128/iai.68.8.4598-4603.2000.

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ABSTRACT The genome of Helicobacter pylori contains numerous simple nucleotide repeats that have been proposed to have regulatory functions and to compensate for the conspicuous dearth of master regulatory pathways in this highly host-adapted bacterium. H. pylori strain 26695, whose genomic sequence was determined by The Institute for Genomic Research (TIGR), contains a repeat of nine cytidines in the fliP flagellar basal body gene that splits the open reading frame in two parts. In this work, we demonstrate that the 26695C9 strain with a split fliP gene as sequenced by TIGR was nonflagellated and nonmotile. In contrast, earlier isolates of strain 26695 selected by positive motility testing as well as pig-passaged derivatives of 26695 were all flagellated and highly motile. All of these motile strains had a C8 repeat and consequently a contiguous fliP reading frame. By screening approximately 50,000 colonies of 26695C9 for motility in soft agar, a motile revertant with a C8 repeat could be isolated, proving that the described switch is reversible. ThefliP genes of 20 motile clinical H. pyloriisolates from different geographic regions possessed intactfliP genes with repeats of eight cytidines or the sequence CCCCACCC in its place. Isogenic fliP mutants of a motile, C8 repeat isolate of strain 26695 were constructed by allelic exchange mutagenesis and found to be defective in flagellum biogenesis. Mutants produced only small amounts of flagellins, while the transcription of flagellin genes appeared unchanged. These results strongly suggest a unique mechanism regulating motility in H. pylori which relies on slipped-strand mispairing-mediated mutagenesis of fliP.

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van Belkum, Alex, Stewart Scherer, Loek van Alphen, and Henri Verbrugh. "Short-Sequence DNA Repeats in Prokaryotic Genomes." Microbiology and Molecular Biology Reviews 62, no. 2 (June 1, 1998): 275–93. http://dx.doi.org/10.1128/mmbr.62.2.275-293.1998.

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SUMMARY Short-sequence DNA repeat (SSR) loci can be identified in all eukaryotic and many prokaryotic genomes. These loci harbor short or long stretches of repeated nucleotide sequence motifs. DNA sequence motifs in a single locus can be identical and/or heterogeneous. SSRs are encountered in many different branches of the prokaryote kingdom. They are found in genes encoding products as diverse as microbial surface components recognizing adhesive matrix molecules and specific bacterial virulence factors such as lipopolysaccharide-modifying enzymes or adhesins. SSRs enable genetic and consequently phenotypic flexibility. SSRs function at various levels of gene expression regulation. Variations in the number of repeat units per locus or changes in the nature of the individual repeat sequences may result from recombination processes or polymerase inadequacy such as slipped-strand mispairing (SSM), either alone or in combination with DNA repair deficiencies. These rather complex phenomena can occur with relative ease, with SSM approaching a frequency of 10−4 per bacterial cell division and allowing high-frequency genetic switching. Bacteria use this random strategy to adapt their genetic repertoire in response to selective environmental pressure. SSR-mediated variation has important implications for bacterial pathogenesis and evolutionary fitness. Molecular analysis of changes in SSRs allows epidemiological studies on the spread of pathogenic bacteria. The occurrence, evolution and function of SSRs, and the molecular methods used to analyze them are discussed in the context of responsiveness to environmental factors, bacterial pathogenicity, epidemiology, and the availability of full-genome sequences for increasing numbers of microorganisms, especially those that are medically relevant.

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de Vries, Nicolette, Dirk Duinsbergen, Ernst J. Kuipers, Raymond G. J. Pot, Patricia Wiesenekker, Charles W. Penn, Arnoud H. M. van Vliet, Christina M. J. E. Vandenbroucke-Grauls, and Johannes G. Kusters. "Transcriptional Phase Variation of a Type III Restriction-Modification System in Helicobacter pylori." Journal of Bacteriology 184, no. 23 (December 1, 2002): 6615–23. http://dx.doi.org/10.1128/jb.184.23.6615-6624.2002.

