I propose to develop a new model system to study how the interactions between nuclear and mitochondrial encoded genes generate mitochondrial malfunctions leading to variety of aberrant adult phenotypes. We will focus on the electron transport system (ETS) of the oxidative phosphorylation (OXPHOS) in the mitochondria, but will extend the genetic analysis to incorporate other nuclear-nuclear and nuclear-mitochondrial interactions affecting mitochondrial functions. This will help us to understand the genetic basis of mitochondrial diseases in humans and will generate a better understanding of apoptosis and aging both of which are fundamental processes important for human health and development. To achieve this goal we will develop new tools for high throughput comparative genetic (SNP genotyping microarray) and genomic (QTL analysis) analyses of complex phenotypes in a parasitic wasp, Nasonia spp. taking advantage of the recently finished genome sequences of Nasonia vitripennis (6x coverage) and N. giraulti/N. longicornis (1x coverage each) (www.hgsc.bcm.tmc.edu/projects/nasonia/). The phenotypes we are interested in are the efficiency of the ETS and mitochondrial malfunctions in hybrids of N. vitripennis and its sister species N. giraulti and N. longicornis. Hybrids of these species are viable and fertile but suffer from nuclear-cytoplasmic incompatibilities, probably due to complex intra- or inter-genomic interactions between nuclear and mitochondrial encoded genes. This proposal will focuses on three topics: - Develop a high throughput and cheap SNP-microarray to be able to genotype a large number of individuals to analyze the genetic basis of complex phenotypes. - Determine the genes that are responsible for the nuclear-cytoplasmic incompatibilities in hybrid crosses. - Generate a suite of recombinant inbred lines (RIL) that allows us to study the effect of nuclear gene interactions and nuclear-mitochondrial gene interaction on complex phenotypes, in particular, efficiency of the different subunits of the mitochondrial ETS, longevity of males and courtship behavior of males. Nasonia can become a non-mammalian model system for the study of mitochondrial dysfunctions/functions that are related to human mitochondrial diseases, apoptosis and aging, because it shares the same mitochondrial genes with humans but has a haploid genome. Beyond a better understanding of the genetic basis of these fundamental processes affecting human welfare. This research can also lead to improvements in the diagnosis, prediction and treatment of human mitochondrial diseases which as a group are arguably one of the most frequent human genetic diseases. ? ? ? ?
