Revolutionizing Biology with Personal Genomes

Melanie Swan Research Fellow

MS Futures Group+1-650-681-9482

@LaBloggam@melanieswan.com

www.melanieswan.com

March 26, 2010 NASA AMES

Project information: DIYgenomics.org

Slides: http://slideshare.net/LaBlogga/slideshows

Image credit: http://www-nmr.cabm.rutgers.edu/photogallery/proteins/gif/dna.gif

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Agenda

Consumer genomic landscape DNA sequencing technology DIYgenomics citizen science

Image credit: http://current.com/1u8qe4c

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Numerous useful applications of genomics

Ancestry Pharmaceutical response Health conditions Pregnancy screening

Prenatal, preconception

Identity (paternity, forensics) Athletic capability and training

MMP3 (Achilles tendon) COL1A1 (collagen, ACL)

Reference: “Cheating is so 1999: A reporter spends a year searching for the athletic holy grail: a sports gene,” Assael, Shaun, ESPN The Magazine, Oct. 6, 2009,

http://www.genome.duke.edu/education/seminars/journal-club/documents/Assael_2009.pdf

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Direct-to-Consumer genomics landscape

Single/few condition Multiple condition Whole genome

Cost

1Whole genome: $68,500; exome: $24,500

OfferingBreadth

Public studies

(specific diseases or traits) (common diseases)

MatchmakingScientificMatch $1,995GenePartner $10-$99

PaternityGenelex $200-$475Identigene $149-$399

Pregnancy ScreeningCounsyl $349

NutrigenomicsAPO E Gene Diet $389Inherent Health $99

Coriell15 conditions

Scripps (Navigenics)28 conditions

Pers. Genome Proj.Conditions undisclosed

Harvard Med. Sch.

Genetic disorders,

PredispositionDNA Direct $200-$3,500Matrix Genomics $199-$799

Drug sensitivity,

Knome

Illumina$48,000

$350,000

$99,500

$68,5001

23andme141 conditions

Navigenics28 conditions

Gene Essence84 conditions

$1,000

$429

Genome-wide health offerings

$2,000

$1,195

$299

Genomics71 conditions

Pathway

$

deCODEme 49 conditions

$985

$2,500

$999

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Example: Breast cancer – Navigenics

Source: http://www.navigenics.com/demo/for_scientists/d/breast_cancer

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Example: Breast cancer – deCODEme

Source: http://demo.decodeme.com/health-watch/details/BCRS

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Example: Breast cancer – 23andme

Source: https://www.23andme.com/you/journal/breastcancer/techreport

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Example: Breast cancer – Pathway Genomics

Source: https://www.pathway.com

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Side-by-side comparison: breast cancer

22 Variants at 15 loci are reviewed

Source: http://www.diygenomics.org/, http://melanieswan.com/documents/multigenic_analysis.xls

Markers reviewed by consumer genomic services for breast cancer

Locus Gene Variant D N 23 PG D N 23

1p11.2 rs11249433 X #102q33.1 CASP8 rs1045485 X X #22q33.1 CASP8 rs17468277 X #22q35 rs13387042 X X X #8 #83p24.1 NEK10 rs4973768 X #15q11.2 MAP3K1 rs4700485 X #45q11.2 MAP3K1 rs889312 X X #45p12 MRPS30 rs4415084 X #95p12 MRPS30 rs10941679 X6q25.1 ESR1 rs2046210 X7q21.2 AKAP9 rs6964587 X8q24 rs672888 X #48q24.21 rs13281615 X X #410q26.13 FGFR2 rs2981582 X X #4 #410q26.13 FGFR2 rs1219648 X X #3,4,5,610q26.13 FGFR2 rs2420946 X #3,4,5,611p15.5 LSP1 rs3817198 X X X #4 #414q24.1 RAD51L1 rs999737 X #1016q12.1 TNRC9 rs3803662 X X X X #8 #8 #4,7,816p12.1 PALB2 1592delT X17q22 COX11 rs7222197 X #122q12.1 CHEK2 1100delC X

15 22 12 7 3 12 6 3 6Legend: D = deCODEme, N = Navigenics, 23 = 23andme, PG = Pathway Genomics

Reference studies

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Why risk interpretation can vary by consumer genomic service

Companies are using different…

Average lifetime risks for the same underlying population

SNP/loci selection criteria

Quantitative risk assignment methodologies

Source: Swan, M. Multigenic Condition Risk Assessment in Direct-to-Consumer Genomic Services. Genet. Med. 2010, in press.

