Sequencing genomes & personal genomics. Some (not all) variation is hereditary.

Sequencing genomes

& personal

genomics

Some (not all) variation is hereditary

DNA

Watson& Crick

1953

Why is variation hereditary?

What is DNA?

A

G

C

T

type of molecule

every cell of every living thing

polymer

nbc, gwryieodr ltame h,hr s, nerof tahgnaiodr

ptnenfnnntdphe leesunF tet ccna

bed orda ahrieatrtospoooaataa

ccietsonuuel iaotnshveo t eyrn

tcr q ieuodore ivt stdneuio aL .e i,

Four score and seven years ago our

fathers brought forth, upon this continent, a new

nation, conceived in Liberty, and

dedicated to the proposition that all

men are created equal.

ACCCTCTTCAGAGCTGCACTAGACATTCACAGGGAATTGAGGTTCCCTATGCAGAAAGGTTTTCAGACAGAGGACCCAGCCCATTTTCTCTCTCCAAATCCTCCTCCCTCCCTCTTTTGTGGTTGCAGCTATAAAATAATGATTCAACAATCAAAGAGCCTCTCATGAGATGGGAGAAGGAAGGGAACGAAAGGGGAAGAGGTGCCCTGGGCTGAAAACCTGTAGATTTTTTCTAAGTGACAAAGGGCAAGGGTCCTTTTTTGAAATTAGGAGAGAGACAGCTGTTTCCTCAATCGAAACTTCGCACATTACAACCAGCCTTGGGAAAAGCCAACACCACCAGGGAGGAAGTGCTATGGGGTTTTGAAGCCAGACACTGATTTCTGGCTGTAATACTTTCCAGCCGTGTCTCTAAGCCTCGGCTTCTGCCTCCATCTGTAGAGTGGGCTTAATAATTTTGACCATCTCACAGAGTTGATGTGAAAATTAAAATAACCCGAACAGAACAGGCGATATATACAGGAATTAATGAAAGATTCCTGACATAATGCTTATAAGTTCATGATGCTTAGGAAGATAAAATTCATTGTAGAGATGCCGAACGGGGGTCTAGAGCTTGCCTTTTCGGGGTCTCTCCCGTCCTTCTCCATCCTCCTTATCTCCTGGGCTGCCCCCTCTCCCCCCGCGCCCCGCTCTCCCTGGCTCGCCCGGGCCTAGGGCGCCGCCTGCAGTTGCGCGCGGCCGCCTCTAGATGGAACTTTCTCACCAACGCAAGGCCCGGCCGGAGCAGCTACCCGGGAGCTGGGCGGCGAGGGGCTACTTTCTCTCATTCCGGCGGGTGCAGGATCGGGGGGCCTGGGCAGTAACTAGTGGGGAGGAGCGCTGGACTGTGCACGTCGAGCCCGGCAGGTTTCCGCATGCGGCATGCGAAGGGAATCCCGAGGTTTCCCTGCAGAACCCGAGCACGGCTCCCCCGGAGTTTCCTGCCCCGCGTCTGCGGCTCCTTGAATCATCTCAATAAAATGACCGTCCCGGTAGCCACCCATGCCCCTTCCTGCGCAGTGCCCGCAGCGGACCGCGCTGTGTGGTACCTCGAGCCCTGGGGACTCTGTTGCACGCGTCCCTCAGACCCTCGGGGGCGGGGAGTGGGGAGACAATCGCCAGAGCCGCGGGGCGGGACAAATGGCGGAACCGCCGCGCGGCGCCAGGCAAACTTTGCAAGGGAACCGCGCGGCTTGCCGGCTCTACTTTAAGCATTCCCGAAAAGAAAGCATGTGGCGGGACACTTGTCATCTACCATGTGTTATTCTCGGTGACGCTTTCTGGAGCTGTGTTCACCGGGGACCCGGGCTCGCGGGTGCTGCCCGCTGTGCTCGGGCGGGCGTCGCGCCTCCCCGCGCCGGTCCCGGGCTCGCCAGGCAGCCGGAGCCGCTGGGCTCCTCCACAACCATATTCCTTCTTCTACCGCTCCCGCTTCTTCCCACCCTCTCACTCTGTAGTTGGGTCCTCCCCTTTTTCTTGGGGGCGGGGAAGGGGGGATGATTTTTAAAAATCAGAACTATTGACATTTCTGGTCTCCTCGTCGCTTCAGGCTGAAGAGCGGAGGGGGATCCGCGGGCCGAGGGTCCCCCTCCCTGCCCGCGCCAGGGCCGCTGGGTGACACCGAAATCCAGAGGCTCCCGCCCCTCGGGGGTTCCTCCTCCCGCTTCCCGAGGTGACTGGTTGGCGCGAAGCGATTGGCGATCCCGGGCGCGATCCTGGCCGCGGCTCCCCGCGCCGCGCCGGGTGAATGGCCGCGGGCGGAGGATCGGGAGGGCCCGGGCGCAGACCAATCGCGGCCGCCGGTGGGAGTATTTGTTATTCACATGGAAGAGACTTGGCGCCTGCTAGGCCAGCTCAGCCCCCTCAGCCCAGAGATCAGCCACAAGTGCGGCCGCTGTGCTCGCCTCACGCGGCGGCGGCGGCGGCGGCGGCGGCGCTGACATGGAGCTGCGGGCCCCCGGCGGGCTTCCTCACCGCGCCCTCTGCGGGGAGCAGGGTAAGACTCGCCGCCCGGCAGCAGAAAGCGGCTCCGAGGAAAGCAAGTGCCGAACCACGGGACAAAAAGCCCCTGGCCCCCAAACTTCCCCAAAACGCCCTGCTTGTTGGAAAAGGAGAATCCCCCCGTTTTATTCCCCTTTCCGTTTTCTTCTCTAAAACCTTTCAGCGGACAGCCAGGTGCACCATTCCTTCTCATATCACTCTAGTGATTTGTTTTTCCTGAGCACAAGTAGATGGCCCTGCATGTCCGTAGTCTGTGAGAGAAATAGCGGGCGGAGGTGACGGGAATGGGGGGAGAAGGAGAGTGGGCACCAGGGGGCGAGGGGCTGGCCGGGCATTGGAGCTTGATTGGGTGTCTGTTGATTTTACGTTGCAAAGAACAAGGCAGCCACCCCTCTTGTCTGCCCATGATTACATTACAGTAAAGAGGTTCAGAAAAGAGGGAGACTTTACCCGGAACTCCCAAGGCTTGGAGATGTGATCCCCCAAAAGTTTAGTCGGCGAATGGGAGACTGAAGGGTGACGGGAAGGGGGCAGGCGCGCTCGGCGCTCTGACTGGGCGTGCGGCGGCAGGATTTTAAAGCGCTCTGCCTCGGATCGTCTGCCCTGGGTGACCTCCCGGACCTGCCCTGGTGGAATCCGGACTTG

