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Primate segmental duplications: crucibles of evolution, diversity and disease

An Erratum to this article was published on 01 November 2006

Key Points

  • Human and great ape genomes show an enrichment of large, interspersed and highly identical duplications, known as segmental duplications, when compared with other species.

  • Primate segmental duplications are organized into complicated structures (duplication hubs) that are made up of many independent duplication events.

  • Analyses of the boundaries between segmental duplications suggest distinct mechanisms for their origin, including Alu repetitive elements, mediated transposition and mechanisms that are mediated by both homology-driven and non-homology-driven events.

  • Segmental duplications are enriched at the breakpoints of chromosomal synteny between human and mammalian genomes.

  • Evolutionary analyses suggest spatial and temporal biases in the emergence of SDs, indicating distinct waves of duplication during the evolution of the human and great ape genomes.

  • Both fusion genes and genes showing signatures of adaptive evolution have been documented among some of the most abundant and recently duplicated intrachromosomal duplications.

  • Segmental duplications mediate rare structural rearrangements and common copy-number polymorphisms that are associated with disease and disease susceptibility.

Abstract

Compared with other mammals, the genomes of humans and other primates show an enrichment of large, interspersed segmental duplications (SDs) with high levels of sequence identity. Recent evidence has begun to shed light on the origin of primate SDs, pointing to a complex interplay of mechanisms and indicating that distinct waves of duplication took place during primate evolution. There is also evidence for a strong association between duplication, genomic instability and large-scale chromosomal rearrangements. Exciting new findings suggest that SDs have not only created novel primate gene families, but might have also influenced current human genic and phenotypic variation on a previously unappreciated scale. A growing number of examples link natural human genetic variation of these regions to susceptibility to common disease.

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Figure 1: The distribution of segmental duplications (SDs) in the human genome.
Figure 2: Models of segmental duplication (SD) formation.
Figure 3: Mechanisms of segmental duplication (SD) divergence.
Figure 4: Non-random mechanisms of segmental duplication (SD) evolution.
Figure 5: Variation in genomic segmental duplication (SD) content between chimpanzees and humans.
Figure 6: Gene innovation in segmental duplications (SDs).

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References

  1. Bailey, J. A., Yavor, A. M., Massa, H. F., Trask, B. J. & Eichler, E. E. Segmental duplications: organization and impact within the current human genome project assembly. Genome Res. 11, 1005–1017 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  3. Cheung, J. et al. Recent segmental and gene duplications in the mouse genome. Genome Biol. 4, R47 (2003).

    PubMed  PubMed Central  Google Scholar 

  4. Tuzun, E., Bailey, J. A. & Eichler, E. E. Recent segmental duplications in the working draft assembly of the brown Norway rat. Genome Res. 14, 493–506 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bailey, J. A., Church, D. M., Ventura, M., Rocchi, M. & Eichler, E. E. Analysis of segmental duplications and genome assembly in the mouse. Genome Res. 14, 789–801 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cheng, Z. et al. A genome-wide comparison of recent chimpanzee and human segmental duplications. Nature 437, 88–93 (2005).

    CAS  PubMed  Google Scholar 

  7. She, X. et al. 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 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cheung, J. et al. Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence. Genome Biol. 4, R25 (2003).

    PubMed  PubMed Central  Google Scholar 

  9. Zhang, L., Lu, H. H., Chung, W. Y., Yang, J. & Li, W. H. Patterns of segmental duplication in the human genome. Mol. Biol. Evol. 22, 135–141 (2005).

    CAS  PubMed  Google Scholar 

  10. Bailey, J. A. et al. Human-specific duplication and mosaic transcripts: the recent paralogous structure of chromosome 22. Am. J. Hum. Genet. 70, 83–100 (2002).

    CAS  PubMed  Google Scholar 

  11. She, X. et al. The structure and evolution of centromeric transition regions within the human genome. Nature 430, 857–864 (2004).

    CAS  PubMed  Google Scholar 

  12. She, X. et al. Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431, 927–930 (2004).

    CAS  PubMed  Google Scholar 

  13. Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    CAS  PubMed  Google Scholar 

  14. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004).

