Colin Semple seminar 23 March 2017

Colin Semple from the University of Edinburgh will present a seminar at this week’s Bioinformatics seminar series/journal club (12:00 on Thursday 23rd in ADB1020):

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

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 TFBSs 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.

All wellcome!

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