What is a genome?

DNA blueprintfor an

organism

ACCCTCTTCAGAGCTGCACTAGACATTCACAGGGAATTGAGGTTCCCTATGCAGAAAGGTTTTCAGACAGAGGACCCAGCCCATTTTCTCTCTCCAAATCCTCCTCCCTCCCTCTTTTGTGGTTGCAGCTATAAAATAATGATTCAACAATCAAAGAGCCTCTCATGAGATGGGAGAAGGAAGGGAACGAAAGGGGAAGAGGTGCCCTGGGCTGAAAACCTGTAGATTTTTTCTAAGTGACAAAGGGCAAGGGTCCTTTTTTGAAATTAGGAGAGAGACAGCTGTTTCCTCAATCGAAACTTCGCACATTACAACCAGCCTTGGGAAAAGCCAACACCACCAGGGAGGAAGTGCTATGGGGTTTTGAAGCCAGACACTGATTTCTGGCTGTAATACTTTCCAGCCGTGTCTCTAAGCCTCGGCTTCTGCCTCCATCTGTAGAGTGGGCTTAATAATTTTGACCATCTCACAGAGTTGATGTGAAAATTAAAATAACCCGAACAGAACAGGCGATATATACAGGAATTAATGAAAGATTCCTGACATAATGCTTATAAGTTCATGATGCTTAGGAAGATAAAATTCATTGTAGAGATGCCGAACGGGGGTCTAGAGCTTGCCTTTTCGGGGTCTCTCCCGTCCTTCTCCATCCTCCTTATCTCCTGGGCTGCCCCCTCTCCCCCCGCGCCCCGCTCTCCCTGGCTCGCCCGGGCCTAGGGCGCCGCCTGCAGTTGCGCGCGGCCGCCTCTAGATGGAACTTTCTCACCAACGCAAGGCCCGGCCGGAGCAGCTACCCGGGAGCTGGGCGGCGAGGGGCTACTTTCTCTCATTCCGGCGGGTGCAGGATCGGGGGGCCTGGGCAGTAACTAGTGGGGAGGAGCGCTGGACTGTGCACGTCGAGCCCGGCAGGTTTCCGCATGCGGCATGCGAAGGGAATCCCGAGGTTTCCCTGCAGAACCCGAGCACGGCTCCCCCGGAGTTTCCTGCCCCGCGTCTGCGGCTCCTTGAATCATCTCAATAAAATGACCGTCCCGGTAGCCACCCATGCCCCTTCCTGCGCAGTGCCCGCAGCGGACCGCGCTGTGTGGTACCTCGAGCCCTGGGGACTCTGTTGCACGCGTCCCTCAGACCCTCGGGGGCGGGGAGTGGGGAGACAATCGCCAGAGCCGCGGGGCGGGACAAATGGCGGAACCGCCGCGCGGCGCCAGGCAAACTTTGCAAGGGAACCGCGCGGCTTGCCGGCTCTACTTTAAGCATTCCCGAAAAGAAAGCATGTGGCGGGACACTTGTCATCTACCATGTGTTATTCTCGGTGACGCTTTCTGGAGCTGTGTTCACCGGGGACCCGGGCTCGCGGGTGCTGCCCGCTGTGCTCGGGCGGGCGTCGCGCCTCCCCGCGCCGGTCCCGGGCTCGCCAGGCAGCCGGAGCCGCTGGGCTCCTCCACAACCATATTCCTTCTTCTACCGCTCCCGCTTCTTCCCACCCTCTCACTCTGTAGTTGGGTCCTCCCCTTTTTCTTGGGGGCGGGGAAGGGGGGATGATTTTTAAAAATCAGAACTATTGACATTTCTGGTCTCCTCGTCGCTTCAGGCTGAAGAGCGGAGGGGGATCCGCGGGCCGAGGGTCCCCCTCCCTGCCCGCGCCAGGGCCGCTGGGTGACACCGAAATCCAGAGGCTCCCGCCCCTCGGGGGTTCCTCCTCCCGCTTCCCGAGGTGACTGGTTGGCGCGAAGCGATTGGCGATCCCGGGCGCGATCCTGGCCGCGGCTCCCCGCGCCGCGCCGGGTGAATGGCCGCGGGCGGAGGATCGGGAGGGCCCGGGCGCAGACCAATCGCGGCCGCCGGTGGGAGTATTTGTTATTCACATGGAAGAGACTTGGCGCCTGCTAGGCCAGCTCAGCCCCCTCAGCCCAGAGATCAGCCACAAGTGCGGCCGCTGTGCTCGCCTCACGCGGCGGCGGCGGCGGCGGCGGCGGCGCTGACATGGAGCTGCGGGCCCCCGGCGGGCTTCCTCACCGCGCCCTCTGCGGGGAGCAGGGTAAGACTCGCCGCCCGGCAGCAGAAAGCGGCTCCGAGGAAAGCAAGTGCCGAACCACGGGACAAAAAGCCCCTGGCCCCCAAACTTCCCCAAAACGCCCTGCTTGTTGGAAAAGGAGAATCCCCCCGTTTTATTCCCCTTTCCGTTTTCTTCTCTAAAACCTTTCAGCGGACAGCCAGGTGCACCATTCCTTCTCATATCACTCTAGTGATTTGTTTTTCCTGAGCACAAGTAGATGGCCCTGCATGTCCGTAGTCTGTGAGAGAAATAGCGGGCGGAGGTGACGGGAATGGGGGGAGAAGGAGAGTGGGCAC

How big is a genome?

Poliovirus 7 thousandHIV virus 10 thousand

E. coli 5 millionM. tuberculosis 4 million

Rice 400 millionMosquito 300 million

Chicken 1 billionMouse 3 billionHuman 3 billion

Opposum 4 billionToad 7 billion

How do we sequence genomes?

(1) Break the DNA in to manageable chunks

(2) Convert A, G, C & T 4 colorsand sequence one chunks at a time

3’-…GACTAGATACGAGCGTGA…-5’ [template]5’-…CTGAT [primer]

…CTGATC…CTGATCT…CTGATCTA…CTGATCTAT…CTGATCTATG…CTGATCTATGC…CTGATCTATGCT…CTGATCTATGCTC…CTGATCTATGCTCG

polymerasedNTPslabeled ddNTPs

3’-…GACTAGATACGAGCGTGA…-5’ [template]5’-…CTGAT [primer]

…CTGATC…CTGATCT…CTGATCTA…CTGATCTAT…CTGATCTATG…CTGATCTATGC…CTGATCTATGCT…CTGATCTATGCTC…CTGATCTATGCTCG

polymerasedNTPslabeled ddNTPs

(3) Assemble the chunks into a genome sequence

DNA sequencing technology

1996 1998 2001

100's 1,000's 1,000,000's

nucleotides sequenced per day

Year

H. influenzae(bacteria)

1995

S. cerevisiae (yeast)

19961998

C. elegans(worm)

D. melanogaster(fruit fly)

2000

M. musculus(mouse)

2001

H. sapiens(human)

2002

P. troglodytes (chimp)

2005

questions?

