In this Master Class, timely topics in genomics research will be addressed. Four renowned researchers will address the latest developments in epigenetics, forensic genomics, personalized medicine, whole genome sequencing, and new genetic variants.
Monday August 18, 2014
Genomic analysis of neurodegenerative disease
I will discuss how we can now find any type of genetic risk: mendelian genes through positional cloning and sequencing, high risk genes through exome or genome sequencing and burden analysis and low risk loci through genome wide association studies. I will show how this is leading to the identification of many loci for all the major neurodegenerative diseases including Alzheimer’s and other dementias and Parkinson’s disease and other movement disorders. I will discuss for these major diseases how much of the risk has been found and show data suggesting that, as we develop this rich understanding of genetic risk it is beginning to give us the first insights into selective vulnerability in the CNS.
Prof. John Hardy
Professor of molecular neuroscience
Reta Lila Weston Research Laboratories, Departmental Chair,
Department of Molecular Neuroscience, UCL Institute of Neurology, England
Tuesday August 19, 2014
The gut microbiome – a new target for understanding, diagnosing and treating disease
The functioning of the human body constitutes a complex interplay of human processes and ‘services’ rendered to us by the 1000 trillion microbial cells we carry. Disruption of this natural microbial flora is linked to infection, autoimmune diseases and cancer, but detailed knowledge about our microbial component remains scarce.
Recent technological advances such as metagenomics and next-generation sequencing permit the study of the various microbiota of the human body at a previously unseen scale. These advances have allowed the initiation of the International Human Microbiome Project, aiming at genomically characterizing the totality of human-associated microorganisms (the “microbiome”).
Here, I will present our work on characterizing the human intestinal flora based upon the analysis of high-throughput meta-omics (metagenomics, metatranscriptomics, metaproteomics) data. I will show how the healthy gut flora can be classified “enterotypes” that are independent from host nationality, age, bmi and gender. I will also show how metagenome-wide association studies (MGWAS) can lead to the detection of diagnostic markers for host properties and disease (e.g. in IBD, diabetes and obesity), and aid in further understanding on how the gut flora disturbances contribute to these pathologies. Finally, I will illustrate how gut microbiota-based treatment strategies are emerging, for example through Faecal Microbiota Transplantation (FMT).
Hildebrand F et al. (2013) Inflammation-associated enterotypes, host genotype, cage and interindividual effects drive gut microbiota variation in common laboratory mice. Genome Biol, 14(1):R4
Qin et al. (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55-60
Arumugam*, Raes* et al. (2011) Enterotypes of the human gut microbiome. Nature 473, 174-180
Prof. Jeroen Raes
Bioinformatics and (eco-)systems biology lab
Department of Microbiology and Immunology, Rega Institute, KU Leuven
VIB Center for the Biology of Disease, Leuven
Department of Microbiology, VUB
Wednesday August 20, 2014
An editorial perspective on the rapid advances in genomics
Over the past decade, genome-wide association studies (GWAS) have identified a very large number of genetic variants that influence common diseases and traits in humans, such as height, BMI, cancer and type 2 diabetes. These traits are complex and likely affected by hundreds, if not thousands, of genetic variants, each with a very small effect, as well as environmental factors. While GWAS have facilitated the key first step to unravelling the genetic basis of so many complex human traits, the genetic variants that have been identified still explain only a very small proportion of the genetic variability that affects these traits at a population level.
More recently, rapid advances in high throughput sequencing techniques have enabled scientists to sequence entire human genomes, in order to find rare genetic variants that may have a much larger individual effect on complex traits than common variants. It was anticipated that these studies would help to explain the missing portion of the genetic component of complex traits. However, some of the first studies to assay rare variation in large numbers of people have identified few rare variants with significant large effects on these traits. It is becoming ever more apparent that, while the enormous and rapid progress in the field of genomics, both in terms of technology and scientific discovery, has provided an important foundation for understanding the genetic architecture of complex human traits, we are still a long way from fully elucidating the entire genetic component. Much larger sample sizes will be needed to power the discovery of new genetic variants, both common and rare, and we are still some way from understanding how these variants may interact with one another, the biological pathways they affect and the role of environmental factors.
There is now a need for more focussed studies to shed light on the exact biological mechanisms underlying the genetic associations identified by GWAS and sequencing studies in order to identify potential drug targets for disease, which could facilitate the development of much-needed targeted therapies. The field of genomics is also entering into the realm of personalised medicine, where treatment for any number of diseases could be tailored according to an individual’s genetic make-up, which will have major implications for public health. It is clear that scientific journals will have an important role in the exchange and progress of genomics research, as the field embarks on these new challenges.
Dr. Sarah Perry
Associate Editor: Nature Communications
Thursday August 21, 2014
Genetics of psychiatric disorders and biological mechanisms from gene to phenotype
Through international collaboration and technological progress more and more genes for psychiatric disorders are being discovered. Genome-wide association studies, thought to be ineffective at first, now turn out to be an excellent tool for gene-finding – where common genetic variants are concerned. Gene-pathway-based and polygenic analyses implicate groups of genes. Next generation sequencing provides additional insights into rare and de novo variants involved in these disorders.
The evidence provided by these methods is of statistical nature, and in many cases, the identified genes have not been implicated in psychiatric disease before. To make genetic findings useful for patient care, we need to clarify the mechanisms from gene to phenotype. Corroborating evidence and even proof of causality can come from model systems. Developing such models is an area that has been neglected in psychiatric research, thus far. I will discuss different options, and what their contribution to solving the puzzle of psychiatric disease could be.
Corroborating evidence and information in how a genetic variant can alter brain structure and function can be provided by imaging genetics analyses. During my presentation, I will provide examples from our own research in attention-deficit/hyperactivity disorder (ADHD) and related phenotypes. To really prove causality of a gene and variant, animal models are required. Given the large numbers of genes one expects to find, a small, cheap and versatile model is required. My group has recently pioneered the use of Drosophila melanogaster, the fruit fly, as a model system for ADHD. I will show how genes involved in ADHD in humans also cause hyperactivity in the fly.
Having proven the involvement of a gene / variant, we are still far away from being able to use the genetic information in the clinic. Some rare variants might find their way into diagnostics, but the largest value of genetic findings for multifactorial disorders lies in the information they provide about the biological pathways underlying disease (etiology). This information can be used for the innovation and individualization of treatment. How this can be achieved through bioinformatics I will discuss in the second part of the presentation.
Prof. Barbara Franke
Professor of Molecular Psychiatry
Departments of Human Genetics and Psychiatry
Donders Institute for Brain, Cognition and Behaviour
Radboud university medical center
Nijmegen, The Netherlands