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Potentials and limits of haplotype trees in exploring population structure and pathogenicity of mutations Hans-Jürgen Bandelt (Hamburg) PowerPoint PPT Presentation


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Potentials and limits of haplotype trees in exploring population structure and pathogenicity of mutations Hans-Jürgen Bandelt (Hamburg). 17. Jahrestagung der Deutschen Gesellschaft für Humangenetik Heidelberg, 08.–11. März 2006. Human mtDNA. HVS-I alias HVR1. from MITOMAP.

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Potentials and limits of haplotype trees in exploring population structure and pathogenicity of mutations Hans-Jürgen Bandelt (Hamburg)

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Slide1 l.jpg

Potentials and limits of haplotype trees in exploring population structure and pathogenicity of mutations

Hans-Jürgen Bandelt (Hamburg)

17. Jahrestagung der Deutschen Gesellschaft für Humangenetik Heidelberg, 08.–11. März 2006


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Human mtDNA

HVS-I

alias HVR1

fromMITOMAP


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The perception of evolution as seen through the lenses of laboratories constitutes an overlay of two different processes:

Perceived evolution =

Natural evolution (of the genome)

+ Artificial evolution (in the lab)


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mtDNA and evolution

α: Natural evolution

Migrational processes (prehistory)


Slide5 l.jpg

ML tree of basal African mtDNA haplogroups

Time

(years)

Coding-region variation displayed Torroni et al. (TIG, June 2006)

1048

4312

6185

9755

11914

12007

200,000

L

3516A

5442

9042

9347

10589

10664

10915

13276

L1’5 = L1’2’3’4’5’6’7

2758

2885

7146

8468

13105

3666

7055

7389

13789

14178

14560

L2’5= L2’3’4’5’6’7

L0

L1

3423

7972

12432

12950

825A

8655

10688

10810

13506

15301

150,000

4586

9818

2395d

5951

6071

8027

9072

10586

12810

13485

14000A

14911

L5

L0ak

2245

5603

11641

15136

15431

L2’6 = L2’3’4’6’7

Ethiopian samples

4104

7521

.

