Why is most of the genetic variance for complex traits undetected by large powerful screens of common variants? The genomics revolution has made it possible to measure thousands of DNA variants in individuals. These variants have been associated with phenotypic outcomes in a range of species. Paradoxically, even very large studies have only accounted for a fraction of the resemblance between relatives that we know exist. Our study will test three specific hypotheses to explain this paradox. A be ....Why is most of the genetic variance for complex traits undetected by large powerful screens of common variants? The genomics revolution has made it possible to measure thousands of DNA variants in individuals. These variants have been associated with phenotypic outcomes in a range of species. Paradoxically, even very large studies have only accounted for a fraction of the resemblance between relatives that we know exist. Our study will test three specific hypotheses to explain this paradox. A better understanding about the genetic architecture for complex traits will improve the efficiency of gene mapping methods, including applications in humans for traits related to productive ageing and a healthy start to life, will lead to more efficient selection programs in agricultural populations and will inform us with respect to past evolutionary events.Read moreRead less
I am a scientist aiming to improve health outcomes by facilitating the collection and unification of data on human genetic variation together with its clinical impact on human health.
The multiplexed diagnosis of arbovirus infections using combinatorial probes. Viruses that cause serious diseases such as hemorrhagic fever or encephalitis must be quickly identified. Diagnostic tests based on DNA hybridisation are accurate and can be rapid but they are expensive. We will test a method for simplifying DNA tests and increasing their capabilities. DNA probes for detecting arboviruses will be designed at the ANU using new bioinformatic methods and their reliability will be model ....The multiplexed diagnosis of arbovirus infections using combinatorial probes. Viruses that cause serious diseases such as hemorrhagic fever or encephalitis must be quickly identified. Diagnostic tests based on DNA hybridisation are accurate and can be rapid but they are expensive. We will test a method for simplifying DNA tests and increasing their capabilities. DNA probes for detecting arboviruses will be designed at the ANU using new bioinformatic methods and their reliability will be modelled using all the available genetic information. Computer predictions will be experimentally tested in the PANBIO laboratory by using the probes to detect viral nucleic acids. The influence of virus genome complexity will be investigatedRead moreRead less
Functional Genomics to Predict and Enhance Response to Interferon. The increasing number and huge cost impost of new therapies to health providers, both worldwide and nationally, has not yet resulted in a concomitant increase in strategies to optimise their use. Many of the new therapies are proteins (recombinant human proteins or humanised monoclonal antibodies). The improved use of one of Australia's most expensive commonly used protein drugs, pegylated interferon ribavirin (Peg-IFN-R), could ....Functional Genomics to Predict and Enhance Response to Interferon. The increasing number and huge cost impost of new therapies to health providers, both worldwide and nationally, has not yet resulted in a concomitant increase in strategies to optimise their use. Many of the new therapies are proteins (recombinant human proteins or humanised monoclonal antibodies). The improved use of one of Australia's most expensive commonly used protein drugs, pegylated interferon ribavirin (Peg-IFN-R), could potentially produce savings to the Pharmaceutical Benefits Scheme (PBS), and improve delivery of healthcare to thousands of Australians.Read moreRead less
Genomic and molecular characterisation of a novel Australian leishmania pathogen. Leishmaniasis is the second most serious protozoal disease after malaria. This project will help characterise the first Leishmania species identified in Australia providing molecular tools to monitor the pathogen and a detailed assessment of any potential risk to human health. Comparative analysis with more pathogenic species will help identify genes and mechanisms that determine the progression of human disease le ....Genomic and molecular characterisation of a novel Australian leishmania pathogen. Leishmaniasis is the second most serious protozoal disease after malaria. This project will help characterise the first Leishmania species identified in Australia providing molecular tools to monitor the pathogen and a detailed assessment of any potential risk to human health. Comparative analysis with more pathogenic species will help identify genes and mechanisms that determine the progression of human disease leading to the potential identification of new drug and vaccine targets. The methodologies and expertise developed will be used will be available to other research groups working on infectious diseases.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668507
Funder
Australian Research Council
Funding Amount
$260,000.00
Summary
Real time PCR and nanoparticle diagnostic facilities for high-throughput quantitative analysis of genomic structure and gene expression. Modern molecular tools have lead to an explosion in genome projects and unification of all areas of biology. The most basic need for such research is access to improving technologies for detecting DNA fingerprints that distinguish genetically-diverse genes, and determining which genes are "switched on" or 'off' in various situations. Real time PCR technology, ....Real time PCR and nanoparticle diagnostic facilities for high-throughput quantitative analysis of genomic structure and gene expression. Modern molecular tools have lead to an explosion in genome projects and unification of all areas of biology. The most basic need for such research is access to improving technologies for detecting DNA fingerprints that distinguish genetically-diverse genes, and determining which genes are "switched on" or 'off' in various situations. Real time PCR technology, pioneered by The University of Queensland (UQ) and Southern Cross University (SCU) using ARC funding in 1996, is now the technology of choice for much of this research. This project will provide high-throughput equipment for real time PCR, and will develop complementary high-throughput "nanoparticle" DNA genotyping technologies, with applications to medicine and agriculture.
