Journal of Molecular Evolution

, Volume 58, Issue 6, pp 722–731 | Cite as

Comparative Analysis of Alu Insertion Sequences in the APP 5′ FlankingRegion in Humans and Other Primates

  • Jordi Clarimón
  • Aida M. Andrés
  • Jaume Bertranpetit
  • David Comas
Article

Abstract

Overexpression of the amyloid precursor protein gene (APP) may play a role in the neuropathology of Alzheimer’s disease. Therefore, elucidating the mechanisms involved in APP gene regulation is of primary importance, and various cis-acting regulatory elements located in 5′ distal regions are known to play a main role. Some of them lie within Alu elements, one of which (Alu1) is only found in humans and apes while the other (Alu2) has a much older history and is also found in rhesus. These Alu insertions harbor sequence motifs that may act as cis-regulatory elements, which may cause differences in APP regulation among primate species and whose functionality may be ascertained through their conservation in a comparative analysis. We have performed a comparative analysis of the region comprising the two Alu elements of the APP promoter in several primates, including humans. We have found a significant decrease in nucleotide diversity in the Alu2 element (inserted in all the species analyzed) compared to the Alu1 (inserted only in apes). This finding can be interpreted as a constriction in the Alu2 sequence variation as a consequence of a functional role of this element in the APP expression. The present results suggest a wider extension of the regulatory elements than the known short consensus regulatory sequences. Moreover, the different conservation of two highly similar and neighboring sequences suggests that, besides the importance of the sequence motifs, their position in relation to the gene suggests that they have played a role in being recruited as regulatory elements.