  15. Eichler, E. E., Clark, R. A. & She, X. An assessment of the sequence gaps: unfinished business in a finished human genome. Nature Rev. Genet. 5, 345–354 (2004).

    CAS  PubMed  Google Scholar 

  16. Courseaux, A. & Nahon, J. L. Birth of two chimeric genes in the Hominidae lineage. Science 291, 1293–1297 (2001).

    CAS  PubMed  Google Scholar 

  17. Horvath, J. E. et al. Punctuated duplication seeding events during the evolution of human chromosome 2p11. Genome Res 15, 914–927 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Johnson, M. E. et al. Positive selection of a gene family during the emergence of humans and African apes. Nature 413, 514–519 (2001).

    CAS  PubMed  Google Scholar 

  19. Courseaux, A. et al. Segmental duplications in euchromatic regions of human chromosome 5: a source of evolutionary instability and transcriptional innovation. Genome Res. 13, 369–381 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Stankiewicz, P., Shaw, C. J., Withers, M., Inoue, K. & Lupski, J. R. Serial segmental duplications during primate evolution result in complex human genome architecture. Genome Res. 14, 2209–2220 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ciccarelli, F. D. et al. Complex genomic rearrangements lead to novel primate gene function. Genome Res. 15, 343–351 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Newman, T. L. et al. A genome-wide survey of structural variation between human and chimpanzee. Genome Res. 15, 1344–1356 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Humphray, S. J. et al. DNA sequence and analysis of human chromosome 9. Nature 429, 369–374 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kirsch, S. et al. Interchromosomal segmental duplications of the pericentromeric region on the human Y chromosome. Genome Res. 15, 195–204 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Guy, J. et al. Genomic sequence and transcriptional profile of the boundary between pericentromeric satellites and genes on human chromosome arm 10p. Genome Res. 13, 159–172 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Guy, J. et al. Genomic sequence and transcriptional profile of the boundary between pericentromeric satellites and genes on human chromosome arm 10q. Hum. Mol. Genet. 9, 2029–2042 (2000).

    CAS  PubMed  Google Scholar 

  27. Brun, M. E., Ruault, M., Ventura, M., Roizes, G. & De Sario, A. Juxtacentromeric region of human chromosome 21: a boundary between centromeric heterochromatin and euchromatic chromosome arms. Gene 312, 41–50 (2003).

    CAS  PubMed  Google Scholar 

  28. Horvath, J., Schwartz, S. & Eichler, E. The mosaic structure of a 2p11 pericentromeric segment: a strategy for characterizing complex regions of the human genome. Genome Res 10, 839–852 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Eichler, E. E. et al. Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity. Hum. Mol. Genet. 6, 991–1002 (1997).

    CAS  PubMed  Google Scholar 

  30. Riethman, H. C. et al. Integration of telomere sequences with the draft human genome sequence. Nature 409, 948–951 (2001).

    CAS  PubMed  Google Scholar 

  31. Linardopoulou, E. V. et al. Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437, 94–100 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Trask, B. et al. Members of the olfactory receptor gene family are contained in large blocks of DNA duplicated polymorphically near the ends of human chromosomes. Hum. Mol. Genet. 7, 13–26 (1998).

    CAS  PubMed  Google Scholar 

  33. Antonell, A., de Luis, O., Domingo-Roura, X. & Perez-Jurado, L. A. Evolutionary mechanisms shaping the genomic structure of the Williams–Beuren syndrome chromosomal region at human 7q11.23. Genome Res. 15, 1179–1188 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bradley, M. E. & Benner, S. A. Phylogenomic approaches to common problems encountered in the analysis of low copy repeats: the sulfotransferase 1A gene family example. BMC Evol. Biol. 5, 22 (2005).

  35. Jin, H. et al. Structural evolution of the BRCA1 genomic region in primates. Genomics 84, 1071–1082 (2004).

    CAS  PubMed  Google Scholar 

  36. Koszul, R., Caburet, S., Dujon, B. & Fischer, G. Eucaryotic genome evolution through the spontaneous duplication of large chromosomal segments. EMBO J. 23, 234–243 (2004).

