At the section Medical Genomics we investigate genome variation in relation with human (disease) phenotypes. In particular, we focus on disorders of the brain. The research program can be subdivided into three research lines. In addition we have a genomics facility for genotyping and sequencing (Dr. P. Rizzu).
Neurodegenerative diseases, such as dementia and parkinsonism are progressive common, age-related diseases, affecting millions of people worldwide. These diseases therefore pose an increasing medical and economic problem due to expected demographic changes in our ageing society. Effective treatment so far is very limited and treatment strategies that halt or slow the progression of the disease are lacking. The causes for these diseases are in most cases still unknown but genetic factors are increasingly recognized in their aetiology, even in a proportion of apparently sporadic cases. Several genes causing monogenic forms of disease have been identified and the molecular pathways identified in these forms have been found to contribute, in different ways, to the pathogenesis of the more common sporadic diseases. The knowledge of the involved genes and molecular pathways is starting to provide the basis for designing strategies towards more effective treatment that is urgently needed.
As the genes and mutations known at present certainly do not yet reflect all of the molecular mechanisms involved, the study of families and the use of well characterized populations, including genetic isolates, will help to identify further components of the pertinent pathogenic pathways. Within the section of Medical Genomics we have several research projects aimed towards the identification of new genes involved in neurodegenerative diseases. In addition we are performing functional studies on identified genes in order to understand the role of these genes in the pathogenesis of disease.
Human behavior shows a large variation within the human population as a result of the interplay between environment and the genetic background of individuals. The section of Medical Genomics performs genetic studies both on normal variation as well as pathological variation in human behavioral traits.
Psychiatric disorders often show a considerable genetic component, a high co-morbidity and symptom overlap and might in fact form a continuous spectrum of disorders. The lifetime prevalence of these psychiatric disorders ranges from ~1% for schizophrenia and bipolar disorder, up to 20% for anxiety and depression, together affecting more than 25% of the global population. According to the WHO, depression will be the second leading cause of disability worldwide by 2020 and costs of over $43 billion/year in the US alone. In collaboration with the Department of Psychiatry we perform genetic linkage and association studies on extensively phenotyped cohorts of patients and families with psychiatric traits such as anxiety, depression, schizophrenia, obsessive compulsive disorder and Gilles de la Tourette Syndrome.
Besides this “disease” focused research we also investigate the normal variation in behavioral phenotypes in the general population. In close collaboration with the Department of Biological Psychiatry we perform genetic studies on attention and cognitive traits on samples from the Netherlands Twin Register.
Much of the genetic differences that can be observed between any two individuals are the result of historic events (like migration, population admixture) and chance (random segregation of alleles in large pedigrees). Buried within this large amount of non-functional variation the presence of different alleles at certain (yet unknown) loci contributes to the phenotypic differences between humans. The ultimate goal of human genetics is to identify these variants that affect specific phenotypes, such as susceptibility to common, heritable disease.
The common theme in this research line is the notion that a functional genetic variant, even with a very minor effect not easily detectable with classical genetic analyses, must have been preferentially transmitted through a large number of generations (i.e. has been subject of some kind of selection). As a result functional variants should exhibit different patterns of (dis-)similarity between populations and/or (closely related) species compared to random variation.
We address this issue both in a comparative genomic approach and studies of human population diversity.
1-We search for genes that affect “human specific” traits by detecting positive selection in the evolutionary linage leading to our species compared to other mammalian lineages. Candidate genes obtained from this approach are tested for genetic association with a variety of human behavioral traits, such as cognitive ability, in collaboration with the Department of Biological Psychiatry.
2-Complex traits are likely to be affected by complex interactions of various genes. We search for such interactions by identifying combinations of loci that are extensively diverged between either human populations or mouse inbred lines. Relevant candidate genes/pathways are followed up in (functional) studies both in the available patient cohorts and in mice in collaboration with other participant groups of the CNCR.
The Medical Genomics Sequencing and Genotyping Facility provides sequencing and genotyping for research groups of the CNCR and external investigators on a fee-for-service basis offering state-of-the-art instrumentation and technological support at a reasonable cost.
Sequencing is the process of determining the nucleotide order of a given DNA fragment, the "blueprint" of a living organism. The DNA sequence provides information that can help biologists to understand the genetics of their study system, and evaluate the progress of their genetic research projects. The facility is equipped with an ABI 3730, 48-capillaries sequencer and a Tecan Freedom Evo liquid handling system.
The sequence reaction is performed by the individual researcher (ready-to-run samples) or, on request, by the Sequencing Facility of Medical Genomics.
Samples are entered into the queue in the order in which they are received. The average turnaround time is one-two working days for 48 or 96 ready-to-run reactions.
Genotyping is an essential tool in studying the genetics of disease and other genetic traits in general allowing identification of candidate gene regions for genetic studies via genome-wide and fine mapping techniques. The platform is involved in two main types of genotyping: Microsatellite and Single Nucleotide Polymorphism (SNP) using the following technologies in 96 and 384 well format.
For further enquiries about sequencing and/or genotyping at our facility contact Patrizia Rizzu.
Tel: 0031(0)20 5989961 or by email: email@example.com