Genetic Determinants Influencing the Maternal Transmission and Somatic Accumulation of Mitochondrial Mutations
Abstract
The focus of the submitted proposal is on mitochondrial diseases. Owing to their evolutionary history, mitochondria have retained a small circular genome that encodes a number of essential components of the electron transport chain, which provides the majority of the energy required for an organism to live. Mutations in the mitochondrial genome can cause the electron transport chains to become dysfunctional. These mutations can be potentially passed to the offspring of the female carrier or accumulate with advancing age. If these mutations reach a high enough level within a tissue, a number of devastating diseases can occur. Remarkably, there is significant evidence to suggest that mechanisms have evolved to prevent the transmission or accumulation of the most deleterious of these mutations. However, even in the presence of these selection mechanisms, diseases involving mtDNA mutations occur. Therefore, it is vital to understand the mechanism(s) that are involved in preventing the accumulation of these mutations either through the germline or during development and aging of the somatic tissue. The proposed research will be the first step in identifying candidate genes involved in this process, which, currently, are completely unknown. To begin to identify these mechanisms, we propose to use the model organism the common fruit fly, Drosophila melanogaster, to pursue two aims. The first aim will focus on using a novel, high accuracy, next-generation sequencing methodology to perform a genome-wide screen for genes involved in selecting against the accumulation and/or transmission of mtDNA mutations. The second aim will focus on characterizing the effects of putative modifiers on mitochondrial bioenergetics and morphology in hopes of providing insight into how these modifiers function. Our findings could eventually be used in genetic counseling to determine the risk of transmitting pathogenic mutations to the next generation. Additionally, a fuller understanding of these mechanisms could potentially uncover therapeutic targets to help prevent maternal transmission or accumulation of pathogenic mutations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610579
Entities
People
- Scott Kennedy
Organizations
- United States Army
- University of Washington