Abnormal open states patterns in the ATXN2 DNA sequence depends on the CAG repeats length.

Hereditary ataxias are one of the «anticipation diseases¼ types. Spinocerebral ataxia type 2 occurs when the number of CAG repeats in the coding region of the ATXN2 gene exceeds 34 or more. In healthy people, the CAG repeat region in the ATXN2 gene usually consists of 22-23 CAG trinucleotides. Mutations that increase the length of CAG repeats can cause severe neurodegenerative and neuromuscular disorders known as trinucleotide repeat expansion diseases. The mechanisms causing such diseases are associated with non-canonical configurations that can be formed in the CAG repeat region during replication, transcription or repair. This makes it relevant to study the zones of open states that arise in the region of CAG repeats under torque. The purpose of this work is to study, using mathematical modeling, zones of open states in the region of CAG repeats of the ATXN2 gene, caused by torque. It has been established that the torque effect on the 1st exon of the ATXN2 gene, in addition to the formation of open states in the promoter region, can lead to the formation of additional various sizes open states zones in the CAG repeats region. Moreover, the frequency of additional large zones genesis increases with increasing number of CAG repeats. The inverse of this frequency correlates with the dependence of the disease onset average age on the CAG repeats length. The obtained results will allow us to get closer to understanding the genetic mechanisms that cause trinucleotide repeat diseases.

Medium viscosity influence on the open states genesis in a DNA molecule.

The studies were carried out by the mathematical modeling of DNA mechanical deformations. Numerical calculations done for the interferon alpha 17 gene, which consists of 980 base pairs. It has been established that the genesis and dynamics of open states in the DNA molecule depends on the magnitude of the external influence (torque) and on the viscosity of the environment. In addition, it is shown that the dynamics of open states zones can have a jump-like character with a small change in the magnitude of the torque. When torque is applied to all 980 base pairs of the gene, the following effect is observed: an increase in the viscosity of the medium leads to an increase in the value of the torque necessary for the occurrence of OS and DNA unwinding, i.e. viscosity plays an important stabilizing role in DNA dynamics. Under the influence of a localized torque on different (by the content of A-T and G-C pairs and location) regions of the interferon alpha 17 gene, it was found that the magnitude of the external torque necessary for the occurrence of open states at all calculated values of viscosity depends on the nucleotide composition. The dependence of the torque magnitude required for the open states occurrence on viscosity is observed when the torque is applied to areas close to the gene boundaries. At the same time, the significance of the end effect, which weakens DNA, decreased with increasing viscosity of the medium.Communicated by Ramaswamy H. Sarma.