Presentation is loading. Please wait.

Presentation is loading. Please wait.

Allele-Specific Copy Number in Tumors

Published byMarsha Fields Modified over 6 years ago

Similar presentations

Presentation on theme: "Allele-Specific Copy Number in Tumors"— Presentation transcript:

1 Allele-Specific Copy Number in Tumors
Itsik Pe’er Department of Computer Science Center for Computational Biology & Bioinformatics Columbia University C2 B2

2 Breakthrough of the Year: Whole-Genome Association
Age-related Macular Degeneration QT Interval Multiple Sclerosis Systemic Lupus Erythematosis ORMDL3 MEIS1 BTBD8 MAP2K5 ABCG8 6q25 2q36 9p21 CF3 IL7R IL2R IRGM ATG16L1 IL23R NKX2-3 5p13 PTPN2 HLA region 12q24 KIAA0350 INS IL-2 IL21 LOXL1 SMAD7 6q23#1 6q23#2 6p21 1p13 TRAF1-C5 DPP6 8q24#1 8q24#2 8q24#3 8q24#4 8q24#5 8q24#6 TCF2 17p PAX5 FTO CDKAL1 CDKN2B/A IGF2BP2 HHEX WF81 SLC30A8 MTHFD1L 9p21 FGFR2 TNCR9 MAP3K1 LSP 16q12 16p12 4q25 [Science] Restless Leg Syndrome Amyotrophic Lateral Sclerosis Acute Lymphoblastic Leukemia Obesity Myocardial Infarction Breast Cancer Biopolar Disorder Rheumatoid Arthritis Celiac Disease Coronary Artery Disease Glaucoma Atrial Fibrillation Asthma Gallstone Disease Prostate Cancer Colorectal Cancer Cholesterol Type II Diabetes Crohn’s Disease Type I Diabetes Venous Thromboembolism TCF7L2 NOS1AP IRF5 CFH HLA-DRB1 IFIH1 IL2RA NOD2 F5 F2 PPARγ SH2B3 KCNJ11 CTLA4 ApoE PTPN22 1981 2000 2001 2002 2003 2004 2005 2006 2007

3 Single Nucleotide Polymorphisms (SNPs)
A A A G A A G A G G G

4 Association & Haplotypes
Cases T G G A G A T C A T G G A C A Controls A G G A C G T G G

5 Association & Haplotypes
Cases T G G A G A T C A T G G A C A Controls A G G A C G T G G

6 Copy Number Variation Amplicons:
Regions whose copy number varies between homologs 6

7 Copy Number Variation Amplicons: Rare event May impact Mbps
Regions whose copy number varies between homologs Rare event May impact Mbps 7

8 Tumor Selects for Amplification
8

9 Recurrent Somatic Amplification in Cancer
Independent tumors show similar amplifications May point to genes selected for in tumor Problem: Segments are too long! 9

10 Amplification Across the Genome
20% Inferred copy number > 2 Inferred copy number > 3 10% Chr_1 Chr_2 Chr_ 10

11 Two Hit Hypothesis Germline Somatic Knudson, 1971 11

12 Two Hit Hypothesis Single Nucleotide Copy Number Germline Somatic
Knudson, 1971 12

13 Hypothesis: Allele Specific Selection for Amplicons
Reverse order. 13

14 Amplification Distortion Test
G A G A G G A G A G A G G G Null: #Amplified A’s ~ Binomial(p=1/2) Alternative: Amplification distortion 14

15 Inspiration: Transmission Disequilibrium Test
AG GG GG AG AG GG … AG GA AG

16 Unique Dataset Genomewide SNPs (240,000) Lung tumors (700) … AAG
Title: Unique data Credit (bottom right: Matthew Meyerson, Broad) Visual: Rectangle, with arrows to indicate samples axis (vertical) + probe axis Animate in 250k SNPs Animate in that these can also call copy number (bars vs. beads) Animate in 1900 samples Unique, significant dataset! Earlier work focused on regions Earlier work possessed ~100 tumor samples at most ~240K SNPs (Single Nucleotide Polymorphisms) Using 250K Affymetrix SNP Platform Diverse: Copy Number and Allelic Information Allows for high-resolution, genome wide analysis for copy number changes ~1900 total tumor samples Comprised of various tissue types Typed for… Data: Matthew Meyerson (Broad) Copy Number Calls: PLASQ (LaFramboise, 2006) 16

17 Genomewide Results SNPs 3- 0-
LOD 6- 3- 0- SNPs How can we interpret theoretical significance? 17

18 Evaluating Significance
Null expectation: One SNP exceeds Pval=10-4 1 Marker 1 Marker 2 Marker M … G A C T 2 No Flip Number of Iterations per Test: 1, 10, 100, 1000 n 18

19 Genomewide Results SNPs 3- 0- Haplotypes 9- 6- 3- 0-
LOD 6- 3- 0- SNPs 9- 6- 3- 0- Haplotypes Genomic control/fitting -priors for uniform p-values 19

20 Experimental validation of top candidates
Quality Control AAG Accuracy of genotype: - 432 Matched normals Accuracy of copy number: - Called over megabases Accuracy of amplified allele: - Filtered vs. computational phasing AG? AGG? AAA? Experimental validation of top candidates

21 Kudos Data: Meyerson Lab NLM Training MAGNet NIH NCI Matthew Freedman
Ninad Dewal Tom LaFramboise

22 Posters by our group G A Ninad Dewal:
Allele-Specific Amplification in Tumors Sasha Gusev: Rapid Identification of Identity-by-Descent Eimear Kenny: Genetics-Genomics of Parkinson’s Disease in Ashkenazis Snehit Prabhu: Overlapping Pools for 2nd-Generation Resequencing

Download ppt "Allele-Specific Copy Number in Tumors"

Similar presentations

What is an association study? Define linkage disequilibrium

What is an association study? Define linkage disequilibrium
Which Phenotypes Can be Predicted from a Genome Wide Scan of Single Nucleotide Polymorphisms (SNPs): Ethnicity vs. Breast Cancer Mohsen Hajiloo, Russell.