The Human

Genome

June 26,2000

What is the Human Genome?

3 billion A’s, G’s, C’s & T’s

23 chromosomes

2 copies each

20,000 genes

Whose genome is “the” human genome?

We are almost (but not exactly) the same

99.9%!

99.0%!

ACCCTCTTCAGAGCTGCACTAGACATTCACAGGGAATTGAGGTTCCCTATGCAGAAAGGTTTTCAGACAGAGGACCCAGCCCATTTTCTCTCTCCAAATCCTCCTCCCTCCCTCTTTTGTGGTTGCAGCTATAAAATAATGATTCAACAATCAAAGAGCCTCTCATGAGATGGGAGAAGGAAGGGAACGAAAGGGGAAGAGGTGCCCTGGGCTGAAAACCTGTAGATTTTTTCTAAGTGACAAAGGGCAAGGGTCCTTTTTTGAAATTAGGAGAGAGACAGCTGTTTCCTCAATCGAAACTTCGCACATTACAACCAGCCTTGGGAAAAGCCAACACCACCAGGGAGGAAGTGCTATGGGGTTTTGAAGCCAGACACTGATTTCTGGCTGTAATACTTTCCAGCCGTGTCTCTAAGCCTCGGCTTCTGCCTCCATCTGTAGAGTGGGCTTAATAATTTTGACCATCTCACAGAGTTGATGTGAAAATTAAAATAACCCGAACAGAACAGGCGATATATACAGGAATTAATGAAAGATTCCTGACATAATGCTTATAAGTTCATGATGCTTAGGAAGATAAAATTCATTGTAGAGATGCCGAACGGGGGTCTAGAGCTTGCCTTTTCGGGGTCTCTCCCGTCCTTCTCCATCCTCCTTATCTCCTGGGCTGCCCCCTCTCCCCCCGCGCCCCGCTCTCCCTGGCTCGCCCGGGCCTAGGGCGCCGCCTGCAGTTGCGCGCGGCCGCCTCTAGATGGAACTTTCTCACCAACGCAAGGCCCGGCCGGAGCAGCTACCCGGGAGCTGGGCGGCGAGGGGCTACTTTCTCTCATTCCGGCGGGTGCAGGATCGGGGGGCCTGGGCAGTAACTAGTGGGGAGGAGCGCTGGACTGTGCACGTCGAGCCCGGCAGGTTTCCGCATGCGGCATGCGAAGGGAATCCCGAGGTTTCCCTGCAGAACCCGAGCACGGCTCCCCCGGAGTTTCCTGCCCCGCGTCTGCGGCTCCTTGAATCATCTCAATAAAATGACCGTCCCGGTAGCCACCCATGCCCCTTCCTGCGCAGTGCCCGCAGCGGACCGCGCTGTGTGGTACCTCGAGCCCTGGGGACTCTGTTGCACGCGTCCCTCAGACCCTCGGGGGCGGGGAGTGGGGAGACAATCGCCAGAGCCGCGGGGCGGGACAAATGGCGGAACCGCCGCGCGGCGCCAGGCAAACTTTGCAAGGGAACCGCGCGGCTTGCCGGCTCTACTTTAAGCATTCCCGAAAAGAAAGCATGTGGCGGGACACTTGTCATCTACCATGTGTTATTCTCGGTGACGCTTTCTGGAGCTGTGTTCACCGGGGACCCGGGCTCGCGGGTGCTGCCCGCTGTGCTCGGGCGGGCGTCGCGCCTCCCCGCGCCGGTCCCGGGCTCGCCAGGCAGCCGGAGCCGCTGGGCTCCTCCACAACCATATTCCTTCTTCTACCGCTCCCGCTTCTTCCCACCCTCTCACTCTGTAGTTGGGTCCTCCCCTTTTTCTTGGGGGCGGGGAAGGGGGGATGATTTTTAAAAATCAGAACTATTGACATTTCTGGTCTCCTCGTCGCTTCAGGCTGAAGAGCGGAGGGGGATCCGCGGGCCGAGGGTCCCCCTCCCTGCCCGCGCCAGGGCCGCTGGGTGACACCGAAATCCAGAGGCTCCCGCCCCTCGGGGGTTCCTCCTCCCGCTTCCCGAGGTGACTGGTTGGCGCGAAGCGATTGGCGATCCCGGGCGCGATCCTGGCCGCGGCTCCCCGCGCCGCGCCGGGTGAATGGCCGCGGGCGGAGGATCGGGAGGCGCCGGGCGCAGACCAATCGCGGCCGCCGGTGGGAGTATTTGTTATTCACATGGAAGAGACTTGGCGCCTGCTAGGCCAGCTCAGCCCCCTCAGCCCAGAGATCAGCCACAAGTGCGGCCGCTGTGCTCGCCTCACGCGGCGGCGGCGGCGGCGGCGGCGGCGCTGACATGGAGCTGCGGGCCCCCGGCGGGCTTCCTCACCGCGCCCTCTGCGGGGAGCAGGGTAAGACTCGCCGCCCGGCAGCAGAAAGCGGCTCCGAGGAAAGCAAGTGCCGAACCACGGGACAAAAAGCCCCTGGCCCCCAAACTTCCCCAAAACGCCCTGCTTGTTGGAAAAGGAGAATCCCCCCGTTTTATTCCCCTTTCCGTTTTCTTCTCTAAAACCTTTCAGCGGACAGCCAGGTGCACCATTCCTTCTCATATCACTCTAGTGATTTGTTTTTCCTGAGCACAAGTAGATGGCCCTGCATGTCCGTAGTCTGTGAGAGAAATAGCGGGCGGAGGTGACGGGAATGGGGGGAGAAGGAGAGTGGGCACCAGGGGGCGAGGGGCTGGCCGGGCATTGGAGCTTGATTGGGTGTCTGTTGATTTTACGTTGCAAAGAACAAGGCAGCCACCCCTCTTGTCTGCCCATGATTACATTACAGTAAAGAGGTTCAGAAAAGAGGGAGACTTTACCCGGAACTCCCAAGGCTTGGAGATGTGATCCCCCAAAAGTTTAGTCGGCGAATGGGAGACTGAAGGGTGACGGGAAGGGGGCAGGCGCGCTCGGCGCTCTGACTGGGCGTGCGGCGGCAGGATTTTAAAGCGCTCTGCCTCGGATCGTCTGCCCTGGGTGACCTCCCGGACCTGCCCTGGTGGAATCCGGACTTG

