Haplotype Trees Using The Evolutionary History of Small DNA Regions To Investigate Common Diseases

Haplotype Trees

Using The Evolutionary History of Small DNA Regions To

Investigate Common Diseases

Replication

Coalesence

Unrooted Haplotype Tree

Intra-Allelic Sequence Variation (ApoE)

Chimp CCACATGGGCGGTTCCCCCA? GT

10 . . . . . . . . . . . . . . . . T . T . T. 1 0 1 2 416 . . . . T. . . . . . . . . . . T . T . T. 1 0 0 1 2ε2 22 . . . . TC. . . T . . . . . . T . T . T . 0 0 0 1 19 . . . . . C. . . . . . . . . . T . T . T . 0 0 1 4 524 . . . . . C. . . . . . . . . . T . T T T . 0 0 0 1 1

26 . . . . TCTC. . . . . . . . T . . . . . 0 0 0 1 121 . . . . . CTC. T . . . . . . T . . . . . 0 0 0 1 14 . . . . T . TC. . . . . . . . T . . . . . 1 5 2 8 1629 . . . . . . TC. . . . . . . GT . . . . . 0 1 0 0 11 . . . . . . TC. . . . . . . . T . . . . . 8 19 11 7 4530 . . . . . . TC. . . . G. . . T . . . . . 0 0 1 0 114 . . . . . . TCA. . . . . . . T . . . . C 0 0 2 0 219 . . . . . . . C. . . . . . . . T . . . . . 1 0 0 0 1

ε3 6 . . . . . . . . . . . . . . . . T . . . . . 3 5 0 0 827 . T . . T . . . . . . . . . G. T . . . . . 1 0 0 0 18 . . . . T . . . . . . . . . . . T . . . . . 2 3 0 0 53 . . . . T . . . . . . A. . . . T . . . . . 8 3 3 1 1511 . . . . . C. . . . . A. . . . T . . . . . 0 0 0 2 22 . . . . . . . . . . . A. . . . T . . . . . 15 6 11 11 4328 . . . T . . . . . . . A. . . . T . . . . . 1 0 0 0 17 . . . . . . . . . . . A. . . . T . . . . C 1 1 4 2 825 . . . . . . . . . . AA. . . . T . . . . C 0 0 1 0 1

17 T . . . . . . . . . . . . . . . . T . . . . 2 0 0 0 212 . . . . . . . . . . . . . . . . . . . . . . 1 0 0 1 213 . . . . T . . . . . . . . . . . . . . C . . 0 0 1 1 220 . . G. T . T . . . . . . . . . . . . . . . 1 0 0 0 1ε423 . . G. . . T . . . . . . . . . . . . . . . 1 0 0 0 115 . . . . . CT . . . A. . . . . . . . . . . 0 0 0 2 218 . . . . . . T . . . A. . . . . . . . C . C 0 0 1 0 15 . . . . . . T . . . A. . . . . . . . . . . 0 5 9 1 15

J C N R T

13 (6.8%)

152 (79.2%)

27 (14%)

31 . . . . . . T . . . A. . C. . . . . . . . 0 0 0 1 1

21

Statistical Vs. Maximum Parsimony

A = AGCTB = TGCTC = TACTD = AAGG

A B

CD

MaximumParsimony

1A↔1T

1A↔1T

2G

2A

2G

2A

3G↔3C 4G↔4T

A B

CD

1A↔1T

1A↔1T

2G

2A

2G

2A

3G↔3C 4G↔4T

StatisticalParsimony

The Apo-protein E Haplotype

Tree

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

ε3

ε2

ε4

What Use Are Haplotype Trees?

