Population Studies and Profiling

Dr Jeremy Jowett
Head, Genomics and Systems Biology
jeremy.jowett@bakeridi.edu.au

Laboratory Research Overview

The Genomics and Systems Biology laboratory is dedicated to understanding the processes that cause obesity, diabetes and cardiovascular disease. These are increasingly common non-communicable diseases that develop in some but not all individuals and "run in families". Knowledge of disease-predisposing genes and their function, and what happens when they go wrong will help our understanding of overall body physiology and disease processes. This will aid in the development of improved therapeutic drugs and tests to ameliorate, cure or prevent the consequences of these serious health problems.

We seek to understand the basis of why some but not all individuals develop these diseases, and why they "run in families". To achieve this goal, we apply the latest technological advances in genetic analysis such as the "Next Gen" DNA sequencing platforms with some innovative modifications combined with gene expression profiling, to our large collection of human family and unrelated cohorts. For example, we have discovered 5 regions of the genome that control blood glucose levels, and currently seek the specific genetic factors in these regions to gain insight into development of diabetes.

In addition to gene discovery, the Genomics and Systems Biology lab is undertaking molecular profiling studies in humans which will provide valuable information about the disease process itself at a very detailed molecular level. Building upon earlier work undertaken through collaboration with US scientists, we have determined that gene activity levels in blood are affected to a large extent by inherited factors (i.e. genes). In a sense, our inherited DNA causes us to be "hard-wired" to a degree in how we as individuals respond dynamically to the environment in which we live. In these new innovative molecular profiling studies we examine not only gene activity levels but also a number of other recently discovered molecular states that can affect gene activity (methylation and microRNAs).

Ultimately our goal is to understand these specific genetic and non-genetic factors that make each of us unique, so that optimal treatment regimens may be applied if a disease becomes manifest. In addition to new and better drugs, we look toward developing personalised medicine options for improvement of health outcomes of each and every Australian.

Research Focus

• Genetics of complex disease such as diabetes and cardiovascular disease
• Human molecular profiling
• Systems biology approaches combining genetic (DNA variation) and genomic (gene expression) to understand disease processes
• Understanding the health consequences of our interaction with our environment
• Novel therapeutic targets for improved patient treatment
• Personalised medicine

Research Projects

Identification of novel genes influencing development of type 2 diabetes

Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the prevalence of type 2 Diabetes Mellitus (T2D) worldwide in part driven by increasing obesity prevalence. Once diagnosed, currently available interventions are inadequate to control disease progression and there are few new therapeutics in the development pipeline due to our limited understanding of the molecular pathogenesis. The complex cause of T2D is thought to involve environmental and genetic risk factors. Individuals with a family history of T2D are 2 to 6 times more likely to develop the disease as compared to those without, independent of the shared familial environment.

Despite recent advances using large scale association approaches and 40 genomic regions implicated, the majority of the increase in familial risk of T2D remains unknown.

Here we apply the latest breakthroughs in massively parallel DNA sequencing to a family cohort where we have identified one of the strongest and widely replicated genetic linkage regions for T2D (Chromosome 12q24). The "next generation sequencing" (NGS) technology will enable a full genetic dissection of the segregating variants contributing to the linkage signal at 12q24 and guarantee identification of the causative gene(s). Genes will be validated by functional genomics approaches, and evaluated for novel drug development.

Novel mechanisms of control of HDL cholesterol homeostasis

Evidence from epidemiological studies has shown that a low serum level of high density lipoprotein "Good" cholesterol (HDL-C) is a strong risk factor for development of cardiovascular disease (CVD) including atherogenesis and coronary heart disease. Major influences on low HDL-C levels include obesity, smoking, sedentary behaviour, type 2 diabetes and genetic factors, with the latter inherited risk contributing to 50% of the total natural variation. As little as a 1% decrease in HDL-C confers a 2-3% increase in risk of CVD translating to a substantial rise in morbidity and mortality at the population level.
Diet and exercise improve HDL-C levels however they have failed to stem the increasing rates of disease in the community. Existing drugs raise HDL-C to a variable degree and it is uncertain whether any reduction in risk is conferred, others have been withdrawn from market due to side-effects. Therefore there is an urgent need for new HDL-C raising therapies.

To address this, we have combined genomic, transcriptomic and functional genetic analyses (using a systems biology approach) to identify novel genes involved in HDL-C homeostasis. In this project we investigate the mechanism of action linking these genes to HDL-C homeostasis to derive novel means for development of therapeutic intervention strategies.

Lab Head Profile

Dr Jowett completed undergraduate training at Melbourne University in Genetics and Microbiology in 1985. After three years studying genetic variation in HIV isolates at the Fairfield Infectious Diseases hospital in Melbourne, he completed a D.Phil (Ph.D degree) at Oxford University (UK) in molecular and cell biology. In 1992, he was awarded a prestigious American Cancer Society fellowship to continue his studies in molecular biology at University of California Los Angeles (UCLA). The studies covered HIV pathogenesis, cell death, apoptosis and mechanisms of disease manifestation. He was promoted to Assistant Researcher Biologist in the Dept of Medicine and continued at UCLA until 1998.

Dr. Jowett returned to Australia and founded the genetics research laboratory at the International Diabetes Institute (IDI) in Melbourne, where he was appointed Director of Genetics Research. Here he established a network of international collaborations in pursuit of genes predisposing to type 2 diabetes. With industry support, he setup a state of the art genetics research lab with the first Sequenom MassArray system in Australia at its core. After the Baker IDI merger he became Head of the Genomics and Systems Biology Research lab. His current interests lie in advancing our understanding of obesity, type 2 diabetes (T2D) and cardiovascular disease pathogenesis through the combination of genetics and molecular profiling in human cohorts.

Achievements/Awards

• American Cancer Society Fellowship (1992)
• NHMRC Career Development Award (2010)
• 7 international patents

Publication Highlights

• Jowett JBM, Planelles V, Poon B, Shah NP, Chen ML, Chen ISY. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. Journal of Virology 1995;69:6304-13.
• Jowett JB *, Curran JE, Elliott KS, Gao Y, Gluschenko K, Wang J, Abel Azim DM, Cai G, Mahaney MC, Comuzzie AG, Dyer TD, Walder KR, Zimmet P, MacCluer JW, Collier GR, Kissebah AH, Blangero J. Genetic variation in selenoprotein S influences inflammatory response. Nature Genetics 2005;37:1234-41.* equal 1st author with Curran JE
• Göring HHH, Curran JE, Johnson MP, Dyer TD, Charlesworth J, Cole SA, Jowett JBM, Abraham LJ, Rainwater DL, Comuzzie AG, Mahaney MC, Almasy L, MacCluer JW, Kissebah AH, Collier GR, Moses EK, Blangero J. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nature Genetics 2007;39:1208-16.
• Jowett JBM, Curran JE, Johnson MP, Carless MA, Göring HHH, Dyer TD, Cole SA, Comuzzie AG, MacCluer JW, Moses EK, Blangero J. Genetic variation at the FTO locus influences RBL2 gene expression. Diabetes 2010;59:726-32.
• Bozaoglu K, Curran JE, Stocker CJ, Zaibi M, Segal D, Konstantopoulos N, Morrison S, Carless M, Dyer TD, Cole SA, Goring HHH, Moses EK, Walder K, Cawthorne MA, Blangero J, Jowett JBM. Chemerin, a novel adipokine in the regulation of angiogenesis. Journal of Clinical Endocrinology and Metabolism 2010;95:2476-85.

Key Staff

Contact

Direct: +613 8532 1775
Email: jeremy.jowett@bakeridi.edu.au