Structural basis of meiotic chromosome organization by the synaptonemal complex.

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Sperm and egg cells are required for the generation of new human life. They are produced through meiosis, a process of cell division in which genetic information is reshuffled to enhance diversity. 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. While the process of meiosis appears conceptually simple, it is in fact a 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.At the heart of meiosis is the process of genetic exchange between pairs of matching chromosomes. In order to be able to align with each other and exchange genetic material, each pair of matching chromosomes needs to be organised in a specific three-dimensional shape which is unique to meiosis. Previous research has shown that a large protein structure known as the synaptonemal complex (SC) is essential for this, by working as a molecular scaffold that holds chromosomes together in the correct way for the exchange of DNA to take place. Although the importance of the SC in meiosis has been known for a long time, we still know little regarding how the SC is constructed and how it functions. We plan to discover how the SC carries out its crucial function in meiosis by studying its complex molecular structure. Our specific aim is to work out exactly how the SC determines the shape of each matching chromosome, folding its DNA into the required three-dimensional structure necessary for the steps of pairing, genetic exchange and eventual separation. We will achieve this by producing a molecular picture at atomic resolution of the protein building blocks of the SC, which will show how they interact with the DNA and with each other, in order to build the correct molecular framework for genetic exchange to occur. Our research into the molecular structure of the SC will help us understand its important role in meiosis and to explain how defects in its assembly can lead to infertility, miscarriage and genetic disease. In addition, our work will improve our knowledge of the different ways in which human cells 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.