Mitochondrial and chromosomal genomics in type 2 diabetes
Abstract: Understanding the mechanisms of complex polygenic diseases like type 2 diabetes (T2D) is as complex as their nature. Cellular processes involved in glucose homeostasis need high and reliable energy supply. Mitochondria are the major energy producers in mammalian cells. Since majority of the mitochondrial genes are encoded by the nuclear genome, a tightly regulated and coordinated nuclear-mitochondrial crosstalk needs to be ensured. Perturbation of this communication will attenuate the cellular response to variable energy demands. To understand the role of nuclear-mitochondrial interactions in T2D, we setup a reciprocal cross between the diabetic GK and the normoglycaemic F344 rats. This reciprocal cross consisted of two individual crosses that shared identical nuclear DNA haplotypes while they differed in the mtDNA haplotypes at 110 nucleotide positions. We performed cross-separated linkage analysis to map QTLs segregating only in the presence of specific mtDNA genotype, which is a first-line indication for the interactions between nuclear QTL and mtDNA. Two genomic loci were found linked to three traits depending on the mtDNA haplotype. Within these loci we were able to identify forty nuclear-encoded mitochondrial genes. One of the identified loci, Niddm71, was dissected further using a congenic rat, C9B. Characterization of the C9B rat revealed that the Niddm71 locus encodes for a defect in insulin secretion and a defect in mitochondrial function. With a combination of bioinformatics and experimental methods we identified several genes and non-coding sequences within Niddm71 that likely play a role in insulin secretion and mitochondrial function. To investigate the role of mtDNA variants on the susceptibility of T2D we sequenced complete mitochondrial genomes of the diabetic GK and normoglycemic F344 rats and identified 110 variable nucleotide positions. To prioritize functionally important nucleotide variants, we further sequenced mitochondrial genomes of 12 commonly used inbred laboratory rat strains. Using different phylogenetic methods we identified several genes and sites in the mtDNA that might be important for mitochondrial function. In this study we have identified nuclear loci which are modulated by the mitochondrial genotype and identified mitochondrial loci that might be of vital importance for its function. The results of our study will provide additional stimulus for further research in understanding nuclear-mitochondrial interactions and their role in metabolic diseases like T2D.
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