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SUMMARY:Discovery and allele frequency estimation of somatic twilight zone
  insertions and deletions - Alexander Schönhuth (CWI Amsterdam)
DTSTART:20140922T150000Z
DTEND:20140922T160000Z
UID:TALK53956@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Locating somatic mutations on the basis of next-generation seq
 uence (NGS) data of\ndisease-control matched samples constitutes an essent
 ial step in cancer and other clinical\nresearch. The detection of these ge
 netic variants remains a major challange\, not only due\nto the impurity a
 nd heterogeneity of the disease sample\, but also because of the inherent\
 nuncertainty present in this type of data. The main\nsources of `noise' in
  NGS data are commonly thought to be alignment and typing uncertainties\,\
 nwhere the first refers to the fact that the origin of the reads\non the g
 enome are unknown\, and the latter reflects the often limited confidence o
 ne has\non whether a read stems from an allele-affected chromosome or not.
  The case of calling\nsomatic twilight zone (or mid-size) indels is consid
 ered exceptionally hard\, due to the\nhigh typing uncertainties involved.\
 nWe present a maximum likelihood approach that allows us to robustly estim
 ate twi-\nlight zone indel allele frequencies while taking the individual 
 read alignment and typing\nuncertainties into account. By means of likelih
 ood factorization\, we can estimate the allele\nfrequencies in the disease
  and in the control sample simultaneously (while accounting for\nimpurity 
 as well). In addition\, we define a likelihood-ratio based signficance tes
 t which\nallows one to test for the presence/absence of a somatic mutation
 .\nThis statistical framework is not only restricted to somatic twilight z
 one indel calling\,\nbut allows for other applications as well\, such as r
 obustly genotpying di- and polyploid\ncells or de novo twilight zone indel
  calling\, all while accounting for alignment and typing\nuncertainties.\n
 \nIn summary\, our results point out that we have the first tool that can 
 discover 'somatic twilight\nzone insertions and deletions' (indels of size
  30-120 bp) at sufficient recall and precision --\nso far hardly any such 
 somatic indels have been discovered. As a consequence\, their extent and\n
 their potential effects have hardly been explored.\n
LOCATION:CRUK CI Lecture Theatre
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