Infertility affects about one in 6 couples and about half of cases are thought to have a genetic cause. Some cases can be treated successfully by in vitro fertilisation but this is expensive, not always available without high cost to the individual, and involves hormone treatments and minor surgery. In men one major genetic cause of infertility is loss of genes from the male Y chromosome. We are trying to understand what some of these and other genes involved do in fertile people with the aim of better understanding what goes wrong in those with fertility problems. To do this we use a range of different types of experiments. Some are designed to work out how chromosomes are assembled during the early stages of making sperm and eggs. Some of these experiments are test tube based. Others experiments can only be done by making changes in the mouse gene equivalent to the human gene we are interested in. Then we have a so-called mouse model and by studying these animals we can make predictions about the effects expected in humans. To reduce the use of animals in this work we are also trying to develop methods based on growing cells from mouse sperm and egg-making tissues in test tubes.

Improving our understanding of genetic differences between species allows us to better interpret genetic risk in people.|We are all at risk of developing a wide range of diseases, some very common, including heart disease, diabetes, dementia and cancer. But such risks differ hugely between individuals, and are to a large degree influenced by the sequence of DNA in our cells.|The big question is which of the many thousands of DNA differences between individuals are responsible for increasing or decreasing their risk of developing a given disease. The historic record of evolution can provide some answers. We can read it as the differences in DNA between species, for example human versus mouse. The pattern of differences between species can reveal functionally important regions of DNA. Contrasting the between species pattern with the differences between people can point to the critically important changes that influence disease risk.|More broadly, we compare how DNA has changed between species with the differences between people. This allows us to study why and where DNA changes (mutations) arise, and what the functional consequences of those changes are. We are applying these methods to understand the genetic basis of many rare and common diseases.

Each human cell contains 2m of DNA, yet our genome has to function within the context of the cell nucleus that is only 10 thousandths of a mm in diameter. This remarkable feat of packing is achieved by folding the DNA sequence up with proteins, to form a structure called chromatin. We now realise that chromatin not only allows the DNA to fit inside of the cell, but that it also controls the way that the DNA is read. Using a combination of biochemistry and microscopy, we are investigating what different chromatin structures there are in mammals, and how they are normally regulated and changed during development to allow different sets of genes to be switched on and off. Once we understand the chromatin architecture of the normal genome, this will allow us to understand how altered chromatin structure can contribute to disease.

ADARs and APOBECs family of enzymes have the properties of being able to change or mutate nucleic acids. This ability would in the first instance appear to be very detrimental to the cell whereas in fact animals have evolved so that it is now essential for life. The ADARs are critical for brain function whereas the APOBEC play an important role in the immune system. The key question we want to address with our research is how these enzymes can distinguish the correct base to modify and what medical disorders arise when these proteins are prevented from functioning precisely. While it is clear what biological role some of these proteins have, the biological role of others like ADAR1 remains elusive and we want to determine what function it has. We use flies as a model system and if they lack the Adar gene they have problems with locomotion suffer age related neurodegeneration with large holes in their brain. We want to determine precisely what class of neurodegeneration this is and which human neurodegenerative disorder is closely related to it. We can then study this disorder in flies and try and find conditions where it can be alleviate.