Skip to main content
SpringerLink
Log in

Polymorphic micro-inversions contribute to the genomic variability of humans and chimpanzees

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

A combination of inter- and intra-species genome comparisons is required to identify and classify the full spectrum of genetic changes, both subtle and gross, that have accompanied the evolutionary divergence of humans and other primates. In this study, gene order comparisons of 11,518 human and chimpanzee orthologous gene pairs were performed to detect regions of inverted gene order that are potentially indicative of small-scale rearrangements such as inversions. By these means, a total of 71 potential micro-rearrangements were detected, nine of which were considered to represent micro-inversions encompassing more than three genes. These putative inversions were then investigated by FISH and/or PCR analyses and the authenticity of five of the nine inversions, ranging in size from ~800 kb to ~4.4 Mb, was confirmed. These inversions mapped to 1p13.2–13.3, 7p22.1, 7p13–14.1, 18p11.21–11.22 and 19q13.12 and encompass 50, 14, 16, 7 and 16 known genes, respectively. Intriguingly, four of the confirmed inversions turned out to be polymorphic: three were polymorphic in the chimpanzee and one in humans. It is concluded that micro-inversions make a significant contribution to genomic variability in both humans and chimpanzees and inversion polymorphisms may be more frequent than previously realized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE (2002) Recent segmental duplications in the human genome. Science 297:1003–1007

    Article  PubMed  CAS  Google Scholar 

  • Britten RJ (2002) Divergence between samples of chimpanzee and human DNA sequences is 5%, counting indels. Proc Natl Acad Sci USA 99:13633–13635

    Article  PubMed  CAS  Google Scholar 

  • Chen FC, Li WH (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68:444–456

    Article  PubMed  CAS  Google Scholar 

  • Cheng Z, Ventura M, She X, Khaitovich P, Graves T, Osoegawa K, Church D, DeJong P, Wilson RK, Paabo S, Rocchi M, Eichler EE (2005) Genome-wide comparison of recent chimpanzee and human segmental duplications. Nature 437:88–93

    Article  PubMed  CAS  Google Scholar 

  • Cosseddu GM, Perez-Enciso M, Fellous M, Vaiman D (2004) Interspecific chromosome-wide transcription profiles reveal the existence of mammalian-specific and species-specific chromosome domains. J Mol Evol 59:317–328

    Article  PubMed  CAS  Google Scholar 

  • Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, de Pooter T, de Rijk P, Del-Favero J, van Broeckhoven C (2005) Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet 14:1753–1762

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Dutrillaux B (1979) Chromosomal evolution in primates: tentative phylogeny from Microcebus murinus (Prosimian) to man. Hum Genet 48:251–314

    Article  PubMed  CAS  Google Scholar 

  • Enard W, Khaitovich P, Klose J, Zollner S, Heissig F, Giavalisco P, Nieselt-Struwe K, Muchmore E, Varki A, Ravid R, Doxiadis GM, Bontrop RE, Paabo S (2002) Intra- and interspecific variation in primate gene expression patterns. Science 296:340–343

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Fischer A, Gilad Y, Man O, Paabo S (2004) Evolution of bitter taste receptors in humans and apes. Mol Biol Evol 22:432–436

    Article  PubMed  CAS  Google Scholar 

  • Fortna A, Kim Y, MacLaren E, Marshall K, Hahn G, Meltesen L, Brenton M, Hink R, Burgers S, Hernandez-Boussard T, Karimpour-Fard A, Glueck D, McGavran L, Berry R, Pollack J, Sikela JM (2004) Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol 2:E207

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Fujiyama A, Watanabe H, Toyoda A, Taylor TD, Itoh T, Tsai SF, Park HS, Yaspo ML, Lehrach H, Chen Z, Fu G, Saitou N, Osoegawa K, de Jong PJ, Suto Y, Hattori M, Sakaki Y (2002) Construction and analysis of a human–chimpanzee comparative clone map. Science 295:131–134

    Article  PubMed  Google Scholar 

  • Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T, Ohashi H, Voullaire L, Larizza D, Giorda R, Weber JL, Ledbetter DH, Zuffardi O (2001) Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet 68:874–883

    Article  PubMed  CAS  Google Scholar 

  • Giglio S, Calvari V, Gregato G, Gimelli G, Camanini S, Giorda R, Ragusa A, Guerneri S, Selicorni A, Stumm M, Tonnies H, Ventura M, Zollino M, Neri G, Barber J, Wieczorek D, Rocchi M, Zuffardi O (2002) Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8) (p16; p23) translocation. Am J Hum Genet 71:276–285

    Article  PubMed  CAS  Google Scholar 

  • Gimelli G, Pujana MA, Patricelli MG, Russo S, Giardino D, Larizza L, Cheung J, Armengol L, Schinzel A, Estivill X, Zuffardi O (2003) Genomic inversions of human chromosome 15q11–q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum Mol Genet 12:849–858

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Goidts V, Szamalek JM, de Jong PJ, Cooper DN, Chuzhanova N, Hameister H, Kehrer-Sawatzki H (2005a) Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 16. Genome Res 15:1232–1242