ACCCTCTTCAGAGCTGCACTAGACATTCACAGGGAATTGAGGTTCCCTATGCAGAAAGGTTTTCAGACAGAGGACCCAGCCCATTTTCTCTCTCCAAATCCTCCTCCCTCCCTCTTTTGTGGTTGCAGCTATAAAATAATGATTCAACAATCAAAGAGCCTCTCATGAGATGGGAGAAGGAAGGGAACGAAAGGGGAAGAGGTGCCCTGGGCTGAAAACCTGTAGATTTTTTCTAAGTGACAAAGGGCAAGGGTCCTTTTTTGAAATTAGGAGAGAGACAGCTGTTTCCTCAATCGAAACTTCGCACATTACAACCAGCCTTGGGAAAAGCCAACACCACCAGGGAGGAAGTGCTATGGGGTTTTGAAGCCAGACACTGATTTCTGGCTGTAATACTTTCCAGCCGTGTCTCTAAGCCTCGGCTTCTGCCTCCATCTGTAGAGTGGGCTTAATAATTTTGACCATCTCACAGAGTTGATGTGAAAATTAAAATAACCCGAACAGAACAGGCGATATATACAGGAATTAATGAAAGATTCCTGACATAATGCTTATAAGTTCATGATGCTTAGGAAGATAAAATTCATTGTAGAGATGCCGAACGGGGGTCTAGAGCTTGCCTTTTCGGGGTCTCTCCCGTCCTTCTCCATCCTCCTTATCTCCTGGGCTGCCCCCTCTCCCCCCGCGCCCCGCTCTCCCTGGCTCGCCCGGGCCTAGGGCGCCGCCTGCAGTTGCGCGCGGCCGCCTCTAGATGGAACTTTCTCACCAACGCAAGGCCCGGCCGGAGCAGCTACCCGGGAGCTGGGCGGCGAGGGGCTACTTTCTCTCATTCCGGCGGGTGCAGGATCGGGGGGCCTGGGCAGTAACTAGTGGGGAGGAGCGCTGGACTGTGCACGTCGAGCCCGGCAGGTTTCCGCATGCGGCATGCGAAGGGAATCCCGAGGTTTCCCCGCAGAACCCGAGCACGGCTCCCCCGGAGTTTCCTGCCCCGCGTCTGCGGCTCCTTGAATCATCTCAATAAAATGACCGTCCCGGTAGCCACCCATGCCCCTTCCTGCGCAGTGCCCGCAGCGGACCGCGCTGTGTGGTACCTCGAGCCCTGGGGACTCTGTTGCACGCGTCCCTCAGACCCTCGGGGGCGGGGAGTGGGGAGACAATCGCCAGAGCCGCGGGGCGGGACAAATGGCGGAACCGCCGCGCGGCGCCAGGCAAACTTTGCAAGGGAACCGCGCGGCTTGCCGGCTCTACTTTAAGCATTCCCGAAAAGAAAGCATGTGGCGGGACACTTGTCATCTACCATGTGTTATTCTCGGTGACGCTTTCTGGAGCTGTGTTCACCGGGGACCCGGGCTCGCGGGTGCTGCCCGCTGTGCTCGGGCGGGCGTCGCGCCTCCCCGCGCCGGTCCCGGGCTCGCCAGGCAGCCGGAGCCGCTGGGCTCCTCCACAACCATATTCCTTCTTCTACCGCTCCCGCTTCTTCCCACCCTCTCACTCTGTAGTTGGGTCCTCCCCTTTTTCTTGGGGGCGGGGAAGGGGGGATGATTTTTAAAAATCAGAACTATTGACATTTCTGGTCTCCTCGTCGCTTCAGGCTGAAGAGCGGAGGGGGATCCGCGGGCCGAGGGTCCCCCTCCCTGCCCGCGCCAGGGCCGCTGGGTGACACCGAAATCCAGAGGCTCCCGCCCCTCGGGGGTTCCTCCTCCCGCTTCCCGAGGTGACTGGTTGGCGCGAAGCGATTGGCGATCCCGGGCGCGATCCTGGCCGCGGCTCCCCGCGCCGCGCCGGGTGAATGGCCGCGGGCGGAGGATCGGGAGACGCCGGGCGCAGACCAATCGCGGCCGCCGGTGGGAGTATTTGTTATTCACATGGAAGAGACTTGGCGCCTGCTAGGCCAGCTCAGCCCCCTCAGCCCAGAGATCAGCCACAAGTGCGGCCGCTGTGCTCGCCTCACGCGGCGGCGGCGGCGGCGGCGGCGGCGCTGACATGGAGCTGCGGGCCCCCGGCGGGCTTCCTCACCGCGCCCTCTGCGGGGAGCAGGGTAAGACTCGCCGCCCGGCAGCAGAAAGCGGCTCCGAGGAAAGCAAGTGCCGAACCACGGGACAAAAAGCCCCTGGCCCCCAAACTTCCCCAAAACGCCCTGCTTGTTGGAAAAGGAGAATCCCCCCGTTTTATTCCCCTTTCCGTTTTCTTCTCTAAAACCTTTCAGCGGACAGCCAGGTGCACCATTCCTTCTCATATCACTCTAGTGATTTGTTTTTCCTGAGCACAAGTAGATGGCCCTGCATGTCCGTAGTCTGTGAGAGAAATAGCGGGCGGAGGTGACGGGAATGGGGGGAGAAGGAGAGTGGGCACCAGGGGGCGAGGGGCTGGCCGGGCATTGGAGCTTGATTGGGTGTCTGTTGATTTTACGTTGCAAAGAACAAGGCAGCCACCCCTCTTGTCTGCCCATGATTACATTACAGTAAAGAGGTTCAGAAAAGAGGGAGACTTTACCCGGAACTCCCAAGGCTTGGAGATGTGATCCCCCAAAAGTTTAGTCGGCGAATGGGAGACTGAAGGGTGACGGGAAGGGGGCAGGCGCGCTCGGCGCTCTGACTGGGCGTGCGGCGGCAGGATTTTAAAGCGCTCTGCCTCGGATCGTCTGCCCTGGGTGACCTCCCGGACCTGCCCTGGTGGAATCCGGACTTG