• Provides an Interpretive Framework When Integrated With Other Analyses

• Evolutionary History Generates Hypotheses About Current Significance

• Provides a Powerful Tool For Detecting Current Genotype-Phenotype Associations

A Haplotype Tree Can Provide an Interpretive Framework When Integrated With Other Analyses

0.0

2.0

4.0

6.0

g056

0 g0

624

g393

7 g4

951

g244

0 g5

361

g244

0 g4

075

g199

8 g3

937

g116

3 g5

361

g083

2 g4

075

g244

0 g4

951

g393

7 g4

075

g199

8 g4

075

g056

0 g3

106

g056

0 g5

361

g116

3 g4

075

g407

5 g5

361

g083

2 g4

951

g116

3 g2

440

g290

7 g3

937

g199

8 g2

907

g244

0 g2

907

g083

2 g3

937

g062

4 g1

163

g062

4 g1

998

g083

2 g5

361

g152

2 g2

440

g062

4 g3

937

g083

2 g2

907

g062

4 g0

832

g116

3 g1

998

g116

3 g3

937

g056

0 g4

075

g083

2 g1

522

g083

2 g3

106

g116

3 g1

522

g062

4 g4

075

g244

0 g3

106

g310

6 g5

361

g116

3 g3

106

g199

8 g4

951

g083

2 g1

998

g056

0 g1

998

g199

8 g2

440

g083

2 g2

440

g393

7 g5

361

g199

8 g5

361

g116

3 g4

951

g244

0 g3

937

g056

0 g3

937

g062

4 g5

361

g062

4 g2

440

g083

2 g1

163

g056

0 g2

440

g056

0 g0

832

g056

0 g1

163

560- 1163**

560-832**

560-2440**

832-1163**

3937-4075

8.0

Hamon and Sing estimated interactions for all 53 pairs of ApoE sites for lnApoE variability

in North Karelia, Females

R2

X 1

00

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

Sites IdentifiedBy Hamon and

Sing That“Interact”

With Site 560

ParallelMutations

At Site560

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

EvolutionaryHypothesis:

Two FunctionalMutations (Occurring

On A SpecificHaplotype

Background)Have Created

Three Allelic CladesFor the PhenotypeOf ln(ApoE); the

Red, Blue and BlackClades

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

The Red Clade IsUniquely Defined

By These Two Sites

The Blue Clade Is Uniquely Defined By

These Two Sites

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

The Red Clade IsNot Uniquely DefinedBy These Two SitesDue to Homoplasy


Tree

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

Sites 560 and 624Fall into an Alu Repeat

Single SNP Analysis of lnApoE in North Karelia, females

**

73 308

471545560624832

1163

15221575

1998

2440

2907

3106

3673

393740364075

4951

5229a5229b5361

Exon 1 Exon 2 Exon 3 Exon 41 Kb

Indicates a significant single site effect*

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

The Single SNPAnalysis Identifies

Sites With A WeakerPhenotypic

Association BecauseIt Cannot Deal WithHomoplasy At Site

560

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

The Single SNPAnalysis Identifies

Sites With A WeakerPhenotypic

Association BecauseIt Cannot Deal WithHomoplasy At Site

560

There is a deliberate attemptTo find SNPs that are

Polymorphic in most or allPopulations and that have

High heterozygosities; that is,SNPs just like the one at

Site 560.

Linkage Disequilibrium Is Frequently Used in Association Studies, But Also Is Frequently

Misinterpreted.Haplotype Trees Can Aid In Understanding The Proper Biological Interpretation

ApoE Gene

Stengård et al. (1996) showed the amino acid replacement alleles at ApoE have a major impact on mortality due to CAD in a longitudinal study.

0

1

2

3

4

5

6

7

CAD MortalityRelative to

CAD Mortalityof 3/3

3/33/42/4 & 4/4

Apoprotein E Gene Region

0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*


0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*

These Two Sites Are in Disequilibrium


Tree

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9


Tree

560

560

560

560560

560

1575

624

624624

624

1522

5361

5361

5361

4951

4951

4951

832

83224401998 1998

3937

5229B

4075

1163 4036

73

471

14

1119

17 20 18

23

1512

25

13

10 16

24

2

22

67 5

1

1575

560

624

624

21

26

4

3

31

3106

28545

27 3673

308

29 3701

8

30

2907

9

These haplotypes Are T at Site 832 &

C At Site 3937

These haplotypes Are G at Site 832 & T At Site 3937


0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*

Site 3937 Is An Amino Acid Polymorphism That Affects ApoE

Function and CAD


0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*


Function and CAD

Suppose Only This Portion Was Sequenced


0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*


Function and CAD


Site 832 Would Appear to Have TheStrongest Association with ApoE

Function and CAD


0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*


Site 832 Would Have TheStrongest Association with ApoE

Function and CAD


0. 0.5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. 5.5

Exon

1

Exon

2

Exon

3

Exon

4

73 308

471

545

560

624

832

1163

1522

1575

1998

2440

2907

3106

3673

3937

4036

4075

4951

5229

A52

29B

5361

3701*


Site 832 Would Have TheStrongest Association with ApoE

Function and CAD

Would you infer

From this Association

That the Marker Closest

to the Functional Site

WasHere?

