Investigating the Role of Genetics in Disease Predisposition

Gametogenesis is the production of sperm and eggs; it takes place through the process of meiosis. Gametogenesis is subject to the acquisition of mutations as with other processes in the body. Many of these mutations are somatic, meaning that they occur during life as part of the process of cell division rather than being passed down from parents. When somatic mutations take place during gametogenesis, there is the potential for hereditary genetic consequences. However, the processes that cause the mutations during gametogenesis and the implications they have for heritability and disease predisposition are poorly understood. The goal of this research is to provide a detailed description of the genetic changes in gonadal tissues, and to understand how mutations acquired during the production of germ cells (sperm and eggs) contribute to the predisposition to a wide range of rare diseases and cancer predisposition in future offspring.

Predisposition to rare disorders and cancers can arise due to mutations (changes in DNA) of sperm cells from father and/or eggs from mother. De novo mutations are genetic alterations that are present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis. Current knowledge about how changes in the sperm and eggs of parents can be inherited by children, is based on genetic sequence analysis of blood from nuclear families. This involved comparison of the changes in DNA of children with that of their parents. Changes that are not present in the blood of parents are likely to have occurred in the sperm and egg of the father and mother. Whilst studying the nuclear family is very useful in order to look at the level of diversity, it will only allow the investigators to study a small number of germ cells making it difficult to ascertain the overall level of diversity that is shown in the sperm and eggs of fathers and mothers. There is also little knowledge of how different factors such as ageing, smoking, BMI and exposure to carcinogens might affect the germ cells of adults and since changes in sperm and eggs can be transmitted to children, it is important to understand how disease causing mutations arise in reproductive tissues. Thus, how such changes can predispose children to rare disorders and cancer predisposition syndromes. Previous studies have shown that the FGFR3 gene accumulates more mutations in normal testes during the natural ageing process which leads to the relative enrichment of mutated sperm over time. In rare cases, it can lead to testicular cancer (spermatocytic seminomas) in older men, but also it increases the likelihood of having children with Achondroplasia, which is caused by mutations in the FGFR3 gene in the sperm of the father. Hence, the investigators aim is to determine the effect of different factors on the recurrence risk of pathogenic (disease causing) mutations in eggs and sperm.