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Abel Gonzalez-PerezResearch Associate
Biomedical Genomics Lab
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0. A word about detection...
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0. A word about detection
1. Annotation of SNVs and small indels. Vocabularies and tools
2. Functional Impact of SNVs. Approaches and tools
3. Somatic mutations in cancer
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NGS technologies compared to Sanger sequencing
B&FG 3eTable 9-1Page 382
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FASTQ format
The FASTQ format stores DNA sequence data as well as associated Phred quality scores of each base.
DNA read
Base quality score
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Next-generation sequence data: visualizing of short reads aligned to a reference genome
reference genome
reads
variant
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B&FG 3eFig.9-13Page 403
home/bioinformatics$ samtools view 030c_S7.bam | lessM01121:5:000000000-A2DTN:1:2111:20172:15571 163 chrM480 60 148M2S = 524 195 AATCTCATCAATACAACCCTCGCCCATCCTACCCAGCACACACACACCGCTGCTAACCCCATACCCCGAACCAACCAAACCCCAAAGACACCCCCCACAGTTTATGTAGCTTACCTCCTCAAAGCAATAACCTGAAAATGTTTAGACGGG BBBBBFFB5@FFGGGFGEGGGEGAAACGHFHFEGGAGFFHAEFDGG?E?EGGGFGHFGHF?FFCHFH00E@EGFGGEEE1FFEEEHBGEFFFGGGG@</01BG212222>F21@F11FGFG1@1?GC<G11?1?FGDGGF=GHFFFHC.-RG:Z:Sample7 XC:i:148 XT:A:U NM:i:3 SM:i:37AM:i:37 X0:i:1 X1:i:0 XM:i:3 XO:i:0 XG:i:0 MD:Z:19C109C0A17
(1)Thequerynameof theread isgiven(M01121…)
(2)Thef l agvalueis163(thisequals1+2+32+128)
(3)Thereferencesequencename,chrM,refersto themitochondrial genome
(4)Position480 istheleft-mostcoordinatepositionof thisread
(5)ThePhred-scaledmappingqualityis60(anerrorrateof1in10 )
(6)TheCIGARstring(148M2S)shows148matchesand2soft-clipped(unaligned)bases
(7)An=signshowsthatthematereferencematchesthereferencename
(8)The1-based leftposition is524
(9)Theinsert sizeis195 bases
(10)ThesequencebeginsAATCT andendsACGGG(itslength is150bases)
(11)Eachbaseisassignedaqualityscore(fromBBBBBendingFHC.-)
(12)Thisreadhasadditional,optionalf i el dst
h
ataccompanytheMiSeqanalysi
Anatomy of a Sequence Alignment/Map (SAM) file
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B&FG 3eTable 9.6Page 411
Variant Call Format (VCF) file summarizes variation
A VCF file includes the following information:
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B&FG 3eFig.9-17Page 412
Variant Call Format (VCF) file summarizes variation
SNP Insertion
Deletion Replacement
Alignment VCFrepresentation1234 POS REF ALTACGT 2 C TATGT
Alignment VCFrepresentation12345 POS REF ALTAC-GT 2 C CTACTGT
Alignment VCFrepresentation1234 POS REF ALTACGT 1 ACG AA--T
Alignment VCFrepresentation1234 POS REF ALTACGT 1 ACG ATA-TT
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1. Annotation of SNVs and small indels. Vocabularies and tools.
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1. Annotation of SNVs and small indels. Vocabularies and tools.
Genomic variant
Effect on transcript
Phenotypic effect
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1. Annotation of SNVs and small indels. Vocabularies and tools.
Genomic variant
Effect on transcript
Phenotypic effect
Functional Impact
Consequence type
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1. Annotation of SNVs and small indels. Vocabularies and tools.
Genomic variant
Effect on transcript
Phenotypic effect
Association studies
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1. Annotation of SNVs and small indels. Vocabularies and tools.
Genomic variant
Effect on transcript
Phenotypic effect
Functional Impact
Consequence type
Annotation
Assessment
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1. Annotation of SNVs and small indels. Vocabularies and tools.
Taken from Ensembl Variation Database
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1. Annotation of SNVs and small indels. Vocabularies and tools.
The Ensembl Variant Effect Predictor
Genomic coordinates/ change of the variant
Map to overlapping genomic features(transcripts, reg. regions, etc)
VEP standalone PERL script using Ensembl APIs
VEP web tool
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1. Annotation of SNVs and small indels. Vocabularies and tools.
The Ensembl Variant Effect Predictor
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1. Annotation of SNVs and small indels. Vocabularies and tools.
The Ensembl Variant Effect Predictor(Example)
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1. Annotation of SNVs and small indels. Vocabularies and tools.