Haplotype Trees Estimate an Evolutionary History That Can

Generate Hypotheses About The Current Significance of Genetic

Variation

73R

55N

52N

1JNR 2JNR

56N

61N

9N

53N

60N

4JN

79R

64J

70R

43J

27J

11J

28J

59N

23J

31J 19J

16J

10J

30J

74R 83R

5NR3JNR 7NR

85R54N41N

42N

57J22J35J

8J

14J

40J

37J

44N

76R

56 59 45

29

637

8

13

317 38

7

8

13

63

38

20

27

26

51N29335663

31

5920

44 19

305033

31

38

54

30

50

3050

60616566

64

2642

26

4256

29 31 33 5659

53 13

65

46

29

7 8

26

53

2565 19 61

58

6566

8

29

8

8 25

6340

5367

24J34J26

4

63

5

1666

41

29 36 69

17J

9

10

19

2 17

14

T-1

36J

5

12

16

31

35

38

39

41

43

44

46

47

60

57

64

T-4

6

15J 33J15

186365

3469

63N

71R 47N

66N

4

45J

19

20

26

27

5359

78

13

6869

62

9

10

11

16

17

214

23

53

69

13J 72R15233469

5958N 75R

53

19 2935365557586138J

5155

T-3

T-240

454968

32374852

29J

19

44

5

9

10

2

16

17222428354155

6

18

558

44

16

19

8 12J80R18J 25J30 35 36 46 58

33

330

55

4981R

39J

77R

67N

48N44

2642

40

53

2741

49N

62N65N

69R

84R

50N

21J

78R46N

20262729

3050

78132933

86R62

35

41323

44

53

4453

30 50

172642

6NR68R

88R

9

10111721232915

4

2627

5

26J

14

15

6

614

6

2832J

1940293536

41

58

67

3

18

25

30

4920J 5 16 19 31 56

a

b

cd

e

f

g

255387R82R

29 4511172123 3159h ij

k

l

m

n

p

q

r

s

t

u

v

w

x

LPL Tree

5NR

2JNR 79R70R

7

8

13

20

29 31 33 56 53

5

65

25

7 813

16

11J

611931J

66 29 36 69

5

16

12

36J

Branch "A"

{

Detecting Recombinantion Events in LPL

=3, =5, =3, p =0.0179, crossover between sites 13 and 29.1 10 20 30 40 50 60 69

2JNR CAGTTTCCCT CAGCACGATC GCAATTGCAC CTCAATGTAT AGTTGTAACC GAGTCCGCAT AACTATAGG5NR CAGTTTATCT CACCACGATA GCAATTGCAC CTCAATGTAT AGTTGTAACC GAGTCCGCAT AACTATAGGNode a CAGTTTATCT CACCACGATC GCAATTGCTC TTTAATGTAT AGTTGTAACC GAATCAGCAT AACTATAGG

=2, =7, =2, p =0.0278, crossover between sites 16 and 19.

Node d CAGTTTATCT CACCACGATC GCAACTGCTC TTTAATGTAT AGTTGTAACC GAATCAGCAT AACTATAGG11J CAGTATATCT CACCATGATC GCAACTGCTC TTTAATGTAT AGTTGTAACC GAATCAGCAT AACTATAGGNode e CAGTATATCT CACCATGAGC GCAATTGCAC TTTAA?GTAT AGTTGTAACC GAATCAGCAT CACTGGAGA