    CAS  PubMed  Google Scholar 

  37. Schacherer, J., de Montigny, J., Welcker, A., Souciet, J. L. & Potier, S. Duplication processes in Saccharomyces cerevisiae haploid strains. Nucleic Acids Res. 33, 6319–6326 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bailey, J. A., Liu, G. & Eichler, E. E. An Alu transposition model for the origin and expansion of human segmental duplications. Am. J. Hum. Genet. 73, 823–834 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Jurka, J., Kohany, O., Pavlicek, A., Kapitonov, V. V. & Jurka, M. V. Duplication, coclustering, and selection of human Alu retrotransposons. Proc. Natl Acad. Sci. USA 101, 1268–1272 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou, Y. & Mishra, B. Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling. Proc. Natl Acad. Sci. USA 102, 4051–4056 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Babcock, M. et al. Shuffling of genes within low-copy repeats on 22q11 (LCR22) by Alu-mediated recombination events during evolution. Genome Res. 13, 2519–2532 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Eichler, E. E., Archidiacono, N. & Rocchi, M. CAGGG repeats and the pericentromeric duplication of the hominoid genome. Genome Res. 9, 1048–1058 (1999).

    CAS  PubMed  Google Scholar 

  43. Woodward, K. J. et al. Heterogeneous duplications in patients with Pelizaeus–Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am. J. Hum. Genet. 77, 966–987 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pentao, L., Wise, C., Chinault, A., Patel, P. & Lupski, J. Charcot–Marie–Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1. 5 Mb monomer unit. Nature Genet. 2, 292–300 (1992).

    CAS  PubMed  Google Scholar 

  45. Shaw, C. J. & Lupski, J. R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13, R57–R64 (2004).

    Google Scholar 

  46. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002).

    CAS  PubMed  Google Scholar 

  47. Reiter, L. T. et al. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am. J. Hum. Genet. 62, 1023–1033 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lopez-Correa, C. et al. Recombination hotspot in NF1 microdeletion patients. Hum. Mol. Genet. 10, 1387–1392 (2001).

    CAS  PubMed  Google Scholar 

  49. Bi, W. et al. Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am. J. Hum. Genet. 73, 1302–1315 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Fredman, D. et al. Complex SNP-related sequence variation in segmental genome duplications. Nature Genet. 36, 861–866 (2004).

    CAS  PubMed  Google Scholar 

  51. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  PubMed  Google Scholar 

  52. Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949–951 (2004).

    CAS  PubMed  Google Scholar 

  53. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nature Genet. 37, 727–732 (2005).

    CAS  PubMed  Google Scholar 

  54. Sharp, A. J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Tayebi, N. et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol. Genet. Metab. 79, 104–109 (2003).

    CAS  PubMed  Google Scholar 

  56. Pavlicek, A., House, R., Gentles, A. J., Jurka, J. & Morrow, B. E. Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome. Genome Res. 15, 1487–1495 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Verrelli, B. C. & Tishkoff, S. A. Signatures of selection and gene conversion associated with human color vision variation. Am. J. Hum. Genet. 75, 363–375 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bosch, E., Hurles, M. E., Navarro, A. & Jobling, M. A. Dynamics of a human interparalog gene conversion hotspot. Genome Res. 14, 835–844 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hurles, M. E., Willey, D., Matthews, L. & Hussain, S. S. Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots. Genome Biol. 5, R55 (2004).

    PubMed  PubMed Central  Google Scholar 

  60. Jeffreys, A. J. & May, C. A. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nature Genet. 36, 151–156 (2004).

    CAS  PubMed  Google Scholar 

  61. Jeffreys, A. J. & Neumann, R. Factors influencing recombination frequency and distribution in a human meiotic crossover hotspot. Hum. Mol. Genet. 14, 2277–2287 (2005).

    CAS  PubMed  Google Scholar 

  62. Jackson, M. S. et al. Evidence for widespread reticulate evolution within human duplicons. Am. J. Hum. Genet. 77, 824–840 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Estivill, X. et al. Chromosomal regions containing high-density and ambiguously mapped putative single nucleotide polymorphisms (SNPs) correlate with segmental duplications in the human genome. Hum. Mol. Genet. 11, 1987–1995 (2002).

