Journal of Molecular Evolution

, Volume 60, Issue 3, pp 365–377 | Cite as

The Biased Distribution of Alus in Human Isochores Might Be Driven by Recombination

  • Michael Hackenberg
  • Pedro Bernaola-Galván
  • Pedro Carpena
  • José L. Oliver
Article

Abstract

Alu retrotransposons do not show a homogeneous distribution over the human genome but have a higher density in GC-rich (H) than in AT-rich (L) isochores. However, since they preferentially insert into the L isochores, the question arises: What is the evolutionary mechanism that shifts the Alu density maximum from L to H isochores? To disclose the role played by each of the potential mechanisms involved in such biased distribution, we carried out a genome-wide analysis of the density of the Alus as a function of their evolutionary age, isochore membership, and intron vs. intergene location. Since Alus depend on the retrotransposase encoded by the LINE1 elements, we also studied the distribution of LINE1 to provide a complete evolutionary scenario. We consecutively check, and discard, the contributions of the Alu/LINE1 competition for retrotransposase, compositional matching pressure, and Alu overrepresentation in introns. In analyzing the role played by unequal recombination, we scan the genome for Alu trimers, a direct product of Alu–Alu recombination. Through computer simulations, we show that such trimers are much more frequent than expected, the observed/expected ratio being higher in L than in H isochores. This result, together with the known higher selective disadvantage of recombination products in H isochores, points to Alu–Alu recombination as the main agent provoking the density shift of Alus toward the GC-rich parts of the genome. Two independent pieces of evidence—the lower evolutionary divergence shown by recently inserted Alu subfamilies and the higher frequency of old stand-alone Alus in L isochores—support such a conclusion. Other evolutionary factors, such as population bottlenecks during primate speciation, may have accelerated the fast accumulation of Alus in GC-rich isochores.

Keywords

Alu LINE1 Retrotransposons Alu–Alu recombination Selection Isochores Human genome 

Notes

Acknowledgments

Helpful comments from A. Marín, J.P. Martínez-Camacho, M. Ruiz-Rejón, and two anonymous reviewers are greatly appreciated. We are also grateful to A. Smit for providing the RepeatMasker computer program. This work was supported by the Spanish Government (Grants BIO2002-04014-C03-01/02 to J.L.O. and P.B. and BFM2002-00183 to P.C. and P.B.) and Plan Andaluz de Investigacion (CVI-162). M.H. acknowledges a predoctoral grant from the University of Granada (Spain). The help of David Nesbitt and Christopher Previti with the English version of the manuscript is also appreciated.

