Exploiting Sexual Differences In Germline Biology To Resolve The Causes Of Germline Mutation
Funder
National Health and Medical Research Council
Funding Amount
$315,914.00
Summary
Mutagenesis during the production of sex cells is a fundamental biological process and the cause of inherited human disorders. These disorders span the entire spectrum of diseases that have a genetic component, such as autoimmune diseases and cancers, therefore influencing all age groups. A better understanding of the mechanisms underlying this process is a priority since it is the essential knowledge required for understanding all of the factors that contribute to this array of debilitating dis ....Mutagenesis during the production of sex cells is a fundamental biological process and the cause of inherited human disorders. These disorders span the entire spectrum of diseases that have a genetic component, such as autoimmune diseases and cancers, therefore influencing all age groups. A better understanding of the mechanisms underlying this process is a priority since it is the essential knowledge required for understanding all of the factors that contribute to this array of debilitating diseases, and for devising effective preventative and diagnostic measures. To attain this understanding necessitates establishing the mechanistic origins of germline mutagenesis. Two basic approaches are employed to understand this process. The first assesses the incidence of mutation in pedigrees. This identifies the spectrum of risk mutations underlying the specific disease surveyed. Because other biological processes also influence these observations, the results from this approach do not reflect the underlying germline mutation spectra and are therefore not translatable between diseases. As mutations are rare events, it is prohibitive to obtain sufficient observations to resolve the underlying mechanisms. The second approach employs comparative genomic data, and uses differences in germline biology to estimate sex-biased effects. This comparative approach benefits from the accumulation of mutations over vast periods of time. The approach has not, however, been applied to diagnose the mechanistic origins of mutations. In this project, we will apply the enormous volume of comparative sequencing data to relate components of the mutagenic spectrum with sexual differences in germline biology. The project will differentiate between different types of mutations, and their association with specific processes will be established. The results will be a determination of the relative contributions of different mechanisms of mutation to germline mutagenesis.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775587
Funder
Australian Research Council
Funding Amount
$532,000.00
Summary
Correlating Genomics and Proteomics for Systems Biology: integrating the '-omics'. Acquisition of the infrastructure requested will maintain and extend the expertise developed by researchers in NSW and will allow retention and attraction of leading researchers who can contribute to understanding how genes and proteins interact in the development of the organism - the central focus of systems biology. The enhancement of the facility will allow a better understanding of biomolecular interactions ....Correlating Genomics and Proteomics for Systems Biology: integrating the '-omics'. Acquisition of the infrastructure requested will maintain and extend the expertise developed by researchers in NSW and will allow retention and attraction of leading researchers who can contribute to understanding how genes and proteins interact in the development of the organism - the central focus of systems biology. The enhancement of the facility will allow a better understanding of biomolecular interactions in health and disease, providing both community and national benefits. The focus of this LIEF application is to provide infrastructure platforms for the study of the systems biology of organisms and additional capacity by the facility for the expected increased demand for this technology in this new area. Read moreRead less
Epigenetic silencing in vertebrates: evolution and function from the bottom-up. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional genomics in Australia, with the research priority of Frontier Technologies for Building and Transforming Australian Industries and priority goals in Breakthrough Science and Frontier Technologies. This project focuses on important biological questions surrounding gene regulation and sex chromosome evolution. Inte ....Epigenetic silencing in vertebrates: evolution and function from the bottom-up. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional genomics in Australia, with the research priority of Frontier Technologies for Building and Transforming Australian Industries and priority goals in Breakthrough Science and Frontier Technologies. This project focuses on important biological questions surrounding gene regulation and sex chromosome evolution. International attention has already resulted in genome characterization of Australian icons (wallaby, Tasmanian devil and platypus), more research on these, and other Australian animals, will further highlight the importance of Australian fauna and impact positively on our scientific profile.Read moreRead less
Origin and evolution of genes on the human X chromosome. Two groups of functionally related genes are found on the human X chromosome in disproportionately high numbers. I will test whether an uneven distribution of genes is common in mammalian genomes, or whether the human X is special. I will test hypotheses of how the gene groups arose on the human X by comparing their location and expression patterns in other mammals, and other vertebrates. It will then be clear whether the ancestral autosom ....Origin and evolution of genes on the human X chromosome. Two groups of functionally related genes are found on the human X chromosome in disproportionately high numbers. I will test whether an uneven distribution of genes is common in mammalian genomes, or whether the human X is special. I will test hypotheses of how the gene groups arose on the human X by comparing their location and expression patterns in other mammals, and other vertebrates. It will then be clear whether the ancestral autosome was ?chosen?, whether it ?selfishly? accumulated these genes, or whether the function of genes changed in response to selective pressures.Read moreRead less
