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
Statistical Methods For Identifying Structural Variation In Tumour Genomes Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$243,458.00
Summary
New DNA sequencing technology can sequence a tumour genome affordably in 2 weeks. This re-sequencing data can be used to find small mutations and large-scale chromosomal rearrangements that together are the drivers of cancer. These may one day be used to guide cancer therapy. This project will develop new algorithms for finding mutations and apply these to discover the genetic basis of drug resistance in a model lymphoma system.
Investigating The Pathogenic Mechanism Of Mutations In IQSEC2 Causing Non-syndromic Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$449,016.00
Summary
Intellectual disability is frequent in the population, as many as 1 in every 50 people in the world affected. Mutations in IQSEC2, an X-chromosome gene, cause intellectual disability. We will screen 1000 families with this disability for mutations in IQSEC2, building the picture of disease symptoms, contributing to informed genetic counselling. We will investigate functional impacts of these mutations in neuronal cultures, increasing our understanding of the causes of intellectual disability.
Cleavage Methods Of Mutation Detection: Improvement And Application In Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,044,349.00
Summary
Genes contain the information to build our body and keep it operating normally. These genes are inherited from our parents and number around 100,000. Faults in these genes can cause inherited diseases such as cystic fibrosis, cancers and common disorders such as Asthma and diabetes. These genes need detecting so that particular genes can be identified as causing the disease and also so that patients can have their disease properly diagnosed so that proper therapy and information can be given to ....Genes contain the information to build our body and keep it operating normally. These genes are inherited from our parents and number around 100,000. Faults in these genes can cause inherited diseases such as cystic fibrosis, cancers and common disorders such as Asthma and diabetes. These genes need detecting so that particular genes can be identified as causing the disease and also so that patients can have their disease properly diagnosed so that proper therapy and information can be given to the patients. In future similar changes (but changes not causing disease) may be searched for in patients to overcome the side effects of drugs. Our centre specializes in the methods of detecting faults and their application. Two of our methods are being used around the world and one is being sold as simple kit. These methods still have drawbacks and the work proposed is to overcome some of these. We propose to apply our and other methods to faults in genes which have recently been shown to cause diseases of the artery. This is an exciting new development that shows that this disease is similar to cancer. We are fortunate to have attracted Dr Paula Bray from the laboratory which discovered this. This new finding needs to be studied in more detail and may identify life-style factors which cause coronary heart disease. Our studies will also assist in gene therapy when it becomes available.Read moreRead less
Molecular Mechanisms Of Inherited Hypocholesterolaemias: Impact Of APOB And MTTP Mutations On Lipoprotein Assembly And Secretion
Funder
National Health and Medical Research Council
Funding Amount
$200,213.00
Summary
Inherited low cholesterol levels can be caused by mutations in either of two genes: APOB and MTTP. These genes encode proteins that are critical for the assembly of fat particles in the body. We plan to use cell lines to study how single amino acid changes out of the 4500 in ApoB and the 900 in the MTTP protein affect protein production, binding with other proteins, and fat particle assembly.