Development And Evaluation Of Statistical Methods And Software For Analysis Of Complex Genetic Disease Data
Funder
National Health and Medical Research Council
Funding Amount
$1,250,371.00
Summary
What are the major factors underpinning complex genetic diseases like diabetes, bipolar disorder or cancer? To answer this question new tools are needed, including software for mining the human genome with interactions between the genome and environment being incorporated. This is our focus. It will form the basis of a superior understanding of the overall process leading to disease and hence better predictions with important ramifications for new treatments and health care planning.
Fine Mapping Of Genes Underlying Asthma And Eosinophilia
Funder
National Health and Medical Research Council
Funding Amount
$278,000.00
Summary
Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent t ....Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent twins, we showed these measures to be genetically linked to two different regions in the genome. Closer examination of these regions found several genes that might be responsible for the linkage. In the present study, we plan to test which of these candidate genes actually causes elevated IgE level or eosinophil count. The approach is to compare the frequency of a putative gene in a child expressing that phenotype to that in their parents. Each child receives one copy of a gene from the father, and one from the mother, making up a complete genotype (two possibly different versions or alleles of the gene). Since each parent transmitted only one allele to the child, the remaining allele from each parent can be used to create a normal control genotype, that is guaranteed to come from the same ethnic background as the asthmatic child. Therefore, we will collect replacement blood samples in those familes where all the previously DNA has been used up in our earlier study. We will extract DNA, and measure the genotypes of parents and children at the 6 genes in our two regions that we think most likely to be involved in eosinophil count or IgE level. This family based test will allow us to decide which genes are genuinely associated with asthma in our population. We will also test if these genes interact with other genes thought to be asthma risk factors. Identification of novel genes involved in asthma will help understand and ultimately treat this condition.Read moreRead less
Atopic dermatitis (AD) or atopic eczema is the third condition making up the atopic triad (asthma, hayfever and eczema). It usually has its onset before two years of age. It is common, affecting approximately 10% of Australian children and 7% of Australian adults, and is increasing in prevalence. As with asthma, genes are known to be important in its causation, and several different genes have been reported to be involved by different investigators. These findings are not always repeatable in di ....Atopic dermatitis (AD) or atopic eczema is the third condition making up the atopic triad (asthma, hayfever and eczema). It usually has its onset before two years of age. It is common, affecting approximately 10% of Australian children and 7% of Australian adults, and is increasing in prevalence. As with asthma, genes are known to be important in its causation, and several different genes have been reported to be involved by different investigators. These findings are not always repeatable in different countries or ethnic groups. One, the mast cell chymase gene seems to be associated with AD in Japan, but not in Australia or Italy. However, this gene may be responsible only for AD where total serum Immunoglobulin E is low, roughly 20% of all AD. Therefore, the previous studies may not have included enough cases of this subtype to reliably detect the association. The present study aims to test all the published genes in two panels of families: one where both AD and asthma or hayfever are present in the family (180 families), the second where AD alone is present (100 families). We will also test for genetic linkage to particular regions of the genome, where the specific gene is yet to be identified, and for newly discovered gene variants in these regions that may be associated with AD. Confirming and refining the nature of genes involved in the causation of AD is useful for the basic understanding of biochemical pathways to disease and ultimately to the design of drugs to interfere with these pathways.Read moreRead less
Clinical Genetic Phenotyping Of Autism Spectrum Disorders
Funder
National Health and Medical Research Council
Funding Amount
$582,114.00
Summary
Individuals with autism spectrum disorders (ASD) have difficulty with communication, social interaction and intellectual disability. The cause is generally not known although most cases have a genetic basis involving multiple genes and possibly environmental factors. We will study families of children with ASD and carefully characterize features related to ASD in family members. This will help us to understand how ASD is inherited and serve as the basis for the discovery of autism genes.
