Functions Of A Novel Conserved DNA Damage Response Protein Family In Telomere Stability
Funder
National Health and Medical Research Council
Funding Amount
$282,825.00
Summary
The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, c ....The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, chromosome ends are covered by a cap, which hides them from the DNA damage response machinery. From these considerations it is clear that there are close connections between the cellular DNA damage response and chromosome ends. Moreover, recently it has become clear that DNA damage proteins are also required to stop normal cells from growing, a process termed senescence. Senescence is a consequence of shortened chromosome ends, and does not occur in cancer cells. Altogether, it is clear that DNA breaks and senescence are two of the major questions for our understanding of cancer development. We have identified a novel conserved protein family that is involved in the response to DNA damage in yeast and humans. In addition, the yeast Mdt1 protein is a very sensitive indicator of changes in the telomere cap. Absence of proteins that organise the cap leads to the addition of several phosphate groups to the Mdt1 protein. We propose that phosphate-coupled Mdt1 prevents chromosome ends from fusion with each other, or from fusing with broken DNA ends after widespread damage. As a consequence, cells that have mild cap defects die at an >1000-fold increased rate in response to DNA damage when they also lack Mdt1. As part of this application we want to find out the precise mechanism by which Mdt1 stabilises chromosome ends, and test our hypothesis that the corresponding human protein termed ASCIZ also has similar functions in protecting chromosome ends.Read moreRead less
Elucidating the neural pathways and genetic basis of speech. The project will elucidate the biological basis of speech, a unique feature of the human condition. The project will do this by i) discovering genes associated with speech disorder and ii) defining the neural pathways associated with speech production. This study will address critical questions regarding gene, brain and behaviour relationships in speech.
The genomic programming of complex organisms. The project will have far-reaching consequences in medicine, agriculture, biotechnology, engineering, information science and associated industries. It will provide a platform for the rationalization of genetic epidemiology and genetic improvement programs, the development of a wide range of new diagnostics and therapies, the development of new core technologies and practical approaches in genetics and genetic diversity, a framework for advanced gen ....The genomic programming of complex organisms. The project will have far-reaching consequences in medicine, agriculture, biotechnology, engineering, information science and associated industries. It will provide a platform for the rationalization of genetic epidemiology and genetic improvement programs, the development of a wide range of new diagnostics and therapies, the development of new core technologies and practical approaches in genetics and genetic diversity, a framework for advanced genetic engineering, the development of new principles and systems for information storage and transmission, and the design of artificial systems capable of self-referential assembly in other environments.Read moreRead less
Evolution, selection and estimation of polygenic epistatic networks in quantitative traits. Traits observed in organisms, such as height, are the result of an individual's genes and how they relate to the environment. But genes do not act alone; they work together in complex interactions. This project aims to understand these interactions and their role in animal production and human disease.
Investigating differences in decision-making ability in older adults. This project aims to investigate how healthy ageing impacts decision making and its associated neural circuits using computation modelling and neurogenetic methods. Decision-making is a fundamental cognitive ability, allowing us to choose the best course of action. This project will investigate the relationship between genes and decision-making performance across the adult lifespan. Expected outcomes include a deeper understan ....Investigating differences in decision-making ability in older adults. This project aims to investigate how healthy ageing impacts decision making and its associated neural circuits using computation modelling and neurogenetic methods. Decision-making is a fundamental cognitive ability, allowing us to choose the best course of action. This project will investigate the relationship between genes and decision-making performance across the adult lifespan. Expected outcomes include a deeper understanding of how decision-making evolves in healthy ageing, and a tool based on genetic scores and computational modelling to predict an individual's trajectory of cognitive function. This could help identify individuals who are at risk for cognitive decline, which could then inform better interventions.Read moreRead less
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
eGenomics - Next generation biomonitoring of threatened species. DNA is the molecule of life and exists everywhere in the environment as a largely untapped source of information on evolution, biodiversity, and ecosystem health. Our overriding aim is to start mining that information to benefit threatened species. Based on optimized ancient DNA methods, powerful sequencing technology, whole genome analyses, and RNA profiling, we present a novel and holistic framework for genetic biomonitoring. In ....eGenomics - Next generation biomonitoring of threatened species. DNA is the molecule of life and exists everywhere in the environment as a largely untapped source of information on evolution, biodiversity, and ecosystem health. Our overriding aim is to start mining that information to benefit threatened species. Based on optimized ancient DNA methods, powerful sequencing technology, whole genome analyses, and RNA profiling, we present a novel and holistic framework for genetic biomonitoring. In two parallel model systems we will study corals and reptiles to improve environmental detection while simultaneously obtaining information on their population health. This will foster more efficient conservation of endangered species that are of tremendous importance to our marine and terrestrial ecosystems.Read moreRead less
The molecular evolution of wings in flightless birds. The flightless Australian emu and New Zealand kiwi have small wings, while the extinct moa had none at all. This project will identify the genetic changes that have lead to wing reduction and loss in flightless birds. The results will shed light on the genetic control of forelimb development and how it has evolved.
Echoes of the earliest Homo sapiens movement out of Africa. The "Out of Africa" and "Multiregional Evolution" theories have proposed sharply different accounts for the origins of our species Homo sapiens. These have converged on opposite readings of the Australian human fossil record. Recent perspectives resulting from research on Pleistocene Australian mitochondrial DNA, and by osteologists on early Homo sapiens remains in Africa and Israel, hint at a chapter, as yet unwritten, in our species' ....Echoes of the earliest Homo sapiens movement out of Africa. The "Out of Africa" and "Multiregional Evolution" theories have proposed sharply different accounts for the origins of our species Homo sapiens. These have converged on opposite readings of the Australian human fossil record. Recent perspectives resulting from research on Pleistocene Australian mitochondrial DNA, and by osteologists on early Homo sapiens remains in Africa and Israel, hint at a chapter, as yet unwritten, in our species' Late Pleistocene dispersal from Africa. This project's collaborative research on fossils from Sri Lanka and Australasia will explore and test the implications for the colonisation history of the Indian Ocean region.Read moreRead less