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SUMMARY:The blind watch-breaker: evolution at regulatory sites in cancer -
  Prof. Colin Semple
DTSTART:20170130T160000Z
DTEND:20170130T170000Z
UID:TALK67003@talks.cam.ac.uk
CONTACT:46487
DESCRIPTION:Disruption of gene regulation is thought to play major roles i
 n carcinogenesis and tumour progression. We have recently characterised th
 e 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 abunda
 nce and patterns of single base substitutions within putatively functional
  binding sites to matched control sites. We observe a strong and significa
 nt excesses of mutations at functional binding sites across most TFs\, and
  show that the substitutions that accumulate in cancers are often more dis
 ruptive than those that are tolerated as germline variants. Putatively fun
 ctional 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 dete
 rmined by replication timing and the mutational signature of the tumor sam
 ple in question\, suggesting that selectively neutral processes underlie t
 he unusual mutation patterns seen at CTCF sites across tumor types. In con
 clusion\, mutations at active TFBSs are common in tumours\, appear to accu
 mulate largely unchecked by selective processes and are largely independen
 t of mutations in coding sequences\, exhibiting distinct rates among tumor
  types. Our study underlines the functional importance and fragility of th
 e regulatory genome in cancer.\n\nProf. Colin Semple's Bio\n\nA critical c
 omponent of normal biological function is the elegantly coordinated expres
 sion of our genes\, reflected in the shifting constellations of thousands 
 of active genes within millions of cells across time and space. The genome
 s of complex organisms have evolved a huge variety of strategies and syste
 ms to reliably achieve this fine scale regulation of gene expression. My g
 roup 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.\nMy PhD was in population genetics at the Univ
 ersity of Edinburgh (1994)\, followed by postdoctoral stints at the Univer
 sity of Michigan and Trinity College Dublin exploring the first genome seq
 uences derived from yeast and worms. In 1998 I joined the MRC Human Geneti
 cs Unit\, studying the initial human genome sequence to understand human d
 isease predisposition. Since 2001 I have led the Bioinformatics Analysis C
 ore at the MRC Institute of Genetics and Molecular Medicine (IGMM)\, one o
 f the largest UK MRC research establishments supporting approximately 500 
 scientists. We provide computational collaborative expertise to IGMM exper
 imental research groups\, and also large research consortia such as the Sc
 ottish Genomes Partnership. I am also a member of the Edinburgh-St Andrews
  MRC Molecular Pathology Hub\, the EpiGeneSys EU-wide network of excellenc
 e in epigenetics and systems biology\, various MRC review panels and journ
 al editorial boards.
LOCATION:CRUK CI Room 215A/B
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