Chromosome Research

, Volume 16, Issue 1, pp 41–56 | Cite as

Molecular mechanisms of chromosomal rearrangement during primate evolution

Article

Abstract

Breakpoint analysis of the large chromosomal rearrangements which have occurred during primate evolution promises to yield new insights into the underlying mechanisms of mutagenesis. Comparison of these evolutionary breakpoints with those that are disease-associated in humans, and which occur during either meiotic or mitotic cell division, should help to identify basic mechanistic similarities as well as differences. It has recently become clear that segmental duplications (SDs) have had a very significant impact on genome plasticity during primate evolution. In comparisons of the human and chimpanzee genomes, SDs have been found in flanking regions of 70–80% of inversions and ∼40% of deletions/duplications. A strong spatial association between primate-specific breakpoints and SDs has also become evident from comparisons of human with other mammalian genomes. The lineage-specific hyperexpansion of certain SDs observed in the genomes of human, chimpanzee, gorilla and gibbon is indicative of the intrinsic instability of some SDs in primates. However, since many primate-specific breakpoints map to regions lacking SDs, but containing interspersed high-copy repetitive sequence elements such as SINEs, LINEs, LTRs, α-satellites and (AT) n repeats, we may infer that a range of different molecular mechanisms have probably been involved in promoting chromosomal breakage during the evolution of primate genomes.