References

  1. Babcock, M, Pavliček, A, Spiteri, E, Kashork, CD, Isohikhes, I, Shaffer, LG, Jurka, J, Morrow, BE 2003Shuffling of genes within low-copy repeats on 22q11 (LCR22) by Alu-mediated recombination events during evolutionGenome Res1325192532PubMedGoogle Scholar
  2. Baker, MD, Read, LR, Beatty, BG, NG, P 1996Requirements for ectopic homologous recombination in mammalian somatic CellsMol Cell Biol1671227132PubMedGoogle Scholar
  3. Batzer, MA, Deininger, PL 2002Alu repeats and human genomic diversityNat Rev Genet3110Google Scholar
  4. Bernaola-Galván, P, Román-Roldán, R, Oliver, JL 1996Compositional segmentation and long-range fractal correlation in DNA sequencesPhys Rev E5351815189Google Scholar
  5. Bernardi, G, Olofson, B, Filipski, J, Zerial, M, Salinas, J, Cuny, G, Meunier-Rotival, M, Rodier, F 1985The mosaic genome of warm-blooded vertebratesScience228953958PubMedGoogle Scholar
  6. Bernardi, G 2000Isochores and the evolutionary genomics of vertebratesGene241317CrossRefPubMedGoogle Scholar
  7. Bernardi, G 2001Misunderstandings about isochors Part 1Gene276313PubMedGoogle Scholar
  8. Boeke, JD 1997LINEs and Alus—The polyA connectionNat Genet1667CrossRefPubMedGoogle Scholar
  9. Britten, RJ 1996DNA sequence insertion and evolutionary variation in gene regulationProc Natl Acad Sci USA9393749377PubMedGoogle Scholar
  10. Brookfield, JF 2001Selection on Alu sequences?Curr Biol11900901Google Scholar
  11. Chu, WM, Ballard, R, Carpick, BW, Williams, BR, Schmid, CW 1998Potential Alu function: Regulation of the activity of double-stranded RNA-activated kinase PKRMol Cell Biol185868PubMedGoogle Scholar
  12. Deininger, PL, Batzer, MA 1999Alu repeats and human diseaseMol Genet Metab67183193PubMedGoogle Scholar
  13. Deininger, PL, Batzer, MA, Hutchison, CA, Edgell, MH 1992Master genes in mammalian repetitive DNA amplificationTrends Genet8307311PubMedGoogle Scholar
  14. Deininger, PL, Moran, TV, Batzer, MA, Kazazian, HH,Jr 2003Mobile elements and mammalian genome evolutionCurr Opin Genet Dev13651658PubMedGoogle Scholar
  15. Dewannieux, M, Esnault, C, Heidmann, T 2003LINE-mediated retrotransposition of marked Alu sequencesNat Genet354148PubMedGoogle Scholar
  16. Filipski, J, Salinas, J, Rodier, F 1989Chromosome localization-dependent compositional bias of point mutations in Alu repetitive sequencesJ Mol Biol206563566PubMedGoogle Scholar
  17. Gu, Z, Wang, H, Nekrutenko, A, Li, WL 2000Densities, length proportions, and other distributional features of repetitive sequences in the human genome estimated from 430 megabases of genomic sequenceGene2598188PubMedGoogle Scholar
  18. Hedges, DJ, Callinan, PA, Cordaux, R, Xing, J, Barnes, E, Batzer, MA 2004Differential Alu mobilization and polymorphism among the human and chimpanzee lineagesGenome Res1410681075PubMedGoogle Scholar
  19. IHGSC 2001Initial sequencing and analysis of the human genomeNature409860921Google Scholar
  20. Jabbari, K, Bernardi, G 1998CpG doublets, CpG islands and Alu repeats in long human DNA sequences from different isochore familiesGene224123127PubMedGoogle Scholar
  21. Jukes, TH, Bhushan, V 1986Silent nucleotide substitutions and G + C content of some mitochondrial and bacterial genesJ Mol Evol243944PubMedGoogle Scholar
  22. Jurka, J 1995Origin and evolution of Alu repetitive elementsMaraia, RJ eds. Impact of short interspersed elements (SINEs) on the host genomeLandes Austin, TX2541Google Scholar
  23. Jurka, J 2000Repbase Update, a database and an electronic journal of repetitive elementsTrends Genet16418419PubMedGoogle Scholar
  24. Jurka, J, Krnjajic, M, Kapitonov, VV, Stenger, JE, Kohkanyy, O 2002Active Alu elements are passed primarily through paternal germlinesTheor Popul Biol61519530PubMedGoogle Scholar
  25. Jurka, J, Kohany, O, Pavlicek, A, Kapitonov, VV, Jurka, MV 2004Duplication, coclustering, and selection of human Alu retrotransposonsProc Natl Acad Sci USA10112681272PubMedGoogle Scholar
  26. Kolomietz, E, Meyn, MS, Pandita, A, Squire, JA 2002The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumorsGenes Chromosomes Cancer3597112PubMedGoogle Scholar