11J CAGTATATCT CACCATGATC GCAACTGCTC TTTAATGTAT AGTTGTAACC GAATCAGCAT AACTATAGGNode e CAGTATATCT CACCATGAGC GCAATTGCAC TTTAA?GTAT AGTTGTAACC GAATCAGCAT CACTGGAGAT-1 CAGTTTATCT CACCACGAGC GCAATTGCAC TTTAA?GTAT AGTTGTAACC GAATCAGCAT CACTGGAGA

Linkage Disequilibrium & TheRecombinational Hotspot in LPL

Haplotype Network in 5’ Region of LPL

5'-1 5'-2 5'-823J

8J14J44N

3

17

13 7 84

5 16 9 10 2

14

36J12

6

15

188

49N

84R

175'-3

5'-4

17

5'-5

5'-6

5'-7

16

4

4

6

32J

9 10

Haplotype Network in 3’ Region of LPL

3'-9

56N

53N

3'-4

64J 43J

59N

3'-12 19J

16J

30J

54N

41N 42N

40J

37J

59 44

50 38 54

50

64

42

65

4661

58

6566

6340

53 6724J34J

4136 69

T-136J

38 39 41 43 44 46 47 60 5764T-4

69

3'-10

3'-11

45J

53

59

75R

53

36

55

58

61

38J

51

55

40

45

3756

3'-8

8J 14J

T-3

48

52

29J44

55

35J

41

T-2

49

68

12J

3'-636

46

58 55

49

81R

39J

49N

50N

78R

46N

503'7

62

4450

26J

61

32J40

36

41 58 67

49 20J

77R

67N 48N

42

41

62

59

3'-161N

60N

56

59 45 63 3'-2

9N44N

38 3863

56 56

3'-351N 63

63 3'-5

53 53

28J

4259 45

5544

40 53

42

53

42

Neutral Genetic Drift, Stable

Population Size

Neutral Genetic Drift, Expanding Population Size

Negative Selection

Positive (Directional) Selection or Bottleneck

Positive (Diversifying) Selection or Subdivision

Peeled Haplotype Network in of LPL

52N

1JNR 2JNR

56N

61N

9N

53N

60N

4JN

79R

64J

70R

43J

27J

11J

28J

59N

23J

31J 19J

16J

10J

30J

40J

37J

56 59 45

29

63

38

30

50

3050

64

2642

26

4256

29 31 33 5659

53 13

65

46

29

7 8

26

53

2565 19 61

58

6566

8

29

8

8 25

6340

5367

34J26

4

63

5

1666

41

29 36 69

17J

9

10

19

2 17

T-1

36J

5

12

16

31

35

38

39

41

43

44

46

47

60

57

64

T-4

5155

T-3

T-240

454968

32374852

29J

19

44

Evolutionary Inferences On LPL

• 5’ End Subject to Directional Selection, With A Selective Sweep Enhanced By Recombination

• 3’ End Subject to Diversifying Selection

• Implies That Most Current Polymorphisms With Functional Significance Are In 3’ End

Haplotype Trees Provide a Powerful Tool For Detecting Current Genotype-Phenotype

Associations

• Nested Clade Analysis

• Tree Scanning

Nested Clade Analysis

• In 1987 Published The Nested Clade Method For Using A Haplotype Tree As A Tool For Discovering Gene/Phenotype Associations

• Nests The Haplotypes in Tree Into Evolutionary Clades (Branches)

• The Resulting Nested Design Provides Asymptotic Independence And A Priori Contrasts For Detecting Phenotypic Associations.

The Drosophila Adh Haplotype Tree


1-11-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11


2-1

2-2

2-3

2-4

2-5


3-1

3-2

Results of Nested Analysis of Variance of Adh Activity Using The Adh Haplotype Tree

***

**

**

**

** Significant at 1% Level*** Significant 0.1% Level

Functional Allelic Categories from the Nested Analysis of Variance of Adh Activity

***

**

**

**

Phenotypic Distributions Identified Though Nested Clade Analysis

0

1

2

3

4

5

6

7

8

9

2.14 2.64 3.14 3.64 4.14 4.64 5.14 5.64 6.14 6.64 7.14 7.64 8.14 8.64 9.14 9.64 10.1