DNA variation Environment

“Personal” genomes

James D. Watson (5/31/2007)

J. Craig Venter (8/4/2007) New York Times,

3/4/08

questions?

DNA sequencing technology

1996 1998 2001 2007

100's 1,000's 1,000,000's 1,000,000,000's

nucleotides sequenced per day

Year

“Next Generation” Sequencing

Personalized Medicine

Genetic variation medical management

Personal Genomes for Health Care

U.S. Health Care = $5,000 / person / year

$1,000 genome / 73 years = $13 / year

Can “personal genomes”:

(1) reduce health care costs?

(2) improve health care outcomes?

Three case studies

Genetic variant disease

Case Study 1: Phenylketonuria (PKU) gene

“recessive”: 2 defective copies of gene disease

1 in 15,000 babies

Untreated MR, seizures

Treated normal development

Case Study 2: the BRCA1 gene

Early onset breast cancer

“dominant”: 1 copy affected

Increases risk to 75%

Treatment ? yearly mammograms ? ? radical mastectomy ?

MC King1990

Case Study 3: the APO-E gene

I don’t want to know!

0 copy low risk1 copies normal risk2 copies high risk

“E4” variant associated with Alzheimer’s disease

No goodtreatments!

PKU, BRCA1, APO-E, …

ABCG8, ABI2, ADAMTS9, ADARB1, AIM1, ANGPTL3, ANGPTL3, DOCK7, ATG4C, ASIP, ATG16L1, B3GALT4, BANK1, BCL11A, BCL7B, TBL2, MLXIPL, BFZB, BMP6, BRDG1, BRUNOL4, BSN, MST1, BTBD9, C12orf30, C8orf13, BLK, CACNA1C, CCDC60, CCL4L2, CCR6, CD226,

CDC123,CAMK1D, CDC91L1, CDH4, CDK6, CDKAL1, CDKN2A, CDKN2B, CDKN2A,CDKN2B, CDKN2B, CELSR2, CELSR2,PSRC1,

CELSR2,PSRC1,SORT1, CERKL, CFH, CHI3L1, CHRNA3, CHRNA3,CHRNA5, CHRNB4, CHRNA3,CHRNA5,CHRNB4, CILP2,

PBX4, CNTN5, COG6, COL1A2, COLIA1, CRP, CSF2RA, CST9L, CST9, CST3, CTBP2, CTDSPL, CTNNA3, CYP2C8, DBC1, DCAMKL1, DGKH,

DLG2, DNAH5, DPP6, DPT, DQ515897, DRB1, ECHDC1,RNF146, EHBP1, EIF3H, ELMO1, ERBB3, ESR1, EXOC2, EYA1, FAM55B, FCER1A,OR10J3, FGFR2, FLJ22536, FLJ44180, FLJ32831, FTO, G6PC2, G6PC2,ABCB11, GAB2, GALNT2, GCKR, GDAP1, GDF5, GGT1, GLUT9, GNA12, GPR126, GPR98, HACE1, HAPLN1, HBB, HCP5, HERC2, HHEX, HHIP, HISTH1D, HLA-C, HMGA2, HNF1A,

HOMER1, HTRA1, IGF2BP2, IGFBP2, IL12A, SCHIP1, IL12B, IL18, IL1RAP, IL1RL1,IL18R1,IL18RAP, SLC9A4, IL21, IL23R, IL2RA, IL6R, IL7RA, IMPA2, IRF4, IRGM, ITGAM, ITGAM, ITGAX, ITPR2, JAZF1, KIA1109,TENR,IL2,, KIAA0350, KIAA1542, KIAA1598, KITLG, KLK3,

LCORL, LEPR, LMTK2, LOXL1, LPA, LPP, LRP5, LRRC18, LSP1, MAP2K5, LBXCOR1, MAP3K1, MATP, MC4R, MCF2L, AB116074,

AK092739, AB0023600, F7, CR603372, F10, PROZ, MEF2C, MEIS1, MHC, C6orf10, MLXIPL, MSMB, MST1, MTHFD1L, MVK,MMAB,

MYR1P, NCAN,CILP2, NEGR1, NEIL3, NKX2-3, NOLA1, NOS1AP, NRG1, NRG3, NUBPL, NUDT10, NUDT11, LOC340602, GSPT2,

MAGED1, NUMB, OBFC1, OPG, OR10J1, ORF DQ515897, PALB2,NDUFAB1,DCTN5, PARD3B, PDE3D, PDE4D, PDGFRA,

PITX2,ENPEP, PKHD1, POLG, PREX1, , PTGS2, PLA2G4A, PTPN1, PTPN2, PVT1, PXK, RAB5B, SUOX, IKZF4, ERBB3, CDK2, RANKL,

RAPGEF5, RGS1, RNF212, RPL21, RPL5, RYR2, RYR2,CHRM3,ZP4, SEC5L1,IRF4, SEMA5A, SH2B3,LNK,TRAFD1,, SLC22A3, SLC24A4,

SLC24A5, SLC2A9, SLC45A2, SLCO3A1, SLIT2, SMAD7, SNRPN, SPACA1, SPATA2, STAT3, SUSD1, TAGAP, TCF2, THADA, TMEFF2, TNCR9,LOC6,43714, TNFAIP3, OLIG3, TNFRSF11B, TNRC9, TPCN2,

