A missing chunk of chromosome 16 leaves some children unable to make enough haemoglobin and also causes mental retardation—and researchers want to know exactly which genes are to blame. The human genome sequence is just a static list of parts. This project treats a specific stretch of chromosome 16 as a test case for understanding how DNA is packaged with proteins into chromatin, how that packaging changes when genes switch on or off, and how the three-dimensional arrangement of chromatin inside the nucleus controls gene activity. The alpha globin genes sit in this region; when they are disrupted, patients develop alpha thalassaemia, a severe anaemia that starves organs of oxygen. A subset of patients also have developmental problems and intellectual disability, because a larger piece of the region is missing. By mapping every gene and regulatory element in this stretch of chromosome 16, and by studying how chromatin organisation changes during blood-cell development, the researchers aim to identify precisely which missing genes cause the neurological symptoms. This is fundamental science—understanding how genome organisation controls gene expression. If successful, it could eventually guide diagnosis for patients with complex developmental syndromes linked to this region, and it will provide a general model for how chromatin structure influences gene regulation across the genome.
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We now have an approximate map of the DNA sequence for the entire human genome. However the basic DNA sequence is only a starting block for understanding the complex interplay of factors which regulate the ability of a gene to make the correct protein at the correct time and in the correct cell type. We have a very detailed map of a region of chromosome 16. We want to characterise this region by identifying all the genes and regulatory features within the sequence, and then to look at additional (epigenetic) factors which can influence when and where a gene becomes active. DNA coils down within a cell nucleus with several proteins to form chromatin. We would like to understand how this chromatin is arranged within a nucleus and what changes may be necessary to allow genes to be switched on or off. Within this region of chromosome 16 lie the alpha globin genes. These genes make part of the molecule haemoglobin which carries oxygen in the blood and lack of haemoglobin will give rise to anaemia, which can cause malfunctions in the organs normally supplied with oxygen. When the alpha globin genes are disrupted in some way, patients develop a severe form of anaemia called alpha thalassaemia. Some patients are born with mental retardation and other developmental problems as well as alpha thalassaemia - these patients have a piece of chromosome 16 missing from the region we are studying. With the information from our mapping work and studies of nuclear organisation, we will identify precisely which genes are missing in these patients and how that loss contributes to their mental and developmental difficulties.
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