    CAS  PubMed  Google Scholar 

  64. Hallast, P., Nagirnaja, L., Margus, T. & Laan, M. Segmental duplications and gene conversion: human luteinizing hormone/chorionic gonadotropin β gene cluster. Genome Res. 15, 1535–1546 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Rozen, S. et al. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature 423, 873–876 (2003).

    CAS  PubMed  Google Scholar 

  66. Gonzalez, I. L. et al. Variation among human 28S ribosomal RNA genes. Proc. Natl Acad. Sci. USA 82, 7666–7670 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Reiter, L. et al. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nature Genet. 12, 288–297 (1996).

    CAS  PubMed  Google Scholar 

  68. Bayes, M., Magano, L. F., Rivera, N., Flores, R. & Perez Jurado, L. A. Mutational mechanisms of Williams–Beuren syndrome deletions. Am. J. Hum. Genet. 73, 131–151 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Visser, R. et al. Identification of a 3.0-kb major recombination hotspot in patients with sotos syndrome who carry a common 1.9-Mb microdeletion. Am. J. Hum. Genet. 76, 52–67 (2005).

    CAS  PubMed  Google Scholar 

  70. Nadeau, J. H. & Taylor, B. A. Lengths of chromosomal segments conserved since divergence of man and mouse. Proc. Natl Acad. Sci. USA 81, 814–818 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Pevzner, P. & Tesler, G. Genome rearrangements in mammalian evolution: lessons from human and mouse genomes. Genome Res. 13, 37–45 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kent, W. J., Baertsch, R., Hinrichs, A., Miller, W. & Haussler, D. Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes. Proc. Natl Acad. Sci. USA 100, 11484–11489 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Pevzner, P. & Tesler, G. Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution. Proc. Natl Acad. Sci. USA 100, 7672–7677 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bourque, G., Pevzner, P. A. & Tesler, G. Reconstructing the genomic architecture of ancestral mammals: lessons from human, mouse, and rat genomes. Genome Res. 14, 507–516 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Armengol, L., Pujana, M. A., Cheung, J., Scherer, S. W. & Estivill, X. 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 (2003).

    CAS  PubMed  Google Scholar 

  76. Bailey, J. A., Baertsch, R., Kent, W. J., Haussler, D. & Eichler, E. E. Hotspots of mammalian chromosomal evolution. Genome Biol. 5, R23 (2004).

    PubMed  PubMed Central  Google Scholar 

  77. Armengol, L. et al. Murine segmental duplications are hot spots for chromosome and gene evolution. Genomics 86, 692–700 (2005).

    CAS  PubMed  Google Scholar 

  78. Murphy, W. J. et al. Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps. Science 309, 613–617 (2005).

    CAS  PubMed  Google Scholar 

  79. Yunis, J. J. & Prakash, O. The origin of man: a chromosomal pictorial legacy. Science 215, 1525–1530 (1982).

    CAS  PubMed  Google Scholar 

  80. Yunis, J. J., Sawyer, J. R. & Dunham, K. The striking resemblance of high-resolution G-banded chromosomes of man and chimpanzee. Science 208, 1145–1148 (1980).

    CAS  PubMed  Google Scholar 

  81. Fan, Y., Linardopoulou, E., Friedman, C., Williams, E. & Trask, B. J. 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 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Yue, Y. et al. Genomic structure and paralogous regions of the inversion breakpoint occurring between human chromosome 3p12.3 and orangutan chromosome 2. Cytogenet. Genome Res. 108, 98–105 (2005).

    CAS  PubMed  Google Scholar 

  83. Kehrer-Sawatzki, H. et al. Breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee (Pan troglodytes). Hum. Mutat. 25, 45–55 (2005).

    CAS  PubMed  Google Scholar 

  84. Szamalek, J. M. et al. Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome. Hum. Genet. 117, 168–176 (2005).

    CAS  PubMed  Google Scholar 

  85. Kehrer-Sawatzki, H., Szamalek, J. M., Tanzer, S., Platzer, M. & Hameister, H. Molecular characterization of the pericentric inversion of chimpanzee chromosome 11 homologous to human chromosome 9. Genomics 85, 542–550 (2005).

