MOLECULAR MECHANISMS OF MEIOTIC RECOMBINATION

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Our germ cells, sperm and egg, form the basis for the generation of new human life. Upon fertilisation, the DNA contained within sperm and egg is combined to provide the full complement of genetic information that defines a unique human being. Germ cells are produced through meiosis, a process of cell division in which genetic information contained in our DNA is reshuffled, to generate diversity in the offspring. Meiosis is a fascinating and complicated process that can frequently go wrong, resulting in either sperm or egg with the incorrect number of chromosomes, or in no germ cell being produced at all, causing miscarriage and infertility. It may also result in children being born with genetic diseases such as Down's syndrome. It is important that we explain the molecular processes of meiosis, so that we can understand how genetic diversity is generated and we can diagnose and possibly intervene when meiosis goes wrong. At the heart of meiosis is the process of genetic exchange between pairs of matching parental chromosomes. During genetic exchange, the chromosomes of each matching pair swap segments of DNA, thus generating novel DNA sequences, in a process known as meiotic recombination. In preparation for the exchange, the chromosomes in each pair must first be brought into alignment with each other. To be paired correctly, the long coils of chromosomal DNA must take up a specific shape, needed to execute the recombination reaction. it is also important that the chromosomes of each matching pair check their alignment, by exchanging homologous DNA strands with their partner at multiple sites along their arms. A large set of proteins are required to carry out the complicated steps of meiotic recombination. Previous research has shown that a large protein structure known as the synaptonemal complex (SC) acts as a molecular scaffold, keeping matching chromosomes together in the correct way for the exchange of DNA to take place. At the same time, dedicated protein enzymes known as recombinases perform the remarkable reactions of homology search and DNA-strand exchange between the aligned chromosomes. The successful outcome of this complex set of reactions leads eventually to the generation of a novel combination of genetic information in each sperm cells, in preparation for fertilisation.Despite the great importance of the reaction of genetic exchange between homologous chromosomes in meiosis, we still know relatively little about the molecular mechanisms that determine the three-dimensional organisation of meiotic chromosomes and their recombination. We plan to discover how Our research will help us improve our molecular understanding of meiotic recombination and explain how defects in its mechanisms, either accidental or inherited, can lead to infertility, miscarriage and genetic disease. In addition, our work will improve our knowledge of the different ways in which human cells organise and handle large chromosomal DNA molecules. This information is important as incorrect sorting of our chromosomes during cellular proliferation, caused by defective packaging of the DNA, can lead to unwanted alterations in the genome and to disease such as cancer.