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ABSTRACT Phase variation is important in bacterial pathogenesis, since it generates antigenic variation for the evasion of immune responses and provides a strategy for quick adaptation to environmental changes. In this study, a Helicobacter pylori clone, designated MOD525, was identified that displayed phase-variable lacZ expression. The clone contained a transcriptional lacZ fusion in a putative type III DNA methyltransferase gene (mod, a homolog of the gene JHP1296 of strain J99), organized in an operon-like structure with a putative type III restriction endonuclease gene (res, a homolog of the gene JHP1297), located directly upstream of it. This putative type III restriction-modification system was common in H. pylori, as it was present in 15 out of 16 clinical isolates. Phase variation of the mod gene occurred at the transcriptional level both in clone MOD525 and in the parental H. pylori strain 1061. Further analysis showed that the res gene also displayed transcriptional phase variation and that it was cotranscribed with the mod gene. A homopolymeric cytosine tract (C tract) was present in the 5′ coding region of the res gene. Length variation of this C tract caused the res open reading frame (ORF) to shift in and out of frame, switching the res gene on and off at the translational level. Surprisingly, the presence of an intact res ORF was positively correlated with active transcription of the downstream mod gene. Moreover, the C tract was required for the occurrence of transcriptional phase variation. Our finding that translation and transcription are linked during phase variation through slipped-strand mispairing is new for H. pylori.

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van Selm, Saskia, Lisette M. van Cann, Marc A. B. Kolkman, Bernard A. M. van der Zeijst, and Jos P. M. van Putten. "Genetic Basis for the Structural Difference between Streptococcus pneumoniae Serotype 15B and 15C Capsular Polysaccharides." Infection and Immunity 71, no. 11 (November 2003): 6192–98. http://dx.doi.org/10.1128/iai.71.11.6192-6198.2003.

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ABSTRACT In a search for the genetic basis for the structural difference between the related Streptococcus pneumoniae capsular serotypes 15B and 15C and for the reported reversible switching between these serotypes, the corresponding capsular polysaccharide synthesis (cps) loci were investigated by keeping in mind that at the structural level, the capsules differ only in O acetylation. The cps locus of a serotype 15B strain was identified, partially PCR amplified with primers based on the related serotype 14 sequence, and sequenced. Sequence analysis revealed, among other open reading frames, an intact open reading frame (designated cps15bM) whose product, at the protein level, exhibited characteristics of previously identified acetyltransferases. Genetic analysis of the corresponding region in a serotype15C strain indicated that the same gene was present but had a premature stop in translation. Closer analysis indicated that the serotype 15B gene contained a short tandem TA repeat consisting of eight TA units. In serotype 15C, this gene contained nine TA units that resulted in a frameshift and a truncated product. Genetic analysis of 17 serotype 15B and 15C clinical isolates revealed a perfect correlation between the serotype and the length of the short tandem repeat in the putative O-acetyltransferase gene. The number of TA repeating units varied between seven and nine in the various isolates. Together, the data strongly suggest that the structural difference between serotypes 15B and 15C is based on variation in the short tandem TA repeat in the O-acetyltransferase gene and that the transition between serotypes is due to slipped-strand mispairing with deletion or insertion of TA units in the cps15bM gene.

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Vogler, Amy J., Christine Keys, Yoshimi Nemoto, Rebecca E. Colman, Zack Jay, and Paul Keim. "Effect of Repeat Copy Number on Variable-Number Tandem Repeat Mutations in Escherichia coli O157:H7." Journal of Bacteriology 188, no. 12 (June 15, 2006): 4253–63. http://dx.doi.org/10.1128/jb.00001-06.

