Training Courses: Variant annotation and interpretation with Alamut

19 Pages·2014·14.16 MB·English

Training
 Courses:

Variant
 annotation
 and

interpretation
 with
 Alamut®
 and

Human
 Splicing
 Finder®

February
 23,
 2014

Ghadi
 RAI,
 PhD
 student

Genetics
 and
 Bioinformatics
 Team

UMR_S910
 Medical
 Genetics
 and
 Functional
 Genomics

Aix-­‐Marseille
 Université
Plan#
####1.#Introduc/on#to#splicing#signals#
####2.#Various#algorithms#to#detect#splicing#mo/fs#
####3.#Introduc/on#to#HSF#
####4.#Training#with#examples#
#
G.#RAI#

1.#Introduc=on#to#splicing#signals:#Major#Splicing#sequences#
The#spliceosome#recognizes#splicing#sites#from#their#sequences#
Exon# Intron# Exon#
G.#RAI#
1.#IntroducCon#to#splicing#signals:#Auxiliary#splicing#sequences#
ISE# ESE# ISE#
SR#
U2# U1#
hnRNP#
ISS#
ESS# ISS#
Inhibitors ! Activators !
Exonic#Splicing#Silencer#(ESS)# Exonic#Splicing#Enhancer#(ESE)#
Intronic#Splicing#Silencer#(ISS)# Intronic#Splicing#Enhancer#(ISE)#
hnRNP#:#heteregenous#nuclear#RiboNucleoProtein#
SR:#SerinAArginin#protein#
G.#RAI#

2.#Various#algorithms#to#detect#splicing#mo9fs#
Simple text search algorithms!
Position weight matrices (PWM)!
Markov models!
Artificial intelligence (Neural Networks)!
G.#RAI#
2.#Various#algorithms#to#detect#splicing#mo9fs#
Algorithm# Principle# Design# Pros# Cons#
Simple#text#search# Exact#mo9fs#only#
text#search# @# Very#simple#
algorithms# Slow#
Need#mul9ple#
Position weight Sensi9ve,#
use#of#specific#matrix# Mul9ple#alignments# sequences#for#
matrices (PWM)! Fast#
alignment#
Need#mul9ple#
Comparison#of# Sensi9ve,# datasets,#efficiency#
Markov#models# use#of#transi9on#rules#
various#datasets# Fast# rely#on#established#
rules#
Learning#model# Do#not#know#
Ar9ficial#intelligence# Sensi9ve,#
?# requiring#large# underlying#model,#
(Neural#Networks)# Fast#
datasets# rely#on#datasets#
G.#RAI#

2.#Various#algorithms#to#detect#splicing#mo9fs#
Algorithm# Tool#/#System#
Simple#text#search#
SpliceAid)2#@#hAp://193.206.120.249/splicing_9ssue.html#
algorithms#
Position weight
Human)Splicing)Finder#@#hAp://www.umd.be/HSF3/#
matrices (PWM)!
Markov#models# MaxEntScan#@#hAp://genes..mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html#
Ar9ficial#intelligence#
NNSplice#@#hAp://www.fruiWly.org/seq_tools/splice.html#
(Neural#Networks)#
G.#RAI#
2.#Various#algorithms#to#detect#splicing#mo9fs#
G.#RAI#

2.#Various#algorithms#to#detect#splicing#mo9fs#
HSF
Sroogle
MaxEnt
SpliceView
SplicePredictor
SplicePort
GeneSplicer
NNSplice
0% 50% 100%
Splice mutation Polymorphism
Splice mutation (no experimental data) Polymorphism (no experimental data)
G.#RAI#
3.#Introduc/on#to#HSF#v3.0#(www.umd.be/HSF3/)#
####1.#An#online#one#stopAshop#for#splicing#signals#
####2.#A#userAfriendly#web#interface##
####3.#A#very#efficient#system#for#mo/f#detec/on#
####4.#A#very#efficient#system#for#muta/on#analysis#
####5.#A#NGS#compliant#system#
G.#RAI#

3.1.#HSF:#An#online#one#stop5shop#for#splicing#signals#
G.#RAI#
3.1.#HSF:#An#online#one#stop5shop#for#splicing#signals#
G.#RAI#

3.1.#HSF:#An#online#one#stop5shop#for#splicing#signals#
G.#RAI#
3.1.#HSF:#An#online#one#stop5shop#for#splicing#signals#
G.#RAI#

3.1.#HSF:#An#online#one#stop5shop#for#splicing#signals#
G.#RAI#
3.2.#A#user-friendly#web#interface#
####1.#Easy#access#to#all#Human#Transcripts#(HG19)#
####2.#Various#analysis#opDons#&#parameters#
-#Analyze#a#sequence# -#Gene#symbol#
-#Analyze#mutaDon(s)# -#Ensembl#Transcript#or#Gene#ID#
-#Branch#point#sequence#analysis# -#Consensus#CDS#
-#Splice#site#analysis# -#RefSeq#PepDde#ID#
-#MulDple#transcripts#analysis# -#PasDng#a#sequence#
####3.#Advanced#graphical#display#(zooming#opDons)#
####4.#Crude#data#tables#(toggle#opDons)#
####...#
G.#RAI#

3.3.#A#very#efficient#system#for#mo5f#detec5on#
####1.#A#worldwide#reference#for#splicing#mo5fs#detec5on#
####2.#Addi5on#of#new#PWM#for#rare#GC#donor#sites#
####2.#Used#by#researchers#and#clinicians#
####3.#Used#for#new#therapies#development#(exonGskipping)#
Google Scholar: 387 citations
Web of Science: 274 citations
G.#RAI#
3.4.#A#very#efficient#system#for#muta8on#analysis#
####1.#The#most#comprehensive#&#efficient#system#for#splicing#mo8fs#
####2.#An#expert#system#for#data#interpreta8on##
####3.#The#overall#most#efficient#system#for#muta8ons#impact#
G.#RAI#

3.5.#A#NGS#compliant#system#
####1.#Use#of#the#HGVS#nomenclature#
####2.#New#webservice#for#NGS#pipeline#integraDon#
####3.#Use#of#the#HG19#genomic#coordinates#(soon)#
G.#RAI#