Evolution of gene regulatory networks after gene duplication

Throughout evolution multicellular organisms have experienced large-scale structural alterations, in which regions of the genome or even the entire genome have been duplicated (1-7). Gene duplication can give rise to novel expression patterns or functions, however, there are few general rules. An important example is the duplication of transcription factors, which could have crucial effects on the regulation of gene expression throughout evolution. In this project the student will use experimental analysis of mammalian immune cells, comparative genomic analysis and laboratory evolution to try to improve our understanding of how gene expression diverges after the duplication of members of the Runx family of transcription factors. In addition to elucidating general principles of genome evolution, understanding Runx gene regulation is important to elucidate diseases such as acute myeloid leukaemia, which can result from Runx mutations. We have recently shown that members of the Runx family of transcription factors have diverged in function, as well as by expression pattern (8). Unexpectedly, weaker Runx gene family members were selectively expressed at branch points in the differentiation of immune cell types, such as regulatory T cells and skin dendritic cells. The expression of weaker family members was important for the integration of Runx transcription factor activity with signaling through the TGF-beta pathway. In the first part of this project the student will extend this work to further interrogate how the Runx transcription factors interact with TGF-beta signalling. For example, signals downstream of TGF-beta could influence the expression of Runx family members. Alternatively, Runx transcription factor activity and signaling through the TGF-beta pathway could be integrated by gene regulatory elements at the level of Runx target genes. We will address this question by characterising the activity of gene regulatory elements, using experimental and computational techniques. In the second part of the project the student will use comparative genomics to reconstruct the evolutionary history of the Runx gene expression network. We will accomplish this by analysing gene regulatory elements of Runx and its target genes in organisms such as sea urchins, which have retained a single Runx gene. In parallel, we will undertake experimental evolution in the nematode C. elegans (9) in order to obtain general principles of how gene expression networks diverge following gene duplication. Altogether this project will offer training in a variety of wet-lab and computational approaches and will offer new insights both into the function of a key regulator of the immune system and into the mechanisms of genome evolution.

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