    CAS  PubMed  Google Scholar 

  86. Locke, D. P. et al. Refinement of a chimpanzee pericentric inversion breakpoint to a segmental duplication cluster. Genome Biol. 4, R50 (2003).

    PubMed  PubMed Central  Google Scholar 

  87. Kehrer-Sawatzki, H., Sandig, C. A., Goidts, V. & Hameister, H. Breakpoint analysis of the pericentric inversion between chimpanzee chromosome 10 and the homologous chromosome 12 in humans. Cytogenet. Genome Res. 108, 91–97 (2005).

    CAS  PubMed  Google Scholar 

  88. Shimada, M. K. et al. Nucleotide sequence comparison of a chromosome rearrangement on human chromosome 12 and the corresponding ape chromosomes. Cytogenet. Genome Res. 108, 83–90 (2005).

    CAS  PubMed  Google Scholar 

  89. Goidts, V. et al. Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 16. Genome Res. 15, 1232–1242 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kehrer-Sawatzki, H. et al. Molecular characterization of the pericentric inversion that causes differences between chimpanzee chromosome 19 and human chromosome 17. Am. J. Hum. Genet. 71, 375–388 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Dennehey, B. K., Gutches, D. G., McConkey, E. H. & Krauter, K. S. Inversion, duplication, and changes in gene context are associated with human chromosome 18 evolution. Genomics 83, 493–501 (2004).

    CAS  PubMed  Google Scholar 

  92. Muller, S., Hollatz, M. & Wienberg, J. Chromosomal phylogeny and evolution of gibbons (Hylobatidae). Hum. Genet. 113, 493–501 (2003).

    PubMed  Google Scholar 

  93. Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).

  94. Feuk, L. et al. Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genet. 1, e56 (2005).

    PubMed  PubMed Central  Google Scholar 

  95. Fortna, A. et al. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2, e207 (2004).

    PubMed  PubMed Central  Google Scholar 

  96. Muller, H. J. Bar duplication. Science 83, 528–530 (1936).

    CAS  PubMed  Google Scholar 

  97. Ohno, S., Wolf, U. & Atkin, N. Evolution from fish to mammals by gene duplication. Hereditas 59, 169–187 (1968).

    CAS  PubMed  Google Scholar 

  98. Taylor, J. S. & Raes, J. Duplication and divergence: the evolution of new genes and old ideas. Annu. Rev. Genet. 38, 615–643 (2004).

    CAS  PubMed  Google Scholar 

  99. Brand-Arpon, V. et al. A genomic region encompassing a cluster of olfactory receptor genes and a myosin light chain kinase (MYLK) gene is duplicated on human chromosome regions 3q13–q21 and 3p13. Genomics 56, 98–110 (1999).

    CAS  PubMed  Google Scholar 

  100. Wong, A. C. et al. Two novel human RAB genes with near identical sequence each map to a telomere-associated region: the subtelomeric region of 22q13.3 and the ancestral telomere band 2q13. Genomics 59, 326–334 (1999).

    CAS  PubMed  Google Scholar 

  101. Wong, A. et al. Diverse fates of paralogs following segmental duplication of telomeric genes. Genomics 84, 239–247 (2004).

    CAS  PubMed  Google Scholar 

  102. Mudge, J. M. & Jackson, M. S. Evolutionary implications of pericentromeric gene expression in humans. Cytogenet. Genome Res. 108, 47–57 (2005).

    CAS  PubMed  Google Scholar 

  103. Grunau, C. et al. Frequent DNA hypomethylation of human juxtacentromeric BAGE loci in cancer. Genes Chromosomes Cancer 43, 11–24 (2005).

    CAS  PubMed  Google Scholar 

  104. Hollox, E. J., Armour, J. A. & Barber, J. C. Extensive normal copy number variation of a β-defensin antimicrobial-gene cluster. Am. J. Hum. Genet. 73, 591–600 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Khaitovich, P. et al. Regional patterns of gene expression in human and chimpanzee brains. Genome Res. 14, 1462–1473 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Birtle, Z., Goodstadt, L. & Ponting, C. Duplication and positive selection among hominin-specific PRAME genes. BMC Genomics 6, 120 (2005).

