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序列中的微小变异相对应。这些可变区非常小，当位于一个基因内时，可能会导致不适当的基因表达，进而导致疾病。了解患者具有的特定疾病基因很重要，因为它可以让临床医生适当地治疗个人，例如，使用旨在补偿突变、缓解症状或治愈疾病的特定药物疗法。一个主要问题是，大多数被发现与疾病相关的可变区远离基因组序列中的任何基因，了解它们是如何导致疾病的是一个谜。在这些情况下，临床医生无法识别疾病基因，这意味着患者可能接受更普遍的治疗，而不是旨在克服特定基因缺陷的特定治疗。因此，大量潜在有用的基因信息不能用于抗击疾病。对于正常、健康的基因表达，众所周知，许多基因需要称为增强子的DNA序列的短区域。增强子可以位于DNA上与它们控制的基因相距较远的地方。事实上，它们可能相距如此之远，以至于往往无法确定它们控制的是哪种基因。然而，我们已经开发出一种新的方法，使我们能够识别基因组中的所有末端增强子，并将它们分配给它们控制的基因。当我们将我们初步的增强剂列表与与疾病相关的基因变异列表进行比较时，我们发现了非常显着的重叠。这意味着许多遥远的疾病相关可变区很可能是远程增强子，因为我们知道哪个增强子控制哪个基因，所以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，我们预计将识别成百上千个潜在的新疾病基因。这些信息将打开数百或数千种专门针对特定疾病原因设计的新临床治疗方法和药物的大门，从而显著减少患者的痛苦，提高临床护理的成功。

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.