Protein Complexes and Human Genetic Disease

许多人类疾病是由遗传引起的--也就是说，你从父母那里继承了基因。不同人的基因之间的微小差异可能会产生广泛的影响。了解这种遗传变异如何导致疾病，对于疾病的预防、诊断和治疗至关重要。虽然近年来在基因和基因组测序技术的帮助下取得了很大进展，但我们对基因间的差异如何导致疾病仍有很多不了解，大多数基因可以被简单地认为是一组如何构建蛋白质的指令。这些被称为“蛋白质编码”基因。蛋白质编码基因的遗传变化可以修改这些指令，从而影响蛋白质，或者通过改变其结构，或者通过引起更多或更少的产生。因此，对于理解遗传疾病非常有用的一件事是考虑蛋白质将如何受到影响。引起蛋白质大变化的遗传变异更有可能导致疾病。这方面经常被忽视的一个方面是大多数蛋白质并不孤立存在。相反，许多蛋白质可以与其他蛋白质结合并形成“蛋白质复合物”。这种蛋白质复合物是几乎所有生物过程的基础。我过去研究的一个主要重点是试图了解蛋白质如何组装成复合物。在目前的研究计划中，我的目标是在此基础上，研究蛋白质复合物如何与人类遗传疾病相关。具体来说，我相信，如果一个基因的变化影响到一个蛋白质，它会组装成一个复合物，这将取决于形成的复合物的类型，更有可能导致疾病。事实上，我在这篇论文中提出的早期结果有力地证明了这一点，这项研究的最终目标是开发出更好的方法来预测基因变化是否可能导致疾病。这样的方法现在已经存在，但它们没有使用蛋白质复合物的信息。通过整合从这个项目中获得的蛋白质复合物的知识，我们应该能够大大改进现有的预测。改进预测的好处是巨大的。特别是，它们将显著提高我们识别导致疾病或影响其他人类特征的特定遗传变化的能力。此外，它们可以用于临床环境，从一个人的基因中预测他们是否可能患上某种特定的疾病，或者诊断他们的症状是否可能由遗传疾病引起。

Many human diseases are caused by genetics -- that is, the genes that you inherited from your parents. Slight variations between the genes of different people can have wide-ranging effects. Understanding how this genetic variation contributes to disease is of huge importance for disease prevention, diagnosis and treatment. While much progress has been made in recent years, aided by the ability to sequence genes and genomes at much lower cost, there is still much we do not understand about how differences between genes can cause disease.Most genes can be thought of quite simply as a set of instructions on how to build a protein. These are called "protein-coding" genes. Genetic changes in protein-coding genes can modify these instructions, thus affecting the protein, either by changing its structure, or by causing more or less to be made. Therefore, one thing that has been quite useful for understanding genetic disease is to consider how proteins will be affected. Genetic variations that cause large changes to proteins are much more likely to cause disease.One aspect of this that has been often ignored is the fact that most proteins do not exist in isolation. Instead, many proteins can bind to other proteins and form "protein complexes". Such protein complexes are fundamental to nearly all biological processes. A major focus of my past research was on trying to understand how proteins assemble into complexes. In the current research proposal, I aim to build upon this, and to study how protein complexes are related to human genetic disease. Specifically, I believe that a genetic change is more likely to cause a disease if it affects a protein that assembles into a complex, and that this will depend upon the type of complex that is formed. In fact, early results I present in this proposal strongly suggest this to be true.The ultimate aim of this research will be to develop improved methods for predicting whether genetic changes are likely to cause disease. Such methods exist now, but they don't use information on protein complexes. By incorporating the knowledge of protein complexes that will be obtained from this project, we should be able to substantially improve upon existing predictions.The benefits of improved predictions are great. In particular, they will significantly enhance our ability to identify specific genetic changes that cause diseases or affect other human traits. Furthermore, they could be used in a clinical setting, to predict from a person's genes whether they are likely to get a specific disease, or to diagnose whether their symptoms could be caused by a genetic disorder.