Key words

cytogenetics evolution primate rearrangement breakpoints segmental duplications 

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References

  1. Antonell A, de Luis O, Domingo-Roura X, Perez-Jurado LA (2005) Evolutionary mechanisms shaping the genomic structure of the Williams–Beuren syndrome chromosomal region at human 7q11.23. Genome Res 15: 1179–1188.PubMedCrossRefGoogle Scholar
  2. Armengol L, Pujana MA, Cheung J, Scherer SW, Estivill X (2003) Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements. Hum Mol Genet 12: 2201–2208.PubMedCrossRefGoogle Scholar
  3. Ayala FJ, Coluzzi M (2005) Chromosome speciation: humans, Drosophila, and mosquitoes. Proc Natl Acad Sci USA 102: 6535–6542.PubMedCrossRefGoogle Scholar
  4. Babcock M, Yatsenko S, Hopkins J et al. (2007) Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/DiGeorge syndrome. Hum Mol Genet 16: 2560–2571.PubMedCrossRefGoogle Scholar
  5. Bailey JA, Eichler EE (2006) Primate segmental duplications: crucibles of evolution, diversity and disease. Nat Rev Genet 7: 552–564.PubMedCrossRefGoogle Scholar
  6. Bailey JA, Gu Z, Clark RA et al. (2002) Recent segmental duplications in the human genome. Science 297: 1003–1007.PubMedCrossRefGoogle Scholar
  7. Bailey JA, Liu G, Eichler EE (2003) An Alu transposition model for the origin and expansion of human segmental duplications. Am J Hum Genet 73: 823–834.PubMedCrossRefGoogle Scholar
  8. Bailey JA, Baertsch R, Kent WJ, Haussler D, Eichler EE (2004) Hotspots of mammalian chromosomal evolution. Genome Biol 5: R23.PubMedCrossRefGoogle Scholar
  9. Ball EV, Stenson PD, Abeysinghe SS, Krawczak M, Cooper DN, Chuzhanova NA (2005) Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 26: 205–213.PubMedCrossRefGoogle Scholar
  10. Carbone L, Vessere GM, ten Hallers BF et al. (2006) A high-resolution map of synteny disruptions in gibbon and human genomes. PLoS Genet 2: e223.PubMedCrossRefGoogle Scholar
  11. Cheng Z, Ventura M, She X et al. (2005) A genome-wide comparison of recent chimpanzee and human segmental duplications. Nature 437: 88–93.PubMedCrossRefGoogle Scholar
  12. Chen FC, Chen CJ, Li WH, Chuang TJ (2007) Human-specific insertions and deletions inferred from mammalian genome sequences. Genome Res 17: 16–22.PubMedCrossRefGoogle Scholar
  13. Demuth JP, De Bie T, Stajich JE, Cristianini N, Hahn MW (2006) The evolution of mammalian gene families. PLoS ONE 1: e85.PubMedCrossRefGoogle Scholar
  14. Dennehey BK, Gutches DG, McConkey EH, Krauter KS (2004) Inversion, duplication, and changes in gene context are associated with human chromosome 18 evolution. Genomics 83: 493–501.PubMedCrossRefGoogle Scholar
  15. Dreszer TR, Wall GD, Haussler D, Pollard KS (2007) Biased clustered substitutions in the human genome: The footprints of male-driven biased gene conversion. Genome Res 17: 1420–1430.PubMedCrossRefGoogle Scholar
  16. Dumas L, Kim YH, Karimpour-Fard A et al. (2007) Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res 31: 1266–1277.CrossRefGoogle Scholar
  17. Dutrillaux B (1979) Chromosomal evolution in primates: tentative phylogeny from Microcebus murinus (Prosimian) to man. Hum Genet 48: 251–314.PubMedCrossRefGoogle Scholar
  18. Dutrillaux B, Rethore MO, Aurias A, Goustard M (1975) Karyotype analysis of 2 species of gibbons (Hylobates lar and H. concolor) with different banding species. Cytogenet Cell Genet 15: 81–91.PubMedGoogle Scholar
  19. Edelmann L, Pandita RK, Spiteri E et al. (1999) A common molecular basis for rearrangement disorders on chromosome 22q11. Hum Mol Genet 8: 1157–1167.PubMedCrossRefGoogle Scholar
  20. Eder V, Ventura M, Ianigro M, Teti M, Rocchi M, Archidiacono N (2003) Chromosome 6 phylogeny in primates and centromere repositioning. Mol Biol Evol 20: 1506–1512.PubMedCrossRefGoogle Scholar