    Article  CAS  Google Scholar 

  • Goidts V, Armengol L, Schempp W, Conroy J, Nowak N, Müller S, Cooper DN, Estivill X, Enard W, Szamalek JM, Hameister H, Kehrer-Sawatzki H (2006) Identification of large-scale human-specific copy number variations by inter-species array comparative genomic hybridization (Hum Genet Submitted for publication)

  • Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kaessmann H, Wiebe V, Weiss G, Paabo S (2001) Great ape DNA sequences reveal a reduced diversity and an expansion in humans. Nat Genet 27:155–156

    Article  PubMed  CAS  Google Scholar 

  • Kasprzyk A, Keefe D, Smedley D, London D, Spooner W, Melsopp C, Hammond M, Rocca-Serra P, Cox T, Birney E (2004) EnsMart: a generic system for fast and flexible access to biological data. Genome Res 14:160–169

    Article  PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H, Schreiner B, Tanzer S, Platzer M, Muller 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

    Article  PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H, Sandig C, Chuzhanova N, Goidts V, Szamalek JM, Tanzer S, Muller S, Platzer M, Cooper DN, Hameister H (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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • King MC, Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188:107–116

    Article  PubMed  CAS  Google Scholar 

  • Koop BF, Tagle DA, Goodman M, Slightom JL (1989) A molecular view of primate phylogeny and important systematic and evolutionary questions. Mol Biol Evol 6:580–612

    PubMed  CAS  Google Scholar 

  • Locke DP, Segraves R, Carbone L, Archidiacono N, Albertson DG, Pinkel D, Eichler EE (2003a) Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization. Genome Res 13:347–357

    Article  CAS  Google Scholar 

  • Locke DP, Archidiacono N, Misceo D, Cardone MF, Deschamps S, Roe B, Rocchi M, Eichler EE (2003b) Refinement of a chimpanzee pericentric inversion breakpoint to a segmental duplication cluster. Genome Biol 4:R50

    Article  Google Scholar 

  • Martin J, Han C, Gordon LA, Terry A, Prabhakar S, She X, Xie G, Hellsten U, Chan YM, Altherr M, Couronne O, Aerts A, Bajorek E, Black S, Blumer H, Branscomb E, Brown NC, Bruno WJ, Buckingham JM, Callen DF, Campbell CS, Campbell ML, Campbell EW, Caoile C, Challacombe JF, Chasteen LA, Chertkov O, Chi HC, Christensen M, Clark LM, Cohn JD, Denys M, Detter JC, Dickson M, Dimitrijevic-Bussod M, Escobar J, Fawcett JJ, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Goodwin LA, Grady DL, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Hildebrand CE, Huang W, Israni S, Jett J, Jewett PB, Kadner K, Kimball H, Kobayashi A, Krawczyk MC, Leyba T, Longmire JL, Lopez F, Lou Y, Lowry S, Ludeman T, Manohar CF, Mark GA, McMurray KL, Meincke LJ, Morgan J, Moyzis RK, Mundt MO, Munk AC, Nandkeshwar RD, Pitluck S, Pollard M, Predki P, Parson-Quintana B, Ramirez L, Rash S, Retterer J, Ricke DO, Robinson DL, Rodriguez A, Salamov A, Saunders EH, Scott D, Shough T, Stallings RL, Stalvey M, Sutherland RD, Tapia R, Tesmer JG, Thayer N, Thompson LS, Tice H, Torney DC, Tran-Gyamfi M, Tsai M, Ulanovsky LE, Ustaszewska A, Vo N, White PS, Williams AL, Wills PL, Wu JR, Wu K, Yang J, Dejong P, Bruce D, Doggett NA, Deaven L, Schmutz J, Grimwood J, Richardson P, Rokhsar DS, Eichler EE, Gilna P, Lucas SM, Myers RM, Rubin EM, Pennacchio LA (2004) The sequence and analysis of duplication-rich human chromosome 16. Nature 432:988–994

    Article  PubMed  CAS  Google Scholar 

  • Marzella R, Viggiano L, Miolla V, Storlazzi CT, Ricco A, Gentile E, Roberto R, Surace C, Fratello A, Mancini M, Archidiacono N, Rocchi M (2000) Molecular cytogenetic resources for chromosome 4 and comparative analysis of phylogenetic chromosome IV in great apes. Genomics 63:307–313

    Article  PubMed  CAS  Google Scholar 

  • McLellan RA, Oscarson M, Alexandrie AK, Seidegard J, Evans DA, Rannug A, Ingelman-Sundberg M (1997) Characterization of a human glutathione S-transferase mu cluster containing a duplicated GSTM1 gene that causes ultrarapid enzyme activity. Mol Pharmacol 52:958–965

    PubMed  CAS  Google Scholar 

  • Muller S, Wienberg J (2001) "Bar-coding" primate chromosomes: molecular cytogenetic screening for the ancestral hominoid karyotype. Hum Genet 109:85–94