Image credit: http://www.tigerteamconsulting.com/TTC_Site/sectors_binf.jsp

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1. Differences in population average lifetime risk

Source: Swan, M. Multigenic Condition Risk Assessment in Direct-to-Consumer Genomic Services. Genet. Med. 2010, in press. http://melanieswan.com/documents/multigenic_analysis.xls

Population average lifetime risk in DTC genomic services

N D 2 N D 21 Abdominal aneurysm 3% 17% n/a 2% 5% n/a2 Age-related macular degeneration 3% 8% 7% 3% 8% 7%3 Alzheimer's disease 9% 6% n/a 17% 12% n/a4 Atrial fibrillation 26% 25% n/a 23% 25% n/a5 Brain aneurysm 1% 5% n/a 1% 5% n/a6 Breast cancer n/a n/a n/a 13% 12% 13%7 Celiac disease 0% 1% 0% 0% 1% 0%8 Colon cancer 6% 6% 6% 5% 6% 4%9 Crohn's disease 1% 1% 1% 1% 1% 0%

10 Diabetes, type 1 0% n/a 1% 0% n/a 1%11 Diabetes, type 2 25% 25% 24% 30% 28% 18%12 Glaucoma 1% 15% 1% 2% 15% 1%13 Graves' disease 1% n/a n/a 2% n/a n/a14 Heart attack 42% 42% 21% 25% 25% 7%15 Lung cancer 8% 17% 9% 6% 12% 6%16 Lupus 0% n/a 0% 0% n/a 0%17 Melanoma 4% n/a n/a 3% n/a n/a18 Multiple sclerosis 0% 0% 0% 1% 1% 1%19 Obesity 34% 40% 64% 32% 40% 59%20 Osteoarthritis 40% n/a n/a 47% n/a n/a21 Prostate cancer 17% 16% 18% n/a n/a n/a22 Psoriasis 4% 2% 11% 4% 2% 10%23 Restless legs syndrome 4% 7% 2% 4% 13% 4%24 Rheumatoid arthritis 2% 1% 2% 3% 1% 4%25 Ulcerative Colitis  n/a 1% 1% n/a 1% 1%26 Venous Thromboembolism 3% 10% 12% 4% 8% 10%

Sources: Legend: http://demo.decodeme.com/summary-report.pdf N Navigenicshttps://www.23andme.com/you/journal/heartattack/overview/ (etc.) D deCODEmehttp://www.navigenics.com/demo 2 23andmePopulation average lifetime risk not available for other DTC companies

Male Female

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2. Differences in SNP/loci selection criteria

Less than a quarter of all loci (22%) are being reviewed by the three biggest companies

Source: Swan, M. Multigenic Condition Risk Assessment in Direct-to-Consumer Genomic Services. Genet. Med. 2010, in press. http://melanieswan.com/documents/multigenic_analysis.xls

Loci overlap for three DTC Genomic Companies

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3. Differences in risk assignment methodology

Relative risk assignment per SNP Debate: include only strong-effect markers

Composite risk assignment per condition

Risk Allele Quantification by DTC Genomic Companies

Condition and SNP N GECeliac disease rs2187668 (HLA-DQA1) T A GG 0.3 CC 1 CC 0.48 GG 7Colorectal & prostate cancer rs6983267 (POU5F1P1) - colorectal G G GT 0.99 GT 1.04 GG 1.16 GT 1.3 rs6983267 (POU5F1P1) - prostate G G GT 0.99 GT 1.26 GG 1.26 GT 1.4Crohn’s disease rs17234657 (PTGER4) G G TT 0.96 TT 1 TT 0.95 GG 2.3Type 2 diabetes rs1111875 (HHEX) C G GG 1.14 CC 1.2 CT 0.98 AA 1.1 rs1801282 (PPARG) C C CG 0.9 CC 1.53 CC 1.02 CC 1.1 rs4402960 (IGF2BP2) T T GG 0.92 GT 1.16 GT 1.05 GG 1.2Glaucoma rs2165241 (LOXL1) T T CC 0.03 CC 1 TT 2.94 TT 2Multiple sclerosis rs6897932 (IL7R) C C CC 1.08 CT 1.46 CC 1.08 CC 1.2Legend: D=deCODEme, N=Navigenics, 2=23andme, GE=Gene Essence

Risk Allele Genotype Example and Assigned Risk ValueD N 2 GE

Source: Swan, M. Multigenic Condition Risk Assessment in Direct-to-Consumer Genomic Services. Genet. Med. 2010, in press. http://melanieswan.com/documents/multigenic_analysis.xls

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Genomics comparison scorecard

Consumer genomic service

# Cond-itions

Cost Report Data access

Visible research quality1

Updates

deCODEme 49 $2,000 + + +23andme 141 $429 Navigenics 28 $999 Pathway Genomics 71 $299 Gene Essence 84 $1,195

Coriell 7-15 public study

PGP (Personal Genome Project)

n/a public study

1Conditions, genes, variants, underlying research references, and methodology white paper(s) available on public website

Which service to buy?