  21. Fan Y, Linardopoulou E, Friedman C, Williams E, Trask BJ (2002) Genomic structure and evolution of the ancestral chromosome fusion site in 2q13–2q14.1 and paralogous regions on other human chromosomes. Genome Res 12: 1651–1662.PubMedCrossRefGoogle Scholar
  22. Feuk L, MacDonald JR, Tang T et al. (2005) Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genet 1: e56.PubMedCrossRefGoogle Scholar
  23. Fortna A, Kim Y, MacLaren E et al. (2004) Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol 2: e207.PubMedCrossRefGoogle Scholar
  24. Frazer KA, Chen X, Hinds DA, Pant PV, Patil N, Cox DR (2003) Genomic DNA insertions and deletions occur frequently between humans and nonhuman primates. Genome Res 13: 341–346.PubMedCrossRefGoogle Scholar
  25. Froenicke L (2005) Origins of primate chromosomes—as delineated by Zoo-FISH and alignments of human and mouse draft genome sequences. Cytogenet Genome Res 108: 122–138.PubMedCrossRefGoogle Scholar
  26. Gibbs RA, Rogers J, Katze MG et al. (2007) Evolutionary and biomedical insights from the rhesus macaque genome. Science 316: 222–234.PubMedCrossRefGoogle Scholar
  27. Goidts V, Szamalek JM, Hameister H, Kehrer-Sawatzki H (2004) Segmental duplication associated with the human-specific inversion of chromosome 18: a further example of the impact of segmental duplications on karyotype and genome evolution in primates. Hum Genet 115: 116–122.PubMedCrossRefGoogle Scholar
  28. Goidts V, Szamalek JM, de Jong PJ et al. (2005) Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 16. Genome Res 15: 1232–1242.PubMedCrossRefGoogle Scholar
  29. Goidts V, Cooper DN, Armengol L et al. (2006) Complex pattern of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome. Hum Genet 120: 270–284.PubMedCrossRefGoogle Scholar
  30. Harris RA, Rogers J, Milosavljevic A (2007) Human-specific changes of genome structure detected by genomic triangulation. Science 316: 235–237.PubMedCrossRefGoogle Scholar
  31. IJdo JW, Baldini A, Ward DC, Reeders ST, Wells RA (1991) Origin of human chromosome 2: an ancestral telomere-telomere fusion. Proc Natl Acad Sci USA 88: 9051–9055.PubMedCrossRefGoogle Scholar
  32. Jauch A, Wienberg J, Stanyon R et al. (1992) Reconstruction of genomic rearrangements in great apes and gibbons by chromosome painting. Proc Natl Acad Sci USA 89: 8611–8615.PubMedCrossRefGoogle Scholar
  33. Johnson ME; National Institute of Health Intramural Sequencing Center Comparative Sequencing Program, Cheng Z, Morrison VA, Scherer S, Ventura M, Gibbs RA, Green ED, Eichler EE (2006) Recurrent duplication-driven transposition of DNA during hominoid evolution. Proc Natl Acad Sci USA 103: 17626–17631.PubMedCrossRefGoogle Scholar
  34. Kasai F, Takahashi E, Koyama K et al. (2000) Comparative FISH mapping of the ancestral fusion point of human chromosome 2. Chromosome Res 8: 727–735.PubMedCrossRefGoogle Scholar
  35. Kehrer-Sawatzki H, Cooper DN (2007) Structural divergence between the human and chimpanzee genomes. Hum Genet 120: 759–778.PubMedCrossRefGoogle Scholar
  36. Kehrer-Sawatzki H, Schreiner B, Tänzer S, Platzer M, Müller S, Hameister H (2002) Molecular characterization of the pericentric inversion that causes differences between chimpanzee chromosome 19 and human chromosome 17. Am J Hum Genet 71: 375–388.PubMedCrossRefGoogle Scholar
  37. Kehrer-Sawatzki H, Sandig C, Chuzhanova N et al. (2005a) Breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee (Pan troglodytes). Hum Mutat 25: 45–55.CrossRefGoogle Scholar
  38. Kehrer-Sawatzki H, Szamalek JM, Tanzer S, Platzer M, Hameister H (2005b) Molecular characterization of the pericentric inversion of chimpanzee chromosome 11 homologous to human chromosome 9. Genomics 85: 542–550.CrossRefGoogle Scholar
  39. Kehrer-Sawatzki H, Sandig CA, Goidts V, Hameister H (2005c) Breakpoint analysis of the pericentric inversion between chimpanzee chromosome 10 and the homologous chromosome 12 in humans. Cytogenet Genome Res 108: 91–97.CrossRefGoogle Scholar
