Date of Award

5-1-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

John V. Planz

Second Advisor

Robert C. Barber

Third Advisor

Abbot F. Clark

Abstract

Oxidative phosphorylation (OXPHOS) is the primary energy generating system in eukaryotic organisms. Consequently, any malfunctions or disruptions in the pathway significantly impact fitness and health. Errors in energy production have been linked to cancer, Alzheimer’s disease, Parkinson’s disease, various neuropathies, and general aging and health degeneration over time. However, there is a fundamental gap in the understanding of the genetic causes of deficiencies in energy production.

The complexes within the OXPHOS pathway are of mixed origin; while most subunit-coding genes are located within the nuclear genome, thirteen are coded for in the mitochondrial genome. There is strong evidence to support coadaptation between the two genomes in these OXPHOS gene regions in order to create tight protein interactions necessary for a functional energetic system. While the effect of separating coevolved alleles is not fully understood, hybrid studies have indicated decreased energy production when combining different ancestral nuclear and mitochondrial backgrounds in various species. This suggests the common human practice of interpopulation matings between ancestrally distinct groupings influences health and relative fitness. The primary hypothesis is that admixture creates maladaptive combinations of nuclear and mitochondrial alleles in the OXPHOS-coding genes that have adverse effects on the efficiency of energy production, leading to a decrease in relative fitness.

This dissertation project has: 1) identified the effects of admixture on OXPHOS activity in Mus musculus populations, showing that high admixture leads to significantly lower basal respiration rates; and 2) assessed the genetic composition of the strains of Mus musculus evaluated to identify to cause of the loss of respiration in highly admixed mice. It was determined that there were no genetic anomalies present that could explain the observations, meaning the cause is likely not due to a mutation, but instead an undetected difference, such as cyto-nuclear incompatibility. It is recommended that further energetic and genetic studies be performed to identify the source of the deficiency. Mice obtained from Jackson Laboratories and a previously published genotype dataset [82] were used for experiments. Laboratory experiments included: Liver and heart extraction, tissue preparation and bioenergetics analysis, statistical analysis, and genetic analysis.

Comments

Zascavage, Roxanne, Admixture Effects on Coevolved Metabolic Systems. Doctor of Philosophy (Biomedical Sciences), April 2016, 132 pp, 24 tables, 14 illustrations, bibliography, 83 titles. Available worldwide May 2017.

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