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ABSTRACT Variable-number tandem repeat (VNTR) loci have shown a remarkable ability to discriminate among isolates of the recently emerged clonal pathogen Escherichia coli O157:H7, making them a very useful molecular epidemiological tool. However, little is known about the rates at which these sequences mutate, the factors that affect mutation rates, or the mechanisms by which mutations occur at these loci. Here, we measure mutation rates for 28 VNTR loci and investigate the effects of repeat copy number and mismatch repair on mutation rate using in vitro-generated populations for 10 E. coli O157:H7 strains. We find single-locus rates as high as 7.0 × 10−4 mutations/generation and a combined 28-locus rate of 6.4 × 10−4 mutations/generation. We observed single- and multirepeat mutations that were consistent with a slipped-strand mispairing mutation model, as well as a smaller number of large repeat copy number mutations that were consistent with recombination-mediated events. Repeat copy number within an array was strongly correlated with mutation rate both at the most mutable locus, O157-10 (r 2 = 0.565, P = 0.0196), and across all mutating loci. The combined locus model was significant whether locus O157-10 was included (r 2 = 0.833, P < 0.0001) or excluded (r 2 = 0.452, P < 0.0001) from the analysis. Deficient mismatch repair did not affect mutation rate at any of the 28 VNTRs with repeat unit sizes of >5 bp, although a poly(G) homomeric tract was destabilized in the mutS strain. Finally, we describe a general model for VNTR mutations that encompasses insertions and deletions, single- and multiple-repeat mutations, and their relative frequencies based upon our empirical mutation rate data.

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Promé, Danielle, Jean-Claude Promé, Henri Wajcman, Jean Riou, Frédéric Galactéros, Nathalie Carte, Emanuelle Leize, and Alain Vandorsselaer. "Hb Neuilly-Sur-Marne, a New Human Hemoglobin Variant with Ser-Asp-Leu Inserted between α86(F7) Leu and α87(F8) His: Characterization by High-Energy Collision-Induced Dissociation Liquid Secondary Ion Mass Spectrometry and Low Energy Collision-Induced Dissociation Tandem Mass Spectrometry in An Ion Trap Fitted with a Nanospray Ionization Source." European Journal of Mass Spectrometry 6, no. 2 (April 2000): 205–11. http://dx.doi.org/10.1255/ejms.325.

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Hemoglobin (Hb) Neuilly-sur-Marne is a new α-chain variant found during a systematic screening. Electrospray mass measurements showed the presence of an abnormal α-chain displaying a shift of +315 u relative to the normal value. Tryptic cleavage of this chain and molecular weight determination of the peptides indicated that the 315 u shift was located into the αT-9 peptide, the molecular weight of which is higher than 3000 Da. High-energy collision spectra of MH+ ions generated by liquid secondary ion mass spectrometry from the normal and abnormal αT-9 afforded mainly amino-terminal containing ions. They indicated that these two peptides have an identical amino acid sequence from their 1st to 25th residues, the mass increase being thus located beyond this point. Too few ions were formed to establish reliably the sequence forward. It was hypothesized that this mass shift could result from a repeated sequence since the sum of the mass of the three residues—leucine, serine and aspartic acid—preceding position 25 is exactly 315 u. To get sequence information above position 25, decomposition of multicharged species was attempted. An ion trap fitted with a nanospray ionization source was used. It produced mainly triply- and quadruply-charged ions. Decomposition of the triply-charged ion afforded a series of singly-charged Y-ions in the expected region, giving a readily interpretable sequence. It confirmed the insertion of a Ser-Asp-Leu sequence above position 25. Surprisingly, decomposition of the quadruply-charged molecular ion gave too few ions to provide sequence information in the expected region. Spectra were dominated by some multicharged Y ions arising from cleavages close to the amino end. Tandem mass spectrometry experiments were performed on the abundant Y303+ ion and produced again a singly-charged Y ion series in the suitable domain which confirmed the above result. In Hb Neuilly-sur Marne this insertion of the Ser-Asp-Leu residues. between positions α-86 and α-87 is very likely due to a slipped strand mispairing mechanism.

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Pei, Y., N. He, K. Wang, M. Kasenda, A. D. Paterson, G. Chan, Y. Liang, et al. "A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds." Journal of the American Society of Nephrology 9, no. 10 (October 1998): 1853–60. http://dx.doi.org/10.1681/asn.v9101853.

