Biomedical subjects

Ran Kafri

Publications and source records attributed to Ran Kafri.

5 recordsLinked to original sources

PubMed2006

The regulatory utilization of genetic redundancy through responsive backup circuits.

Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes. One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses. Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime. In contrast, numerous reports describe instances of functional overlaps that have been conserved throughout extended evolutionary periods. More interestingly, many such backed-up genes were shown to be transcriptionally responsive to the intactness of their redundant partner and are up-regulated if the latter is mutationally inactivated. By manual inspection of the literature, we have compiled a list of such "responsive backup circuits" in a diverse list of species. Reviewing these responsive backup circuits, we extract recurring principles characterizing their regulation. We then apply modeling approaches to explore further their dynamic properties. Our results demonstrate that responsive backup circuits may function as ideal devices for filtering nongenetic noise from transcriptional pathways and obtaining regulatory precision. We thus challenge the view that such redundancies are simply leftovers of ancient duplications and suggest they are an additional component to the sophisticated machinery of cellular regulation. In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.

Animals↗

PubMed2005

Transcription control reprogramming in genetic backup circuits.

A key question in molecular genetics is why severe mutations often do not result in a detectably abnormal phenotype. This robustness was partially ascribed to redundant paralogs that may provide backup for one another in case of mutation. Mining mutant viability and mRNA expression data in Saccharomyces cerevisiae, we found that backup was provided predominantly by paralogs that are expressed dissimilarly in most growth conditions. We considered that this apparent inconsistency might be resolved by a transcriptional reprogramming mechanism that allows the intact paralog to rescue the organism upon mutation of its counterpart. We found that in wild-type cells, partial coregulation across growth conditions predicted the ability of paralogs to alter their transcription patterns and to provide backup for one another. Notably, the sets of regulatory motifs that controlled the paralogs with the most efficient backup activity deliberately overlapped only partially; paralogs with highly similar or dissimilar sets of motifs had suboptimal backup activity. Such an arrangement of partially shared regulatory motifs reconciles the differential expression of paralogs with their ability to back each other up.

Kinetics↗

PubMed2005

Polymer GARD: computer simulation of covalent bond formation in reproducing molecular assemblies.

The basic Graded Autocatalysis Replication Domain (GARD) model consists of a repertoire of small molecules, typically amphiphiles, which join and leave a non-covalent micelle-like assembly. Its replication behavior is due to occasional fission, followed by a homeostatic growth process governed by the assembly's composition. Limitations of the basic GARD model are its small finite molecular repertoire and the lack of a clear path from a 'monomer world' towards polymer-based living entities. We have now devised an extension of the model (polymer GARD or P-GARD), where a monomer-based GARD serves as a 'scaffold' for oligomer formation, as a result of internal chemical rules. We tested this concept with computer simulations of a simple case of monovalent monomers, whereby more complex molecules (dimers) are formed internally, in a manner resembling biosynthetic metabolism. We have observed events of dimer 'take-over' - the formation of compositionally stable, replication-prone quasi stationary states (composomes) that have appreciable dimer content. The appearance of novel metabolism-like networks obeys a time-dependent power law, reminiscent of evolution under punctuated equilibrium. A simulation under constant population conditions shows the dynamics of takeover and extinction of different composomes, leading to the generation of different population distributions. The P-GARD model offers a scenario whereby biopolymer formation may be a result of rather than a prerequisite for early life-like processes.

Computer Simulation↗

PubMed2004

Probability rule for chiral recognition.

Molecular Chirality is of central interest in biological studies because enantiomeric compounds, while indistinguishable by most inanimate systems, show profoundly different properties in biochemical environments. Enantioselective separation methods, based on the differential recognition of two optical isomers by a chiral selector, have been amply documented. Also, great effort has been directed towards a theoretical understanding of the fundamental mechanisms underlying the chiral recognition process. Here we report a comprehensive data examination of enantio separation measurements for over 72000 chiral selector-select and pairs from the chiral selection compendium CHIRBASE. The distribution of alpha = k'(D)/k'(L) values was found to follow a power law, equivalent to an exponential decay for chiral differential free energies. This observation is experimentally relevant in terms of the number of different individual or combinatorial selectors that need to be screened in order to observe alpha values higher than a preset minimum. A string model for enantiorecognition (SMED) formalism is proposed to account for this observation on the basis of an extended Ogston three-point interaction model. Partially overlapping molecular interaction domains are analyzed in terms of a string complementarity model for ligand-receptor complementarity. The results suggest that chiral selection statistics may be interpreted in terms of more general concepts related to biomolecular recognition.

Algorithms↗

PubMed2002

Test of a statistical model for molecular recognition in biological repertoires.

A chance encounter between members of a random repertoire and a molecular target is characteristic of different biological systems, including the immune and olfactory pathways as well as combinatorial libraries. In such systems, the affinity between the target and members of the repertoire is distributed with a probability function describing the propensity of obtaining a particular affinity value. We have previously proposed a phenomenological receptor affinity distribution (RAD) formalism, which describes this probability function based on simple statistical considerations. In the present analysis, we use published data from diverse experimental systems, including phage display libraries, immunoglobulins and enzymes, to test the RAD model and to compare it to other affinity distribution formalisms. The RAD model is found to provide the best description for binding data for over eight orders of magnitude on the affinity scale, and to account for a relationship between repertoire size and the maximal obtainable affinity within different repertoires. This approach points to a potential universality of the rules that govern affinity distributions in biology.

Animals↗