Repeat-induced mutagenesis in Huntington's disease

亨廷顿氏病（HD）是一种大脑疾病，其中脑细胞（神经元）丢失。神经元的丧失会导致运动、记忆、思考和行为方面的问题。随着时间的推移，这些症状会逐渐恶化，在首次出现症状后15-20年导致死亡。目前没有任何治疗方法可以减缓或阻止这种情况的发生。亨廷顿舞蹈症是由一种叫做亨廷顿蛋白的基因中特定DNA序列的重复次数增加引起的。重复DNA序列基序为CAG。在未受影响的人群中，CAG重复的数量很少（少于36）。在HD患者中，有更多的重复序列（超过39），更长的重复序列导致更严重的症状出现在更年轻的年龄。换句话说，一个人重复次数越多，病情就越严重。重要的是，DNA序列中重复序列的数量会随着时间的推移而增加。这一过程受到CAG重复序列附近的其他小DNA序列的影响，因此可以在疾病严重程度中发挥作用。我们目前还不了解这些额外序列的变化是如何在人体中产生的。本研究旨在找到这些问题的答案。为了做到这一点，我们将使用最先进的技术，使我们能够研究我们感兴趣的DNA序列，在从HD患者身上收集的细胞中，在实验室培养的细胞中，并在试管中使用纯化的蛋白质和DNA。我们将从人们身上收集细胞，看看我们能否在HD患者身上找到与我们在实验室培养的细胞中发现的相同的结果。我们还将突变细胞中的特定序列，并研究它们如何影响重复通道周围突变的外观。我们将获得的结果将提高我们对近重复序列如何产生以及它们是否与疾病症状相关的理解。

Huntington's disease (HD) is a brain disorder in which brain cells (neurons) are lost. This loss of neurons causes problems with movement, memory, thinking, and behaviour. These symptoms gradually worsen over time, leading to death 15-20 years after the first symptoms are seen. No treatment is available that can slow or stop this from happening.HD is caused by an increase in the number of repeats of a specific DNA sequence, within a gene called huntingtin. The repeating DNA sequence motif is CAG. In unaffected people, the number of CAG repeats is small (less than 36). In people with HD, there are more repeats (over 39), with longer repeats leading to worse symptoms that appear at a younger age. In other words, the disease is more severe when a person has more repeats. Importantly, the number of repeats in the DNA sequence can increase in size over time. This process is affected by other small DNA sequences close to the CAG repeat sequence and can therefore play a part in disease severity. We do not currently understand how changes in these additional sequences are generated in people. This study aims to find the answer to these questions. To do this, we will use state of the art techniques that allow us to investigate the DNA sequences we are interested in, in cells collected from people affected by HD, in cells grown in the laboratory, and using purified proteins and DNA in a test tube. We will collect cells from people to see if we can find the same results in people affected by HD that we find in cells grown in the laboratory. We will also mutate specific sequences in cells and study how they affect the appearance of mutations around the repeat tract.The results we will obtain will improve our understanding of how sequences near repeats are generated and whether they correlate with disease symptoms.