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Fundamentals of Analysis of Exomes
Diego Forero, MD, PhDAssistant Professor
Director, Laboratory of NeuroPsychiatric GeneticsDirector, Medical Research Office
School of MedicineAntonio Nariño University
Bogotá, ColombiaEditor, hum-molgen.org
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Online Mendelian Inheritance in Man
Mendelian Disorders
Autosomal Sex-linked Total
Causal Gene Known
3.175 266 3.441
Causal Gene Unknown
1.633 140 1.773
CAUSAL GENES FOR MENDELIAN DISORDERS
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2005 2006 2007 2008 2009 2010 2011 2012 2013
Year
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2013: ~ 800 papers
2014: ~ 1200 papers
Forero DA, 2012
Exomes: Publication Trends
Total: 925 (Oct 2012)
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GENOMICS: PLATFORMS
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Majewski, J Med Genet 2011
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Majewski, J Med Genet 2011
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From Data Generation to Data Analysis
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A timeline illustrating technological breakthroughs and hallmark publications for Mendelian disease gene
identification
Gilissen, Genom Biol 2011
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A timeline illustrating technological breakthroughs and hallmark publications for Mendelian disease gene
identification
Gilissen, Genom Biol 2011
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"We focus here on the variants in a person’s ‘exome,’ which is the set of exons in a genome..."
Ng, PLoS Genet 2008
First Published Exome
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A representation of the relationship between the size of the mutational target and the frequency of disease for
disorders caused by de novo mutations
Gilissen, Genom Biol 2011
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Majewski, J Med Genet 2011
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Bamshad, Nat Rev Genet 2011
Strategies for finding disease-causing rare variants using exome sequencing
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Typical heuristic filtering applied to exome sequencing projects aimed at novel gene discovery for Mendelian
disorders
Stitziel, Genom Biol 2011
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Bamshad, Nat Rev Genet 2011
Mean number of coding variants in two populations
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First identification of the causal gene for a monogenic disorder by exome sequencing
Freeman–Sheldon syndrome (MYH3)
Ng, Nature 2009
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Pierce, Am J Hum Genet 2010
Exome Analysis for One Patient
Perrault syndrome (HSD17B4)
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VarSifterhttp://research.nhgri.nih.gov/software/VarSifter/index.shtml
Exome Variant Server (6503 exomes)http://evs.gs.washington.edu/EVS/
wANNOVARhttp://wannovar.usc.edu/
Useful In Silico Tools
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EVAhttp://plateforme-genomique-irib.univ-rouen.fr/EVA/index.php
TREAThttp://ndc.mayo.edu/mayo/research/biostat/stand-alone-packages.cfm
KGGSeqhttp://statgenpro.psychiatry.hku.hk/limx/kggseq/
Atlas2 Suite http://sourceforge.net/p/atlas2/wiki/Atlas2%20Suite/
IBD2http://compbio.charite.de/contao/index.php/ibd2.html
Useful In Silico Tools
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Exomes-Service Providers
Axeq (USA)50x; Illumina TrueSeq/HiSeq200. $2,300 USD per sample
Macrogen (Korea)50x; Illumina TrueSeq/HiSeq200. $2,499 USD per sample
BaseClear (Netherlands)30x; Nimblegen/Illumina. € 2,499 per sample
PerkinElmer (USA)30x; Agilent/Illumina. $3,500 USD per sample
BGI Americas (USA)30x; $3,500 USD per sample
EdgeBio (USA)50x; SOLiD 4. $5,500 USD per sample
DNAVision (Belgium)
30x; Agilent/Illumina. 5,990 € per sample
Knome (USA)30x; Illumina. $8,750 USD per sample
Source BioScience (UK)50x; Agilent/Illumina. 5,850GBP per sample
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http://www.ncbi.nlm.nih.gov/omim
Need for in-house exome data. Possible Noise from dbSNP and OMIM
Data from Human Gene Mutation Database?
Example of Data Provided
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Candidate genes prioritization
Endeavourhttp://homes.esat.kuleuven.be/~bioiuser/endeavour/tool/endeavourweb.php
ToppGenehttp://toppgene.cchmc.org/prioritization.jsp
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Thusberg J, Olatubosun A, Vihinen M.Performance of mutation pathogenicity prediction methods on missense variants.
Hum Mutat. 2011 Apr;32(4):358-68.
Tools for mutation pathogenicity prediction
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MutPredhttp://mutpred.mutdb.org/
SNPs&GOhttp://snps-and-go.biocomp.unibo.it/snps-and-go/
PolyPhen-2http://genetics.bwh.harvard.edu/pph2/
SIFThttp://sift.bii.a-star.edu.sg/
Tools for mutation pathogenicity prediction
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www.daforerog.co.cc
“This is an excellent resource for anyone who is generally interested in how these technologies work”. Stephen Turner, PhDCenter for Human Genetics Research, Vanderbilt University.
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www.daforerog.co.cc