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Somatic Signature of Brain-Specific Single Nucleotide Variations in Sporadic Alzheimer's Disease

Article type: Research Article

Authors: Parcerisas, Antonia; b | Rubio, Sara E.a; b | Muhaisen, Ashrafa; b | Gómez-Ramos, Albertob; c | Pujadas, Lluísa; b | Puiggros, Montserratd | Rossi, Danielaa; b | Ureña, Jesúsa; b | Burgaya, Ferrána; b | Pascual, Martaa; b | Torrents, Davida; e | Rábano, Albertof | Ávila, Jesúsb; c; 1; * | Soriano, Eduardoa; b; f; g; 1; *

Affiliations: [a] Department of Cell Biology, University of Barcelona, Barcelona, Spain | [b] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain | [c] Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain | [d] Joint IRB-BSC Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain | [e] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain | [f] Fundación CIEN, Vallecas, Madrid, Spain | [g] Vall d'Hebrón Institut de Recerca (VHIR), Barcelona, Spain

Correspondence: [*] Correspondence to: Dr. Eduardo Soriano, Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain. Tel.: +34 93 4037117; E-mail: [email protected] and Dr. Jesús Ávila, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid E-28049, Spain. Tel.: +34 91 1964564; E-mail: [email protected].

Note: [1] The senior authors contributed equally to this study.

Keywords: Alzheimer's disease, exome sequencing, somatic variations

DOI: 10.3233/JAD-140891

Journal: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1357-1382, 2014

Accepted 14 May 2014
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Published: 10 October 2014
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Abstract

Background:

Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer’s disease (SAD), the molecular mechanisms responsible remain largely unknown.

Objective:

The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples.

Methods:

By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients.

Results:

We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients.

Conclusion:

Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.

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