Evolution and the immune system: genetic differences in immune response between human populations due to adaptation to living in different geo-climatic locations. The project, which investigates the genetics of inter-population differences in immune response, will lead to advances in immunology and population genetics research, explain present population specific differences in disease incidence and possibly forecast future population trends of diseases such as asthma and allergy. The study will ....Evolution and the immune system: genetic differences in immune response between human populations due to adaptation to living in different geo-climatic locations. The project, which investigates the genetics of inter-population differences in immune response, will lead to advances in immunology and population genetics research, explain present population specific differences in disease incidence and possibly forecast future population trends of diseases such as asthma and allergy. The study will strengthen ties with collaborators around the world, thus promoting excellence in Australian research and gain Australia prestige in the international community as a country that produces research of global significance. Understanding the immune system's 'recent evolutionary roots' has implications for the health of Australians, especially in light of Australia's increasingly multi-ethnic background.Read moreRead less
A shipload of consequences: studying the impact of Old World diseases on native South American populations via ancient DNA. This pioneering project will give the first real-time picture of the genetic changes induced by epidemics in human populations. This will reveal important new information about the likely impact of future epidemics on the genetic diversity of the immune system in modern human populations and will be of substantial use in building epidemiological models. By proposing to comb ....A shipload of consequences: studying the impact of Old World diseases on native South American populations via ancient DNA. This pioneering project will give the first real-time picture of the genetic changes induced by epidemics in human populations. This will reveal important new information about the likely impact of future epidemics on the genetic diversity of the immune system in modern human populations and will be of substantial use in building epidemiological models. By proposing to combine state-of-the-art science with global problems of humanity, we will address Australia's interests in expanding scientific expertise beyond its borders and place Australia at the leading edge of disease impact studies.Read moreRead less
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
The role of epigenetics in the early gestational programming of adult phenotype by ethanol. The concept of foetal programming is changing the way we think about the aetiology of complex disease in adults. Our studies would emphasise that adverse events during pregnancy can have long-term health implications, with concomitant social and economic consequences. In America, the prevalence of foetal alcohol syndrome is comparable with rates for Down syndrome. The Aboriginal community in Australia ....The role of epigenetics in the early gestational programming of adult phenotype by ethanol. The concept of foetal programming is changing the way we think about the aetiology of complex disease in adults. Our studies would emphasise that adverse events during pregnancy can have long-term health implications, with concomitant social and economic consequences. In America, the prevalence of foetal alcohol syndrome is comparable with rates for Down syndrome. The Aboriginal community in Australia has been identified as a high-risk group. The knowledge gained from this project could aid in the development of screening strategies to predict the likelihood of disease developing later in life, providing an opportunity for presymptomatic healthcare.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
The control of chromosome division during female meiosis. Mammalian eggs are stored life-long and finally mature in the hours before ovulation. This project examines how the chromosomes in the egg are separated properly so as to produce a mature egg capable of being fertilized by a sperm. Often in eggs chromosome division is imprecisely executed, and this project will help us understand why this occurs.
Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of hea ....Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of healthy, genetically intact sperm. This project draws together an international team to investigate a phenomenon with implications for new understanding of normal developmental processes and the response of cells/tissues to disease conditions.Read moreRead less
Marsupial germ cells and genes. Germ cells are the most fascinating cells in the body, since theirs is the unique responsibility for transmitting life from generation to generation. Studies in mice have suggested that position in the embryo determines their origin, but the early embryology of the mouse is so different from that of other mammals that the events need confirming and extending in another species. The simplified embryology of the tammar wallaby makes it ideal for studying one of the ....Marsupial germ cells and genes. Germ cells are the most fascinating cells in the body, since theirs is the unique responsibility for transmitting life from generation to generation. Studies in mice have suggested that position in the embryo determines their origin, but the early embryology of the mouse is so different from that of other mammals that the events need confirming and extending in another species. The simplified embryology of the tammar wallaby makes it ideal for studying one of the most fundamental questions in the whole of biology: what is the basis for the primal distinction between sex and soma?Read moreRead less
How does the unilaminar blastocyst form an embryo? Marsupials are synonymous with Australia and they are scientifically amazing. An understanding how the single-layered marsupial blastocyst cells are directed to form the complex organisation of an embryo would help us understand the biology underlying the developmental potential of all cells. Understanding these processes is not only of great fundamental interest to developmental biology but also for the development of embryonic stem cell lines. ....How does the unilaminar blastocyst form an embryo? Marsupials are synonymous with Australia and they are scientifically amazing. An understanding how the single-layered marsupial blastocyst cells are directed to form the complex organisation of an embryo would help us understand the biology underlying the developmental potential of all cells. Understanding these processes is not only of great fundamental interest to developmental biology but also for the development of embryonic stem cell lines. This research will continue Australia's high profile in reproductive biology using one of our iconic native mammals. A greater understanding of marsupial reproduction will also contribute to management of our threatened marsupial populations.Read moreRead less
Taming the intruders: the domestication of Tigger transposable elements in mammals. It has become apparent that most of the DNA that makes us what we are is actually comprised of the remnants of invading parasitic DNA acquired over time. A continual battle exists between host which tries to silence or remove this DNA, and the parasite that tries to multiply and spread. We are currently investigating an intriguing aspect of this process that involves host genomes 'domesticating' parasitic DNA to ....Taming the intruders: the domestication of Tigger transposable elements in mammals. It has become apparent that most of the DNA that makes us what we are is actually comprised of the remnants of invading parasitic DNA acquired over time. A continual battle exists between host which tries to silence or remove this DNA, and the parasite that tries to multiply and spread. We are currently investigating an intriguing aspect of this process that involves host genomes 'domesticating' parasitic DNA to provide novel functions, thereby facilitating the evolution of specific characteristics within species.Read moreRead less