DNA quadruplexes and dynamical genetics.

In a recent paper, we have put forward the hypothesis that there exist smart purposive mechanisms - tandem repeat length managers - which regulate the length of some tandem repeat, or cause rearrangements, and are almost always driven by some variable number tandem repeat. We have called the framework in which such mechanisms act 'dynamical genetics'. The purpose of this paper is to contribute to lay the foundations of a molecular study of the above mechanisms, by proposing a hypothesis, based on various kinds of supporting evidence and plausibility arguments, about the special importance of DNA quadruplexes for dynamical genetics, and by considering the involved enzymes. This hypothesis states that a tandem repeat length manager acts almost always by monitoring a DNA tract that has the characteristics of being a variable number tandem repeat and/or forming a DNA quadruplex, and that it is almost always driven by at least one of them.

On new hypotheses about autosomal dominant polycystic kidney disease type 1.

The purpose of this paper is to suggest a partial explanation of the aetiology of autosomal dominant polycystic kidney disease type 1, one of the most common genetic diseases in humans. To this aim we put forward a number of interconnected ideas, based on a number of experimental evidences and plausibility arguments. We stress the major role played by the instability of some genomic tandem repeats, together with the DNA structures known as quadruplexes, the pseudogenes and the gene conversion. The model we propose can be considered a multi-hit generalization of the well-known two-hit model, a generalization that could well have a validity also outside the specific context. We finally provide an indication of the likely guilty DNA segment for the above disease, and we propose a possible simple experimental line of action aimed to confirm or disproof our suggestion.

A new look at the challenging world of tandem repeats.

Recent research has shown a correlation between some genetic diseases and genomic sequences tandemly repeated a variable and excessive number of times. The excessive number of tandem repeats is usually caused by a progressive expansion, generally considered as purely harmful. We put forward a number of hypotheses: the main one is that the number of repeats has normally a specific significance, and that there exist purposive mechanisms having as a primary function the management of tandem repeats length; such a function is generally useful and only rarely may it become harmful, because of some malfunctioning. These hypotheses are suggested by plausibility arguments, and are supported by a number of recent experimental results. They could provide a simple and unifying explanation of many pathological and non-pathological phenomena replacing many ad hoc assumptions. We finally propose to call the study of the above tandem repeat managing mechanisms 'dynamical genetics'.

Are only repeated triplets guilty?

It is well known that in some places of the human genome one finds a variable number of tandem repeats of trinucleotides; it is now commonly acknowledged that in many cases an excessive expansion of such a number is the cause of nervous system diseases. Moreover there exist cases of genetic disorders linked with loci where a variable number of tandem repeats of sequences longer than three bases has been found. The abnormal number of these repeats in few cases has been associated with the onset of the disease. Considering the above facts, we have performed an extensive study of published sequences of genes connected with various diseases. We have examined, inside or near those genes, all possible tandem repeats. The analysis has led to the detection of a large number of repeats of both triplets and longer sequences, many of which, as far as we know, had not been pointed out before. The results of our analysis lead us to put forward the hypothesis that in more cases than those till now established, a variable number of tandem repeats of generic sequences, not only of triplets, could be associated with disease onset. Finally we suggest to allocate experimental researches for all the possible tandem repeats and their possible correlation with the neurodegenerative disorders and with other kinds of syndromes.

Paroxetine efficacy in the treatment of generalized anxiety disorder.

Recently, there has been a renewed interest in alternatives to the benzodiazepines for the treatment of generalized anxiety disorder (GAD). The aim of the present study was to compare the efficacy of paroxetine vs. imipramine and 2'-chlordesmethyldiazepam in 81 patients with a DSM-IV diagnosis of GAD. Approximately two-thirds of the patients who completed the study improved greatly or moderately on all three active drugs. During the first 2 weeks of treatment, 2'-chlordesmethyldiazepam treatment resulted in the greatest improvement in anxiety ratings. Both paroxetine and imipramine treatment resulted in more improvement than 2'-chlordesmethyldiazepam by the fourth week of treatment. Paroxetine and imipramine affect predominantly psychic symptoms, whereas 2'-chlordesmethyldiazepam affects predominantly somatic symptoms. Our results suggest that paroxetine is effective for the treatment of GAD.