Discovery And Analysis Of Vertebrate Intestinal Development Genes That May Play A Role In Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$376,613.00
Summary
Colorectal cancer (CRC) causes more cancer deaths in Australia than any other cancer. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities ( ....Colorectal cancer (CRC) causes more cancer deaths in Australia than any other cancer. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a lifetime. Together the mutated genes produce changes in cell behaviour in processes such as growth, migration, angiogenesis (the ability to attract a blood supply) and cell death. All of these processes are active during normal development of a vertebrate organism, but are generally shutdown in the adult state, except in cancer. In this study we will analyse a group of genes that we have recently shown to be indispensable for normal intestinal development in zebrafish. Zebrafish are small tropical fish that are used frequently for genetic studies. They are very closely related to mammals and it has been shown that the genetic pathways that control the development of this animal are highly conserved in fish and mammals. Importantly, the genetic pathways that lead to cancer in humans are also strikingly similar in zebrafish. Our experiments will use mouse models to discover whether the zebrafish genes we have identified can lead to cancer when they are aberrantly expressed in the intestines of mice. Any genes that are found to contribute to the development of cancer in these models could become potential new targets for cancer therapy.Read moreRead less
Characterisation Of A New Localisation For Susceptibility To Inflammatory Bowel Disease On Chromosome 12
Funder
National Health and Medical Research Council
Funding Amount
$76,125.00
Summary
One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases in order to develop more effective therapies. Although there have been advances in treatment over the last few years, the causes of IBD are still not known. The existence of a genetic predisposition to IBD is now well established, and there is strong evidence that the disease is the result of the interaction of a number of different genes. To date, two genetic locali ....One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases in order to develop more effective therapies. Although there have been advances in treatment over the last few years, the causes of IBD are still not known. The existence of a genetic predisposition to IBD is now well established, and there is strong evidence that the disease is the result of the interaction of a number of different genes. To date, two genetic localisations (one on chromosome 16 and a second on chromosome 12) have been confirmed in multicentre studies. We have identified a novel localisation for disease susceptibility on chromosome 12 in the Australian population during the course of a genome scan on 73 multiplex inflammatory bowel disease families. (The importance of this localisation has been confirmed in English and American families.) This localisation is quite separate from that originally described and many genes separate the two localisations. We will refine the new localisation by fine scale mapping in the region of the localisation that we originally identified in pure Crohn's disease families. At this stage, the localisation appears not to be important in families suffering from ulcerative colitis or in families in which both CD and UC occurs (known as mixed families), though this finding will be tested. Using state of the art molecular genetics, we will then identify and characterise the gene involved. The significance of this project lies in the importance of this localisation to the understanding of underlying biochemistry and genetics of a complex disease in which multiple genes are segregating and interacting in, some as yet undefined manner.Read moreRead less
Genetic Dissection Of A QTL Influencing The Development Of Type 2 Diabetes And The Metabolic Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$129,875.00
Summary
Diabetes is usually associated with obesity and is often part of a wider disturbance affecting an individuals metabolism. These other factors include high blood pressure and the control of fats (eg cholesterol), and sugars (glucose) in the blood stream. Physicians have noted that these abnormalities often cluster together in individuals and have called it the metabolic syndrome, the main long term implication of which is to increase a persons risk of developing heart disease and disorders in blo ....Diabetes is usually associated with obesity and is often part of a wider disturbance affecting an individuals metabolism. These other factors include high blood pressure and the control of fats (eg cholesterol), and sugars (glucose) in the blood stream. Physicians have noted that these abnormalities often cluster together in individuals and have called it the metabolic syndrome, the main long term implication of which is to increase a persons risk of developing heart disease and disorders in blood circulation. The number of affected people with one the major components of the metabolic syndrome, type 2 diabetes, has trebled since 1981 in Australia and is still increasing. Apart from individual suffering, this presents a major public health burden for the country (approx $3 billion annually). Currently available lifestyle based and pharmaceutical therapies