Somatic genomic changes in single Alzheimer’s disease neurons

  • Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).

    CAS 
    Article 

    Google Scholar 

  • Hyman, B. T. et al. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8, 1–13 (2012).

    Article 

    Google Scholar 

  • Braak, H. & Braak, E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 16, 271–278 (1995).

    CAS 
    Article 

    Google Scholar 

  • Gabbita, S. P., Lovell, M. A. & Markesbery, W. R. Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J. Neurochem. 71, 2034–2040 (1998).

    CAS 
    Article 

    Google Scholar 

  • Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    CAS 
    Article 

    Google Scholar 

  • Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    CAS 
    Article 

    Google Scholar 

  • Osorio, F. G. et al. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Cell Rep. 25, 2308–2316 (2018).

    CAS 
    Article 

    Google Scholar 

  • Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS 
    Article 

    Google Scholar 

  • Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).

    CAS 
    Article 

    Google Scholar 

  • Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    CAS 
    Article 

    Google Scholar 

  • Lu, T. et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature 507, 448–454 (2014).

    CAS 
    Article 

    Google Scholar 

  • Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    Article 

    Google Scholar 

  • Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS 
    Article 

    Google Scholar 

  • Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS 
    Article 

    Google Scholar 

  • Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

    CAS 
    Article 

    Google Scholar 

  • Hazen, J. L. et al. The complete genome sequences, unique mutational spectra, and developmental potency of adult neurons revealed by cloning. Neuron 89, 1223–1236 (2016).

    CAS 
    Article 

    Google Scholar 

  • Bhagwat, A. S. et al. Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli. Proc. Natl Acad. Sci. USA 113, 2176–2181 (2016).

    CAS 
    Article 

    Google Scholar 

  • Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. Cell 177, 821–836 (2019).

    CAS 
    Article 

    Google Scholar 

  • Sala Frigerio, C. et al. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer’s disease patients. Alzheimers Dement. 11, 1265–1276 (2015).

    Article 

    Google Scholar 

  • Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).

    CAS 
    Article 

    Google Scholar 

  • Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019).

    CAS 
    Article 

    Google Scholar 

  • Leng, K. et al. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat. Neurosci. 24, 276–287 (2021).

    CAS 
    Article 

    Google Scholar 

  • Bohrson, C. L. et al. Linked-read analysis identifies mutations in single-cell DNA-sequencing data. Nat. Genet. 51, 749–754 (2019).

    CAS 
    Article 

    Google Scholar 

  • Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell 176, 1282–1294 (2019).

    CAS 
    Article 

    Google Scholar 

  • Xing, D., Tan, L., Chang, C.-H., Li, H. & Xie, X. S. Accurate SNV detection in single cells by transposon-based whole-genome amplification of complementary strands. Proc. Natl Acad. Sci. USA 118, e2013106118 (2021).

    CAS 
    Article 

    Google Scholar 

  • Madabhushi, R. et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161, 1592–1605 (2015).

    CAS 
    Article 

    Google Scholar 

  • Min, S. et al. Absence of coding somatic single nucleotide variants within well-known candidate genes in late-onset sporadic Alzheimer’s disease based on the analysis of multi-omics data. Neurobiol. Aging 108, 207–209 (2021).

    CAS 
    Article 

    Google Scholar 

  • Lee, M. H. et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563, 639–645 (2018).

    CAS 
    Article 

    Google Scholar 

  • Kim, J. et al. APP gene copy number changes reflect exogenous contamination. Nature 584, E20–E28 (2020).

    CAS 
    Article 

    Google Scholar 

  • Jager, M. et al. Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer. Genome Res. 29, 1067–1077 (2019).

    CAS 
    Article 

    Google Scholar 

  • Mecocci, P., MacGarvey, U. & Beal, M. F. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 36, 747–751 (1994).

    CAS 
    Article 

    Google Scholar 

  • Chun, H. et al. Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2 production. Nat. Neurosci. 23, 1555–1566 (2020).

