A paradigm for single nucleotide polymorphism analysis: The case of the acetylcholinesterase gene

Authors

  • Yehudit Hasin,

    1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    2. Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
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    • Yehudit Hasin and Nili Avidan contributed equally to this work.

  • Nili Avidan,

    1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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    • Yehudit Hasin and Nili Avidan contributed equally to this work.

  • Dani Bercovich,

    1. Department of Molecular Genetics, MIGAL-Galilee Technology Center, Kiryat Shmona, Israel
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  • Amos Korczyn,

    1. Department of Neurology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Israel Silman,

    1. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
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  • Jacques S. Beckmann,

    1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    2. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois UNIL, Lausanne, Switzerland
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    • Jacques S. Beckmann is the Hermann Mayer Professor of Molecular Genetics.

  • Joel L. Sussman

    Corresponding author
    1. Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel
    • Department of Structural Biology, Weizmann Institute of Science, Rehovot, 76100 Israel
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    • Joel L. Sussman is the Morton and Gladys Pickman Professor of Structural Biology.


  • Communicated by Michael Dean

Abstract

Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. It is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goal of the present study was to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene. To this end, the genomic coding sequences for acetylcholinesterase of 96 unrelated control individuals from three distinct ethnic groups were analyzed. A total of 13 ACHE SNPs were identified, 10 of which are newly described, and five that should produce amino acid substitutions [c.101G>A (p.Arg34Gln), c.169G>A (p.Gly57Arg), c.1031A>G (p.Glu344Gly), c.1057C>A (p.His353Asn), and c.1775C>G (p.Pro592Arg)]. Population frequencies of 11 of the 13 SNPs were established in four different populations: African Americans, Ashkenazi Jews, Sephardic Jews, and Israeli Arabs; 15 haplotypes and five ethnospecific alleles were identified. The low number of SNPs identified until now in the ACHE gene is ascribed to technical hurdles arising from the high GC content and the presence of numerous repeat sequences, and does not reflect its intrinsic heterozygosity. Among the SNPs resulting in an amino acid substitution, three are within the mature protein, mapping on its external surface: they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein–protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes—such as adverse drug responses to AChE inhibitors employed in treatment of Alzheimer patients and hypersensitivity to pesticides. Hum Mutat 24:408–416, 2004. © 2004 Wiley-Liss, Inc.

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