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Mitochondria and disease. mutation and expression landscape of mitochondria-associated genes in different disease types
Mitochondria and disease. mutation and expression landscape of mitochondria-associated genes in different disease types
Mitochondria are indispensable organelles of eukaryotic cells, takes part in the efficient generation of energy required for the cellular activities. They also converge to accomplish various functions such as intrinsic apoptotic pathway, fatty acid beta oxidation, cellular balance of reactive oxygen species (ROS), iron sulphur cluster biogenesis and so-forth which are necessary for the viability of the cell. Ominous diseases may arise of incompetent mitochondrial function activity, for example, cardiomyopathy, optic atrophy and diabetes mellitus. Mitochondrial disorders may emerge as a result of mutations not only in the mitochondria DNA (mtDNA) but also in the nuclear DNA (nDNA) encoding proteins, which forms part of the mitochondrial proteome. The advent of next generation sequencing (NGS) data has hugely accelerated the generation of millions of DNA sequences and opened up avenues to study diseases at a rapid pace. NGS enables transcriptome sequencing of both the normal and the disease samples realised by the RNA sequencing (RNA-seq) technology. This facilitate the measure of the gene expression in the diseases compared to their normal samples, in addition to the capture of disease specific mutations. In this thesis, workflows to extract mutation and expression data from the RNAseq samples using well developed bioinformatics tools have been achieved. Mitochondria encompassing crucial cellular functions are fulfilled by protein coding genes encoded by both mtDNA and nDNA. In this thesis, an overall model termed as mitochondrial model (MitoModel) is developed, which at present includes 17 mitochondria specific processes with 659 genes further grouped into functional clusters. The MitoModel forms a network model with genes connected not only within a single function but also across functions. It is an interactive model with an option to map mutation and expression data and further the MitoModel provide users several information including enrichment analysis of most affected mitochondrial function and a downloadable variants file. The usage of MitoModel has proved the efficiency of the approach to understand the behaviour of the mitochondria from the RNA-seq data in HCT116 5/4, RPE1 5/3 12/3 and RPE1H2B 21/3 aneuploidy cell lines generated by collaborators. It also throws light on the differences in the mitochondrial metabolism and physiology in the extreme stress reactivity mice from the expression data. Finally, MitoModel was successfully used to emphasize on the representative mitochondrial genes that were consistently affected in the RNA-seq data of 16 samples of primary colorectal cancer and corresponding liver metastases samples.
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Siddana Gowda Koti, Prasanna
2016
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Siddana Gowda Koti, Prasanna (2016): Mitochondria and disease: mutation and expression landscape of mitochondria-associated genes in different disease types. Dissertation, LMU München: Faculty of Biology
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Abstract

Mitochondria are indispensable organelles of eukaryotic cells, takes part in the efficient generation of energy required for the cellular activities. They also converge to accomplish various functions such as intrinsic apoptotic pathway, fatty acid beta oxidation, cellular balance of reactive oxygen species (ROS), iron sulphur cluster biogenesis and so-forth which are necessary for the viability of the cell. Ominous diseases may arise of incompetent mitochondrial function activity, for example, cardiomyopathy, optic atrophy and diabetes mellitus. Mitochondrial disorders may emerge as a result of mutations not only in the mitochondria DNA (mtDNA) but also in the nuclear DNA (nDNA) encoding proteins, which forms part of the mitochondrial proteome. The advent of next generation sequencing (NGS) data has hugely accelerated the generation of millions of DNA sequences and opened up avenues to study diseases at a rapid pace. NGS enables transcriptome sequencing of both the normal and the disease samples realised by the RNA sequencing (RNA-seq) technology. This facilitate the measure of the gene expression in the diseases compared to their normal samples, in addition to the capture of disease specific mutations. In this thesis, workflows to extract mutation and expression data from the RNAseq samples using well developed bioinformatics tools have been achieved. Mitochondria encompassing crucial cellular functions are fulfilled by protein coding genes encoded by both mtDNA and nDNA. In this thesis, an overall model termed as mitochondrial model (MitoModel) is developed, which at present includes 17 mitochondria specific processes with 659 genes further grouped into functional clusters. The MitoModel forms a network model with genes connected not only within a single function but also across functions. It is an interactive model with an option to map mutation and expression data and further the MitoModel provide users several information including enrichment analysis of most affected mitochondrial function and a downloadable variants file. The usage of MitoModel has proved the efficiency of the approach to understand the behaviour of the mitochondria from the RNA-seq data in HCT116 5/4, RPE1 5/3 12/3 and RPE1H2B 21/3 aneuploidy cell lines generated by collaborators. It also throws light on the differences in the mitochondrial metabolism and physiology in the extreme stress reactivity mice from the expression data. Finally, MitoModel was successfully used to emphasize on the representative mitochondrial genes that were consistently affected in the RNA-seq data of 16 samples of primary colorectal cancer and corresponding liver metastases samples.