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
Population-based Detection Of Hereditary Non-polyposis Colorectal Cancer: Development Of New Best Practice
Funder
National Health and Medical Research Council
Funding Amount
$356,250.00
Summary
Approximately 1-2% of all large bowel cancers are thought to be caused by inherited defects in genes involved in the repair of DNA. These cancers are indistinguishable from those that occur in the general population and this has made it difficult to identify individuals and families with the defective gene. It has been estimated that only about 10-20% of individuals affected by this familial cancer syndrome are being referred to specialized genetic service centres for testing. The large majority ....Approximately 1-2% of all large bowel cancers are thought to be caused by inherited defects in genes involved in the repair of DNA. These cancers are indistinguishable from those that occur in the general population and this has made it difficult to identify individuals and families with the defective gene. It has been estimated that only about 10-20% of individuals affected by this familial cancer syndrome are being referred to specialized genetic service centres for testing. The large majority of familial colorectal cancers occur in young patients aged less than 60 years at diagnosis. Identification of these cases would allow genetic testing to be carried out on other family members who might also carry the mutant gene, thus allowing regular surveillance and a far greater likelihood of early detection and therefore cure. The aim of this project is to use a relatively simple laboratory-based method to test for the possibility that colorectal cancer in young patients (<60 years) may be inherited. From our preliminary data we expect that about 2% of all large bowel cancers, or 20 cases per year in Western Australia, may be familial. These individuals will be referred to Genetic Services WA for proper evaluation of their family history for cancer and for further DNA testing in an attempt to identify the defective gene. For positive cases, affected family members could then be tested for the gene after appropriate genetic counselling.Read moreRead less
Understanding Causes Of The Rising Incidence Of Thyroid Cancer – What Can Mutations In The BRAF Oncogene Tell Us About Causes And Diagnostic Pathways For Thyroid Cancer?
Funder
National Health and Medical Research Council
Funding Amount
$610,222.00
Summary
The occurrence of thyroid cancer has increased rapidly over the last 25 years but the cause is unknown. The increase may reflect ‘over-diagnosis’ of less harmful cancers or greater exposure to causes of this cancer. Evidence suggests that a gene mutation (BRAF) in thyroid cancers is important in understanding the drivers of the increase. This study will examine the increase in thyroid cancer by investigating causes and diagnostic pathways considering the presence or absence of BRAF mutations.
Analysis And Regulation Of Leptospiral Virulence Factors.
Funder
National Health and Medical Research Council
Funding Amount
$630,465.00
Summary
Leptospirosis is a globally important infectious disease caused by Leptospira spp. This project aims to identify and characterise factors which play a role in disease development by knocking out genes, then investigating the impact on overall gene-protein expression in the mutant strain and its ability to cause disease. This will allow us to gain insights on mechanisms by which Leptospira spp. cause disease, leading to development of better methods of disease control and prevention.
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.
Oxidation Of Mismatch: A New Concept For Mutation Detection Which Avoides A Separation Method In Mutation Scanning
Funder
National Health and Medical Research Council
Funding Amount
$143,000.00
Summary
Detection of faults (mutations) in genes is expensive but essential for proper genetic health care. Because of the cost of such tests many people are not diagnosed either through diagnostic labs or research of the cost of such tests many people are not diagnosed either through diagnostic labs or research projects. Such research projects are inhibited due to the complexity of the current methods. Current methods are complex and expensive, especially looking for a possible fault, due to what is ca ....Detection of faults (mutations) in genes is expensive but essential for proper genetic health care. Because of the cost of such tests many people are not diagnosed either through diagnostic labs or research of the cost of such tests many people are not diagnosed either through diagnostic labs or research projects. Such research projects are inhibited due to the complexity of the current methods. Current methods are complex and expensive, especially looking for a possible fault, due to what is called a preparation step on complex and expensive equipment. We will develop and commercialise a simpler test because separation is avoided.Read moreRead less
Gene Discovery And Characterisation In The Familial Focal Epilepsies
Funder
National Health and Medical Research Council
Funding Amount
$428,065.00
Summary
Around 2% of people have epilepsy at some time in their lives. A large proportion of cases are thought to have a genetic cause, but genes have not yet been identified for most patients. The aim of this project is to use state-of-the-art genetic methods to identify genetic mutations causing epilepsy and to then study the effects of these mutations to better understand the biological causes of epilepsy. This in turn will lead to better diagnosis of epilepsy and improved treatment for patients.
Factor V Leiden Mutation: A Contributory Factor For Cerebral Palsy?
Funder
National Health and Medical Research Council
Funding Amount
$72,595.00
Summary
Cerebral palsy is the commonest physical disability in childhood. It has a major impact on individuals and families. In a significant proportion of cases, the cause is unknown so further research is essential to define the reasons for this condition, and thereby develop preventative strategies. Two mutations have been identified that predispose carriers to develop blood clots (called thrombosis). These mutations are the Factor V Leiden mutation and the coagulation gene for prothrombin (also know ....Cerebral palsy is the commonest physical disability in childhood. It has a major impact on individuals and families. In a significant proportion of cases, the cause is unknown so further research is essential to define the reasons for this condition, and thereby develop preventative strategies. Two mutations have been identified that predispose carriers to develop blood clots (called thrombosis). These mutations are the Factor V Leiden mutation and the coagulation gene for prothrombin (also known as the G20210A mutation). If blood clots form in, or travel to the brain (embolism), they can obstruct the blood supply causing damage that may result in cerebral palsy in young children. Our research will investigate both mothers of children with cerebral palsy, and the children themselves. The study of the mothers will determine whether those that are carriers of these mutations are at an increased risk of having children with cerebral palsy. Factors that may precipitate the development of blood clots, such as smoking during pregnancy, will be investigated. The children with cerebral palsy will be studied to determine whether they carry the mutations, and if so, whether they have brain scan evidence of previous blood clots. Children will be tested for the mutation using the blood spot taken routinely early in life. These blood spots are stored on cards (Guthrie cards) and are available for research following parental consent. The mothers will be tested for the mutation by using a saliva sample and will also be interviewed to obtain details of their pregnancies. As a result of this project, useful information will be provided for families and health care providers. It will be established whether these mutations play a role in the genesis of cerebral palsy. In addition, data about possible factors which may increase the risk in carrier mothers, such as smoking, will be provided.Read moreRead less
Analysis Of Circulating Tumour DNA For Mutational Characterisation And Tracking Disease Progression In Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$908,676.00
Summary
Multiple myeloma is cancer of plasma cells in the bone marrow and presents at multiple sites with dissimilar genetic information (GI) across these sites. Invasive biopsies of multiple sites are required to determine the GI. Cancer cells shed small amounts of DNA into the blood stream and this circulating DNA (ctDNA) contains GI from multiple cancer sites. This project will evaluate the utility of ctDNA to determine GI and to predict treatment response in MM patients.