  40. Kirkpatrick M, Barton N (2006) Chromosome inversions, local adaptation and speciation. Genetics 173: 419–434.PubMedCrossRefGoogle Scholar
  41. Koehler U, Bigoni F, Wienberg J, Stanyon R (1995) Genomic reorganization in the concolor gibbon (Hylobates concolor) revealed by chromosome painting. Genomics 30: 287–292.PubMedCrossRefGoogle Scholar
  42. Larkin DM, Everts-van der Wind A, Rebeiz M et al. (2003) A cattle-human comparative map built with cattle BAC-ends and human genome sequence. Genome Res 13: 1966–1972.PubMedGoogle Scholar
  43. Linardopoulou EV, Williams EM, Fan Y, Friedman C, Young JM, Trask BJ (2005) Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437: 94–100.PubMedCrossRefGoogle Scholar
  44. Locke DP, Archidiacono N, Misceo D et al. (2003a) Refinement of a chimpanzee pericentric inversion breakpoint to a segmental duplication cluster. Genome Biol 4: R50.CrossRefGoogle Scholar
  45. Locke DP, Segraves R, Carbone L et al. (2003b) Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization. Genome Res 13: 347–357.CrossRefGoogle Scholar
  46. Lu J, Li WH, Wu CI (2003) Comment on “Chromosomal speciation and molecular divergence-accelerated evolution in rearranged chromosomes”. Science 302: 988.PubMedCrossRefGoogle Scholar
  47. Marques-Bonet T, Sànchez-Ruiz J, Armengol L et al. (2007) On the association between chromosomal rearrangements and genic evolution in humans and chimpanzees. Genome Biol 8: R230.PubMedCrossRefGoogle Scholar
  48. Mikkelsen TS, Hillier LW, Eichler EE et al. (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437: 69–87.CrossRefGoogle Scholar
  49. Müller S, Wienberg J (2001) “Bar-coding” primate chromosomes: molecular cytogenetic screening for the ancestral hominoid karyotype. Hum Genet 109: 85–94.PubMedCrossRefGoogle Scholar
  50. Müller S, Hollatz M, Wienberg J (2003) Chromosomal phylogeny and evolution of gibbons (Hylobatidae). Hum Genet 113: 493–501.PubMedCrossRefGoogle Scholar
  51. Müller S, Finelli P, Neusser M, Wienberg J (2004) The evolutionary history of human chromosome 7. Genomics 84: 458–467.PubMedCrossRefGoogle Scholar
  52. Murphy WJ, Larkin DM, Everts-van der Wind A et al. (2005a) Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps. Science 309: 613–617.CrossRefGoogle Scholar
  53. Murphy WJ, Agarwala R, Schaffer AA et al. (2005b) A rhesus macaque radiation hybrid map and comparative analysis with the human genome. Genomics 86: 383–395.CrossRefGoogle Scholar
  54. Navarro A, Barton H (2003a) Chromosomal speciation and molecular divergence–accelerated evolution in rearranged chromosomes. Science 300: 321–324.CrossRefGoogle Scholar
  55. Navarro A, Barton NH (2003b) Accumulating postzygotic isolation genes in parapatry: a new twist on chromosomal speciation. Evolution Int J Org Evolution 57: 447–459.Google Scholar
  56. Newman TL, Tuzun E, Morrison VA et al. (2005) A genome-wide survey of structural variation between human and chimpanzee. Genome Res 15: 1344–1356.PubMedCrossRefGoogle Scholar
  57. Nie W, Rens W, Wang J, Yang F (2001) Conserved chromosome segments in Hylobates hoolock revealed by human and H. leucogenys paint probes. Cytogenet Cell Genet 92: 248–253.PubMedCrossRefGoogle Scholar
  58. Noor MA, Grams KL, Bertucci LA, Reiland J (2001) Chromosomal inversions and the reproductive isolation of species. Proc Natl Acad Sci USA 98: 12084–12088.PubMedCrossRefGoogle Scholar
  59. Ortíz-Barrientos D, Reiland J, Hey J, Noor MA (2002) Recombination and the divergence of hybridizing species. Genetica 116: 167–178.PubMedCrossRefGoogle Scholar
  60. Perry GH, Tchinda J, McGrath SD et al. (2006) Hotspots for copy number variation in chimpanzees and humans. Proc Natl Acad Sci USA 103: 8006–8011.PubMedCrossRefGoogle Scholar