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Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Linkage studies have shown that the majority (approximately 85%) of cases are due to mutations in PKD1 on chromosome 16p, while mutations in PKD2 on chromosome 4q account for most of the remaining cases. Locus heterogeneity in ADPKD is known to contribute to differences in disease severity, with PKD1-linked families having earlier onset of end-stage renal disease (ESRD) than PKD2-linked families (mean age at ESRD: 56 versus 70, respectively). In this study, 11 Canadian families with ADPKD were screened for PKD2 mutations. In four families, linkage to PKD2 was previously documented. In the remaining seven smaller families, one or more affected members had late-onset ESRD at age 70 or older. Using single-stranded conformational polymorphism analysis, one affected member from each family was screened for mutations in all 15 exons of PKD2, which were PCR-amplified from genomic templates. A spectrum of mutations was found in approximately 73% (8 of 11) of the families screened, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In three unrelated families, insertion or deletion of an adenosine in a polyadenosine tract (i.e., (A)8 at nt 2152-2159) was found on exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from "slipped strand mispairing." All mutations, scattered between exons 1 and 11, are predicted to result in a truncated polycystin 2 that lacks both the calcium-binding EF-hand domain and the two cytoplasmic domains required for the interaction of polycystin 2 with polycystin 1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. Thus, these findings are consistent with other recently published reports and suggest that most PKD2 mutations are inactivating.

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Levine, J. G., R. M. Schaaper, and D. M. DeMarini. "Complex frameshift mutations mediated by plasmid pKM101: mutational mechanisms deduced from 4-aminobiphenyl-induced mutation spectra in Salmonella." Genetics 136, no. 3 (March 1, 1994): 731–46. http://dx.doi.org/10.1093/genetics/136.3.731.

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Abstract We used colony probe hybridization and polymerase chain reaction/DNA sequence analysis to determine the mutations in approximately 2,400 4-aminobiphenyl (4-AB) +S9-induced revertants of the -1 frameshift allele hisD3052 and of the base-substitution allele hisG46 of Salmonella typhimurium. Most of the mutations occurred at sites containing guanine, which is the primary base at which 4-AB forms DNA adducts. A hotspot mutation involving the deletion of a CG or GC within the sequence CGCGCGCG accounted for 100 and 99.9%, respectively, of the reversion events at the hisD3052 allele in the pKM101 plasmid-minus strains TA1978 (uvr+) and TA1538 (delta uvrB). In strain TA98 (delta uvrB, pKM101), which contained the SOS DNA repair system provided by the pKM101 plasmid, approximately 85% of the revertants also contained the hotspot deletion; the remaining approximately 15% contained one of two types of mutations: (1) complex frameshifts that can be described as a -2 or +1 frameshift and an associated base substitution and (2) deletions of the CC or GG sequences that flank the hotspot site (CCGCGCGCGG). We propose a misincorporation/slippage model to account for these mutations in which (1) pKM101-mediated misincorporation and translesion synthesis occurs across a 4-AB-adducted guanine; (2) the instability of such a mispairing and/or the presence of the adduct leads to strand slippage in a run of repeated bases adjacent to the adducted guanine; and (3) continued DNA synthesis from the slipped intermediate produces a frameshift associated with a base substitution. This model readily accounts for the deletion of the CC or GG sequences flanking the hotspot site, indicating that these mutations are, in fact, complex mutations in disguise (i.e., cryptic complex frameshifts). The inferred base-substitution specificity associated with the complex frameshifts at the hisD3052 allele (primarily G.C-->T.A transversions) is consistent with the finding that 4-AB induced primarily G.C-->T.A transversions at the hisG46 base-substitution allele. The model also provides a framework for understanding the different relative mutagenic potencies of 4-AB at the two alleles in the various DNA repair backgrounds of Salmonella.

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Di Pierro, Elena, Valentina Brancaleoni, Valeria Moriondo, and Maria D. Cappellini. "Two Functional Mutations in cis of the Ferrochelatase Gene (FECH) Cause Erythropoietic Protoporphyria (EPP)." Blood 106, no. 11 (November 16, 2005): 3544. http://dx.doi.org/10.1182/blood.v106.11.3544.3544.