  107. Semple, C. A., Rolfe, M. & Dorin, J. R. Duplication and selection in the evolution of primate β-defensin genes. Genome Biol. 4, R31 (2003).

    PubMed  PubMed Central  Google Scholar 

  108. Feuk, L., Carson, A. R. & Scherer, S. W. Structural variation in the human genome. Nature Rev. Genet. 7, 85–97 (2006).

    CAS  PubMed  Google Scholar 

  109. Eichler, E. E. Widening the spectrum of human genetic variation. Nature Genet. 38, 9–11 (2006).

    CAS  PubMed  Google Scholar 

  110. Perry, G. H. et al. Hotspots for copy number variation in chimpanzees and humans. Proc. Natl Acad. Sci. USA 103, 8006–8011 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Wilson, E. B. The sex chromosomes. Arch. Mikrosk. Anat. Entwicklungsmech. 77, 249–271 (1911).

    Google Scholar 

  112. Levine, P., Katzin, E. M. & Burnham, L. Isoimmunizationin pregnancy: its possible bearing on the etiology of erythroblastosis foetalis. JAMA 116, 825–827 (1941).

    Google Scholar 

  113. Cooley, T. B. & Lee, P. A series of cases of splenomegaly inchildren with anemia and peculiar bone changes. Trans. Am. Pediatr. Soc. 37, 29 (1925).

  114. Fucharoen, S. & Winichagoon, P. Thalassemia and abnormal hemoglobin. Int. J. Hematol. 76 (Suppl. 2), 83–89 (2002).

    PubMed  Google Scholar 

  115. Wagner, F. F. & Flegel, W. A. Review: the molecular basis of the Rh blood group phenotypes. Immunohematol. 20, 23–36 (2004).

    CAS  Google Scholar 

  116. Deeb, S. S. The molecular basis of variation in human color vision. Clin. Genet. 67, 369–377 (2005).

    CAS  PubMed  Google Scholar 

  117. Lupski, J. R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).

    CAS  PubMed  Google Scholar 

  118. Stefansson, H. et al. A common inversion under selection in Europeans. Nature Genet 37, 129–137 (2005).

    CAS  PubMed  Google Scholar 

  119. Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005).

    CAS  PubMed  Google Scholar 

  120. Aitman, T. J. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–855 (2006).

    CAS  PubMed  Google Scholar 

  121. Kleinjan, D. A. & van Heyningen, V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76, 8–32 (2005).

    CAS  PubMed  Google Scholar 

  122. Lee, J. A. et al. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol. 59, 398–403 (2006).

    CAS  PubMed  Google Scholar 

  123. Velagaleti, G. V. et al. Position effects due to chromosome breakpoints that map approximately 900 kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am. J. Hum. Genet. 76, 652–662 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Paulding, C. A., Ruvolo, M. & Haber, D. A. The Tre2 (USP6) oncogene is a hominoid-specific gene. Proc. Natl Acad. Sci. USA 100, 2507–2511 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Zody, M. C. et al. Analysis of the DNA sequence and duplication history of human chromosome 15. Nature 440, 671–675 (2006).

    CAS  PubMed  Google Scholar 

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Correspondence to Evan E. Eichler.

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FURTHER INFORMATION

Chimpanzee Segmental Duplication Database, Genome Sciences, University of Washington

Ensembl Genome Browsers

Human Genome Segmental Duplication Database, Hospital for Sick Children, University of Toronto

Human Segmental Duplication Database, Genome Sciences, University of Washington

UCSC Genome Bioinformatics

Glossary

Low copy repeat

A term with variable meaning that is sometimes used synonymously with segmental duplication. It can denote a group of juxtaposed duplicons (duplication block), individual segmental duplication events or individual duplicons. The term emphasizes the low copy number of repeats (2–50 copies) relative to most transposable elements.

