Comparative Analysis of Alu Insertion Sequences in the APP 5′ FlankingRegion in Humans and Other Primates Authors
Received: 11 July 2003 Accepted: 09 December 2003 DOI:
Cite this article as: Clarimón, J., Andrés, A.M., Bertranpetit, J. et al. J Mol Evol (2004) 58: 722. doi:10.1007/s00239-004-2594-y
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.
Alu element APP gene
References Apoil, PA, Roubinet, F, Despiau, S, Mollicone, R, Oriol, R, Blancher, A 2000 Evolution of alpha 2-fucosyltransferase genes in primates: Relation between an intronic Alu-Y element and red cell expression of ABH antigens Mol Biol Evol 17 337 351 PubMed Austin, GE, Lam, L, Zaki, SR,, et al. 1993 Sequence comparison of putative regulatory DNA of the 5′ flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells Leukemia 7 1445 1450 PubMed Batzer, MA, Deininger, PL 2002 Alu repeats and human genomic diversity Nat Rev Genet 3 370 379 CrossRef PubMed Batzer, MA, Deininger, PL, Hellmann-Blumberg, U, Jurka, J, Labuda, D, Rubin, CM, Schmid, CW, Zietkiewicz, E, Zuckerkandl, E 1996 Standardized nomenclature for Alu repeats J Mol Evol 42 3 6 CrossRef PubMed Boffelli, D, McAuliffe, J, Ovcharenko, D, Lewis, KD, Ovcharenko, I, Pachter, L, Rubin, EM 2003 Phylogenetic shadowing of primate sequences to find functional regions of the human genome Science 299 1391 1394 PubMed Brini, AT, Lee, GM, Kinet, JP 1993 Involvement of Alu sequences in the cell-specific regulation of transcription of the gamma chain of Fc and T cell receptors J Biol Chem 268 1335 1361 Britten, RJ 1994 Evidence that most human Alu sequences were inserted in a process that ceased about 30 million years ago Proc Natl Acad Sci USA 91 6148 6150 PubMed Brosius, J 2003 How significant is 98.5% ‘junk’ in mammalian genomes? Bioinformatics 19 ii35 PubMed Brosius, J, Gould, SJ 1992 On “nomenclature”: A comprehensive (and respectful) taxonomy for pseudogenes and other “junk DNA.” Proc Natl Acad Sci USA 89 10706 10710 PubMed 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 CrossRef PubMed Comas, D, Plaza, S, Calafell, F, Sajantila, A, Bertranpetit, J 2001 Recent insertion of an Alu element within a polymorphic human-specific Alu insertion Mol Biol Evol 18 85 88 PubMed Cooper, DN, Krawczak, M 1989 Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes Hum Genet 83 181 188 PubMed Felsenstein, J 1989 PHYLIP Phylogeny inference package (version 3.2) Cladistic 5 164 l66 Fornasari, D, Battaglioli, E, Flora, A, Terzano, S, Clementi, F 1997 Structural and functional characterization of the human alpha3 nicotinic subunit gene promoter Mol Pharmacol 51 250 261 PubMed Grilli, M, Ribola, M, Alberici, A, Valerio, A, Memo, M, Spano, P 1995 Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene J Biol Chem 270 26774 26777 PubMed Hambor, JE, Mennone, J, Coon, ME, Hanke, JH, Kavathas, P 1993 Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene Mol Cell Biol 13 7056 7070 PubMed Kapitonov, V, Jurka, J 1996 The age of Alu subfamilies J Mol Evol 42 59 65 PubMed Kimura, M 1980 A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences J Mol Evol 16 111 120 PubMed Kumar, S, Tamura, K, Jakobsen, I, Nei, M 2001MEGA2: Molecular Evolutionary Genetics Analysis software. Arizona State University, Tempe Tempe Arizona State University Fauci, G, Lahiri, DK, Salton, SR, Robakis, NK 1989 Characterization of the 5′-end region and the first two exons of the beta-protein precursor gene Biochem Biophys Res Commun 159 297 304 PubMed Lahiri, DK, Robakis, NK 1991 The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences Brain Res Mol Brain Res 9 253 257 PubMed Lahiri, DK, Nail, C, Ge, YW 1999 Promoter activity of the beta-amyloid precursor protein gene is negatively modulated by an upstream regulatory element Brain Res Mol Brain Res 71 32 41 PubMed Lahiri, DK, Song, W, Ge, YW 2000 Analysis of the 5′-flanking region of the beta-amyloid precursor protein gene that contributes to increased promoter activity in differentiated neuronal cells Brain Res Mol Brain Res 77 185 198 PubMed Lev-Maor, G, Sorek, R, Shomron, N, Ast, G 2003 The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exons Science 300 1288 1291 PubMed Li, WH, Gu, Z, Wang, H, Nekrutenko, A 2001 Evolutionary analyses of the human genome Nature 409 847 849 PubMed Makalowski, W 2003 Not junk after all Science 300 1246 1247 PubMed Martinez-Arias, R, Calafell, F, Mateu, E, Comas, D, Andres, A, Bertranpetit, J 2001 Sequence variability of a human pseudogene Genome Res 11 1071 1085 PubMed McHaffie, GS, Ralston, SH 1995 Origin of a negative calcium response element in an ALU-repeat: Implications for regulation of gene expression by extracellular calcium Bone 17 11 14 PubMed Norris, J, Fan, D, Aleman, C, Marks, JR, Futreal, PA, Wiseman, RW, Iglehart, JD, Deininger, PL, McDonnell, DP 1995 Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers J Biol Chem 270 22777 22782 PubMed Piedrafita, FJ, Molander, RB, Vansant, G, Orlova, EA, Pfahl, M, Reynolds, WF 1996 An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element J Biol Chem 271 14412 14420 PubMed Pollwein, P, Masters, CL, Beyreuther, K 1992 The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter Nucleic Acids Res 20 63 68 PubMed Quitschke, WW, Goldgaber, D 1992 The amyloid beta-protein precursor promoter A region essential for transcriptional activity contains a nuclear factor binding domain. J Biol Chem 267 17362 17368 Rowold, DJ, Herrera, RJ 2000 Alu elements and the human genome Genetica 108 57 72 PubMed Rozas, J, Rozas, R 1999 DnaSP version 3: An integrated program for molecular population genetics and molecular evolution analysis Bioinformatics 15 174 175 CrossRef PubMed Ruvolo, M 1997 Molecular phylogeny of the hominoids: Inferences from multiple independent DNA sequence data sets Mol Biol Evol 14 248 265 PubMed Salbaum, JM, Weidemann, A, Lemaire, HG, Masters, CL, Beyreuther, K 1988 The promoter of Alzheimer’s disease amyloid A4 precursor gene EMBO J 7 2807 2813 PubMed Song, W, Lahiri, DK 1998 Molecular cloning of the promoter of the gene encoding the Rhesus monkey beta-amyloid precursor protein: Structural characterization and a comparative study with other species Gene 217 151 164 PubMed Stoneking, M, Fontius, JJ, Clifford, SL, Soodyall, H, Arcot, SS, Saha, N, Jenkins, T, Tahir, MA, Deininger, PL, Batzer, MA 1997 Alu insertion polymorphisms and human evolution: evidence for a larger population size in Africa Genome Res 7 1061 1071 PubMed Vansant, G, Reynolds, WF 1995 The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element Proc Natl Acad Sci USA 92 8229 8233 PubMed