Comparative Analysis of Alu Insertion Sequences in the APP 5′ FlankingRegion in Humans and Other Primates
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.
KeywordsAlu element APP gene Alzheimer’s disease Promoter Regulatory region
Primate samples were kindly supplied by Barcelona Zoo with the cooperation agreement between Barcelona Zoo and the Evolutionary Biology Unit, Universitat Pompeu Fabra. This study was supported by the Dirección General de Investigación (Spanish Government), Grant BMC2001-0772 to J.B. We are particularly grateful to Dr. Dario Bofelli for phylogenetic shadowing advice. We especially thank Mònica Vallés for technical support and Oscar Lao for recommendations. We also thank Michelle Gardner for advice and help in the preparation of the manuscript.
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