A new and surprising insight into the variability of human genes has been obtained by researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and GenProfile AG (Berlin-Buch) in one of the most comprehensive studies that has ever been published. They have comparatively analyzed the sequence of the so-called mu opioid receptor gene (abbr.: OPRM1) in about 250 blood samples. This gene carries information for the synthesis of a protein which has a number of important roles including regulating the binding of analgesics and drugs of addiction, such as morphine, in the brain. In the blood samples studied, the physician and molecular geneticist, Dr. Margret Hoehe (MDC and Genprofile AG) found a total of 52 individually different forms of this gene. Commenting on her finding, Dr. Hoehe said: ”This result and the strategies we have taken to analyse the relationship between mu opioid receptor gene forms and the disease are important for identifying the causes of disease and developing new, specific-acting treatments tailor-made for individual patients. In addition, our research shows just how variable genes really are and, therefore, how difficult it is to identify any direct relationship between genetic predisposition and common, complex diseases.” This study by Dr. Hoehe and her colleagues, together with US researchers at the universities of Harvard, Yale, and Pennsylvania State, has been published in the British journal Human Molecular Genetics (Vol. 9, No. 19, 2000, pp. 2895-2908)*.

Dr. Hoehe and her colleagues analyzed over 1.7 million base-pairs for this research. In order to be able to generate this huge amount of data, the gene researchers used high-throughput methods developed in their own laboratories. These are techniques which allow the simultaneous analysis of lots of DNA fragments. They have also developed new bioinformatics approaches to be able to understand the implications of this huge amount of information. In this work, they did not look at a single variant in the gene investigated, but looked at the combinations of all variants – i.e. the forms of this gene inherited from both the mother and father - in their evaluation. This is considered as a haplotype concept. A haplotype is the form of a gene inherited from one parent.

This research has been referred to as a milestone in this area of gene research by Prof. Jürg Ott, Director of the Department of Statistical  Genetics, Rockefeller University, New York (USA). In particular, Prof. Ott regards the haplotype concept as having a promising future for the analysis of so-called candidate genes. These are genes which may be associated with certain diseases and, therefore, key target structures for drug research.

Prof. Hans Lehrach, Director of the Max Planck Institute of Molecular Genetics in Berlin and one of the major players in the German Human Genome Project, claimed: ”This research is an example of how we can investigate key problems, such as the variability of genes in healthy subjects and patients, by developing new technologies and then going on to develop appropriate bioinformatic strategies which allow us to analyse and interpret the variability of the human genome. This represents one of the greatest challenges in the future."

The MDC is one of the 16 member institutions of the Hermann von Helmholtz Association of German Research Centers. It combines basic and clinical research. It closely collaborates with two clinics of the Charité of the Humboldt University, Berlin, as well as with companies of the Biotechnology Park on the Berlin-Buch Campus. The MDC was established in 1992 in Berlin-Buch. It receives 90 per cent of its funding from the Federal Ministry of Research and 10 per cent from Berlin (Land).

GenProfile AG was founded in 1998 as the largest spin-off from the German Human Genome Project at that time, and according to its own figures raised about 15 million marks in its first round of financing with the 3i Group plc., London, Europe’s leading venture capital company, as lead investor. The company is involved in the systematic application of the high-throughput methods of modern genome analysis to investigate the genetic variability of medically important genes, particularly in patients affected by common diseases and people exhibiting different responses to drugs. The founders and chairmen of GenProfile AG are Dr. Hoehe and Dr. Rolf Zettl, who was previously in charge of the Resource Center of the German Human Genome Project.

*Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence

Barbara Bachtler

Press and Public Affairs

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch

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