Keywords

Alu element APP gene Alzheimer’s disease Promoter Regulatory region 

References

  1. Apoil, PA, Roubinet, F, Despiau, S, Mollicone, R, Oriol, R, Blancher, A 2000Evolution of alpha 2-fucosyltransferase genes in primates: Relation between an intronic Alu-Y element and red cell expression of ABH antigensMol Biol Evol17337351PubMedGoogle Scholar
  2. Austin, GE, Lam, L, Zaki, SR,,  et al. 1993Sequence comparison of putative regulatory DNA of the 5′ flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cellsLeukemia714451450PubMedGoogle Scholar
  3. Batzer, MA, Deininger, PL 2002Alu repeats and human genomic diversityNat Rev Genet3370379CrossRefPubMedGoogle Scholar
  4. Batzer, MA, Deininger, PL, Hellmann-Blumberg, U, Jurka, J, Labuda, D, Rubin, CM, Schmid, CW, Zietkiewicz, E, Zuckerkandl, E 1996Standardized nomenclature for Alu repeatsJ Mol Evol4236CrossRefPubMedGoogle Scholar
  5. Boffelli, D, McAuliffe, J, Ovcharenko, D, Lewis, KD, Ovcharenko, I, Pachter, L, Rubin, EM 2003Phylogenetic shadowing of primate sequences to find functional regions of the human genomeScience29913911394PubMedGoogle Scholar
  6. Brini, AT, Lee, GM, Kinet, JP 1993Involvement of Alu sequences in the cell-specific regulation of transcription of the gamma chain of Fc and T cell receptorsJ Biol Chem26813351361Google Scholar
  7. Britten, RJ 1994Evidence that most human Alu sequences were inserted in a process that ceased about 30 million years agoProc Natl Acad Sci USA9161486150PubMedGoogle Scholar
  8. Brosius, J 2003How significant is 98.5% ‘junk’ in mammalian genomes?Bioinformatics19ii35PubMedGoogle Scholar
  9. Brosius, J, Gould, SJ 1992On “nomenclature”: A comprehensive (and respectful) taxonomy for pseudogenes and other “junk DNA.”Proc Natl Acad Sci USA891070610710PubMedGoogle Scholar
  10. Chen, FC, Li, WH 2001Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzeesAm J Hum Genet68444456CrossRefPubMedGoogle Scholar
  11. Comas, D, Plaza, S, Calafell, F, Sajantila, A, Bertranpetit, J 2001Recent insertion of an Alu element within a polymorphic human-specific Alu insertionMol Biol Evol188588PubMedGoogle Scholar
  12. Cooper, DN, Krawczak, M 1989Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomesHum Genet83181188PubMedGoogle Scholar
  13. Felsenstein, J 1989PHYLIP Phylogeny inference package (version 3.2)Cladistic5164l66Google Scholar
  14. Fornasari, D, Battaglioli, E, Flora, A, Terzano, S, Clementi, F 1997Structural and functional characterization of the human alpha3 nicotinic subunit gene promoterMol Pharmacol51250261PubMedGoogle Scholar
  15. Grilli, M, Ribola, M, Alberici, A, Valerio, A, Memo, M, Spano, P 1995Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein geneJ Biol Chem2702677426777PubMedGoogle Scholar
  16. Hambor, JE, Mennone, J, Coon, ME, Hanke, JH, Kavathas, P 1993Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha geneMol Cell Biol1370567070PubMedGoogle Scholar
  17. Kapitonov, V, Jurka, J 1996The age of Alu subfamiliesJ Mol Evol425965PubMedGoogle Scholar
  18. Kimura, M 1980A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequencesJ Mol Evol16111120PubMedGoogle Scholar
  19. Kumar, S, Tamura, K, Jakobsen, I, Nei, M 2001MEGA2: Molecular Evolutionary Genetics Analysis software. Arizona State University, TempeTempeArizona State UniversityGoogle Scholar
  20. Fauci, G, Lahiri, DK, Salton, SR, Robakis, NK 1989Characterization of the 5′-end region and the first two exons of the beta-protein precursor geneBiochem Biophys Res Commun159297304PubMedGoogle Scholar
  21. Lahiri, DK, Robakis, NK 1991The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequencesBrain Res Mol Brain Res9253257PubMedGoogle Scholar
  22. Lahiri, DK, Nail, C, Ge, YW 1999Promoter activity of the beta-amyloid precursor protein gene is negatively modulated by an upstream regulatory elementBrain Res Mol Brain Res713241PubMedGoogle Scholar
  23. Lahiri, DK, Song, W, Ge, YW 2000Analysis of the 5′-flanking region of the beta-amyloid precursor protein gene that contributes to increased promoter activity in differentiated neuronal cellsBrain Res Mol Brain Res77185198PubMedGoogle Scholar
  24. Lev-Maor, G, Sorek, R, Shomron, N, Ast, G 2003The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exonsScience30012881291PubMedGoogle Scholar
  25. Li, WH, Gu, Z, Wang, H, Nekrutenko, A 2001Evolutionary analyses of the human genomeNature409847849PubMedGoogle Scholar
  26. Makalowski, W 2003Not junk after allScience30012461247PubMedGoogle Scholar
  27. Martinez-Arias, R, Calafell, F, Mateu, E, Comas, D, Andres, A, Bertranpetit, J 2001Sequence variability of a human pseudogeneGenome Res1110711085PubMedGoogle Scholar
  28. McHaffie, GS, Ralston, SH 1995Origin of a negative calcium response element in an ALU-repeat: Implications for regulation of gene expression by extracellular calciumBone171114PubMedGoogle Scholar
  29. Norris, J, Fan, D, Aleman, C, Marks, JR, Futreal, PA, Wiseman, RW, Iglehart, JD, Deininger, PL, McDonnell, DP 1995Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancersJ Biol Chem2702277722782PubMedGoogle Scholar
  30. Piedrafita, FJ, Molander, RB, Vansant, G, Orlova, EA, Pfahl, M, Reynolds, WF 1996An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response elementJ Biol Chem2711441214420PubMedGoogle Scholar
  31. Pollwein, P, Masters, CL, Beyreuther, K 1992The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoterNucleic Acids Res206368PubMedGoogle Scholar
  32. Quitschke, WW, Goldgaber, D 1992The amyloid beta-protein precursor promoterA region essential for transcriptional activity contains a nuclear factor binding domain. J Biol Chem2671736217368Google Scholar
  33. Rowold, DJ, Herrera, RJ 2000Alu elements and the human genomeGenetica1085772PubMedGoogle Scholar
  34. Rozas, J, Rozas, R 1999DnaSP version 3: An integrated program for molecular population genetics and molecular evolution analysisBioinformatics15174175CrossRefPubMedGoogle Scholar
  35. Ruvolo, M 1997Molecular phylogeny of the hominoids: Inferences from multiple independent DNA sequence data setsMol Biol Evol14248265PubMedGoogle Scholar
  36. Salbaum, JM, Weidemann, A, Lemaire, HG, Masters, CL, Beyreuther, K 1988The promoter of Alzheimer’s disease amyloid A4 precursor geneEMBO J728072813PubMedGoogle Scholar
  37. Song, W, Lahiri, DK 1998Molecular cloning of the promoter of the gene encoding the Rhesus monkey beta-amyloid precursor protein: Structural characterization and a comparative study with other speciesGene217151164PubMedGoogle Scholar
  38. Stoneking, M, Fontius, JJ, Clifford, SL, Soodyall, H, Arcot, SS, Saha, N, Jenkins, T, Tahir, MA, Deininger, PL, Batzer, MA 1997Alu insertion polymorphisms and human evolution: evidence for a larger population size in AfricaGenome Res710611071PubMedGoogle Scholar
  39. Vansant, G, Reynolds, WF 1995The consensus sequence of a major Alu subfamily contains a functional retinoic acid response elementProc Natl Acad Sci USA9282298233PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Jordi Clarimón
    • 1
  • Aida M. Andrés
    • 1
  • Jaume Bertranpetit
    • 1
  • David Comas
    • 1
  1. 1.Unitat de Biologia Evolutiva, Facultat de Ciències de la Salut i de la VidaUniversitat Pompeu FabraBarcelonaSpain

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