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Potentials and limits of haplotype trees in exploring population structure and pathogenicity of mutations Hans-Jürgen Bandelt (Hamburg) 17. Jahrestagung.

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Presentation on theme: "Potentials and limits of haplotype trees in exploring population structure and pathogenicity of mutations Hans-Jürgen Bandelt (Hamburg) 17. Jahrestagung."— Presentation transcript:

1 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

2 Human mtDNA from MITOMAP HVS-I alias HVR1

3 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)

4 Migrational processes (prehistory) mtDNA and evolution α : Natural evolution

5 1048 4312 6185 9755 11914 12007 769 1018 3594 7256 13650 648 723 1413 5471 5580 5746 10750 14182 14861 965+3C 1461 4964 5267 6002 6284 9332 10978 11116 11743 12405 12714 12771 14533A 14791 14959 15244 3357 5460 6167 7376 7762 7775 8473 8631 8697 10373 11253 11344 11485 11653 12280 12414 13174 13344 14000A 14302 870 2159 2332 3254A 3434 6231 8856 9130A 9554 9941 10700 10955 11353 11944 12630 13239 14845 15263 15458 15703 15777C 825A 8655 10688 10810 13506 15301 4104 7521 750 1438 2706 4769 7028 8860 11719 14766 15326 12705 8701 9540 10398 10873 15301 12345678 721 2357 5310 10184 10314 12618 12816 13443 13708 14461 14566 14851 15553 24 1719 2831 3777 4388 4859 5300 7055 8767 9509 9827 10044 10289 11563 11590 11963 14410 2707 3879 4122 5147 5460 5567 5813 5930 8020 9098 9254 9380 9965 11440 12469 13080 13755 2223 13105 678 792 3582 4491 5393 7394 8835 9337 9682 11944 12373 14221 14371 14560 14587 15833 3459 5046 5605 6272 6680 6842 1193 3441 5211 5581 9477 10373 11002 15299 151617 1822 3666 7819A 8527 8932 11440 14769 3396 4218 15514 15944d 5601 9950 3197 3693 4048 4350 5194 7270 8853 12507 12634 14148 15106 15952 959 1692 4643 5181 6293 6480 6602 8158 8251 8400 9932 10604 11176 11770 14590 15940 745+T 1719 1842 5821 9365 15314 15479 18192021 rCRS 10819 7645 14040 14395 2158 8598 10679 11260 13687 13800A 1112 2352 14212 4715 8392 12561 15367 1314 3435 3621 5894+T 6392 7129 8041 8197 8928 9941 12340 14034 3483 6401 8311 8817 13708 5899+C 14750 15172 910 813 3604 3705 4375 4793 6671 12346 13635 15514 25 50,000 0 100,000 150,000 200,000 Time (years) 10400 14783 15043 L0 3516A 5442 9042 9347 10589 10664 10915 13276 L3 5231 5460 8428 8566 11176 12720 14308 L0a L L5 L2’6 = L2’3’4’6’7 L3bd = L3bcd L3ex = L3eix L3x L3i L3e L3f L3f1 L4’6 = L3’4’6’7 L3’7 = L3’4’7 L1’5 = L1’2’3’4’5’6’7 M N R L3h 6446 6680 12403 12950C 14110 M1 3666 7055 7389 13789 14178 14560 L1 2395d 5951 6071 8027 9072 10586 12810 13485 14000A 14911 L1c 2416 8206 9221 10115 13590 L2 3693 L2d L3d 3450 5773 6221 9449 10086 13914A 15311 15824 15944d 5147 7424 8618 13886 14284 L3b L3c 3918 8104 9855 12609 13470 L4 L7 L6 709 770 961 13710 15289 15499 L3a 5441 8222 12630 14818 15388 15944d 2758 2885 7146 8468 13105 L2’5= L2’3’4’5’6’7 7861 9575 5186 14905 2417G 3027 3720 4976 5213 8152 9809C 10493 11065 11260 11701 12188 12215 12546T 12714 12810 13569 13830 15383 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 1598 2220 5162 5899+C 6962 10031 11164 11252 11959 12477 12540 15929 11143 14755 3423 7972 12432 12950 5147 5711 6257 8460 9bp-del 11172 L0a2 9545 9554 13116 L0a2a L1c1’2 10321 12049 13149 L1c2 921 L3d1 750 L3e5 6150 6253 7076 7337 8784 8877 10792 10793 11654 L1c2a 2245 5603 11641 15136 15431 L0af 4586 9818 L0ak ML tree of basal African mtDNA haplogroups Coding-region variation displayed Torroni et al. (TIG, June 2006). Ethiopian samples