appear inadequate to control the increasing numbers of affected individuals. Unfortunately the cause of disease is poorly understood, although genetic factors are known to be important, in other words it runs in the family. This project proposes to identify some of these factors (genes) and how they contribute to the disease. Using molecular flags on the DNA (like DNA fingerprinting) we have previously found that a small region on chromosome 3 is likely to carry one or more of these disease genes. But there are over 100 genes in the region, so to help choose the most likely candidates first for testing, we have developed an automated computer database searching program that narrowed the list to the six most likely genes. This project will determine which if any of these genes are involved. A successful finding means we will know more about the mechanism of disease development and be able to better develop new therapies for treatment and prevention. If none of these genes are the culprit, we would continue examination of the next set of genes likely to be involved and so on until we are successful.Read moreRead less
Identifying Modifiers For Plasmacytoma Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
Many oncogenes and tumour suppressor genes have been identified. Activation or deletion of these genes can have profound effects on the control of cell growth and result in tumours. Many tumour suppressor genes give carriers an elevated risk of disease. However in many cases the incidence of these mutations causing cancer is much lower than would be expected, due to other influencing factors. This project aims to try and understand the reasons behind this in a mouse model of cancer, plasmacytoma ....Many oncogenes and tumour suppressor genes have been identified. Activation or deletion of these genes can have profound effects on the control of cell growth and result in tumours. Many tumour suppressor genes give carriers an elevated risk of disease. However in many cases the incidence of these mutations causing cancer is much lower than would be expected, due to other influencing factors. This project aims to try and understand the reasons behind this in a mouse model of cancer, plasmacytomas. Modifers of tumour incidence are proposed for human disease but very little is known about the identity of the genes involved or in the biological pathways regulating tumour incidence. The search for these genes in humans is difficult. We have begun studies to find modifiers of tumourigenesis using the E -v-abl transgenic model of plasmacytomas. This is the mouse equivalent of multiple myeloma. Studies have shown that some strains of mice have markedly different incidences of tumours. C57BL-6 animals are less susceptible with 20% of animals developing tumour by 12 months of age. In contrast, 90% of transgenic animals on the BALB-c background develop tumour by 12 months of age. There is also a significant sex difference with males being more susceptible than females. There is a similar difference in susceptibility in humans to multiple myeloma.Read moreRead less
A Genome-wide Search For Genes Underlying The Developmental Origins Of Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,022,552.00
Summary
Epidemic rises in the incidence of many chronic diseases such as obesity, type 2 diabetes, hypertension, coronary artery disease and mental illness have occurred in Australia over the last two decades. Antenatal, early life and childhood factors have been consistently associated with the development of such diseases. We propose to conduct a genome-wide scan in an exceptional longitudinal birth cohort in order to identify the genetic mechanisms linking early life event and adult disease.
Variation And Inheritance Of Retrotransposon Epigenotype In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$355,500.00
Summary
It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way gene ....It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way genes are used. Epigenetic factors can be passed from one generation to the next like the DNA itself, and this can make it difficult to know if a trait is encoded in the DNA itself or is epigenetic. We have found that some epigenetic traits in mice are caused by retrotransposons, which are parasitic elements that reside in and among genes, and can reproduce themselves, but do not have any known function (nearly half the human genome is made up of retrotransposons). Retrotransposons are generally kept silent by epigenetic factors, but may sometimes become active; when they do they may disturb normal patterns of gene activity and cause changes in traits and even disease. Much variation in humans may thus be due to variation in the epigenetic state (epigenotype) of retrotransposons. We propose to investigate variation and inheritance of epigenotype in mice, focussing on retrotransposons. We will use simple methods to compare epigenotype of a number of retrotransposons in genetically identical mice, and we will ask if any differences we find are heritable. We will also investigate the resetting of epigenotype the point in development when epigenetic factors are cleared and reset. We suspect that this occurs in early development. These studies may reveal a system of variation and inheritance with rules completely different from those found by Mendel, which may have a pervasive influence on traits, including sporadic diseases in humans.Read moreRead less