MicroRNA buffering of gene duplications and aneuploidy

非整倍体和大规模染色体复制是许多细胞系的共同特征，包括那些来自癌症的细胞系。尽管有这些大规模的基因组变化，这些细胞系仍然活着。因此，缓冲基因复制和缺失影响的细胞过程是细胞存活的关键。MicroRNAs是一种通过翻译抑制来调节基因功能的短RNA分子，经常被描述为基因剂量的缓冲器。该项目将使用计算和遗传方法相结合的方法来研究microRNAs作为基因和染色体复制缓冲区的作用。我们将分析现有的细胞系基因组中常见的蛋白质编码基因和microRNAs的丢失和复制，以及作为基因和microRNA表达数据来源的现有转录数据。我们将提出以下问题：1.在不同的细胞系中，常见的蛋白质编码基因和microRNA基因是复制的还是丢失的？2.在细胞系中复制或丢失的基因更有可能成为microRNAs的靶标吗？3.microRNA和/或靶基因的复制对其表达水平有什么影响？我们将在动物模型系统的细胞系中操纵microRNAs及其靶基因的表达，模拟基因复制的影响。将使用各种分析来评估microRNA和目标基因对缓冲基因复制和非整倍体的贡献。了解microRNA如何缓冲非整倍体的后果将提供对细胞活力的关键见解，包括在癌症等疾病中的细胞活力，以及基因复制的后果。这个项目将提供对鲜为人知的基因调控机制的作用的洞察，因此对于理解动物生物学的许多(可以说是所有)领域是基础的。包括癌症在内的许多遗传病涉及基因拷贝数的变化，因此，增加对这些基因变化缓冲的理解影响到BBSRC“生物科学促进对健康的综合理解”的战略主题。该项目涉及整合计算方法以了解进化和功能，并在实验室中验证预测和目标相互作用。湿的和干的方面将迭代地相互反馈，因此湿的实验室实验将为预测提供更好的模型。这一方法符合BBSRC“变革性技术”的主题，以及“支持数学和计算方法，以便从可获得的海量和多样性的生物数据中产生新知识”的目标。

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".