On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients

• DOI: 10.1016/j.jalz.2015.02.007
• Publication Date: 2015-05-02T16:55:01Z
• Authors: Carlo Sala Frigerio; Pierre Lau; Claire Troakes; Vincent Deramecourt; Patrick Gele; Peter Van Loo; Thierry Voet; Bart De Strooper
• Keywords: Mosaic; Identification

The cause of sporadic Alzheimer's disease (AD) remains unclear. Given the growing evidence that protein aggregates can spread in a "prion-like" fashion, we reasoned small population brain cells producing such particles due to postzygotic acquired mutation would be sufficient trigger disease. Deep DNA sequencing technology should principle allow detection mosaics.To detect somatic mutations genes causing AD present number cells, developed targeted deep approach scrutinize genomic loci APP, PSEN1, and PSEN2 extracted from entorhinal cortex, one regions showing earliest signs pathology. We also included analysis MAPT gene because may promote tangle formation. validated candidate with an independent ultradeep amplicon technique.We demonstrate our single-nucleotide mosaic variants 1% allele frequency copy as few 10% cells. screened 72 58 control samples identified three low allelic (∼1%): two novel patients known variant Braak II subject. Moreover, detected both pathogenic nonmosaic heterozygous PSEN1 this cohort patients.Our results show frequencies AD-relevant brain-derived DNA, but larger need investigated before more definitive conclusion regard pathogenicity mosaics made.