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Consumer resource: AccessDNA.com

Information on genetic tests from 65 companies

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DIYgenomics.org genomics comparison

PersonalGenomics Android app and web app

1. 20 conditions 2. Locus/SNP detail 3. Reference detail 4. PubMed detail

Application developed by: Michael Kolb, Lawrence S. Wong, Melanie Swan

Source: http://www.diygenomics.org

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Agenda

Consumer genomic landscape DNA sequencing technology DIYgenomics citizen science

Image credit: http://current.com/1u8qe4c

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Early sequencing technology

Sanger sequencing (chain termination) Make millions of different-length copies Print on electrophoresis gel

Read lengths small to large Fluorescent indicators denote bases

Reassemble small segments with shotgun sequencing

Sources: http://www.phgfoundation.org/tutorials/dna/5.html, http://www.genomicseducation.ca/files/images/information_articles/sequencing.gif

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Contemporary (2nd-gen) sequencing technology

Illumina Solexa, ABI SOLiD, 454 Illumina example

Attach adaptors to short sequences Amplify by growing clusters Add nucleotides, primers Activate a laser to read bases as

incorporated Assemble clusters simultaneously

Improved read time Two gigabases/day at $0.001 per

1000 bases vs. Sanger sequencing (one year at $0.10 per 1000 bases)

Hiseq (Jan 2010): 25 gigabases/day

Source: http://www.wellcome.ac.uk/News/2009/Features/WTX056032.htm

Illumina sequencing

1

2

3

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3rd-generation sequencing

Sequencing by synthesis pyrosequencing example: Pacific Biosciences SMRT (30,000-fold improvement)

Sources: http://www.pacificbiosciences.com/video_lg.html, http://www.sciencemag.org/cgi/content/abstract/323/5910/133, Science 2 January 2009: Vol. 323. no. 5910, pp. 133 – 138, DOI: 10.1126/science.1162986

Phospholinked nucleotides

DNA polymerase wrapped around DNA chain Label fluoresces as cleaved

1

2

3

Zero-mode waveguide reads sequence

4

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4th-generation sequencing technology

Electronic sequencing Ion Torrent, NABsys, Oxford

Nanopore Technologies, Agilent, Sequenom, IBM

Electron microscope reads ZS Genetics, Halcyon Molecular

George Church’s list of next-gen sequencing technologies http://arep.med.harvard.edu/Polonator

Sources: http://www.nanoporetech.com/sequences, http://www.youtube.com/watch?v=wvclP3GySUY

Oxford Nanopore Technologies

Ion Torrent

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DNA sequencing and genetic variation

Genome 3 billion base pairs

Variation #1: SNP differences (single nucleotide polymorphism) Little variation (0.1%)

Variation #2: structural Significant variation (12%) Copy-number variation Insertions Deletions Inversions

Image credit: http://im.encyklopedie.seznam.cz/wiki_cz//image/27/119427-180px-dna-snp.svg.png

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Contemporary research in genomics

Copy number variation (CNV) Cancer Pharmacogenomics Aging Microbiome Individual, family, community

medical records

Image credit: http://www.uchsc.edu/vivat/2006/September2006/images/DNA_strand.jpg

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Moore’s Law in life sciences: Carlson curves

Killer apps of DNA:

Sequencing (reading)

Synthesizing (writing)

Source: http://www.synthesis.cc/carlson_DNA_cost_curves_Sept_09.jpg

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Agenda

Consumer genomic landscape DNA sequencing technology DIYgenomics citizen science

Image credit: http://current.com/1u8qe4c

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Example: what to do with your data

Check if you have the risk allele for the BDNF gene Determine related SNP/rsID#, rs6265 (neuroplasticity) Search genomic data for rs6265 genotype (e.g., CC) Determine the risk allele (which letter?) (e.g.; G1) Opportunity: genomic database with three minimal fields:

gene, rsid# and risk allele Current genomics search resources

PharmGKB, dbSNP, GWAS catalog, SNPedia

Source: http://www.wired.com/wiredscience/2009/10/genetically-bad-driving1Ribeiro, L. et. Al., The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in

Mexican-Americans. Cellular, Molecular and Developmental Neuroscience. May 8, 2007.