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Abstract Erythropoietic protoporphyria is an autosomal dominant disease with incomplete penetrance, due to reduced activity of ferrochelatase (FECH), a mitochondrial enzyme that catalyzes the final step of the heme biosynthetic pathway. The clinical phenotype of EPP results from coinheritance of a mutated allele and a wild-type low expressed allele of the FECH gene. To date, more than 100 different mutations have been identified in the FECH gene of EPP patients. Different evidence suggests that an entire haplotype (−251G, IVS1-23T, and IVS3-48C) reduces allele expression. In two Italian EPP patients carring the −250G>C mutation in the promoter region we recently demonstrated the loss of an SP1 binding site causing a strong impairment of promoter activity. In both patients we searched for the GTC haplotype on the other allele. Family segregation studies established that the GTC haplotype was in trans to the −250C mutation. Indeed, asymptomatic parents carried either the three polymorphisms or the point mutation. In both patients only the IVS3-48C polymorphism was in apparent homozygosity since family studies established the absence of Mendelian segregation. To reduce the possibility of interfering polymorphisms in the primer sites, a second set of sequencing primers was designed. Apparent homozygosity was confirmed. We assumed the presence of an intronic deletion on the same allele carrying the −250G>C mutation. In order to establish the size of the deletion we performed a semiquantitative RT-PCR analysis on fresh RNA and XL-PCR analysis on DNA. In both cases the primers were situated in regions outside the heterozygotic polymorphisms. As expected RNA analysis revealed the presence of a normal fragment of 612bp and a shorter fragment of 343bp that was less abundant compared to controls. Sequence analysis on the isolated abnormal fragment showed loss of exons 3 and 4. DNA analysis revealed the presence of two fragments of 21440bp and 15864bp respectively. We performed an internal long PCR to obtain two shorter fragments 9717bp and 4141bp respectively. Sequence analysis on the isolated abnormal fragment showed a 5576bp deletion defined by two short direct repeats of about 40bp. The deleted region includes both a first repeat and interposed sequence. These results showed the presence of two functional mutations on the same allele. Deletion contributed to create a null allele preventing formation of the correct mRNA that is already strongly impaired by the −250G>C mutation. The deletion is caused by slipped strand mispairing or more probably by unequal intragenic recombination. These two mutations in the promoter region and intron 3 respectively, are located in the same regions as the −251G and ivs3-48C polymorphisms, strongly suggesting a functional relationship between these two regions.

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"Slipped-strand mispairing: a major mechanism for DNA sequence evolution." Molecular Biology and Evolution, May 1987. http://dx.doi.org/10.1093/oxfordjournals.molbev.a040442.

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"Slipped-strand mispairing in a plastid gene: rpoC2 in grasses (Poaceae)." Molecular Biology and Evolution, January 1994. http://dx.doi.org/10.1093/oxfordjournals.molbev.a040084.

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40

Kurukulasuriya, Shakya P., Mo H. Patterson, and Janet E. Hill. "Slipped strand mispairing in the gene encoding sialidase NanH3 in Gardnerella spp." Infection and Immunity, December 23, 2020. http://dx.doi.org/10.1128/iai.00583-20.

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Cell wall proteins with sialidase activity are involved in carbohydrate assimilation, adhesion to mucosal surfaces, and biofilm formation. Gardnerella spp. inhabit the human vaginal microbiome and encode up to three sialidase enzymes, two of which are suspected to be cell wall associated. Here we demonstrate that the gene encoding extracellular sialidase NanH3 is found almost exclusively in G. piotii and closely related Gardnerella genome sp. 3, and its presence correlates with sialidase positive phenotype in a collection of 112 Gardnerella isolates. The nanH3 gene sequence includes a homopolymeric repeat of cytosines that varies in length within cell populations, indicating that this gene is subject to slipped-strand mispairing, a mechanisms of phase variation in bacteria. Variation in the length of the homopolymer sequence results in encoding of either the full length sialidase protein or truncated peptides lacking the sialidase domain due to introduction of reading-frame shifts and premature stop codons. Phase variation in NanH3 may be involved in immune evasion or modulation of adhesion to host epithelial cells, and formation of biofilms characteristic of the vaginal dysbiosis known as bacterial vaginosis.

