Detection of Rare-Alleles and Their Carriers Using Compressed Se(que)nsing Or Zuk Broad Institute of...
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Detection of Rare-Alleles and Their Carriers Using Compressed Se(que)nsing Or Zuk Broad Institute of MIT and Harvard [email protected] In collaboration
Detection of Rare-Alleles and Their Carriers Using Compressed
Se(que)nsing Or Zuk Broad Institute of MIT and Harvard
[email protected] In collaboration with: Amnon Amir Dept. of
Physics of Complex Systems, Weizmann Inst. of Science Noam Shental
Dept. of Computer Science, The Open University of Israel
Slide 2
The Problem Identify genotypes (disease) in a large population
AB AA genotypes Specifics: Large populations (hundreds to tens of
thousands) Rare alleles Pre-defined genomic regions
Slide 3
Nave Approach Targeted selection + Next Gen Seq.: One Test per
Individual collect DNA samples Apply 9 independent tests AB AA
fraction of Bs out of tested alleles 0 1/2 000 000 Problem: Rare
alleles require profiling a high number of individuals. Still very
costly. Multiplexing/barcoding provides partial solution
(laborious, expensive, often not enough different barcodes)
Targeted selection
Slide 4
Our approach - Targeted Selection + Smart pooling + Next Gen
seq. collect DNA samples. Prepare Pools Advantages: Fewer pools
Reduced sample preparation and sequencing costs Can still achieve
accurate genotypes Apply 3 pooled tests AB AA fraction of Bs out of
tested alleles 0 1/2 000 000 Targeted selection Reconstruct
genotypes
Slide 5
Application 1: Rare recessive genetic diseases CarrierHealthy!
NormalHealthy GenotypePhenotype AffectedSick Identify carriers of
known deleterious mutations
Specific mutations - notation A B Reference genome AGCGTTCT
AGTGTTCT Single-nucleotide polymorphism (SNPs) AGGTTCT
Insertions/Deletions (InDels) Carrier test screen: Amplify a sample
of DNA and then test AA AB fraction of Bs out of tested alleles 1/2
0
Slide 9
Application 2: Genome Wide Association Studies collect DNA
samples AB BBABBBAA AB CasesControls AAAB AA ABAA Count:
CasesControls AAX AA Y AA ABX AB Y AB BBX BB Y BB Try ~10 5 10 6
different SNPs. Significant ones called discoveries/associations
Statistical test, p-value
Slide 10
What Associations are Detected? [T.A. Manolio et al. Nature
2009] Goal: push further Find Novel mutations associated with
common disease and their carriers
Slide 11
What Associations are Detected? Find Novel mutations associated
with common disease and their carriers Proposed approaches: Profile
larger populations. Look at SNPs with lower Minor Allele Frequency
Re-sequencing in regions with common SNPs found, and other regions
of interest
Slide 12
infer/reconstruct Compressed Sensing Based Group Testing Next
Generation Sequencing Technology compressed sensing (CS) a few
tests instead of 9 fraction of Bs
Slide 13
Rare Allele Identification in a CS Framework individuals in the
pool # rare alleles
