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Biomedical subjects

J Ninio

Publications and source records attributed to J Ninio.

17 recordsLinked to original sources
PubMed1991

Connections between translation, transcription and replication error-rates.

The analysis of published data from E coli suggests that in all three processes of translation, transcription, and replication, a minority of errors are produced by sub-classes of error-prone components. These add to the basal level of errors a noise of about 10 to 30%. Each one of the three processes contributes to the noisiness of the two others in a loose manner: a large increase in one error-rate produces a moderate increase in another error-rate. The strongest influence is that of transcription on translation errors. There it is possible that a majority of the misacylation errors are produced during the encounter of a correct amino acyl-tRNA ligase with a mistranscribed tRNA. Extreme mutator mutants are expected to produce a moderate increase in translation errors.

DNA Replication↗
PubMed1991

Transient mutators: a semiquantitative analysis of the influence of translation and transcription errors on mutation rates.

A population of bacteria growing in a nonlimiting medium includes mutator bacteria and transient mutators defined as wild-type bacteria which, due to occasional transcription or translation errors, display a mutator phenotype. A semiquantitative theoretical analysis of the steady-state composition of an Escherichia coli population suggests that true strong genotypic mutators produce about 3 x 10(-3) of the single mutations arising in the population, while transient mutators produce at least 10% of the single mutations and more than 95% of the simultaneous double mutations. Numbers of mismatch repair proteins inherited by the offspring, proportions of lethal mutations and mortality rates are among the main parameters that influence the steady-state composition of the population. These results have implications for the experimental manipulation of mutation rates and the evolutionary fixation of frequent but nearly neutral mutations (e.g., synonymous codon substitutions).

Bacteria↗
PubMed1990

The revised genetic code.

Recent findings on the genetic code are reviewed, including selenocysteine usage, deviations in the assignments of sense and nonsense codons, RNA editing, natural ribosomal frameshifts and non-orthodox codon-anticodon pairings. A multi-stage codon reading process is presented.

Genetic Code↗
PubMed1989

String analysis and energy minimization in the partition of DNA sequences.

Two approaches to the understanding of biological sequences are confronted. While the recognition of particular signals in sequences relies on complex physical interactions, the problem is often analysed in terms of the presence or absence of literal motifs (strings) in the sequence. We present here a test-case for evaluating the potential of this approach. We classify DNA sequences as positive or negative depending on whether they contain a single melted domain in the middle of the sequence, which is a global physical property. Two sets of positive "biological" sequences were generated by a computer simulation of evolutionary divergence along the branches of a phylogenetic tree, under the constraint that each intermediate sequence be positive. These two sets and a set of random positive sequences were subjected to pattern analysis. The observed local patterns were used to construct expert systems to discriminate positive from negative sequences. The experts achieved 79% to 90% success on random positive sequences and up to 99% on the biological sets, while making less than 2% errors on negative sequences. Thus, the global constraints imposed on sequences by a physical process may generate local patterns that are sufficient to predict, with a reasonable probability, the behaviour of the sequences. However, rather large sets of biological sequences are required to generate patterns free of illegitimate constraints. Furthermore, depending upon the initial sequence, the sets of sequences generated on a phylogenetic tree may be amenable or refractory to string analysis, while obeying identical physical constraints. Our study clarifies the relationship between experts' errors on positive and negative sequences, and the contributions of legitimate and illegitimate patterns to these errors. The test-case appears suitable both for further investigations of problems in the theory of sequence evolution and for further testing of pattern analysis techniques.

Base Sequence↗
PubMed1988

Nucleotide excision by E. coli DNA polymerase I in proofreading and non-proofreading modes.

Escherichia coli DNA polymerase I exists in at least two distinct kinetic forms. When it binds to a template, the proofreading activity is usually switched off. As the enzyme progresses along the template, it becomes more and more competent for excision. This phenomenon introduces a link between fidelity and processivity. Processivity is best studied when the chain-length distributions of synthesized polymers are stationary. Even then, however, one cannot avoid multiple initiations on a given template by the same molecule of the enzyme. When synthesis is initiated with primers of lengths 15 or 20, a strange phenomenon is observed. It seems that the polymerase starts by hydrolyzing the primer down to a length of 7-10 nucleotides and only then starts to add nucleotides. It does so in a low-accuracy mode, suggesting that, while the exonuclease is clearly active, it does not contribute to proofreading. The warm-up of the proofreading function is therefore reinterpreted as a switch between two modes of behaviour: a mode 1 of low accuracy in which the 3'----5' exonuclease, while active, is uncoupled from the polymerase and does not contribute to proofreading, and a mode 2 of high accuracy in which the exonuclease is kinetically linked to the polymerase activity.

DNA Polymerase I↗
PubMed1987

Variations with position of replication errors due to exonuclease warm-up.