  27. Lambert, S, Saintigny, Y, Delacote, F, Amiot, F, Chaput, B, Lecomte, M, Huck, S, Bertrand, P, Lopez, BS 1999Analysis of intrachromosomal homologous recombination in mammalian cell, using tandem repeat sequencesMutat Res433159168PubMedGoogle Scholar
  28. Lev-Maor, G, Sorek, R, Shomron, N, Ast, G 2003The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exonsScience30012881291PubMedGoogle Scholar
  29. Li, W 2001Delineating relative homogeneous G + C domains in DNA sequencesGene2765772PubMedGoogle Scholar
  30. Lobachev, KS, Stenger, JE, Kozyreva, OG, Jurka, J, Gordenin, DA, Resnick, MA 2000Related inverted Alu repeats unstable in yeast are excluded from the human genomeEMBO J1938223833PubMedGoogle Scholar
  31. Martínez Zapater, JM, Marín, A, Oliver, JL 1993Evolution of base composition in T-DNA genes from AgrobacteriumMol Biol Evol10437448Google Scholar
  32. Medstrand, P, Lagemaat, LN, Mager, DL 2002Retroelement distributions in the human genome: variations associated with age and proximity to genesGenome Res1214831495PubMedGoogle Scholar
  33. Mighell, AJ, Markham, AF, Robinson, PA 1997Alu sequencesFEES Lett41715Google Scholar
  34. Nei, M, Kumar, S 2000Molecular evolution and phylogeneticsOxford University PressOxfordGoogle Scholar
  35. Oliver, JL, Marín, A, Martínez Zapater, JM 1990Chloroplast genes transferred to the nuclear plant genome have adjusted to nuclear base composition and codon usageNucleic Acids Res186573PubMedGoogle Scholar
  36. Oliver, JL, Bernaola-Galván, P, Carpena, P, Román-Roldán, R 2001Isochore chromosome maps of eukaryotic genomesGene2764756PubMedGoogle Scholar
  37. Oliver, JL, Carpena, P, Román-Roldán, R, Mata-Balaguer, T, Mejías-Romero, A, Hackenberg, M, Bernaola-Galván, P 2002Isochore chromosome maps of the human genomeGene300117127PubMedGoogle Scholar
  38. Oliver, JL, Carpena, P, Hackenberg, M, Bernaola-Galván, P 2004IsoFinder: computational prediction of isochores in genome sequencesNucleic Acids Res32W287W292PubMedGoogle Scholar
  39. Paces, J, Zika, R, Paces, V, Pavliček, A, Clay, O, Bernardi, G 2004Representing GC variation along eukaryotic chromosomesGene333135141PubMedGoogle Scholar
  40. Pavliček, A, Jabbari, K, Paces, J, Paces, V, Henjar, J, Bernardi, G 2001Similar integration but different stability of Alus and LINES in the human genomeGene2763945PubMedGoogle Scholar
  41. Pavliček, A, Clay, O, Bernardi, G 2002Transposable elements encoding functional proteins: pitfalls in unprocessed genomic data?FEES Lett523252253Google Scholar
  42. Rynditch, A, Zoubak, S, Tsyba, L, Tryapitsina-Guley, N, Bernardi, G 1998The regional integration of retroviral sequences into the mosaic genomes of mammalsGene222116PubMedGoogle Scholar
  43. Schmid, CW 1998Does SINE evolution preclude Alu function? Nucleic Acids Res2645414550PubMedGoogle Scholar
  44. Smit, AFA 1999Interspersed repeats and other mementos of transposable elements in mammalian genomesCurr Opin Genet Dev9657663PubMedGoogle Scholar
  45. Sorek, R, Ast, G, Graur, D 2002Alu-containing exons are alternatively splicedGenome Res1210601067PubMedGoogle Scholar
  46. Stenger, JE, Lobachev, KS, Gordenin, D, Darden, TA, Jurka, J, Resnick, MA 2001Biased distribution of inverted and direct Alus in the human genome: Implications for insertion, exclusion, and genome stabilityGenome Res111227PubMedGoogle Scholar
  47. Tamura, K, Nei, M 1993Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzeesMol Biol Evol10512526PubMedGoogle Scholar
  48. Waldman, AS, Liskay, RM 1988Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homologyMol Cell Biol853505357PubMedGoogle Scholar
  49. Wolfe, K, Sharp, P, Li, W-H 1989Mutation rates differ among regions of the mammalian genomeNature337283285PubMedGoogle Scholar
  50. Zoubak, S, Clay, O, Bernardi, G 1996The gene distribution of the human genomeGene17495102PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Michael Hackenberg
    • 1
  • Pedro Bernaola-Galván
    • 2
  • Pedro Carpena
    • 2
  • José L. Oliver
    • 1
  1. 1.Departamento de GenéticaFacultad de Ciencias, Universidad de GranadaSpain
  2. 2.Departamento de Fisica Aplicada IIUniversidad de Málaga, MálagaSpain

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