title: Resolving rates of mutation in the brain using single-neuron genomics.
abstract: Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies.
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children's Hospital, Boston, United States.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.|Department of Pediatrics, Harvard Medical School, Boston, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Gilad D
authors.initials: GD
authors.lastname: Evrony
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, United States.|Division of Genetics, Brigham and Women's Hospital, Boston, United States.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, United States.|Division of Genetics, Brigham and Women's Hospital, Boston, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children's Hospital, Boston, United States.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Department of Neurology, Harvard Medical School, Boston, United States.|Department of Pediatrics, Harvard Medical School, Boston, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D001921:Brain / Q000502:physiology*; D019295:Computational Biology; D015894:Genome, Human; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D059645:Mutation Rate; D009474:Neurons / Q000502:physiology*; D059010:Single-Cell Analysis / Q000379:methods*; D014481:United States
keywords: LINE-1; brain; evolutionary biology; genomics; human; mosaicism; neuroscience; retrotransposons; single-cell genomics; somatic mutation