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Finding your BDNF data, variant rs6265

Consumer genomic services genotype 600,000-1m variants but only map a few up to the annotation browser

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Consumer genomics enables peer research

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15 citizen science genomic projects http://diygenomics.pbworks.com

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Project #1: MTHFR mutation & Vit B12 deficiency http://diygenomics.pbworks.com/MTHFR

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Project #2: Longevity and genomicsBU Centenarian study, Alzheimer’s disease

Source: Green RC, Roberts JS. The Impact and Utility of Personalized Genomic Information: Insights from the REVEAL Study. Page 30. Consumer Genetics Show. Hynes Convention Center, Boston, MA, June 9-11, 2009. http://cancercontrol.cancer.gov/od/phg/presentations/Green.pdf

No clinical treatment currently available ε4 positive participants reported health behavior changes

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DIYbio: self-genotyping

DNA Extraction

Sources: http://www.instructables.com/id/5_minute_DNA_Extraction_in_a_Shot_Glass, http://www.boston.com/news/science/articles/2009/05/11/do_it_yourself_genetic_sleuthing, DNA 2.0 Gene Designer, https://www.dna20.com/index.php?pageID=220, http://openwetware.org/wiki/User:Jonathan_Cline/Notebook/Melaminometer

DNA Design Melaminometer

Hemochromatosis self-testKatherine Aull

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Next-generation citizen science

Exome cohort, RNA sequencing of mutations Infer copy number variation from sequence/genotype Algorithm/artificial intelligence (NLP) projects

Generate phenotypic databases (e.g.; Framingham data) Generate core SNP list by condition using algorithms Spider Pubmed for all SNPs related to conditions

‘Environmentome’ projects Cancer maps and EPA data meets web 2.0 & mobiletech Personal screening apps (environmentome & microbiome)

MicrobiomePhenotype EnvironmentGenotype

Preventive medicine health data streams

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Societal impact of genomics

Image credit: "Primo Posthuman“, Natasha Vita-More, 1997.

Good & bad sides of newtech First trimester sex determination Counsyl: hearing loss condition

“Pathologizing” new classes of conditions Discovery/cure lag

Genetic privacy: ‘the real identity theft’ GINA

Adoption/non-adoption ethics of radical enhancement technologies

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Personal genome analysis startups / tools Crossbow (UMD/College Park, MD): a scalable software pipeline

for whole genome resequencing analysis DNA Guide (Sebastopol, CA): GIS technology used to create a

personal ‘Goolge Earth map’ of the genome DNAnexus (Palo Alto, CA): web technologies on a cloud computing

infrastructure to create a compute platform for the genome era Genomera (Sunnyvale, CA): Personal genomics community

(“genomes like me”) GenoViz (SourceForge.net): Tools for genomic data visualization SNP Dr. from DNA Electronics (London, UK): SNP Dr. hand-held

lab-on-a-chip device for point-of-care SNP sequencing in 15-30 minutes to evaluate patient drug response

HolGenTech (Sunnyvale, CA): Android application using genetic markers for nutrition choice, video.

SNPedia (Maryland & the Netherlands): Open-source database for genome sharing and genome interpretation via Promethease report

Portable Genomics (France): smartphone genome browser

Sources: http://openthoughtspace.pbworks.com/Personal-Genome-Analysis

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Resources

Consumer genomic resources http://diygenomics.org http://www.accessdna.com

Genomics 101 http://www.pgpstudy.org

Conferences, podcasts and video http://www.consumergeneticsshow.com http://www.phgfoundation.org/tutorials/dna

DIYbio meetup, email list, resources http://www.meetup.com/diybio http://diybio.org http://biocurious.org

Public genomic studies http://www.personalgenomes.org http://coriell.org

Image credit: http://www.rsc.org/images/DNA-scrunching-350_tcm18-68641.jpg

Thank you!

Melanie SwanResearch Fellow

MS Futures Group+1-650-681-9482

@LaBloggam@melanieswan.com

www.melanieswan.com

Slides: http://slideshare.net/LaBlogga/slideshows

Creative Commons 3.0 license

Image credit: http://www-nmr.cabm.rutgers.edu/photogallery/proteins/gif/dna.gif