TRAF1-C5, TRIB1, TRIP11,ATXN3, TSPAN8,LGR5, TYR, TYRP1, ZBTB38, ZBTB40, ZFP64, ZMAT4, ZNF536,

Osteonecrosis of the jaw, Crohn's disease, Juvenile idiopathic arthritis, Fasting plasma glucose, Warfarin maintenance dose, Fasting plasma blood glucose, Smoking cessation, Response to iloperidone treatment (PANSS-T score), Response to iloperidone treatment (QT prolongation), Melanoma, Blond vs. brown hair, Blue vs. green eyes, Burning and freckling, Freckles, Red vs. non-red hair, Skin sensitivity to sun, Black vs. blond hair color, Black vs. red hair color, Neuroblastoma, Protein quantitative trait loci, Knee osteoarthritis, Waist circumference and related phenotypes, Body mass index, Alzheimer's disease, Bone mineral density, Bone mineral density (hip), Bone mineral density (spine), C-reactive protein, YKL-40 levels, Height, Psoriasis, Lung cancer, Nicotine dependence, lung cancer and peripheral arterial disease, Colorectal cancer, Type 2 diabetes, Environmental confusion in the home, Breast cancer, Schizophrenia, Serum urate, Obesity, Bipolar disorder 1, Celiac disease, Methamphetamine dependence, Prostate cancer, Prostate cancer (aggressive), LDL cholesterol, Fetal hemoglobin levels, Recombination rate (females), Recombination rate (males), Iris color, General cognitive ability, Systemic lupus erythematosus in women, Systemic lupus erythematosus, Type 1 diabetes, Response to interferon beta therapy, HDL cholesterol, Triglycerides, Early onset extreme obesity, Amyotrophic lateral sclerosis, Coronary spasm in women, Rheumatoid arthritis, Skin pigmentation by reflectance spectroscopy, Lupus, Select biomarker traits, BMI, Waist circumference traits, Sleep duration, Sleepiness, Cystatin C, Thyroid stimulating hormone, Urinary albumin excretion, Blood lipid traits, Hip geometry, Atrial fibrillation, Heart failure, Major CVD, Blood pressure, Tonometry, Aging traits, Morbidity-free survival traits (free of CVD, cancer & dementia), Diabetes related insulin traits, Incident diabetes, Electrocardiographic traits, Heart rate variability traits, Coronary artery calcification, Other subclinical atherosclerosis traits, Cognitive test performance, Volumetric brain MRI, Echocardiographic traits, Endothelial function traits, Exercise treadmill test traits, Mean forced vital capacity from 2 exams, Other pulmonary function traits, Factor VII, Hemostatic factors and hematological phenotypes, Type 2 diabetes and 6 quantitative traits, F-cell distribution, Exfoliation glaucoma, Irritable bowel syndrome, Diabetic nephropathy, Neuroticism, Multiple sclerosis, Childhood asthma, ORMDL3 expression, Obesity-related traits:, (body mass index, hip circumference, body weight), HIV1 viral setpoint, Restless legs syndrome, Coronary disease, Gallstones, Atrial fibrillation/atrial flutter, APOE*e4 carriers with late onset Alzheimer's disease, Bipolar disorder, Hypertension, Response to ximelagatran treatment, Stroke, Myocardial infarction, Episodic memory, Nicotine dependence, Late onset Alzheimer's disease, End-stage renal disease, Progressive supranuclear palsy, Addiction, Inflammatory bowel disease, Memory performance, Wet age-related macular degeneration, Parkinson's disease, QT interval prolongation, Age-related macular degeneration,

“Direct-to-consumer” personal genomics

Thanks for

listening...

Questions?

Thanks to:

• David Spencer

• Bob Waterston

• Debbie Nickerson

• Josh Akey

• My lab

Genome Wide Association Studies

Thousands of cases & thousands of controls

Hundreds of thousands of single nucleotide polymorphisms

Compare allele frequencies in cases & controls

Hereditary

…variation, but imper..

...fect. Strongest survive.

DNA sequencing technology

19771977 2001

Why do we resemble our parents?

Pythagoros

Aristotle

van Leeuwenhoek

preformationism?

Moore’s Law

evolution?

Charles Darwin

The Origin of Species (1859)

Why do we resemble our parents?

Variation is hereditary

… but mutations happen

Survival of the fittest

Browsing the Human Genome

http://genome.ucsc.edu/

• Questions to think through at the end

• Pause points in the middle for each section for people to ask questions