Linking Regulatory Elements Harboring Common Disease-Associated Variants to Their Target Genes

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Scientists and clinicians have compared the DNA sequences of millions of healthy and sick individuals and found that the presence of a particular traits, diseases or disease symptoms often correspond with small variations in an individuals DNA sequence. These variable regions are quite small, and when located within a gene can lead to inappropriate gene expression, which in turn causes disease. Knowing the particular disease gene a patient has is important because it allows clinicians to treat individuals appropriately, for example, with specific therapies of medicines designed to compensate for the mutation and alleviate symptoms or cure the disease. A major problem is that most of the variable regions found to be associated with disease lie far from any gene in the genomic sequence, and understanding how they contribute to disease is a mystery. In these cases clinicians cannot identify a disease gene, meaning the patient is likely to receive more generalized treatment rather than a specific treatment designed to overcome the specific genetic fault. Thus a great deal of potentially useful genetic information cannot be used in the fight against disease. For normal, healthy gene expression, it is known that many genes require short regions of DNA sequence called enhancers. Enhancers can be located at considerable distances along the DNA from the genes that they control. In fact they can be so far away that it is often not possible to identify which gene they control. However, we have developed a new method to allow us to identify all distal enhancers in the genome and assign them to the genes that they control. When we compared our preliminary list of enhancers to a list of genetic variations associated with disease we found a highly significant overlap. This means that many of the distant disease-associated variable regions are likely to be long-range enhancers, and because we know which enhancer controls which gene, we can identify the potential disease causing gene. Using the information we will gain from the proposed experiments we expect to identify hundreds to thousands of potential new disease genes. This information will open the door to hundreds or thousands of new clinical treatments and medicines that are specifically designed to treat the specific causes of disease, thereby significantly decreasing patient suffering and improving the success of clinical care.