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Noncoding RNAs As Prognostic Markers And Therapeutic Targets In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$550,283.00
Summary
Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our labo ....Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our laboratory and others have shown that most of our genome and that of other mammals is actually expressed as noncoding RNA, which appears to be developmentally regulated. These RNAs (of which there appear to be tens of thousands, well outnumbering the protein-coding mRNAs) have been referred to as the hidden layer or dark matter of our genome, as they have barely been studied, but appear to play a central role in both normal and abnormal development in humans. There is now increasing evidence that many noncoding RNAs, including small regulatory RNAs called microRNAs, are perturbed in cancer and that these perturbations may be directly involved in, and be an accurate indicator of, cancer state and the direction of cancer progression. If this is true we need to understand the expression and functions of these RNAs in order to develop better diagnostics and perhaps powerful new therapeutics for cancer, based on RNA technology and generic delivery systems. This project will explore the patterns of noncoding RNA expression in normal breast development and in breast cancer, to identify those RNAs that direct or accompany the differentiation of these tissues, and to test the effects of interfering with their expression on these processes. These foundation studies lie at the leading edge of a new understanding of human genetics and cancer, and will provide a platform for future applications in medicine that utilize this information and understanding.Read moreRead less
Detection Of Alternative Lengthening Of Telomeres In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate ....In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate themselves many times, and therefore they need to find a method to prevent their telomeres shortening. We discovered one such method, called Alternative Lengthening of Telomeres (ALT), that is used by some cancers. It has been shown in principle that cancer cells can be killed by disrupting their ability to prevent telomere shortening. Therefore, in another project we are developing methods needed to find drugs that inhibit ALT. In the meantime, we have found the first evidence that some normal cells have an ALT-like mechanism. Our speculation is that cancer cells are able to dysregulate and subvert this normal mechanism in order to prevent their telomeres from shortening. In this project, we will analyse the ALT-like mechanism in mice, to determine its characteristics, and to determine what tissues use it. This information will provide critically important insights into the ALT mechanism itself, and the likely side effects of drugs that inhibit ALT.Read moreRead less
Genetic Models Of Cancer Development And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$645,250.00
Summary
We are taking advantage of the powerful genetic tools in fruit flies to study the genetics of cancer. 72% of cancer genes are conserved between humans and fruit flies, making it a particularly suitable system. This project has two main aims: 1- to build tumours in fruit flies in an effort to understand better the individual genetic lesions that contribute to cancer It takes on average 4-7 mutations for a tumour to develop. While many genes associated with cancer have been identified, there are m ....We are taking advantage of the powerful genetic tools in fruit flies to study the genetics of cancer. 72% of cancer genes are conserved between humans and fruit flies, making it a particularly suitable system. This project has two main aims: 1- to build tumours in fruit flies in an effort to understand better the individual genetic lesions that contribute to cancer It takes on average 4-7 mutations for a tumour to develop. While many genes associated with cancer have been identified, there are many more that have not. What is more, it is still not clear precisely what mutations are responsible for a given tumour as tumours contain many genetic lesions most of which are incidental. We have a collection of fruit flies strains that represent various stages of the progress toward cancer development, and we intend to test different genetic combinations of these to determine which combinations result in cancer. 2- to identify a class of genes we have called 'oncogene suppressor genes' which may have the ability to prevent tumours from forming. Recently, it has been discovered that oncogenes may be required for both the INITIATION of tumours and the MAINTENANCE of tumours. This means that suppressing oncogene function may not only prevent tumour formation, but also tumour maintenance - in other words, it may make tumours go away. Thus, oncogene suppressor genes may represent exciting therapeutic targets for the treatment and possibly also prevention of cancer. At this time it is not clear whether oncogenes are generally required for tumour maintenance, or whether this is a property of only one or a few oncogenes. As these experiments are difficult and expensive to conduct in mammalian systems, we have devised simple, rapid tests in fruit flies instead. We plan to use these tests to investigate the effect of 'oncogene suppressor genes' on tumour initiation and maintenance in fruit flies. Ultimately, we believe these genes may represent therapeutic targets.Read moreRead less