  61. Pevzner P, Tesler G (2003) Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution. Proc Natl Acad Sci USA 100: 7672–7677.PubMedCrossRefGoogle Scholar
  62. Ranz JM, Maurin D, Chan YS et al. (2007) Principles of genome evolution in the Drosophila melanogaster species group. PLoS Biol 5: e152.PubMedCrossRefGoogle Scholar
  63. Redon R, Ishikawa S, Fitch KR et al. (2006) Global variation in copy number in the human genome. Nature 444: 444–454.PubMedCrossRefGoogle Scholar
  64. Roberto R, Capozzi O, Wilson RK et al. (2007) Molecular refinement of gibbon genome rearrangements. Genome Res 17: 249–257.PubMedCrossRefGoogle Scholar
  65. Robinson TJ, Ruiz-Herrera A, Froenicke L (2006) Dissecting the mammalian genome–new insights into chromosomal evolution. Trends Genet 22: 297–301.PubMedCrossRefGoogle Scholar
  66. Royle NJ, Baird DM, Jeffreys AJ (1994) A subterminal satellite located adjacent to telomeres in chimpanzees is absent from the human genome. Nat Genet 6: 52–56.PubMedCrossRefGoogle Scholar
  67. Ruiz-Herrera A, Ponsa M, Garcia F, Egozcue J, Garcia M (2002) Fragile sites in human and Macaca fascicularis chromosomes are breakpoints in chromosome evolution. Chromosome Res 10: 33–44.PubMedCrossRefGoogle Scholar
  68. Ruiz-Herrera A, Garcia F, Mora L, Egozcue J, Ponsa M, Garcia M (2005) Evolutionary conserved chromosomal segments in the human karyotype are bounded by unstable chromosome bands. Cytogenet Genome Res 108: 161–174.PubMedCrossRefGoogle Scholar
  69. Ruiz-Herrera A, Castresana J, Robinson TJ (2006) Is mammalian chromosomal evolution driven by regions of genome fragility? Genome Biol 7: R115.PubMedCrossRefGoogle Scholar
  70. Sharp AJ, Locke DP, McGrath SD et al. (2005) Segmental duplications and copy number variation in the human genome. Am J Hum Genet 77: 78–88.PubMedCrossRefGoogle Scholar
  71. She X, Horvath JE, Jiang Z et al. (2004) The structure and evolution of centromeric transition regions within the human genome. Nature 430: 857–864.PubMedCrossRefGoogle Scholar
  72. She X, Liu G, Ventura M et al. (2006) A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications. Genome Res 16: 576–583.PubMedCrossRefGoogle Scholar
  73. Shimada MK, Kim CG, Kitano T, Ferrell RE, Kohara Y, Saitou N (2005) Nucleotide sequence comparison of a chromosome rearrangement on human chromosome 12 and the corresponding ape chromosomes. Cytogenet Genome Res 108: 83–90.PubMedCrossRefGoogle Scholar
  74. Stankiewicz P, Park SS, Inoue K, Lupski JR (2001) The evolutionary chromosome translocation 4;19 in Gorilla gorilla is associated with microduplication of the chromosome fragment syntenic to sequences surrounding the human proximal CMT1A-REP. Genome Res 11: 1205–1210.PubMedCrossRefGoogle Scholar
  75. Stankiewicz P, Shaw CJ, Withers M, Inoue K, Lupski JR (2004) Serial segmental duplications during primate evolution result in complex human genome architecture. Genome Res 14: 2209–2220.PubMedCrossRefGoogle Scholar
  76. Szamalek JM, Goidts V, Chuzhanova N, Hameister H, Cooper DN, Kehrer-Sawatzki H (2005) Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome. Hum Genet 117: 168–176.PubMedCrossRefGoogle Scholar
  77. Szamalek JM, Cooper DN, Goidts V, Hameister H, Kehrer-Sawatzki H (2006a) Characterization of the human-specific pericentric inversion that discriminates human chromosome 1 from the homologous chromosomes in great apes. Hum Genet 120: 126–138.CrossRefGoogle Scholar
  78. Szamalek JM, Goidts V, Searle JB, Cooper DN, Hameister H, Kehrer-Sawatzki H (2006b) The chimpanzee-specific pericentric inversions that distinguish humans and chimpanzees have identical breakpoints in Pan troglodytes and Pan paniscus. Genomics 87: 39–45.CrossRefGoogle Scholar
  79. Szamalek JM, Cooper DN, Schempp W et al. (2006c) Polymorphic micro-inversions contribute to the genomic variability of humans and chimpanzees. Hum Genet 119: 103–112.CrossRefGoogle Scholar