Adh Activity

Number of Lines

Clade 1-4 Remainder 3-1

0

1

2

3

4

5

6

7

8

9

2.14 2.64 3.14 3.64 4.14 4.64 5.14 5.64 6.14 6.64 7.14 7.64 8.14 8.64 9.14 9.64 10.1

Adh Activity

Number of Lines

Clade 3-1 Clade 3-2

0

1

2

3

4

2.14 2.64 3.14 3.64 4.14 4.64 5.14 5.64 6.14 6.64 7.14 7.64 8.14 8.64 9.14 9.64 10.1

Adh Activity

Number of Lines

Haplotype 19 Haplotype 23 Remainder 3-2

Nested Clade Analyses

• Greater Statistical Power By Focusing On Fewer Comparisons

• Greater Biological Power In Detecting Mutations With Phenotypic Effects

• Deals With High Levels of Genetic Variation Through Pooling Into Clades

• Deals With Linkage Disequilibrium Through Haplotypes And Tree Branches

• Useful In Ultimately Identifying Causative Mutations

Nested Clade Analyses

• Although Nesting Is Common In Statistics and Evolutionary Biology, It Is Unfamiliar and Daunting To Others

• The Analysis Finds Phenotypic Associations With Haplotypes or Groups of Haplotypes: Does Not Deal Directly With Dominance Effects Or Genotypes.

• Is Inherently A Single Locus (Or Smaller) Analysis: Does Not Deal Directly With Epistasis

Tree Scanning

A New Method for Using Haplotype Trees At Candidate Loci To Investigate Genotype-

Phenotype Associations.

E.g., A Genome Scan for Lupus (Gray-McGuire et al. 2000)

Tree Scanning

• Make All Possible Bi-Allelic Partitions of the Haplotype Tree.

• Test For Phenotypic Heterogeneity Among the Resulting Genotypes Using Standard Statistics (ANOVA, t-Tests, Etc.)

• Because Tests Are Not Independent Across The Bi-Allelic Partitions, Randomly Permute Phenotypes Across Genotypes 10,000 Times To Determine the Treewise Type I Error Rate

Scanning The Drosophila Adh Haplotype Tree



Significant Results of Adh Tree Scan(Proportion of Phenotypic Variance Explained)

Sequential Adh Tree Scan(Fix Two or More Alleles From First Scan Defined By Distinct Peaks,

Then Examine All Possible Partitions Into Three Alleles)







Significant Peaks In Second Round of the Sequential Adh Tree Scan (Color Changes)

vs. The Nested Clade Analysis (*)

*

*

*

*

Tree Scanning• Is Less Powerful Statistically Than A Nested Clade

Analysis, But Tends To Identify The Same Functional Allelic Categories

• Is Easier To Implement and Automate Than A Nested Clade Analysis

• Detects Phenotypic Heterogeneity Among Genotypes And Therefore Can Detect Dominance Effects, Etc.

• Is Superior To Single SNP Association Tests• It Is Computationally Feasible To Exhaustively Examine

All Combinations of Bi-Allelic Partitions At Two Separate Genes And Therefore Detect Epistasis

Haplotype Trees

Provide a valuable tool in the investigation of common diseases

whose potential has not yet been fully explored or developed.

Genomic Approaches to Common Chronic Disease

A Research Project Supported by: National Institute of General Medical Sciences (NIGMS), P50-GM65509

U. of MichiganAnn Arbor, MI

Charles F. Sing (PI, Component 4)Sharon L. Kardia

Kathy L. Klos Northwestern U. U. of Alabama

Kiang Liu Heather McCreath O. Dale Williams

Cornell, U.Ithaca, NY

Andrew G. Clark (Component 3)S. Malia Fullerton

U. of Texas Houston, TX

James E. Hixson (Component 1)

U. of Texas Houston, TX

Eric Boerwinkle (Component 2)Myriam Fornage

Craig Hanis

Andrei Rodin

Washington U. St. Louis, MO

Alan R. Templeton (Project Consultant)

Support From MDECODE andA Burroughs-Wellcome Fund

Innovation Award In Functional Genomics Are Gratefully

Acknowledged

Documents

Haplotype Trees Using The Evolutionary History of Small DNA Regions To Investigate Common Diseases