    CAS 
    Article 

    Google Scholar 

  • Pao, P. C. et al. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nat. Commun. 11, 2484 (2020).

    CAS 
    Article 

    Google Scholar 

  • Nouspikel, T. & Hanawalt, P. C. Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol. Cell. Biol. 20, 1562–1570 (2000).

    CAS 
    Article 

    Google Scholar 

  • Seplyarskiy, V. B. et al. Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations. Nat. Genet. 51, 36–41 (2019).

    CAS 
    Article 

    Google Scholar 

  • Huang, J. C., Svoboda, D. L., Reardon, J. T. & Sancar, A. Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5′ and the 6th phosphodiester bond 3′ to the photodimer. Proc. Natl Acad. Sci. USA 89, 3664–3668 (1992).

    CAS 
    Article 

    Google Scholar 

  • Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    CAS 
    Article 

    Google Scholar 

  • Soheili-Nezhad, S., van der Linden, R. J., Olde Rikkert, M., Sprooten, E. & Poelmans, G. Long genes are more frequently affected by somatic mutations and show reduced expression in Alzheimer’s disease: Implications for disease etiology. Alzheimers Dement. 17, 489–499 (2020).

    Article 

    Google Scholar 

  • Crabtree, G. R. Our fragile intellect. Part I. Trends Genet. 29, 1–3 (2013).

    CAS 
    Article 

    Google Scholar 

  • Fragola, G. et al. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat. Commun. 11, 1962 (2020).

    CAS 
    Article 

    Google Scholar 

  • Gonzalez-Pena, V. et al. Accurate genomic variant detection in single cells with primary template-directed amplification. Proc. Natl Acad. Sci. USA 118, e2024176118 (2021).

    CAS 
    Article 

    Google Scholar 

  • Luquette, L. J. et al. Ultraspecific somatic SNV and indel detection in single neurons using primary template-directed amplification. Preprint at bioRxiv https://doi.org/10.1101/2021.04.30.442032 (2021).

  • Kaur, U. et al. Reactive oxygen species, redox signaling and neuroinflammation in Alzheimer’s disease: the NF-κB connection. Curr. Top. Med. Chem. 15, 446–457 (2015).

    CAS 
    Article 

    Google Scholar 

  • Butterfield, D. A., Castegna, A., Lauderback, C. M. & Drake, J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol. Aging 23, 655–664 (2002).

    Article 

    Google Scholar 

  • David, D. C. et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 280, 23802–23814 (2005).

    CAS 
    Article 

    Google Scholar 

  • Khurana, V. et al. A neuroprotective role for the DNA damage checkpoint in tauopathy. Aging Cell 11, 360–362 (2012).

    CAS 
    Article 

    Google Scholar 

  • Sakofsky, C. J. et al. Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation. PLoS Biol. 17, e3000464 (2019).

    CAS 
    Article 

    Google Scholar 

  • Mandrekar-Colucci, S. & Landreth, G. E. Microglia and inflammation in Alzheimer’s disease. CNS Neurol. Disord. Drug Targets 9, 156–167 (2010).

    CAS 
    Article 

    Google Scholar 

  • Rottkamp, C. A. et al. Redox-active iron mediates amyloid-beta toxicity. Free Radic. Biol. Med. 30, 447–450 (2001).

    CAS 
    Article 

    Google Scholar 

  • Huang, A. Y. et al. Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain. Proc. Natl Acad. Sci. USA 117, 13886–13895 (2020).

    CAS 
    Article 

    Google Scholar 

  • Dean, F. B., Nelson, J. R., Giesler, T. L. & Lasken, R. S. Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification. Genome Res. 11, 1095–1099 (2001).

    CAS 
    Article 

    Google Scholar 

  • Evrony, G. D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).

    CAS 
    Article 

    Google Scholar 

  • Zheng, G. X. Y. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).

