• R. Jayaraman

      Articles written in Journal of Genetics

    • Cairnsian mutagenesis inEscherichia coli: Genetic evidence for two pathways regulated bymutS andmutL genes

      R. Jayaraman

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      The phenomenon of Cairnsian mutagenesis was studied inEscherichia coli mutants bearing mutations inmutS,mutL,recA andlexA genes. It is shown that development of resistance to exogenous valine could be used as an example of Cairnsian response. Strains defective inmutS andmutL show a high frequency of Cairnsian mutagenesis to valine resistance. The response inmutS mutants is dependent upon cleavability of the LexA protein whereas that inmutL is not. The latter is independent ofrecA also. The need for LexA protein cleavage inmutS mutants can be bypassed by over-production of the RecA protein due to arecA operator constitutive mutation. Genetic evidence is presented to show that the products ofmutS andmutL genes negativelycontrol two pathways of Cairnsian mutagenesis. Cairnsian response is also elicited whenmutS ormutL strains are grown under conditions wherein a required nutrient is present in sub-optimal concentrations. Random, unselected mutagenic events are likely to occur during or after Cairnsian mutagenesis provided the cells are SOS inducible.

    • Genetic evidence for interaction betweenfitA, fitB andrpoB gene products and its implication in transcription control inEscherichia coli

      M. Hussain Munavar R. Jayaraman

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      ThefitB mutation (Fit, factor involved in transcription) inE. coli was earlier identified as an extragenic suppressor of thefitA76 mutation, which confers a temperaturesensitive transcription defect. Here we show that thefitB mutation by itself confers a temperature-sensitive phenotype depending on the presence or absence of NaCl or glucose, or both, in the medium. ThefitB mutation suppresses the temperature-sensitive phenotype due to thefitA24 mutation also. However, suppression offit A24 byfit B is restricted to rich medium, unlike suppression in thefitA76 fitB combination where it is independent of the medium. The strain harbouringfitA76, fitA24 andfitB mutations shows the extragenically suppressed (as infit A76 fit B) phenotype. Severalrif (rpoB) alleles isolated in afitB genetic background affect growth of thefit B mutant, depending on the medium of growth, temperature, and presence or absence of rifampicin. We propose a model for interaction betweenfitA andfitB gene products and involvement of thefit genes in transcription controlin vivo.

    • Leakiness of genetic markers and susceptibility to post-plating mutagenesis inEscherichia coli

      R. Jayaraman

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      WhenEscherichia coli strain AB1157 is subjected to starvation for threonine or leucine on solid media, threonine-independent or leucine-independent colonies continue to emerge for several days after plating. This process is strongly streptomycin dependent. Under identical conditions arginine-independent colonies do not arise when arginine starvation is imposed. Since thethr1 andleuB6 alleles of AB1157 could be classified as ‘leaky’ while theargE3 allele cannot be so classified, there seems to be a correlation between leakiness of mutant genetic markers and post-plating mutagenesis which counters the effect of the mutations. Some of the threonine-independent variants acquired the ability to increase the leakiness of otherwise nonleaky markers such asargE3 and permit development of arginine independence in arecA-dependent,lexA-independent manner. I show that these variants harbour a mutation, tentatively namedadi (adaptation inducer), at around 72 min on the genetic map, and that theadi mutation increases the intrinsic leakiness of alacZ (ochre) mutation, perhaps by enhanced translational error. These observations are discussed in relation to the phenomenon of ‘adaptive’ mutagenesis, its possible mechanism, and its specificity.

    • Emergence of a mutagenic ochre suppressor mutation under lactose selection in appm mutant ofEscherichia coli harbouring the F′lacZU118 episome

      R. Jayaraman

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      WhenEscherichia coli harbouring theppm (earlier calledadi) mutation and the F′lacZU118 episome is subjected to lactose selection in the presence of suboptimal concentrations of glycerol, Lac+ colonies emerge after 5–6 days. They are shown to harbour an ochre suppressor mutation at 15.15 min. Inactivation ofrecA results in approximately four-fold reduction in the response. In theppm — ochre suppressor double mutant background the leakiness of thelacZ allele carried by F′ CC105 is enhanced, suggesting misreading of a valine codon (GUG) as glutamic acid codon (GAG). This is accompanied by reversion of thelacZ mutation tolacZ+ (GTG → GAG). In LB medium both the leakiness and reversion are inhibited by streptomycin. Inactivation ofrecA did not affect leakiness but abolished reversion. These data are discussed in relation to the importance of allele leakiness and restricted growth in stationary-phase (adaptive) mutagenesis.

    • Modulation of allele leakiness and adaptive mutability inEscherichia coli

      R. Jayaraman

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      It is shown that partial phenotypic suppression of two ochre mutations (argE3 andlacZU118) and an amber mutation (inargE) by sublethal concentrations of streptomycin in anrpsL+ (streptomycin-sensitive) derivative of theEscherichia coli strain AB1157 greatly enhances their adaptive mutability under selection. Streptomycin also increases adaptive mutability brought about by theppm mutation described earlier. Inactivation ofrecA affects neither phenotypic suppression by streptomycin nor replication-associated mutagenesis but abolishes adaptive mutagenesis. These results indicate a causal relationship between allele leakiness and adaptive mutability.

    • Mutators and hypermutability in bacteria: the Escherichia coli paradigm

      R. Jayaraman

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      Mutators (also called hypermutators) are mutants which show higher than normal spontaneous mutation frequencies, ranging from 10–20 fold to 100–1000 fold higher, or sometimes even more, than wild-type cells. Being a mutator is advantageous to the organism when adapting to environmental changes or stressful situations, such as moving from one habitat to another, one host to another, exposure to antibiotics etc. However, this advantage is only a short-term benefit. In the long run, hypermutability leads to a fitness disadvantage due to accumulation of deleterious mutations or antagonistic pleiotropy or both. Contrary to intuitive expectations, hypermutability is commonly encountered in natural bacterial populations, especially among clinical isolates. It is believed to be involved in the emergence of antibiotic resistance and a hindrance to the treatment of infectious diseases. Here, I review the state of knowledge on the common mechanisms of hypermutability such as errors/defects in DNA replication, proof reading, mismatch repair, oxidative DNA damage, mistranslation etc., as well as phenomena associated with these processes, using Escherichia coli as a paradigmatic organism.

    • Hypermutation and stress adaptation in bacteria

      R. Jayaraman

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      Hypermutability is a phenotype characterized by a moderate to high elevation of spontaneous mutation rates and could result from DNA replication errors, defects in error correction mechanisms and many other causes. The elevated mutation rates are helpful to organisms to adapt to sudden and unforeseen threats to survival. At the same time hypermutability also leads to the generation of many deleterious mutations which offset its adaptive value and therefore disadvantageous. Nevertheless, it is very common in nature, especially among clinical isolates of pathogens. Hypermutability is inherited by indirect (second order) selection along with the beneficial mutations generated. At large population sizes and high mutation rates many cells in the population could concurrently acquire beneficial mutations of varying adaptive (fitness) values. These lineages compete with the ancestral cells and also among themselves for fixation. The one with the ‘fittest’ mutation gets fixed ultimately while the others are lost. This has been called ‘clonal interference’ which puts a speed limit on adaptation. The original clonal interference hypothesis has been modified recently. Nonheritable (transient) hypermtability conferring significant adaptive benefits also occur during stress response although its molecular basis remains controversial. The adaptive benefits of heritable hypermutability are discussed with emphasis on host–pathogen interactions.

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