MicroRNA buffering of gene duplications and aneuploidy

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".