  80. Szamalek JM, Cooper DN, Hoegel J, Hameister H, Kehrer-Sawatzki H (2007) Chromosomal speciation of humans and chimpanzees revisited: studies of DNA divergence within inverted regions. Cytogenet Genome Res 116: 53–60.PubMedCrossRefGoogle Scholar
  81. Tsend-Ayush E, Grutzner F, Yue Y et al. (2004) Plasticity of human chromosome 3 during primate evolution. Genomics 83: 193–202.PubMedCrossRefGoogle Scholar
  82. Vallender EJ, Lahn BT (2004) Effects of chromosomal rearrangements on human-chimpanzee molecular evolution. Genomics 84: 757–761.PubMedCrossRefGoogle Scholar
  83. Ventura M, Mudge JM, Palumbo V et al. (2003) Neocentromeres in 15q24–26 map to duplicons which flanked an ancestral centromere in 15q25. Genome Res 13: 2059–2068.PubMedCrossRefGoogle Scholar
  84. Ventura M, Weigl S, Carbone L et al. (2004) Recurrent sites for new centromere seeding. Genome Res 14: 1696–1703.PubMedCrossRefGoogle Scholar
  85. Ventura M, Antonacci F, Cardone MF et al. (2007) Evolutionary formation of new centromeres in macaque. Science 316: 243–246.PubMedCrossRefGoogle Scholar
  86. Weise A, Starke H, Mrasek K, Claussen U, Liehr T (2005) New insights into the evolution of chromosome 1. Cytogenet Genome Res 108: 217–222.PubMedCrossRefGoogle Scholar
  87. Weise A, Gross M, Schmidt S, Reichelt F, Claussen U, Liehr T (2007) New aspects of chromosomal evolution in the gorilla and the orangutan. Int J Mol Med 19: 437–443.PubMedGoogle Scholar
  88. Wells RD (2007) Non-B DNA conformations, mutagenesis and disease. Trends Biochem Sci 32: 271–278.PubMedCrossRefGoogle Scholar
  89. Wells RD, Dere R, Hebert ML, Napierala M, Son LS (2005) Advances in mechanisms of genetic instability related to hereditary neurological diseases. Nucleic Acids Res 33: 3785–3798.PubMedCrossRefGoogle Scholar
  90. Wienberg J (2005) Fluorescence in situ hybridization to chromosomes as a tool to understand human and primate genome evolution. Cytogenet Genome Res 108: 139–160.PubMedCrossRefGoogle Scholar
  91. Wienberg J, Jauch A, Ludecke HJ et al. (1994) The origin of human chromosome 2 analyzed by comparative chromosome mapping with a DNA microlibrary. Chrom Res 2: 405–410.PubMedCrossRefGoogle Scholar
  92. Wilson GM, Flibotte S, Missirlis PI et al. (2006) Identification by full-coverage array CGH of human DNA copy number increases relative to chimpanzee and gorilla. Genome Res 16: 173–181.PubMedCrossRefGoogle Scholar
  93. Yue Y, Grossmann B, Ferguson-Smith M, Yang F, Haaf T (2005) Comparative cytogenetics of human chromosome 3q21.3 reveals a hot spot for ectopic recombination in hominoid evolution. Genomics 85: 36–47.PubMedCrossRefGoogle Scholar
  94. Yue Y, Tsend-Ayush E, Grutzner F, Grossmann B, Haaf T (2006) Segmental duplication associated with evolutionary instability of human chromosome 3p25.1. Cytogenet Genome Res 112: 202–207.PubMedCrossRefGoogle Scholar
  95. Yunis JJ, Prakash O (1982) The origin of man: a chromosomal pictorial legacy. Science 215: 1525–1530.PubMedCrossRefGoogle Scholar
  96. Zhang J, Wang X, Podlaha O (2004) Testing the chromosomal speciation hypothesis for humans and chimpanzees. Genome Res 14: 845–851.PubMedCrossRefGoogle Scholar
  97. Zhang L, Lu HH, Chung WY, Yang J, Li WH (2005) Patterns of segmental. duplication in the human genome. Mol Biol Evol 22: 135–141.PubMedCrossRefGoogle Scholar
  98. Zhao S, Shetty J, Hou L et al. (2004) Human, mouse, and rat genome large-scale rearrangements: stability versus speciation. Genome Res 14: 1851–1860.PubMedCrossRefGoogle Scholar

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© Springer 2008

Authors and Affiliations

  1. 1.Institute of Human GeneticsUniversity of UlmUlmGermany
  2. 2.Institute of Medical Genetics, School of MedicineCardiff UniversityCardiffUK

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