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Gallo, Mary C., Charmaine Kirkham, Samantha Eng, Remon S. Bebawee, Yong Kong, Melinda M. Pettigrew, Hervé Tettelin, and Timothy F. Murphy. "Changes in IgA Protease Expression Are Conferred by Changes in Genomes during Persistent Infection by NontypeableHaemophilus influenzaein Chronic Obstructive Pulmonary Disease." Infection and Immunity 86, no. 8 (May 14, 2018). http://dx.doi.org/10.1128/iai.00313-18.

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ABSTRACTNontypeableHaemophilus influenzae(NTHi) is an exclusively human pathobiont that plays a critical role in the course and pathogenesis of chronic obstructive pulmonary disease (COPD). NTHi causes acute exacerbations of COPD and also causes persistent infection of the lower airways. NTHi expresses four IgA protease variants (A1, A2, B1, and B2) that play different roles in virulence. Expression of IgA proteases varies among NTHi strains, but little is known about the frequency and mechanisms by which NTHi modulates IgA protease expression during infection in COPD. To assess expression of IgA protease during natural infection in COPD, we studied IgA protease expression by 101 persistent strains (median duration of persistence, 161 days; range, 2 to 1,422 days) collected longitudinally from patients enrolled in a 20-year study of COPD upon initial acquisition and immediately before clearance from the host. Upon acquisition, 89 (88%) expressed IgA protease. A total of 16 of 101 (16%) strains of NTHi altered expression of IgA protease during persistence. Indels and slipped-strand mispairing of mononucleotide repeats conferred changes in expression ofigaA1,igaA2, andigaB1. Strains withigaB2underwent frequent changes in expression of IgA protease B2 during persistence, mediated by slipped-strand mispairing of a 7-nucleotide repeat, TCAAAAT, within the open reading frame ofigaB2. We conclude that changes inigagene sequences result in changes in expression of IgA proteases by NTHi during persistent infection in the respiratory tract of patients with COPD.

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Harhay, Gregory P., Dayna M. Harhay, James L. Bono, Sarah F. Capik, Keith D. DeDonder, Michael D. Apley, Brian V. Lubbers, Bradley J. White, Robert L. Larson, and Timothy P. L. Smith. "A Computational Method to Quantify the Effects of Slipped Strand Mispairing on Bacterial Tetranucleotide Repeats." Scientific Reports 9, no. 1 (December 2019). http://dx.doi.org/10.1038/s41598-019-53866-z.

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AbstractThe virulence and pathogenicity of bacterial pathogens are related to their adaptability to changing environments. One process enabling adaptation is based on minor changes in genome sequence, as small as a few base pairs, within segments of genome called simple sequence repeats (SSRs) that consist of multiple copies of a short sequence (from one to several nucleotides), repeated in series. SSRs are found in eukaryotes as well as prokaryotes, and length variation in them occurs at frequencies up to a million-fold higher than bacterial point mutations through the process of slipped strand mispairing (SSM) by DNA polymerase during replication. The characterization of SSR length by standard sequencing methods is complicated by the appearance of length variation introduced during the sequencing process that obscures the lower abundance repeat number variants in a population. Here we report a computational approach to correct for sequencing process-induced artifacts, validated for tetranucleotide repeats by use of synthetic constructs of fixed, known length. We apply this method to a laboratory culture of Histophilus somni, prepared from a single colony, and demonstrate that the culture consists of populations of distinct sequence phase and length variants at individual tetranucleotide SSR loci.

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Harhay, Gregory P., Dayna M. Harhay, James L. Bono, Sarah F. Capik, Keith D. DeDonder, Michael D. Apley, Brian V. Lubbers, Bradley J. White, Robert L. Larson, and Timothy P. L. Smith. "Publisher Correction: A Computational Method to Quantify the Effects of Slipped Strand Mispairing on Bacterial Tetranucleotide Repeats." Scientific Reports 10, no. 1 (January 28, 2020). http://dx.doi.org/10.1038/s41598-020-58622-2.

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Journal articles on the topic 'Slipped strand mispairing'

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