Gene conversion

Used here in the general sense as the transfer of genetic information from one sequence to another based on homology — the strict definition is non-reciprocal meiotic exchange resulting in products with a 3:1 ratio of alleles.

Molecular clock

A molecular clock is said to exist when the rate of nucleotide change is approximately constant over evolutionary time; this rate can then be used to estimate the age of duplication or speciation events.

Whole-genome shotgun sequencing

A sequencing strategy that involves random fragmentation of the entire genome. The fragments are sequenced, and highly refined algorithms are used to reassemble the original genomic DNA sequence.

Fluorescence in situ hybridization

A technique in which a fluorescently labelled DNA probe is used to detect a particular chromosome region or gene by fluorescence microscopy. The intensity of the signal can be used to detect copy-number differences between the labelled chromosomal regions.

Hominoid

A primate superfamily that includes the great apes (orangutans, gorillas, chimpanzees and bonobos) and humans(hominids).

Effective ancestral population size

Approximately the number of breeding individuals that produce offspring that live to reproductive age. It influences the rate of loss of genetic variation, the efficiency of natural selection and the accumulation of beneficial and deleterious mutations. It is frequently much smaller than the number of individuals in a population.

Pericentromeric region

The sequence adjacent to the centromere that is often defined as the first chromosomal sub-band or by defined physical distances of 2–5 Mb from the higher-order α-satellite arrays that comprise the centromere.

Interstitial region

An arbitrary name given to the euchromatic sequence within a chromosome arm that is bounded by the pericentromeric and subtelomeric regions.

Duplicon

A duplication, or portion thereof, that is traceable to an ancestral or donor location; a secondary duplication event can be composed of multiple duplicons. Also sometimes referred to as a low copy repeat.

Microrearrangements

Rearrangements that are less than a megabase in size.

Non-allelic homologous recombination

Homologous recombination between paralogous sequence (for example, segmental duplication and repetitive sequence); a major mechanism of recurrent rearrangements, also known as unequal crossing-over.

Immunoglobulin heavy-chain class-switch recombination

Non-homologous recombination that occurs during the development of B lymphocytes to produce difference classes (isotypes) of heavy-chain molecule.

α-Satellite

A class of 170 bp repetitive sequences that are found at the centromeres of most primates. They are present in tandem arrays that constitute megabases of sequence.

Genomic disorder

A disease that results from the gain, loss or alteration of dosage-sensitive gene(s) as a result of genomic rearrangement (such as duplication, deletion and inversion).

Recombination hot spots

Regions of sequence that undergo increased meiotic rates of recombination.

Single nucleotide polymorphism

(SNP). A single nucleotide difference between orthologous sites. A strict definition requires a population frequency of at least 1% for the rare allele. SNPs represents 90% of the genetic variation within the human population in terms of numbers of variants.

Paralogous sequence variant

A single nucleotide difference between copies of a segmental duplication (or any paralogous sequence), which can be variant or fixed in a population.

Complete hydatidiform mole

Placental mass with uncontrolled growth due to the fertilization of an enucleated egg with one (90%) or two (10%) sperm — useful for genetic studies as those derived from single sperm represent a haploid genome.

Chromosome painting

Visualization of individual, whole chromosomes by fluorescence in situ hybridization.

Synteny

A term originally meaning simply 'on the same chromosome' (regardless of linkage) which has now been co-opted to refer to a continuous block of sequence with a shared organization (conserved linkage) between two or more species.

Exaptation

When a gene or part of a gene (such as a domain or exon) is used for a new potentially adaptive function. Can also be used to describe cases where splicing occurs in non-genic sequence to create a new exon. This is a type of domain accretion, which is the addition of an exon or exons to a gene or transcript.

Duplication block

A group of juxtaposed duplicons that might be duplicated as part of a larger secondary duplication. Also sometimes referred to as a low copy repeat.

Duplication core

The central sequence around which a complex pattern of duplication forms common to a subset of interspersed duplications.

Xenobiotic

A compound that is foreign to biological systems, often referring to man-made compounds that are resistant to biodegradation.

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Bailey, J., Eichler, E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nat Rev Genet 7, 552–564 (2006). https://doi.org/10.1038/nrg1895

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