A.A mismatch errors occurring during poly(dA) replication with the Klenow fragment of E. coli DNA polymerase I have been quantified. The A/T ratio measured for chains extended by 1-25 nucleotides decreases by a factor of at least 15 from beginning to end. The deduced true error rate may decrease by a factor of 2.5 at each successive nucleotide addition. When ddATP is used instead of dATP, the ddA/T ratio indicates little variation of the misincorporation probability with position. Thus, the accuracy improvement in the first case is due to a warm-up of the proofreading function.

Base Composition↗
PubMed1987

Catalysis by a prebiotic nucleotide analog of histidine.

A ribosylated derivative of adenine, N6 ribosyl adenine, likely to have formed under prebiotic synthesis conditions, is shown to be as active as histidine in the model reaction of p-nitrophenyl acetate hydrolysis. This property widens the range of reactions accessible to RNA catalysis.

Adenosine↗
PubMed1979

Prediction of pairing schemes in RNA molecules-loop contributions and energy of wobble and non-wobble pairs.

Previously published models for predicting pairing schemes in RNA molecules, when applied to tRNA, give the clover leaf structure in only half the cases. We made a systematic investigation of the predictability of the clover leaf structure under various assumptions concerning the energetic contributions of single and double-stranded regions. We tested 21 different models and variants on a set of 100 tRNA sequences and many other variants on a smaller set of sequences. In our models we allowed not only G.C, A.U and G.U pairing, but also every other pair. Under conditions which are much less restrictive than those of previous attempts, we can nevertheless reach 90 per cent predictability for the clover leaf structure of tRNA. A most surprising and far-reaching result is that we can assign to C.G and C.C pairs binding energies quite close to the energies of G.U pairs, and still predict the clover leaf. The following ranking for non-complementary pairs was obtained : G.U, G.G and C.C, U.U, C.A, A.A and G.A, U.C. The main practical innovation which made possible the improvements in predictability are: i) not counting the stacking of base pairs separated by a bulge loop; ii) making the terminal C.C's in stems more stable than the terminal A.U's by merely -- 0.7 kcal; iii) replacing the distinction between G.C and A.U-closed loops by a distinction based on the presence of loop-favoring residues; iv) carefully adjusting the energetic balance between the various kinds of loops; v) narrowing the gap between the GC/GC and the GC/AU contributions; vi) using observations on nearest-neighbours in tRNA sequences to refine the contributions of G.U pairs.

Base Composition↗
PubMed1978

Heteropolynucleotides as templates for non-enzymatic polymerizations.

We have studied a number of condensation reactions involving ImpU, ImpT, ImpC, ImpA, ImpG, ImpUgG and ImpCpA as activated nucleotide donors and a variety of homo- and hetero-polynucleotides as templates. We did not not obtain any evidence of a template effect with ImpU and ImpT, but observed some condensation of ImpC with GpG on appropriate templates. ImpA and ImpG take part in a number of more or less efficient template-directed reactions, as do ImpUpG and ImpCpA. Our results suggest that, on the primitive Earth, pyrimidine nucleotides could most easily have been incorporated into polymers as constituents of short oligomers, which contained one or more purine nucleotide. The linkage of the product depends strongly on the nature of the substrates; the percentage of the natural 3'-5'-linkage was, in some cases, less than 10% and, in others, as high as 70%. Wobble-pairing was often very effective in promoting condensations, suggesting that transition mutations would have been very frequent in prebiotic polynucleotide replication.

Chemical Phenomena↗
PubMed1977

The geometry of the correspondence between two retinal projections.

Since each retinal projection of an object has some definite geometric relation to it, the two projections of a same object are related to each other. The correspondences between points, linear segments, and orientations on the two retinas are discussed thoroughly in three-dimensional geometry, and the constraints that tie the projections (the 'projective invariants') are presented. Some widely held conceptions on disparity or the ambiguity problem in binocular stereopsis appear to be based upon representation that are correct in particular situations, but are misleading in the general case. I suggest that in order to achieve binocular stereopsis, the brain does not proceed by complete trial and error, but may guide its search for correspondences by taking advantage of the geometric constraints. There are at least four major possible strategies: (i) a metric strategy, as initially proposed by Julesz; (ii) a projective strategy based on the law of invariance of the anharmonic ratio and Desargue's theorem; (iii) a perspective strategy discussed in relation to the homology relationships between vanishing points and in relation to physiological studies on cells of visual cortex; and (iv) a more dynamic strategy based upon the geometric properties of the Zöllner illusion.

Animals↗
PubMed1975

Kinetic amplification of enzyme discrimination.

The dependence of the accuracy of enzymatic systems on the mechanism of the catalyzed reaction is investigated, using a probabilistic approach. Certain mechanisms of reaction, involving a delay in one of the steps act as kinetic amplifiers of molecular discriminations. The relationship between our scheme for a delayed reaction [1] and Hopfield's scheme [i] is discussed.

DNA Nucleotidyltransferases↗