The blind watch-breaker: evolution at regulatory sites in cancer

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• Prof. Colin Semple
• Monday 30 January 2017, 16:00-17:00
• CRUK CI Room 215A/B.

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Disruption of gene regulation is thought to play major roles in carcinogenesis and tumour progression. We have recently characterised the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of mutation at the binding sites of 87 different transcription factors (TFs) by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to matched control sites. We observe a strong and significant excesses of mutations at functional binding sites across most TFs, and show that the substitutions that accumulate in cancers are often more disruptive than those that are tolerated as germline variants. Putatively functional CTCF binding sites suffer an exceptionally high mutational load in cancer relative to control sites, and those involved in the architecture of higher order chromatin structures are the most highly mutated. However, the mutational load at CTCF -binding sites appears to be dominantly determined by replication timing and the mutational signature of the tumor sample in question, suggesting that selectively neutral processes underlie the unusual mutation patterns seen at CTCF sites across tumor types. In conclusion, mutations at active TFB Ss are common in tumours, appear to accumulate largely unchecked by selective processes and are largely independent of mutations in coding sequences, exhibiting distinct rates among tumor types. Our study underlines the functional importance and fragility of the regulatory genome in cancer.

Prof. Colin Semple’s Bio

A critical component of normal biological function is the elegantly coordinated expression of our genes, reflected in the shifting constellations of thousands of active genes within millions of cells across time and space. The genomes of complex organisms have evolved a huge variety of strategies and systems to reliably achieve this fine scale regulation of gene expression. My group uses computational approaches to understand these regulatory systems in the human genome, how they are disrupted in diseases such as cancers, and how they have evolved. My PhD was in population genetics at the University of Edinburgh (1994), followed by postdoctoral stints at the University of Michigan and Trinity College Dublin exploring the first genome sequences derived from yeast and worms. In 1998 I joined the MRC Human Genetics Unit, studying the initial human genome sequence to understand human disease predisposition. Since 2001 I have led the Bioinformatics Analysis Core at the MRC Institute of Genetics and Molecular Medicine (IGMM), one of the largest UK MRC research establishments supporting approximately 500 scientists. We provide computational collaborative expertise to IGMM experimental research groups, and also large research consortia such as the Scottish Genomes Partnership. I am also a member of the Edinburgh-St Andrews MRC Molecular Pathology Hub, the EpiGeneSys EU-wide network of excellence in epigenetics and systems biology, various MRC review panels and journal editorial boards.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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