Mutational Scanning

正确诊断遗传病对患者及其家属非常重要。由于基因组测序技术的进步，医生现在能够列出患者基因组中存在的所有突变，但解释这些突变很困难。在我们的实验室里，我们使用酵母和人类细胞的实验来研究在人类患者身上发现的突变的后果。我们的实验集中在选定的基因上，包括PAX6，导致眼睛畸形的突变，以及TP53，经常在癌症中突变。在我们之前的实验中，我们发现导致酵母生长缓慢的PAX6基因突变与损害患者眼睛发育的同一基因突变之间有着惊人的一致性。这使我们能够预测以前从未在患者中发现的数千种突变的严重程度。我们现在的目标是超越疾病预测，了解为什么某些突变比其他突变更有害。为了研究这一点，我们将测量每个突变如何影响细胞中发现的所有RNA分子的集合，即转录组。我们还将在显微镜下分析数千个突变细胞。将人工智能方法应用于这些测量将有助于我们理解为什么突变是有害的，并有助于找到适当的治疗方法。最后，我们将测量候选mRNA疗法在人体细胞中的表现，以便为设计新的mRNA疗法开发方案和软件。

Proper diagnosis of genetic diseases is very important for patients and their families. Thanks to advances in genome sequencing, doctors are now able to list all the mutations present in a patient’s genome - but the interpretation of these mutations is difficult. In our lab, we use experiments in yeast and human cells to study the consequences of mutations found in human patients.Our experiments are focused on selected genes including PAX6, mutations in which cause eye malformations, and TP53, frequently mutated in cancer. In our previous experiments, we found a surprisingly good agreement between mutations in PAX6 that cause slow growth of yeast, and mutations in the same gene that damage eye development in patients. This allows us to predict the severity for thousands of mutations that were never previously seen in patients.We now aim to move beyond disease prediction and understand why certain mutations are more harmful than others. To study this, we will measure how each mutation influences the collection of all RNA molecules found in cells, known as the transcriptome. We will also analyse thousands of mutated cells under the microscope. Applying artificial intelligence methods to these measurements will help us understand why mutations are harmful, and help find appropriate treatments. Finally we will measure the performance of candidate mRNA therapeutics in human cells, in order to develop protocols and software for the design of new mRNA therapies.