Hisanori Kiryu1, Kiyoshi Asai. 1. Department of Computational Biology, Faculty of Frontier Science, The University of Tokyo, Kashiwa, Chiba, Japan. kiryu-h@k.u-tokyo.ac.jp
Abstract
MOTIVATION: Measuring the effects of base mutations is a powerful tool for functional and evolutionary analyses of RNA structures. To date, only a few methods have been developed for systematically computing the thermodynamic changes of RNA secondary structures in response to base mutations. RESULTS: We have developed algorithms for computing the changes of the ensemble free energy, mean energy and the thermodynamic entropy of RNA secondary structures for exhaustive patterns of single and double mutations. The computational complexities are O(NW(2)) (where N is sequence length and W is maximal base pair span) for single mutations and O(N(2)W(2)) for double mutations with large constant factors. We show that the changes are relatively insensitive to GC composition and the maximal span constraint. The mean free energy changes are bounded ~7-9 kcal/mol and depend only weakly on position if sequence lengths are sufficiently large. For tRNA sequences, the most stabilizing mutations come from the change of the 5(')-most base of the anticodon loop. We also show that most of the base changes in the acceptor stem destabilize the structures, indicating that the nucleotide sequence in the acceptor stem is highly optimized for secondary structure stability. We investigate the 22 tRNA genes in the human mitochondrial genome and show that non-pathogenic polymorphisms tend to cause smaller changes in thermodynamic variables than generic mutations, suggesting that a mutation which largely increases thermodynamic variables has higher possibility to be a pathogenic or lethal mutation. AVAILABILITY AND IMPLEMENTATION: The C++ source code of the Rchange software is available at http://www.ncrna.org/software/rchange/.
MOTIVATION: Measuring the effects of base mutations is a powerful tool for functional and evolutionary analyses of RNA structures. To date, only a few methods have been developed for systematically computing the thermodynamic changes of RNA secondary structures in response to base mutations. RESULTS: We have developed algorithms for computing the changes of the ensemble free energy, mean energy and the thermodynamic entropy of RNA secondary structures for exhaustive patterns of single and double mutations. The computational complexities are O(NW(2)) (where N is sequence length and W is maximal base pair span) for single mutations and O(N(2)W(2)) for double mutations with large constant factors. We show that the changes are relatively insensitive to GC composition and the maximal span constraint. The mean free energy changes are bounded ~7-9 kcal/mol and depend only weakly on position if sequence lengths are sufficiently large. For tRNA sequences, the most stabilizing mutations come from the change of the 5(')-most base of the anticodon loop. We also show that most of the base changes in the acceptor stem destabilize the structures, indicating that the nucleotide sequence in the acceptor stem is highly optimized for secondary structure stability. We investigate the 22 tRNA genes in the human mitochondrial genome and show that non-pathogenic polymorphisms tend to cause smaller changes in thermodynamic variables than generic mutations, suggesting that a mutation which largely increases thermodynamic variables has higher possibility to be a pathogenic or lethal mutation. AVAILABILITY AND IMPLEMENTATION: The C++ source code of the Rchange software is available at http://www.ncrna.org/software/rchange/.
Authors: Zsuzsanna Sükösd; Bjarne Knudsen; James W J Anderson; Adám Novák; Jørgen Kjems; Christian N S Pedersen Journal: BMC Bioinformatics Date: 2013-01-21 Impact factor: 3.169
Authors: Radhakrishnan Sabarinathan; Hakim Tafer; Stefan E Seemann; Ivo L Hofacker; Peter F Stadler; Jan Gorodkin Journal: Hum Mutat Date: 2013-04 Impact factor: 4.878