Which Phenotypes Can be Predicted from a Genome Wide Scan of Single Nucleotide Polymorphisms (SNPs): Ethnicity vs. Breast Cancer Mohsen Hajiloo, Russell.
Genetic Analysis in Human Disease

Genetic Analysis in Human Disease
November 17, 2007Georgia Tech / ORNL Bioinformatics Conference1 Opportunities at the NIH Peter Good, Ph.D. NHGRI November 17, 2007 6th Georgia Tech / ORNL.

November 17, 2007Georgia Tech / ORNL Bioinformatics Conference1 Opportunities at the NIH Peter Good, Ph.D. NHGRI November 17, th Georgia Tech / ORNL.
Perspectives from Human Studies and Low Density Chip Jeffrey R. O’Connell University of Maryland School of Medicine October 28, 2008.

Perspectives from Human Studies and Low Density Chip Jeffrey R. O’Connell University of Maryland School of Medicine October 28, 2008.
Understanding GWAS Chip Design – Linkage Disequilibrium and HapMap Peter Castaldi January 29, 2013.

Understanding GWAS Chip Design – Linkage Disequilibrium and HapMap Peter Castaldi January 29, 2013.
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls The Wellcome Trust Case Control Consortium, Nature, 2007.

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls The Wellcome Trust Case Control Consortium, Nature, 2007.
Genetics for Imagers: How Geneticists Model Quantitative Phenotypes

Genetics for Imagers: How Geneticists Model Quantitative Phenotypes
Computational Tools for Finding and Interpreting Genetic Variations Gabor T. Marth Department of Biology, Boston College

Computational Tools for Finding and Interpreting Genetic Variations Gabor T. Marth Department of Biology, Boston College
Positional Cloning LOD Sib pairs Chromosome Region Association Study Genetics Genomics Physical Mapping/ Sequencing Candidate Gene Selection/ Polymorphism.

Positional Cloning LOD Sib pairs Chromosome Region Association Study Genetics Genomics Physical Mapping/ Sequencing Candidate Gene Selection/ Polymorphism.
Single nucleotide polymorphisms Usman Roshan. SNPs DNA sequence variations that occur when a single nucleotide is altered. Must be present in at least.

Single nucleotide polymorphisms Usman Roshan. SNPs DNA sequence variations that occur when a single nucleotide is altered. Must be present in at least.
Genomewide Association Studies.  1. History –Linkage vs. Association –Power/Sample Size  2. Human Genetic Variation: SNPs  3. Direct vs. Indirect Association.

Genomewide Association Studies.  1. History –Linkage vs. Association –Power/Sample Size  2. Human Genetic Variation: SNPs  3. Direct vs. Indirect Association.
SNPs DNA differs between humans by 0.1%, (1 in 1300 bases) This means that you can map DNA variation to around 10,000,000 sites in the genome Almost all.

SNPs DNA differs between humans by 0.1%, (1 in 1300 bases) This means that you can map DNA variation to around 10,000,000 sites in the genome Almost all.
Single nucleotide polymorphisms and applications Usman Roshan BNFO 601.

Single nucleotide polymorphisms and applications Usman Roshan BNFO 601.
Common Disease Findings (case study on diabetes) GWAS Workshop Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute May 1, 2007.

Common Disease Findings (case study on diabetes) GWAS Workshop Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute May 1, 2007.
Large-Scale Copy Number Polymorphism in the Human Genome J. Sebat et al. Science, 305:525 Luana Ávila MedG 505 Feb. 24 th 2005 1/24.

Large-Scale Copy Number Polymorphism in the Human Genome J. Sebat et al. Science, 305:525 Luana Ávila MedG 505 Feb. 24 th /24.
Genetic Analysis in Human Disease. Learning Objectives Describe the differences between a linkage analysis and an association analysis Identify potentially.

Genetic Analysis in Human Disease. Learning Objectives Describe the differences between a linkage analysis and an association analysis Identify potentially.
Epigenome 1. 2 Background: GWAS Genome-Wide Association Studies 3.

Epigenome 1. 2 Background: GWAS Genome-Wide Association Studies 3.
The medical relevance of genome variability Gabor T. Marth, D.Sc. Department of Biology, Boston College

The medical relevance of genome variability Gabor T. Marth, D.Sc. Department of Biology, Boston College
Computational research for medical discovery at Boston College Biology Gabor T. Marth Boston College Department of Biology

Computational research for medical discovery at Boston College Biology Gabor T. Marth Boston College Department of Biology

Similar presentations

Ads by Google