    CAS 
    Article 

    Google Scholar 

  • Fan, J. et al. Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Nat. Methods 13, 241–244 (2016).

    CAS 
    Article 

    Google Scholar 

  • Dong, X. et al. Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat. Methods 14, 491–493 (2017).

    CAS 
    Article 

    Google Scholar 

  • Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS 
    Article 

    Google Scholar 

  • McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS 
    Article 

    Google Scholar 

  • Keogh, M. J. et al. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nat. Commun. 9, 4257 (2018).

    Article 

    Google Scholar 

  • Park, J. S. et al. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nat. Commun. 10, 3090 (2019).

    Article 

    Google Scholar 

  • Luquette, L. J., Bohrson, C. L., Sherman, M. A. & Park, P. J. Identification of somatic mutations in single cell DNA-seq using a spatial model of allelic imbalance. Nat. Commun. 10, 3908 (2019).

    Article 

    Google Scholar 

  • Cai, X. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 8, 1280–1289 (2014).

    CAS 
    Article 

    Google Scholar 

  • Baslan, T. et al. Genome-wide copy number analysis of single cells. Nat. Protoc. 7, 1024–1041 (2012).

    CAS 
    Article 

    Google Scholar 

  • Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Campbell, P. J. & Stratton, M. R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).

    CAS 
    Article 

    Google Scholar 

  • Blokzijl, F., Janssen, R., van Boxtel, R. & Cuppen, E. MutationalPatterns: comprehensive genome-wide analysis of mutational processes. Genome Med. 10, 33 (2018).

    Article 

    Google Scholar 

  • Kim, J. et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat. Genet. 48, 600–606 (2016).

    CAS 
    Article 

    Google Scholar 

  • Bates, D., Mächler, M., Bolker, B. & Walker, S. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1–48 (2015).

    Article 

    Google Scholar 

  • Kuznetsova, A., Brockhoff, P. B. & Christensen, R. H. B. lmerTest Package: tests in linear mixed effects models. J. Stat. Softw. 82, 1–26 (2017).

    Article 

    Google Scholar 

  • Consortium, G. T. et al. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article 

    Google Scholar 

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article 

    Google Scholar 

  • Young, M. D., Wakefield, M. J., Smyth, G. K. & Oshlack, A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 11, R14 (2010).

    Article 

    Google Scholar 

  • Green, P. et al. Transcription-associated mutational asymmetry in mammalian evolution. Nat. Genet. 33, 514–517 (2003).

    CAS 
    Article 

    Google Scholar 

  • Polak, P. & Arndt, P. F. Transcription induces strand-specific mutations at the 5′ end of human genes. Genome Res. 18, 1216–1223 (2008).

    CAS 
    Article 

    Google Scholar 

  • Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article 

    Google Scholar 

  • Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    CAS 
    Article 

    Google Scholar 

  • Coppede, F. & Migliore, L. DNA damage and repair in Alzheimer’s disease. Curr. Alzheimer Res. 6, 36–47 (2009).

    CAS 
    Article 

    Google Scholar 

  • Hoang, M. L. et al. Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc. Natl Acad. Sci. USA 113, 9846–9851 (2016).

    CAS 
    Article 

    Google Scholar 

  • Franco, I. et al. Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Nat. Commun. 9, 800 (2018).

    Article 

    Google Scholar 

  • Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc. Natl Acad. Sci. USA 116, 9014–9019 (2019).

    CAS 
    Article 

    Google Scholar 

  • Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    CAS 
    Article 

    Google Scholar 

  • Franco, I. et al. Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type. Genome Biol. 20, 285 (2019).

    CAS 
    Article 

    Google Scholar 

  • Brunet, J. P., Tamayo, P., Golub, T. R. & Mesirov, J. P. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl Acad. Sci. USA 101, 4164–4169 (2004).

    CAS 
    Article 

    Google Scholar 

  • Read original article here

    Leave a Comment