The Ensembl Variant Effect Predictor(Example)
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2. Functional Impact of SNVs. Approaches and tools
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2. Functional Impact of SNVs. Approaches and tools
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2. Functional Impact of SNVs. Approaches and tools
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2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs
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2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs:three exemplary tools
http://sift.jcvi.org/
SIFT
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2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs:three exemplary tools
Query sequence + aminoacid change
Psi-Blast +Motif
Closely related sequences
MSA
Closely related sequences
PSSM
Ng and Henikoff, 2001. Genome Research
SIFT
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2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs:three exemplary tools
http://genetics.bwh.harvard.edu/pph2/PolyPhen2
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2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs:three exemplary tools
2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs:three exemplary tools
Adzhubei et al, 2010. Nature Methods
PolyPhen2
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2. Functional Impact of SNVs. Approaches and tools
Predicting functional impact of nsSNVs:three exemplary tools
Adzhubei et al, 2010. Nature Methods
PolyPhen2
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2. Functional Impact of SNVs. Approaches and tools
SNVs catalogs
1000 Genomes Project:genetic variants with frequencies of at least 1% in the populations studied
~2,504 individuals so far
http://www.1000genomes.org/
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2. Functional Impact of SNVs. Approaches and tools
SNVs catalogs
1000 Genomes Project:genetic variants with frequencies of at least 1% in the populations studied
~2,504 individuals so far
http://www.1000genomes.org/
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2. Functional Impact of SNVs. Approaches and tools
SNVs catalogs
http://www.ncbi.nlm.nih.gov/projects/SNP/
dbSNPCentral repository of SNVs without allele frequency limitation
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2. Functional Impact of SNVs. Approaches and tools
SNVs catalogs
http://hapmap.ncbi.nlm.nih.gov/
HAPMAPProject to characterize haplotypes (close co-ocurring variants)
in human populations
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2. Functional Impact of SNVs. Approaches and tools
SNVs catalogs
https://www.gwascentral.org/
GWAS Centralcentralized compilation of summary level findings from genetic
association studies, both large and small
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2. Functional Impact of SNVs. Approaches and tools
Navigating variants in Ensembl http://www.ensembl.org
SMARCA4: genomic region
SMARCA4: transcripts
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2. Functional Impact of SNVs. Approaches and tools
Navigating variants in Ensembl
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2. Functional Impact of SNVs. Approaches and tools
Navigating variants in Ensembl
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2. Functional Impact of SNVs. Approaches and tools
Navigating variants in Ensembl
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3. A word about somatic mutations in cancer
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Mike Stratton. EMBO Molecular Medicine (2013)
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Mutagenic processes
(internal and external)
Mechanisms of DNA repair
Mutational processes
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Mutagenic processes
(internal and external)
Mechanisms of DNA repair
This interaction affects he genome at different levels of resolution
Mutational processes
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Mutational processes
UV light signature
Tobacco smoke
Mutation burden and mutationsignature affecting the whole
genome
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Mutational processes
Sabarinathan et al. Nature. 2016
More mutations in transcription factor binding sites of melanocytes
Schuster-Böckler and Lehner et al. Nature 2012
More mutations in closed chromatin regions
More mutations in regions lowly expressed genes
Lawrence et al. Nature. 2013
Fewer mutations in exons than expectedin POLE-mutant tumorsFrigola, Sabarinathan et al. Nature Genetics. 2017
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3. Interpreting somatic mutations in cancer
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Understand the genomic mechanisms that fuel the tumor phenotypes
Drivers of cancer
Hanahan and Weinberg. Cell 2011
Driver versus passenger events
Needle in a haystack
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Which mutations in driver genes are drivers?
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How deleterious are cancer driver mutations?
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How deleterious are cancer driver mutations?
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How deleterious are cancer driver mutations?
Deleteriousness
Driv
erne
ss
Yes
No
Yes No
● Highly deleterious mutations affecting cancer genes
● Highly deleterious mutations affecting non-cancer genes
● Lowly deleterious mutations that contribute to tumor phenotype?
● Lowly deleterious mutations affecting non-cancer genes
Pas
seng
er
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How deleterious are cancer driver mutations?
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Carter et al., 2009. Cancer Research
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How deleterious are cancer driver mutations?
It depends on the mode of action of the gene!!
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OncodriveFM
OncodriveCLUST
MuSiC-SMG
F
C
RUsing complementary signals help obtaining a more comprehensive list of cancer drivers
Tamborero et al., Scientific Reports 2013
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How about other types of variants?
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Copy Number Alterations
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Other genomic rearrangements
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Other genomic rearrangements
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Repositories of known oncogenic variants
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PTEN*
Temsirolimus
Vemurafenib(V600E) (R130G)
PI3K
AKT
mTOR
BRAF*
(R175H)
TP53*
rAd-p53
Strategies to target cancer drivers
IndirectGene Therapy
Direct
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