APP Gene Copy Number Changes Reflect Exogenous Contamination

Abstract

Various types of somatic mutations occur in cells of the human body and cause human diseases including cancer and some neurological disorders1. Recently, Lee et al.2 (hereafter “the Lee study”) reported somatic copy number gains of the APP gene, a known risk locus of Alzheimer’s disease (AD), in 69% and 25% of neurons of AD patients and controls. The authors argue that the mechanism of these copy number gains was somatic integration of APP mRNA into the genome, creating what they called genomic cDNA (gencDNA). Our reanalysis of the data from the Lee study and two additional whole exome sequencing (WES) datasets by the authors of the Lee study3 and Park et al.4 revealed evidence that APP gencDNA originates mainly from exogenous contamination by APP recombinant vectors, nested PCR products, and human and mouse mRNA, respectively, rather than from true somatic integration of endogenous APP. We further present our own single-cell whole genome sequencing (scWGS) data that show no evidence for somatic APP retrotransposition in AD neurons or in neurons from normal individuals of various ages.