L1c

2416

8206

9221

10115

13590

L4’6 = L3’4’6’7

L0af

10321

709

851

930

1822

4496

5004

5111

5147

5656

6182

6297

7424

7873

8155

8188

8582

8754

9305

9329

9899

11015

11025

11881

12236

13105

13722

14212

14239

14581

14905

14971

15217

15884

3594

7256

13650

L1c1’2

709

770

961

13710

15289

15499

100,000

5231

5460

8428

8566

11176

12720

14308

12049

13149

L2

L3’7 = L3’4’7

L1c2

769

1018

3693

6150

6253

7076

7337

8784

8877

10792

10793

11654

L2d

L6

L3

L7

3918

8104

9855

12609

13470

7861

9575

13105

8701

9540

10398

10873

15301

10400

14783

15043

3396

4218

15514

15944d

L0a

L3a

L3bd = L3bcd

10819

870

2159

2332

3254A

3434

6231

8856

9130A

9554

9941

10700

10955

11353

11944

12630

13239

14845

15263

15458

15703

15777C

L3h

3357

5460

6167

7376

7762

7775

8473

8631

8697

10373

11253

11344

11485

11653

12280

12414

13174

13344

14000A

14302

3450

5773

6221

9449

10086

13914A

15311

15824

15944d

M

5147

7424

8618

13886

14284

2417G

3027

3720

4976

5213

8152

9809C

10493

11065

11260

11701

12188

12215

12546T

12714

12810

13569

13830

15383

5147

5711

6257

8460

9bp-del

11172

L3c

L3f

5601

9950

N

965+3C

1461

4964

5267

6002

6284

9332

10978

11116

11743

12405

12714

12771

14533A

14791

14959

15244

L4

2707

3879

4122

5147

5460

5567

5813

5930

8020

9098

9254

9380

9965

11440

12469

13080

13755

6446

6680

12403

12950C

14110

L3ex = L3eix

1719

2831

3777

4388

4859

5300

7055

8767

9509

9827

10044

10289

11563

11590

11963

14410

678

792

3582

4491

5393

7394

8835

9337

9682

11944

12373

14221

14371

14560

14587

15833

3483

6401

8311

8817

13708

959

1692

4643

5181

6293

6480

6602

8158

8251

8400

9932

10604

11176

11770

14590

15940

50,000

L3f1

L1c2a

12705

7645

14040

14395

L3d

2352

14212

721

2357

5310

10184

10314

12618

12816

13443

13708

14461

14566

14851

15553

R

1598

2220

5162

5899+C

6962

10031

11164

11252

11959

12477

12540

15929

3197

3693

4048

4350

5194

7270

8853

12507

12634

14148

15106

15952

L0a2

M1

921

L3x

L3i

3435

3621

5894+T

6392

7129

8041

8197

8928

9941

12340

14034

L3b

L3e

750

1438

2706

4769

7028

8860

11719

14766

15326

L3d1

648

723

1413

5471

5580

5746

10750

14182

14861

11143

14755

813

3604

3705

4375

4793

6671

12346

13635

15514

1193

3441

5211

5581

9477

10373

11002

15299

750

1822

3666

7819A

8527

8932

11440

14769

745+T

1719

1842

5821

9365

15314

15479

L0a2a

3459

5046

5605

6272

6680

6842

5441

8222

12630

14818

15388

15944d

2158

8598

10679

11260

13687

13800A

L3e5

4715

8392

12561

15367

9545

9554

13116

5899+C

14750

15172

5186

14905

0

rCRS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25


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One of the first views of the East Asian mtDNA phylogeny (Ozawa,Herz 1994)

all mutations that distinguish haplogroups M and R (part of N)

incorrect rooting

CRS

R

M


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Star-burst of autochthonous mtDNA lineages in Eurasia (haplogroup N and its subhaplogroup R)

pre-HV

JT

U

W

R2

N1

R5

X

R1

R6

N5

R7

N

R

R8

R30

A

9140 6755

15607

R31

West Eurasia

8404

N9

South Asia

R9

East Asia

P

R11

S

B

O

Oceania

Palanichamy et al (Amer J Hum Genet, 2004)


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... and a massive burst in haplogroup M, as e.g. seen in India:

Sun et al (Mol Biol Evol, March 2006)


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An Out-of-Africa model based on mtDNA analysis

Kivisild et al (Springer-Verlag, April 2006)


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Sketch of the phylogeny of basal European mtDNA haplogroups

N

N2

N1

X

R

N1b

N1a’I

W

U

JT

R0=pre-HV

I

N1a

R0a=(pre-HV)1

HV

H

HV0=pre-V

H1

H3

HV0a

V

Torroni et al (TIG, June 2006)


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Spatial frequency distributions of haplogroups H1, H3, V, and U5b reveal signature of post-LGM expansions

Torroni et al (TIG, June 2006)


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mtDNA and evolution

β: Artificial evolution

Laboratory-specific processes (error and fraud)


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Major sources of error in mtDNA sequence data

Artificial Recombination through contamination or sample mix-up (or targeting nuclear inserts of mtDNA)

Phantom mutations sequencing errors at electrophoresis

Documentation errorsincurred by casual reading or writing


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Impurifying selection is the driving force in artificial evolution

inasmuch as incorrect data are more flexible to interpret and can support sexy stories — seemingly told by DNA — which are then disseminated by high-impact factor journals (e.g. Science and Nature).

Worst case: mtDNA in cancer research (Salas et al, PLoS Medicine 2005)


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Case of mtDNA sample mix-up, mis-interpreted as somatic mutations;

data generated with MitoChip by Maitra et al (Genome Res, 2004)

Data re-analysis by Bandelt et al (J Med Genet, 2005)


Slide16 l.jpg

10410 @9824

F

B

D

F

A

C

E

1

3000

6000

9000

12000

15000

16569

NDsq0168

M7a2

F1a1b

M7a

NDsq0167

F1a1b

M7a

F1a1b

A case of cross-over in the 672 human complete mtDNA sequences from Tanaka et al (2004)

