Each cell in our body contains an identical DNA blueprint inherited from our parents (excepting sperm and eggs that contain half a copy). The decoding and expression of these genes needs to be finely regulated to make different cell types and govern cell metabolism. This is achieved by 'epigenetic' modifications to the DNA. One form of epigenetic regulation is achieved by marking certain regions of the genome with methyl groups that tend to block gene expression. Most of this DNA methylation is faithfully inherited every time cells divide and so acts as a semi-permanent regulator of how genes operate. When sperm fertilises egg the methylation marks on each are largely erased in the first few days after conception and a new 'methylome' is created for the embryo. We have studied a seasonal experiment of nature in rural Gambia whereby conceptions occur against very different dietary and nutritional conditions. We have shown that certain 'environmentally-sensitive hotspots' across the genome are very sensitive to the baby's season of conception. These hotspots have a characteristic signature indicating that they are permanently altered in the very early embryo. We believe that they may have evolved to SENSE the mother's (nutritional) environment, RECORD that information, and ADAPT the developing fetus to be best suited to the predicted future conditions. If the future conditions are different these changes may become maladaptive and cause disease. We have already shown that certain of these variable regions may be linked to diseases such as obesity, cancer and thyroid disease. In this grant, we seek to better understand HOW diet affects the laying down of these methylation marks, WHICH areas of the methylome are especially sensitive to such influences, HOW they influence the development of the placenta and fetus, and ultimately WHAT effects these changes have on the baby's development and life-long health. To achieve this, we will follow rural Gambian families planning to conceive and collect data and blood samples within +/-15 days of conception to much better characterise the environmental factors that are driving the epigenetic changes we study. We will use advanced metabolomic methods to measure differences in the pathways required for DNA methylation and search for possible factors beyond diet (including pesticide and other toxic exposures, pharmaceuticals, etc). We will also search for seasonal differences in the mothers' gut microbiome to see if that may be influencing the changes we see. We will use new finely-targeted epigenetic arrays to study our hotspots of interest and learn how and why they might have evolved, playing special attention to how these changes affect genomic processes (such as imprinting) that are crucial for placental (and hence fetal) development. Finally we will examine the effects of these changes on the babies born in the new cohort and follow them into the future. This will create an open, accessible 'Early Developmental Epigenetic BioResource' for researchers worldwide.