This project will investigate how genetic variation in the human genome, with a focus on the mitochondrial genome, contributes to health and disease. We aim to characterize patterns of variation in mitochondrial DNA (mtDNA), quantify constraint across the mitochondrial genome, and use these and related models to interpret the functional and clinical relevance of observed variants. We will also explore how mitochondrial variants interact with variation in the nuclear genome to shape molecular and physiological traits.
Key research questions include: (i) which regions of the mitochondrial genome are most intolerant to variation, and how does this relate to known or predicted variant effects; (ii) how can measures of evolutionary constraint and variant deleteriousness be integrated to improve interpretation of mitochondrial variants; (iii) how combinations of mitochondrial and nuclear variants contribute to differences in phenotypes and disease risk.
Our objectives are to: (1) Develop next generation models of mitochondrial constraint using population-scale variation data; (2) Analyze patterns of rare and common variation to identify potentially deleterious variants; (3) Assess how variation in mtDNA and nuclear genes influence phenotypes and disease outcomes; (4) Generate broadly applicable variant interpretation resources for research and clinical use.
The scientific rationale is that mtDNA remains underutilized in large-scale human genetics, and integrating statistical models, genome-wide data, and phenotype information will advance our understanding of variant effect and disease mechanisms.
