This proposal uses the zebra fish system, which it is uniquely suited to investigate the regulation of disease genes. In all of these diseases preliminary work has already been performed and screening assays have been developed in a previous project (ZF-MODELS). In addition, the project will investigate genetic abnormalities of the eye and visual processing, genetic pathways underlying tissue regeneration and repair, and homologs of human genes related to diabetes and obesity, as well as infecti ....This proposal uses the zebra fish system, which it is uniquely suited to investigate the regulation of disease genes. In all of these diseases preliminary work has already been performed and screening assays have been developed in a previous project (ZF-MODELS). In addition, the project will investigate genetic abnormalities of the eye and visual processing, genetic pathways underlying tissue regeneration and repair, and homologs of human genes related to diabetes and obesity, as well as infectious disease and cancer. The Australian component will perform a systematic characterisation of enhancer elements of potential disease genes. This characterisation will build on the concept of genomic regulatory blocks (GRBs) which contain highly conserved non-coding elements (HCNEs) acting as long-range enhancers of developmental genes (recently discovered by T. Becker in the ZF-MODELS project).Read moreRead less
Use Of The Norfolk Island Genetic Isolate For Disease Gene Mapping
Funder
National Health and Medical Research Council
Funding Amount
$978,500.00
Summary
This gene mapping study will use a unique founder effect population to investigate two major public health disorders. We aim to identify genes that play a role in migraine and in cardiovascular disease, using a population from Norfolk Island. The Norfolk Island community is a population of ~1200 permanent residents, the majority of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women. We will undertake a full genome scan to identify migraine gene loci and QTL ....This gene mapping study will use a unique founder effect population to investigate two major public health disorders. We aim to identify genes that play a role in migraine and in cardiovascular disease, using a population from Norfolk Island. The Norfolk Island community is a population of ~1200 permanent residents, the majority of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women. We will undertake a full genome scan to identify migraine gene loci and QTL that influence cardiovascular disease using samples from this population isolate.Read moreRead less
Retroviral Expression Cloning Using An Arrayed Full Length CDNA Gene Set
Funder
National Health and Medical Research Council
Funding Amount
$1,841,500.00
Summary
The sequencing of the human genome has revealed the blueprint for life, but the identities and-or functions of the majority of genes remain unknown. Here we propose to establish a radically modified retroviral expression cloning system that will, in principle, allow identification of all genes that confer a particular dominant phenotype. To do this we will establish an arrayed retroviral library of sequence-verified genes covering the entire human transcriptome. This technology will be used to i ....The sequencing of the human genome has revealed the blueprint for life, but the identities and-or functions of the majority of genes remain unknown. Here we propose to establish a radically modified retroviral expression cloning system that will, in principle, allow identification of all genes that confer a particular dominant phenotype. To do this we will establish an arrayed retroviral library of sequence-verified genes covering the entire human transcriptome. This technology will be used to identify genes involved in a wide range of medically-important biological processes.Read moreRead less
Identifying Long-range Regulatory Elements Of The Breast Cancer Susceptibility Gene, BRCA1
Funder
National Health and Medical Research Council
Funding Amount
$612,842.00
Summary
BRCA1 is a breast cancer susceptibility gene implicated in both familial and sporadic breast cancers. The mechanisms controlling BRCA1 expression are poorly understood. We will identify DNA sequences critical for regulation of the BRCA1 gene. We hypothesise that these regions are mutational hot spots conferring an increased breast cancer risk. A better understanding of the pathways responsible for promoting BRCA1-associated breast cancer will provide important diagnostic and treatment targets.