    Article  PubMed  CAS  Google Scholar 

  • Muller S, Stanyon R, O'Brien PC, Ferguson-Smith MA, Plesker R, Wienberg J (1999) Defining the ancestral karyotype of all primates by multidirectional chromosome painting between tree shrews, lemurs and humans. Chromosoma 108:393–400

    Article  PubMed  CAS  Google Scholar 

  • Murphy WJ, Larkin DM, Everts-van der Wind A, Bourque G, Tesler G, Auvil L, Beever JE, Chowdhary BP, Galibert F, Gatzke L, Hitte C, Meyers SN, Milan D, Ostrander EA, Pape G, Parker HG, Raudsepp T, Rogatcheva MB, Schook LB, Skow LC, Welge M, Womack JE, O'brien SJ, Pevzner PA, Lewin HA (2005) Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps. Science 309:613–617

    Article  PubMed  CAS  Google Scholar 

  • Nickerson E, Nelson DL (1998) Molecular definition of pericentric inversion breakpoints occurring during the evolution of humans and chimpanzees. Genomics 50:368–372

    Article  PubMed  CAS  Google Scholar 

  • Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, Hubisz MJ, Fledel-Alon A, Tanenbaum DM, Civello D, White TJ, Sninsky J, Adams MD, Cargill M (2005) A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol 3(6):e170 (Epub 2005 May 3)

    Google Scholar 

  • Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A, Costa T, Grebe T, Cox S, Tsui LC, Scherer SW (2001) A 1.5 million-base pair inversion polymorphism in families with Williams–Beuren syndrome. Nat Genet 29:321–325

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Scherer SW, Gripp KW, Lucena J, Nicholson L, Bonnefont J-P, Pérez-Jurado LA, Osborne LR (2005) Observation of a parental inversion variant in a rare Williams–Beuren syndrome family with two affected children. Hum Genet 117:383–388

    Article  PubMed  CAS  Google Scholar 

  • Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528

    Article  PubMed  CAS  Google Scholar 

  • Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R, Oseroff VV, Albertson DG, Pinkel D, Eichler EE (2005) Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77:78–88

    Article  PubMed  CAS  Google Scholar 

  • She X, Jiang Z, Clark RA, Liu G, Cheng Z, Tuzun E, Church DM, Sutton G, Halpern AL, Eichler EE (2004) Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431:927–930

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K (2005) A common inversion under selection in Europeans. Nat Genet 37:129–137

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Thomas PD, Kejariwal A, Campbell MJ, Mi H, Diemer K, Guo N, Ladunga I, Ulitsky-Lazareva B, Muruganujan A, Rabkin S, Vandergriff JA, Doremieux O (2003a) PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification. Nucleic Acids Res 31:334–341

    Article  CAS  Google Scholar 

  • Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, Diemer K, Muruganujan A, Narechania A (2003b) PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 13:2129–2141

    Article  CAS  Google Scholar 

  • Tuzun E, Sharp AJ, Bailey JA, Kaul R, Morrison VA, Pertz LM, Haugen E, Hayden H, Albertson D, Pinkel D, Olson MV, Eichler EE (2005) Fine-scale structural variation of the human genome. Nat Genet 37:727–732

    Article  PubMed  CAS  Google Scholar 

  • Visser R, Shimokawa O, Harada N, Kinoshita A, Ohta T, Niikawa N, Matsumoto N (2005) 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

    Article  PubMed  CAS  Google Scholar 

  • Yu N, Jensen-Seaman MI, Chemnick L, Kidd JR, Deinard AS, Ryder O, Kidd KK, Li WH (2003) Low nucleotide diversity in chimpanzees and bonobos. Genetics 164:1511–1518

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Yunis JJ, Sawyer JR, Dunham K (1980) The striking resemblance of high-resolution G-banded chromosomes of man and chimpanzee. Science 208:1145–1148

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Antje Kollak and Helene Spöri for technical assistance. This research was funded by the Deutsche Forschungsgemeinschaft (DFG KE 724/2-1).

Author information

Authors and Affiliations

  1. Department of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    Justyna M. Szamalek, Peter Minich, Matthias Kohn, Josef Hoegel, Violaine Goidts, Horst Hameister & Hildegard Kehrer-Sawatzki

  2. Institute of Medical Genetics, Cardiff University, Heath Park, CF14 4XN, Cardiff, UK

    David N. Cooper

  3. Institute of Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany

    Werner Schempp

Authors
  1. Justyna M. Szamalek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David N. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Werner Schempp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Minich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Kohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Josef Hoegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Violaine Goidts
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Horst Hameister
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hildegard Kehrer-Sawatzki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hildegard Kehrer-Sawatzki.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Szamalek, J.M., Cooper, D.N., Schempp, W. et al. Polymorphic micro-inversions contribute to the genomic variability of humans and chimpanzees. Hum Genet 119, 103–112 (2006). https://doi.org/10.1007/s00439-005-0117-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-005-0117-6

Keywords

Search

Navigation