Department of Cell, Molecular, and Cancer Biology
Bioinformatics | Genetic Phenomena | Genetics and Genomics | Nervous System Diseases | Neuroscience and Neurobiology
Mutations that occur in cells of the body, called somatic mutations, cause human diseases including cancer and some neurological disorders1. In a recent study published in Nature, 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 the neurons of AD-patients and controls (69% vs 25% of neurons with at least one APP copy gain on average). 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). We reanalyzed the data from the Lee study, revealing evidence that APP gencDNA originates mainly from contamination by exogenous APP recombinant vectors, rather from true somatic retrotransposition of endogenous APP. Our reanalysis of two recent whole exome sequencing (WES) datasets—one by the authors of the Lee study3 and the other by Park et al.4—revealed that reads claimed to support APP gencDNA in AD samples resulted from contamination by PCR products and mRNA, respectively. Lastly, we 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.
genomics, Alzheimer’s disease, APP gene
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 706788; doi: https://doi.org/10.1101/706788. Link to preprint on bioRxiv service.
Kim J, Zhao B, Yue Huang A, Miller MB, Lodato MA, Walsh CA, Lee EA. (2019). Evidence that APP gene copy number changes reflect recombinant vector contamination. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/706788. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1691
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.