MicroRNA buffering of gene duplications and aneuploidy

非整倍性和大规模染色体复制是许多细胞系的共同特征，包括源自癌症的那些。尽管这些大规模的基因组变化，这些细胞系仍然是可行的。因此，缓冲基因复制和缺失影响的细胞过程是细胞活力的关键。MicroRNA是通过翻译抑制调节基因功能的短RNA分子，并且经常被表征为基因剂量的缓冲剂。该项目将使用计算和遗传方法的组合来研究microRNA作为基因和染色体复制缓冲器的作用。我们将分析可用的细胞系基因组中蛋白质编码基因和microRNA的常见丢失和重复，以及可用的转录组数据作为基因和microRNA表达数据的来源。我们将提出以下问题：1。常见的蛋白质编码和microRNA基因组在不同的细胞系中是复制还是丢失？2.在细胞系中复制或丢失的基因是否更有可能被microRNA靶向？3. microRNA和/或靶基因的复制对其表达水平有什么影响？我们将操纵microRNA及其靶基因的表达，模拟来自动物模型系统的细胞系中基因复制的影响。将使用各种测定来评估microRNA和靶基因两者对缓冲基因复制和非整倍性的贡献。了解microRNA如何缓冲非整倍体的后果将提供关键的见解细胞活力，包括在疾病，如癌症，和基因复制的后果。该项目将提供深入了解的基因调控机制的作用，因此是了解动物生物学的许多（可以说是所有）领域的基础。包括癌症在内的许多遗传疾病都涉及基因拷贝数的变化，因此，对这些遗传变化的缓冲作用的进一步了解影响了生物科学研究委员会“生物科学促进对健康的综合了解”的战略主题。该项目涉及整合计算方法来理解进化和功能，并在实验室中验证预测和目标相互作用。湿和干方面将反复相互反馈，因此湿实验室实验将为更好的预测模型提供信息。这一方法符合生物安全研究中心的主题“变革性技术”，以及“支持数学和计算方法，从现有的大量和多样性生物数据中产生新知识”的既定目标。

Aneuploidy and large-scale chromosomal duplications are common characteristics of many cell lines, including those derived from cancers. Despite these large-scale genome changes, these cell lines remain viable. Cellular processes that buffer against the effects of gene duplication and deletion are therefore key to cell viability. MicroRNAs are short RNA molecules that modulate gene function through translational repression, and are frequently characterised as buffers for gene dosage. This project will use a combination of computational and genetic approaches to study the roles of microRNAs as buffers of gene and chromosome duplications. We will analyse available genomes of cell lines for common losses and duplications of protein-coding genes and microRNAs, and available transcriptomic data as a source of gene and microRNA expression data. We will ask the following questions: 1. Are common sets of protein-coding and microRNA genes duplicated or lost in diverse cell lines?2. Are genes that are duplicated or lost in cell lines more or less likely to be targeted by microRNAs?3. What is the effect of duplication of microRNA and/or target gene on their expression levels?We will manipulate the expression of both microRNAs and their target genes, simulating the effects of gene duplication, in cell lines derived from animal model systems. A variety of assays will be used to assess the contribution of both microRNA and target genes to buffering gene duplication and aneuploidy. Understanding how microRNAs buffer the consequences of aneuploidy will provide key insights into cell viability, including in diseases such as cancer, and the consequences of gene duplication.This project will provide insight into the role of poorly understood gene regulatory mechanisms, and is thus fundamental to the understanding of many (arguably all) areas of animal biology. Many genetic diseases, including cancer, involve changes in gene copy number, and therefore increased understanding of the buffering of these genetic changes impacts the BBSRC strategic theme of "Bioscience for an integrated understanding of health". The project involves the integration of computational approaches to understand evolution and function, with validation of predictions and target interactions in the laboratory. The wet and dry aspects will feed back to each other iteratively, so wet laboratory experiments will inform better models for prediction. This approach matches the BBSRC's theme of "Transformative technologies", and the stated objective to "support mathematical and computational approaches to generate new knowledge from the huge volume and diversity of biological data available".