Genetic Variation Of Mitochondrial Complex I: Its Role In Rare And Common Diseases
Funder
National Health and Medical Research Council
Funding Amount
$628,415.00
Summary
Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the uniqu ....Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This grant focuses on the most common energy generation disorder, known as Complex I deficiency. Complex I requires 46 separate components to be assembled together in order to work properly, but mutations in the 46 genes encoding these components only seem to explain disease in about half of all patients. Our aim is to identify new disease genes and to determine whether some patients have mutations in two different genes that interact to cause disease, rather than in a single gene. We will use a number of methods to pinpoint where in the genome the causative genes are located and then home in on the exact changes in the genes that cause disease. Identifying these genes will allow us to improve future diagnosis and prevention of mitochondrial disease. We will also generate mice in which one of the Complex I genes has been knocked out. These mice will allow us to better understand the basic disease mechanisms that link gene changes to disease. Understanding the basic biology may allow us to develop new methods of treatment. The mouse models will also be useful for trialling new treatments and for investigating the role of milder mitochondrial problems in common diseases such as diabetes and Parkinson disease. Any new treatments could potentially have wide application.Read moreRead less
Molecular and genetic analysis of epigenetic components in a model plant. Australia is a major exporter of agricultural food crops thus producers must maintain their competitive advantage in order to compete on the world stage. Food crops unfortunately have large, complex genomes that are not sequenced and a generation time of months that makes research outcomes slow to achieve. This project proposes to utilise a model plant that has a small completely sequenced genome and a short generation tim ....Molecular and genetic analysis of epigenetic components in a model plant. Australia is a major exporter of agricultural food crops thus producers must maintain their competitive advantage in order to compete on the world stage. Food crops unfortunately have large, complex genomes that are not sequenced and a generation time of months that makes research outcomes slow to achieve. This project proposes to utilise a model plant that has a small completely sequenced genome and a short generation time making it ideal to study the fundamental biological process of RNA silencing. Discoveries and outcomes from this project may have the potential to benefit Australian crops, ecosystems and human health.Read moreRead less
The sponge genome project and the evolution of multicellularity: using comparative genomics and developmental biology to reconstruct the first animals. Recently the entire genome from a living fossil - a sponge from the Great Barrier Reef - was sequenced (jointly supported by the ARC and US Department of Energy). As this genome is assembled and analysed, many of the fundamental biological processes that underlie the construction and evolution of all animals, including humans, will be revealed. ....The sponge genome project and the evolution of multicellularity: using comparative genomics and developmental biology to reconstruct the first animals. Recently the entire genome from a living fossil - a sponge from the Great Barrier Reef - was sequenced (jointly supported by the ARC and US Department of Energy). As this genome is assembled and analysed, many of the fundamental biological processes that underlie the construction and evolution of all animals, including humans, will be revealed. In addition, sponge genomics will fuel innovations in medicine and biotechnology. Specifically, sponges are renowned for their capacity to synthesise bioactive compounds used in drug development, and high-grade silica used for semi-conductor construction. This project will identify the gene networks controlling these biosynthetic processes.Read moreRead less
Early animal evolution: reconstructing the last common metazoan ancestor through the analysis of developmental and structural genes in sponges. All animals, from the simplest invertebrates to humans, arose from a common ancestor. Reconstruction of this ancestor requires the comparison of metazoan developmental genetic architectures. Here we contribute to this pursuit by studying a phylogenetically and biological appropriate metazoan system - marine sponge embryos and larvae. Using high-throughp ....Early animal evolution: reconstructing the last common metazoan ancestor through the analysis of developmental and structural genes in sponges. All animals, from the simplest invertebrates to humans, arose from a common ancestor. Reconstruction of this ancestor requires the comparison of metazoan developmental genetic architectures. Here we contribute to this pursuit by studying a phylogenetically and biological appropriate metazoan system - marine sponge embryos and larvae. Using high-throughput gene profiling techniques, we will analyse the developmental genetics underlying the sponge body plan. Commonalities shared between sponges and more sophisticated animals are likely to have been present in the "genetic toolkit" of the most ancient metazoan ancestor and, as such, is the genetic foundation from which all animal biodiversity arose.Read moreRead less
Does developmental noise have an epigenetic basis? One's ultimate phenotype is the result of a combination of genotype and environment, and includes a poorly understood component termed ?developmental noise?. The molecular basis of developmental noise remains unknown, but it appears to be established in early development and to be retained for the life of the organism. We propose that the molecular basis of developmental noise is the epigenetic state of the genome. The stochastic nature of th ....Does developmental noise have an epigenetic basis? One's ultimate phenotype is the result of a combination of genotype and environment, and includes a poorly understood component termed ?developmental noise?. The molecular basis of developmental noise remains unknown, but it appears to be established in early development and to be retained for the life of the organism. We propose that the molecular basis of developmental noise is the epigenetic state of the genome. The stochastic nature of the establishment of epigenetic state, combined with its heritability during mitosis, provides all the essential components for developmental noise. If our hypothesis proves correct, our work will have a major impact on the understanding of one of the most basic concepts in genetics.Read moreRead less