Variations of Mitochondrial DNA: Individualizing the Ischemic Stroke Genome
The entire human mitochondrial DNA genome (mtDNA) is a covalently closed circular double stranded genome of 16,569 bp. It encodes for 22 transfer RNAs, 2 ribosomal RNAs and 13 polypeptides. The functions as well as the gene products of all the mitochondrial genes have been assigned and all the 13 polypeptides encoded are subunits of the ETC enzyme complexes.
Genome–wide association studies have proven to be effective in the identification of common genetic determinants in disease. Nevertheless, this research does not account for influence of the ~16.5 kb of closed circular mitochondrial genome (mtDNA). The mitochondrial organelle is comprised of both nuclear and mtDNA encoded proteins, and its dysfunction is hypothesized to play a prominent role in age–associated neurologic degeneration. Thus, we propose sequence and copy number analysis of the entire 16.5kb mtDNA genome to complement our existing genome–wide association study in ischemic stroke. We will use Affymetrix mtDNA re–sequencing arrays and lymphocyte–derived DNA from our North American Caucasian concordant sib–pairs with ischemic stroke. Association analysis of mtDNA genetic variability contributing to ischemic stroke will be performed. Genetic mtDNA variability identified will be validated in larger series of ischemic stroke patients and normal control subjects. The scientific aim of our proposal is to identify variation within the mtDNA genome that associates with ischemic stroke. Associated variants may inform the development of functional cellular or animal models, act as preclinical biomarkers, define high–responder populations in clinical trials, and direct future first–in–class pharmaco–therapeutic intervention strategies.