Discovery Early Career Researcher Award - Grant ID: DE190100085
Funder
Australian Research Council
Funding Amount
$414,864.00
Summary
Elucidating a novel mechanism for coping with harmful mutations. This project aims to improve our understanding of the complex regulatory mechanisms that increase genetic and phenotypic robustness. Survival of organisms depends on their ability to cope with genetic variation. A novel process of genetic compensation has recently been identified, producing a normal phenotype in a homozygous mutant, that would be expected to have deleterious effects. This project will reveal how compensation is ach ....Elucidating a novel mechanism for coping with harmful mutations. This project aims to improve our understanding of the complex regulatory mechanisms that increase genetic and phenotypic robustness. Survival of organisms depends on their ability to cope with genetic variation. A novel process of genetic compensation has recently been identified, producing a normal phenotype in a homozygous mutant, that would be expected to have deleterious effects. This project will reveal how compensation is achieved by examining the molecular pathways that are activated following genetic mutation. This project is expected to strengthen Australian reputation in evolutionary genetics, and in turn enhance our understanding of how organisms adapt to changing environments.Read moreRead less
Designer DNA-binding factors. This project aims to use a natural transcription factor family to enhance the efficiency and functionality of designer DNA-binding factors. Research into the structure and function of zinc finger transcription factors, TAL effectors and CRISPR created designer DNA-binding factors. However, though research has improved the specificity of these factors’ genome-wide binding, their efficacy in regulating the expression of genes requires improvement. Using sequencing, th ....Designer DNA-binding factors. This project aims to use a natural transcription factor family to enhance the efficiency and functionality of designer DNA-binding factors. Research into the structure and function of zinc finger transcription factors, TAL effectors and CRISPR created designer DNA-binding factors. However, though research has improved the specificity of these factors’ genome-wide binding, their efficacy in regulating the expression of genes requires improvement. Using sequencing, the project intends to enhance the efficiency and function of these factors by designing modules to improve the stability of DNA binding and effectiveness in functionally regulating gene expression. The project outcomes could include knowledge enabling the use of genetically engineered DNA-binding proteins to artificially control gene expression, with significant scientific and economic implications.Read moreRead less
Road rules for traffic on DNA - gene regulation by encounters between transcribing RNA polymerases and DNA-bound proteins. This project addresses a widespread but poorly understood phenomenon in gene regulation. The work will support Australian industries by supplying new tools for manipulation of gene expression for industrial and medical applications and will provide unique opportunities for Australian students in this emerging field.
Discovery Early Career Researcher Award - Grant ID: DE140101033
Funder
Australian Research Council
Funding Amount
$315,220.00
Summary
Genomic Diversity in the Human Brain: the Functional Role of Expandable DNA Repeats. Neuronal cells accumulate genetic changes during development and adult life, and recent evidence suggests that the resulting genomic diversity may underlie neuronal functional diversity. To date only a few types of somatic genetic variation have been characterised in the human brain. Trinucleotide repeats (TNR) are hotspots of genomic instability and TNR expansions at specific loci cause dozens of brain disorder ....Genomic Diversity in the Human Brain: the Functional Role of Expandable DNA Repeats. Neuronal cells accumulate genetic changes during development and adult life, and recent evidence suggests that the resulting genomic diversity may underlie neuronal functional diversity. To date only a few types of somatic genetic variation have been characterised in the human brain. Trinucleotide repeats (TNR) are hotspots of genomic instability and TNR expansions at specific loci cause dozens of brain disorders, suggesting that the human brain is particularly vulnerable to this type of genetic variation. This project aims to investigate, for the first time, TNR somatic instability in the human brain on a genome-wide scale, therefore, addressing the genetic diversity of the brain from a novel and highly relevant angle. Read moreRead less
Non-coding RNAs in mammalian reproduction. This project aims to investigate the role of non-coding RNAs in mammalian sex chromosome biology and reproduction. Non-protein coding RNAs are a major regulatory mechanism in eukaryotic genomes; they can bind other RNAs or chromatin modifying complexes. However, the evolutionary trajectory and function of non-coding RNAs in sex chromosome biology and sexual development is largely unknown. This project will study non-coding RNAs in Australian mammals to ....Non-coding RNAs in mammalian reproduction. This project aims to investigate the role of non-coding RNAs in mammalian sex chromosome biology and reproduction. Non-protein coding RNAs are a major regulatory mechanism in eukaryotic genomes; they can bind other RNAs or chromatin modifying complexes. However, the evolutionary trajectory and function of non-coding RNAs in sex chromosome biology and sexual development is largely unknown. This project will study non-coding RNAs in Australian mammals to try to answer fundamental questions about how non-coding RNAs function in mammalian sexual development.Read moreRead less
Chromatin structure and pervasive transcription. This project aims to understand mechanisms that repress pervasive transcription and to identify chromatin characteristics that repress transcription initiation outside the promoter regions. Chromatin characteristics, such as position, occupancy and turnover-rate of nucleosomes, establish an elaborate genomic indexing mechanism, which defines functional units in the genome. Defects in this process increase pervasive transcription, toxic accumulatio ....Chromatin structure and pervasive transcription. This project aims to understand mechanisms that repress pervasive transcription and to identify chromatin characteristics that repress transcription initiation outside the promoter regions. Chromatin characteristics, such as position, occupancy and turnover-rate of nucleosomes, establish an elaborate genomic indexing mechanism, which defines functional units in the genome. Defects in this process increase pervasive transcription, toxic accumulation of non-coding transcripts and genomic instability. This work aims to understand eukaryotic genome organisation and may have long-term therapeutic implications for cancer and ageing-related diseases.Read moreRead less