NDsq0167

NDsq0178

16519 16140 15422 8005 5899+C 4435 2218 965+CC 961 249

15618 200 195

M7a

15301

10873

10398

9540

8701

16209 4958 4386 2772 2626

15043

14783

10400

489

N

12771

98246455

rCRS

M7

M

L3

12705

16223

R

R9

10310

6392

249d

F

13928C

16304

3970

12882 12406

16519 10609

6962 522-523d

F1

F1a’c

F1a

F1a1

13759

16172 4086

16162 9548

16129

9053

14002

63

64

F1a1b

@6455 965.2+CC

NDsq0015

NDsq0168


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Prime example of a phantom mutation (Brandstätter et al, Electrophoresis 2005)


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Electropherogram from

Nasidze and Stoneking (2001)

generated 1997 / 1998

and for the first time presented in Stoneking and Nasidze (Ann Hum Genet, 2006)

rCRS


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Phantom mutations can be found in excess in the HVS-I Caucasus data of Nasidze and Stoneking (2001).

In view of additional problems, this may be regarded as the worst data set ever published in the realm of molecular anthropology;

see Bandelt and Kivisild (Ann Hum Genet 2006) for data re-analysis


Slide20 l.jpg

Sequences with phantom transitions at 16280-16281 in those Caucasus data

CodeMutation (16000+)Haplogroup

AR31067 279G280281 355HV1

AR483069 126 145 280281 367CJ

AZ2280281?

AZ342280281 298pre-V

AZ6154 168A280281 356 384?

CH444111 214G 249 280281 327 388U1b

CH451280281 292?

DAR23129 223 278 280281?

DAR36258 280281384?

KAB408224 280281 311K

This mutation pair has never been observed in >40,000 HVS-I sequences!


Slide21 l.jpg

Electropherogram presented by Stoneking and Nasidze(Ann Hum Genet, 2006)

rCRS


Slide22 l.jpg

Phantom mutations in the HVS-I data of Plaza et al (Ann Hum Genet, 2003)

(267 samples)

SampleMutation (16000+)Haplogroup

Algeria279N285N ?

Andalusia129 182C 183C 189 223 249 311 359 371M1

Andalusia129 281?

Andalusia281?

Catalonia093 192 270 281 290A 304 311U5b

Catalonia224 281 311 K

Morroco093 224 242 311 371K

Morroco124 223 284C285T 300 319 374TL2d

Morroco126 187 189 223 264 270 278 293 311 371374L1b

Morroco126 284C 292 294T2

Morroco183C 189 223 278 382GX

Morroco189 192 270 369TU5b

Saharawi093 172 185 223 327 382GL3e1

Saharawi172 281 311U6?

Saharawi189 382G?


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Comparison with 1624 complete sequences stored in the mtDB database

Variation in 16279-16285:

Only 20 transitional variants at 16284

Variation in 16369-16389:

Only 1+1+6 transitional variants at 16371, 16380, and 16381


Slide24 l.jpg

Re-evaluation of the mtDNA data from the lab of Min-Xin Guan

rCRS

R

M

N

missing mutations

misscored mutations in red

Yao et al (Hum Genet, 2006)


Slide25 l.jpg

Strategies of authors to deal with errors

1st:Publishing a corrigendum [rare event]

2nd:No correction — but avoiding similar errors in future work [common practice]

3rd: No action — and committing the same errors as before [e.g.as Min-Xin Guan and colleagues do]

4th: Fraudulent action — performing fake analyses and giving false statements [as done by Mark Stoneking and Ivane Nasidze in the Ann Hum Genet]


Slide26 l.jpg

... only L strand, no H strand information shown!

Stoneking and Nasidze (2006)


Slide27 l.jpg

Human Mitochondrial DNA and the Evolution of Homo sapiensSeries: Nucleic Acids and Molecular Biology, Vol.18 Volume package:Human Mitochondrial DNA

Bandelt, Hans-Jürgen; Richards, Martin; Macaulay, Vincent (Eds.) 2006, Approx. 250 p., 31 illus., 2 in colour., HardcoverISBN: 3-540-31788-0Springer-Verlag

Due: April 2006


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