Dynamic Genome

This FSP was originally dedicated to a wide range of phenomena that contribute to changes in the genome, such as mutations, meiotic recombination, the transposition of mobile DNA elements, and the multiplication, dissemination, diversification and homogenization of repetitive DNA sequences. After some fluctuation in the participating groups, the present focus is on meiotic recombination as the major source of genome reshuffling. Meiosis is a cellular division that leads to the formation of gametes (eggs and sperm). During meiosis the two complete parental chromosome sets of normal body cells are halved, so that only a single set (a mixture of paternal and maternal chromosomes) is handed down to the offspring. This reduction compensates for the doubling of genomes at fertilization. Another important process is the exchange of parts of the corresponding (homologous) parental chromosomes before they disjoin. Exchange of genetic information encoded by the chromosomes (recombination) contributes significantly to the genetic diversity in populations. Moreover, recombination between homologous chromosomes is accompanied by their transient physical linkage, which is essential to their orderly distribution to the gametes. Failures in this process lead to aberrant chromosome numbers (aneuploidies), which in humans are the cause of Down syndrome and other inherited diseases. The FSP consists of four projects, three of which study aspects of meiosis in the bakers yeast, Saccharomyces cerevisiae, and one in the nematode worm, Caenorhabditis elegans. Homology recognition and chromosome pairing (J. Loidl): Genetic exchange is legitimate only between corresponding members (homologues) of the two parental chromosome sets, and it requires their spatial proximity (chromosome pairing). (Recombination between wrong partners are the cause of chromosomal anomalies and severe clinical defects in humans.) The mechanisms by which chromosomes recognize each other and by which they are moved toward each other are studied. It was found that when yeast cells transit from the mitotic to the meiotic pathway, a global change of the arrangement of chromosomes, from the clustering of all centromeres to the clustering of all telomeres, takes place inside the nucleus. This reorganization of the nuclear architecture seems to be a precondition for meiotic levels of chromosome pairing. Initiation of recombination and its molecular machinery (Franz Klein): This project studies the early molecular steps in meiotic recombination and their relation to chromosome pairing. Most if not all meiotic recombination initiates by a DNA double-stranded break. The broken DNA ends are modified to yield single stranded ends, which will recruit the homologous chromosome as template for repair. In the course of this repair process, long tracts of DNA can be physically exchanged between the participating chromosomes. The roles of several enzymes which form part of the complex that initiates recombination and other components with roles in repair and chromosome pairing that are recruited to recombination sites, are studied in this project. One remarkable result is the observation that the enzyme which induces the DNA break is present at break sites also during repair, suggesting a new and unexpected role in recombination. Segregation - the reduction of the rearranged genetic material and its distribution to reproductive cells (Kim Nasmyth): In normal somatic cell division, a protein complex ("Cohesin") which links the half-chromosomes (sister chromatids), has to be removed from the chromosomes in order to allow the disjunction of sister chromatids to the daughter nuclei. In meiosis, a modified cohesin is removed only from those parts of paired chromosomes where exchanged portions of chromosomes maintain the connection between homologous chromosomes. This allows the separation of the homologous chromosomes. In a second round, cohesion is released in the remaining chromosome regions, which then allows the sister chromatids to separate. The result of the meiotic process with two subsequent divisions, are four products with a single unreplicated paternal-maternal mosaic chromosome set. Kim Nasmyth studies the regulation of the differential loss of cohesion, by which the two divisions are coordinated, in the yeast model system. Recently, the Nasmyth group found a protein that promotes the attachment of sister centromeres to microtubules from the same pole. This is another function that guarantees the separation of homologues rather than sisters at the first of the two meiotic divisions. Pairing, recombination and segregation in a multicellular eukaryote - what is common, what is different? (Dieter Schweizer): This project is devoted to meiosis in C. elegans. It is studied if and to what degree meiotic processes, as best known from the budding yeast, are conserved in multicellular organisms. Moreover, for processes of meiotic chromosome condensation, pairing and disjunction, which cannot be studied properly in yeast, owing to its poor amenability to cytological analysis, C. elegans is a superior experimental system. These experiments include the identification of genes of interest on the basis of their homology to yeast meiotic genes and analysis of the mutant phenotype after RNAi-mediated depletion of the gene product. Recently, a meiosis-specific cohesin component, the ortholog of yeast Rec8p was identified and characterized.