6
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      High prevalence of focal and multi-focal somatic genetic variants in the human brain

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.

          Abstract

          Similar to cancers, somatic mutations might lead to neurodegenerative diseases. Here, the authors perform ultra-deep sequencing of 102 genes in 173 adult human brains, detect somatic mutations in 54 brains, and develop a mathematical model to estimate the frequency of mutated foci in human brains.

          Related collections

          Most cited references 25

          • Record: found
          • Abstract: found
          • Article: not found

          Analysis of genetic inheritance in a family quartet by whole-genome sequencing.

          We analyzed the whole-genome sequences of a family of four, consisting of two siblings and their parents. Family-based sequencing allowed us to delineate recombination sites precisely, identify 70% of the sequencing errors (resulting in > 99.999% accuracy), and identify very rare single-nucleotide polymorphisms. We also directly estimated a human intergeneration mutation rate of approximately 1.1 x 10(-8) per position per haploid genome. Both offspring in this family have two recessive disorders: Miller syndrome, for which the gene was concurrently identified, and primary ciliary dyskinesia, for which causative genes have been previously identified. Family-based genome analysis enabled us to narrow the candidate genes for both of these Mendelian disorders to only four. Our results demonstrate the value of complete genome sequencing in families.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Alpha-synuclein and neurodegenerative diseases.

             M Goedert (2001)
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Cell death during development of the nervous system.

               R Oppenheim (1990)
                Bookmark

                Author and article information

                Contributors
                pfc25@cam.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                15 October 2018
                15 October 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Clinical Neurosciences, , University of Cambridge, Cambridge Biomedical Campus, ; Cambridge, CB2 0QQ UK
                [2 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Mathematics, , Imperial College London, ; London, SW7 2AZ UK
                [3 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Institute of Neuroscience, , Newcastle University, Campus for Aging and Vitality, ; Newcastle upon Tyne, NE4 5PL UK
                [4 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Institute of Genetic Medicine, Central Parkway, , Newcastle University, ; Newcastle Upon Tyne, NE1 3BZ UK
                [5 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, , Newcastle University, ; Newcastle Upon Tyne, NE1 7RU UK
                [6 ]ISNI 0000 0004 4658 1277, GRID grid.459934.6, Personalis Inc, ; 1330O’Brien Dr, Menlo Park, CA 94025 USA
                [7 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, EPSRC Centre for Mathematics of Precision Healthcare, , Imperial College London, ; London, SW7 2AZ UK
                [8 ]ISNI 0000000121885934, GRID grid.5335.0, MRC Mitochondrial Biology Unit, , University of Cambridge, ; Cambridge, CB2 0XY UK
                Article
                6331
                10.1038/s41467-018-06331-w
                6189186
                a23ee074-ad98-4a34-a6a8-11725f9c6eac
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 212219/Z/18/Z
                Award ID: 101876/Z/13/Z
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000265, Medical Research Council (MRC);
                Award ID: MC_UP_1501/2
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2018

                Uncategorized

                Comments

                Comment on this article