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

科学家和临床医生比较了数百万健康和患病个体的DNA序列，发现特定特征、疾病或疾病症状的存在往往与个体DNA序列的微小变化相对应。这些可变区域非常小，当位于基因内时可能导致不适当的基因表达，从而导致疾病。了解患者的特定疾病基因非常重要，因为它使临床医生能够适当地治疗个体，例如，使用旨在补偿突变并减轻症状或治愈疾病的特定药物疗法。一个主要的问题是，大多数被发现与疾病相关的可变区域远离基因组序列中的任何基因，并且了解它们如何导致疾病是一个谜。在这些病例中，临床医生无法识别疾病基因，这意味着患者可能会接受更广泛的治疗，而不是旨在克服特定遗传缺陷的特定治疗。因此，大量可能有用的遗传信息不能用于对抗疾病。对于正常、健康的基因表达，已知许多基因需要称为增强子的DNA序列短区域。增强子可以位于与它们所控制的基因相当远的DNA上。事实上，他们可能离得太远，以至于往往无法确定他们控制的是哪个基因。然而，我们已经开发了一种新方法，使我们能够识别基因组中的所有远端增强子，并将它们分配到它们控制的基因上。当我们将初步的增强子列表与与疾病相关的遗传变异列表进行比较时，我们发现了高度显著的重叠。这意味着许多远端疾病相关的可变区域很可能是远端增强子，因为我们知道哪个增强子控制哪个基因，我们可以识别潜在的致病基因。利用我们将从拟议的实验中获得的信息，我们预计将识别数百到数千个潜在的新疾病基因。这一信息将为数百或数千种专门用于治疗特定疾病原因的新的临床治疗和药物打开大门，从而显著减少患者的痛苦并提高临床护理的成功率。

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.