6 CRS RM all mutations that distinguish haplogroups M and R (part of N) incorrect rooting One of the first views of the East Asian mtDNA phylogeny (Ozawa, Herz 1994)

7 U pre- HV JT R1 R5 R6 R7 R30 R31 R9 P R11 R8 B N5 S O X A N9 West Eurasia South Asia East Asia Oceania 15607 9140 6755 8404 N N1 W R R2 Palanichamy et al (Amer J Hum Genet, 2004) Star-burst of autochthonous mtDNA lineages in Eurasia (haplogroup N and its subhaplogroup R)

8 ... and a massive burst in haplogroup M, as e.g. seen in India: Sun et al (Mol Biol Evol, March 2006)

9 An Out-of-Africa model based on mtDNA analysis Kivisild et al (Springer-Verlag, April 2006)

10 HV HV0 = pre -V HV0a H3 H1 H V R0a = ( pre -HV)1 R0 = pre -HV U JT R X N2 W N1bN1a’I N1 N1a I N Sketch of the phylogeny of basal European mtDNA haplogroups Torroni et al (TIG, June 2006)

11 Spatial frequency distributions of haplogroups H1, H3, V, and U5b reveal signature of post-LGM expansions Torroni et al (TIG, June 2006)

12 Laboratory-specific processes (error and fraud) mtDNA and evolution β : Artificial evolution

13 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 errors incurred by casual reading or writing

14 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)

15 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)

16 M7a N F NDsq0168 @6455 965.2+CC NDsq0178 rCRS L3 R 12771 64 16129 9053 13928C 16304 3970 10310 6392 249d F1 15618 200 195 NDsq0167 NDsq0015 16223 M F1a F1a’c 16172 4086 16209 4958 4386 2772 2626 9824 6455 15043 14783 10400 489 15301 10873 10398 9540 8701 M7 12705 R9 12882 12406 10410 @9824 13759 16519 10609 6962 522-523d 16519 16140 15422 8005 5899+C 4435 2218 965+CC 961 249 16162 9548 14002 F1a1 F1a1b ACE BDFF 1300060009000120001500016569 M7a 2 M7aF1a1b NDsq0168 M7a NDsq0167 F1a1b 63 A case of cross-over in the 672 human complete mtDNA sequences from Tanaka et al (2004)

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

18 rCRS Electropherogram from Nasidze and Stoneking (2001) generated 1997 / 1998 and for the first time presented in Stoneking and Nasidze (Ann Hum Genet, 2006)

19 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

20 Sequences with phantom transitions at 16280-16281 in those Caucasus data CodeMutation (16000+)Haplogroup AR31067 279G 280 281 355HV1 AR483069 126 145 280 281 367CJ AZ2280 281? AZ342280 281 298pre-V AZ6154 168A 280 281 356 384? CH444111 214G 249 280 281 327 388U1b CH451280 281 292? DAR23129 223 278 280 281? DAR36258 280 281 384? KAB408224 280 281 311K This mutation pair has never been observed in >40,000 HVS-I sequences!

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

22 Phantom mutations in the HVS-I data of Plaza et al (Ann Hum Genet, 2003) (267 samples) SampleMutation (16000+)Haplogroup Algeria279N 285N ? 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 284C 285T 300 319 374TL2d Morroco126 187 189 223 264 270 278 293 311 371 374L1b Morroco126 284C 292 294T2 Morroco183C 189 223 278 382GX Morroco189 192 270 369TU5b Saharawi093 172 185 223 327 382GL3e1 Saharawi172 281 311U6? Saharawi189 382G?

23 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

24 Re-evaluation of the mtDNA data from the lab of Min-Xin Guan missing mutations misscored mutations in red Yao et al (Hum Genet, 2006) N M rCRS R

25 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 ]

26 ... only L strand, no H strand information shown! Stoneking and Nasidze (2006)

27 Human Mitochondrial DNA and the Evolution of Homo sapiens Series: Nucleic Acids and Molecular Biology, Vol.18 Volume package: Human Mitochondrial DNANucleic Acids and Molecular BiologyHuman Mitochondrial DNA Bandelt, Hans-Jürgen; Richards, Martin; Macaulay, Vincent (Eds.) 2006, Approx. 250 p., 31 illus., 2 in colour., Hardcover ISBN: 3-540-31788-0 Springer-Verlag Due: April 2006


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