Small is beautiful: Did gene-rich regions of mammal chromosomes evolve from microchromosomes? Most birds and reptile genomes feature many tiny microchromosomes. These are not junk, as previously thought, but contain most of the genes. Mammals lack microchromosomes, but contain gene-rich regions with similar attributes. We suggest that microchromosomes originated by genome duplication, and evolved into the gene-rich regions of mammalian chromosomes. We will test this hypothesis by comparing seque ....Small is beautiful: Did gene-rich regions of mammal chromosomes evolve from microchromosomes? Most birds and reptile genomes feature many tiny microchromosomes. These are not junk, as previously thought, but contain most of the genes. Mammals lack microchromosomes, but contain gene-rich regions with similar attributes. We suggest that microchromosomes originated by genome duplication, and evolved into the gene-rich regions of mammalian chromosomes. We will test this hypothesis by comparing sequences and genes in microchromosomes of birds, reptiles and monotremes. This will clarify the origin and evolution of the ?microgenome?, establish its suitability as a model for vertebrate genome organisation, and demonstrate whether microchromosomes are the ancestors of the gene-rich regions of mammalian chromosomes.Read moreRead less
Origin and Evolution of Mammalian Dosage Compensation. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional comparative genomics in Australia, with the research priority of 'Frontier Technologies for Building and Transforming Australian Industries' and priority goals in 'Breakthrough Science and Frontier Technologies'. This project addresses fundamental questions about the evolution of mammalian X-chromosome inactivation, of importance as a mo ....Origin and Evolution of Mammalian Dosage Compensation. The primary benefits are contribution to Australia's knowledge base and raising the profile of functional comparative genomics in Australia, with the research priority of 'Frontier Technologies for Building and Transforming Australian Industries' and priority goals in 'Breakthrough Science and Frontier Technologies'. This project addresses fundamental questions about the evolution of mammalian X-chromosome inactivation, of importance as a model for epigenetic change, and sex chromosomes, which has engaged some of the greatest genetic minds over nearly a century. Therefore my results will attract wide international interest and impact positively on Australia's scientific profile, and further highlight the importance of Australian mammals.Read moreRead less
Epigenesis and sociality: Unraveling the link between nutrition and the genome - how do genes and environment interact to produce phenotypes? This project has the capacity to transform our understanding of how genes and environment interact to produce whole-organism phenotypes. It will provide novel data on how an entire genome responds to nutrition and how external factors can enforce a differential expression of a common heritable genetic program. The national and community benefits of the pro ....Epigenesis and sociality: Unraveling the link between nutrition and the genome - how do genes and environment interact to produce phenotypes? This project has the capacity to transform our understanding of how genes and environment interact to produce whole-organism phenotypes. It will provide novel data on how an entire genome responds to nutrition and how external factors can enforce a differential expression of a common heritable genetic program. The national and community benefits of the project will be to maintain Australian leadership in epigenetics and advanced genetics of complex self-organizing systems. The findings of this project have the potential to be applicable to explaining regulatory networks underlying diet induced changes in human gene expression.Read moreRead less
Further Genetic and Molecular studies of an Important Prokaryotic Regulator Protein TyrR. Genomes encode many functions whose expression varies dramatically depending on particular cellular environments. Special proteins called Regulator Proteins act as sensors to detect subtle changes in the environment and, in response, to influence the expression of certain genes either dampening them down or stimulating their activity. We are working with the TyrR regulator protein of the simple bacterium E ....Further Genetic and Molecular studies of an Important Prokaryotic Regulator Protein TyrR. Genomes encode many functions whose expression varies dramatically depending on particular cellular environments. Special proteins called Regulator Proteins act as sensors to detect subtle changes in the environment and, in response, to influence the expression of certain genes either dampening them down or stimulating their activity. We are working with the TyrR regulator protein of the simple bacterium Escherichia coli to elucidate the molecular strategies used in these controls. Because this protein controls the expression of a number of genes with diverse functions, evolution has selected equally diverse mechanisms to achieve appropriate transcriptional responses. The detailed knowledge of the E.coli genome and of the various genes regulated by TyrR make it an excellent system for such fundamental studies.Read moreRead less
Molecular characterization of marsupial genome organization, function and evolution. I will initiate a coherent investigation of the genome of an Australian marsupial (the tammar wallaby), exploiting new resources, new techniques and the hugely increased capacity for large-scale investigations of genomes at the molecular level. I will isolate and characterize large-insert (BAC) clones of the gene-rich region of the Y chromosome, ancient, added and controlling regions of the X chromosome, and aut ....Molecular characterization of marsupial genome organization, function and evolution. I will initiate a coherent investigation of the genome of an Australian marsupial (the tammar wallaby), exploiting new resources, new techniques and the hugely increased capacity for large-scale investigations of genomes at the molecular level. I will isolate and characterize large-insert (BAC) clones of the gene-rich region of the Y chromosome, ancient, added and controlling regions of the X chromosome, and autosomal imprinted regions. Comparisons with the homologous regions of the human and mouse genomes will identify and characterize new mammalian genes and control signals, untangle complex regulatory systems, and discover how mammalian genes, and the mammalian genome, evolved.Read moreRead less