Bioinformatics Seminars

Current Bioinformatics Seminar

25 September 2018

Evolutionary analysis of alterations to gene regulatory networks in cancer

David Goode

The evolution of multicellularity was accompanied by formation of gene regulatory networks (GRNs) that promoted cellular differentiation and enforced co-operation between cell types, traits that are lost in most cancers. We overlaid sequence conservation, mutation and gene expression data onto human GRNs and found the impact of somatic mutations is strongly associated with the evolutionary origins and the evolved regulatory roles of the affected genes. Genes that arose early in metazoan evolution were the most enriched for recurrent mutations. Point mutations were most prevalent in genes linking those regions of the GRN conserved with unicellular organisms with more recently evolved regions specific to multicellular species. In contrast, recurrent gains and losses were predominantly located in distinctly unicellular and multicellular regions. De novo construction of GRNs based on gene expression correlation revealed widespread rewiring at the interface between unicellular and multicellular regulatory modules in cancer, often associated with chromosomal amplifications. Our results suggest strong selection disruption of crosstalk between unicellular and multicellular genes can drive tumourigenesis, by breaking crucial regulatory links formed early in metazoan evolution to control the activity of ancient, core biological processes.

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