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DNA mutation motifs in the genes associated with inherited diseases

Mutations in human genes can be responsible for inherited genetic disorders and cancer. Mutations can arise due to environmental factors or spontaneously. It has been shown that certain DNA sequences are more prone to mutate. These sites are termed hotspots and exhibit a higher mutation frequency th...

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Autores principales: Růžička, Michal, Kulhánek, Petr, Radová, Lenka, Čechová, Andrea, Špačková, Naďa, Fajkusová, Lenka, Réblová, Kamila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540541/
https://www.ncbi.nlm.nih.gov/pubmed/28767725
http://dx.doi.org/10.1371/journal.pone.0182377
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author Růžička, Michal
Kulhánek, Petr
Radová, Lenka
Čechová, Andrea
Špačková, Naďa
Fajkusová, Lenka
Réblová, Kamila
author_facet Růžička, Michal
Kulhánek, Petr
Radová, Lenka
Čechová, Andrea
Špačková, Naďa
Fajkusová, Lenka
Réblová, Kamila
author_sort Růžička, Michal
collection PubMed
description Mutations in human genes can be responsible for inherited genetic disorders and cancer. Mutations can arise due to environmental factors or spontaneously. It has been shown that certain DNA sequences are more prone to mutate. These sites are termed hotspots and exhibit a higher mutation frequency than expected by chance. In contrast, DNA sequences with lower mutation frequencies than expected by chance are termed coldspots. Mutation hotspots are usually derived from a mutation spectrum, which reflects particular population where an effect of a common ancestor plays a role. To detect coldspots/hotspots unaffected by population bias, we analysed the presence of germline mutations obtained from HGMD database in the 5-nucleotide segments repeatedly occurring in genes associated with common inherited disorders, in particular, the PAH, LDLR, CFTR, F8, and F9 genes. Statistically significant sequences (mutational motifs) rarely associated with mutations (coldspots) and frequently associated with mutations (hotspots) exhibited characteristic sequence patterns, e.g. coldspots contained purine tract while hotspots showed alternating purine-pyrimidine bases, often with the presence of CpG dinucleotide. Using molecular dynamics simulations and free energy calculations, we analysed the global bending properties of two selected coldspots and two hotspots with a G/T mismatch. We observed that the coldspots were inherently more flexible than the hotspots. We assume that this property might be critical for effective mismatch repair as DNA with a mutation recognized by MutSα protein is noticeably bent.
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spelling pubmed-55405412017-08-12 DNA mutation motifs in the genes associated with inherited diseases Růžička, Michal Kulhánek, Petr Radová, Lenka Čechová, Andrea Špačková, Naďa Fajkusová, Lenka Réblová, Kamila PLoS One Research Article Mutations in human genes can be responsible for inherited genetic disorders and cancer. Mutations can arise due to environmental factors or spontaneously. It has been shown that certain DNA sequences are more prone to mutate. These sites are termed hotspots and exhibit a higher mutation frequency than expected by chance. In contrast, DNA sequences with lower mutation frequencies than expected by chance are termed coldspots. Mutation hotspots are usually derived from a mutation spectrum, which reflects particular population where an effect of a common ancestor plays a role. To detect coldspots/hotspots unaffected by population bias, we analysed the presence of germline mutations obtained from HGMD database in the 5-nucleotide segments repeatedly occurring in genes associated with common inherited disorders, in particular, the PAH, LDLR, CFTR, F8, and F9 genes. Statistically significant sequences (mutational motifs) rarely associated with mutations (coldspots) and frequently associated with mutations (hotspots) exhibited characteristic sequence patterns, e.g. coldspots contained purine tract while hotspots showed alternating purine-pyrimidine bases, often with the presence of CpG dinucleotide. Using molecular dynamics simulations and free energy calculations, we analysed the global bending properties of two selected coldspots and two hotspots with a G/T mismatch. We observed that the coldspots were inherently more flexible than the hotspots. We assume that this property might be critical for effective mismatch repair as DNA with a mutation recognized by MutSα protein is noticeably bent. Public Library of Science 2017-08-02 /pmc/articles/PMC5540541/ /pubmed/28767725 http://dx.doi.org/10.1371/journal.pone.0182377 Text en © 2017 Růžička et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Růžička, Michal
Kulhánek, Petr
Radová, Lenka
Čechová, Andrea
Špačková, Naďa
Fajkusová, Lenka
Réblová, Kamila
DNA mutation motifs in the genes associated with inherited diseases
title DNA mutation motifs in the genes associated with inherited diseases
title_full DNA mutation motifs in the genes associated with inherited diseases
title_fullStr DNA mutation motifs in the genes associated with inherited diseases
title_full_unstemmed DNA mutation motifs in the genes associated with inherited diseases
title_short DNA mutation motifs in the genes associated with inherited diseases
title_sort dna mutation motifs in the genes associated with inherited diseases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540541/
https://www.ncbi.nlm.nih.gov/pubmed/28767725
http://dx.doi.org/10.1371/journal.pone.0182377
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