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      New insights into the generation and role of de novo mutations in health and disease

      review-article
      1 , 2 , 3 , , 2
      Genome Biology
      BioMed Central

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          Abstract

          Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent–offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.

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          Most cited references136

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          Global variation in copy number in the human genome.

          Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.
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            Performance comparison of benchtop high-throughput sequencing platforms.

            Three benchtop high-throughput sequencing instruments are now available. The 454 GS Junior (Roche), MiSeq (Illumina) and Ion Torrent PGM (Life Technologies) are laser-printer sized and offer modest set-up and running costs. Each instrument can generate data required for a draft bacterial genome sequence in days, making them attractive for identifying and characterizing pathogens in the clinical setting. We compared the performance of these instruments by sequencing an isolate of Escherichia coli O104:H4, which caused an outbreak of food poisoning in Germany in 2011. The MiSeq had the highest throughput per run (1.6 Gb/run, 60 Mb/h) and lowest error rates. The 454 GS Junior generated the longest reads (up to 600 bases) and most contiguous assemblies but had the lowest throughput (70 Mb/run, 9 Mb/h). Run in 100-bp mode, the Ion Torrent PGM had the highest throughput (80–100 Mb/h). Unlike the MiSeq, the Ion Torrent PGM and 454 GS Junior both produced homopolymer-associated indel errors (1.5 and 0.38 errors per 100 bases, respectively).
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              The environment and schizophrenia.

              Psychotic syndromes can be understood as disorders of adaptation to social context. Although heritability is often emphasized, onset is associated with environmental factors such as early life adversity, growing up in an urban environment, minority group position and cannabis use, suggesting that exposure may have an impact on the developing 'social' brain during sensitive periods. Therefore heritability, as an index of genetic influence, may be of limited explanatory power unless viewed in the context of interaction with social effects. Longitudinal research is needed to uncover gene-environment interplay that determines how expression of vulnerability in the general population may give rise to more severe psychopathology.
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                Author and article information

                Contributors
                joris.veltman@radboudumc.nl
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central (London )
                1474-7596
                1474-760X
                28 November 2016
                28 November 2016
                2016
                : 17
                : 241
                Affiliations
                [1 ]Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands
                [2 ]Department of Human Genetics, Donders Institute of Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands
                [3 ]Department of Clinical Genetics, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
                Article
                1110
                10.1186/s13059-016-1110-1
                5125044
                27894357
                abadf489-c909-47cc-a33d-1767c2384e60
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Funding
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NL)
                Award ID: 918-15-667
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003246, Nederlandse Organisatie voor Wetenschappelijk Onderzoek;
                Award ID: SH-271-13
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100006209, Radboud Universitair Medisch Centrum;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 281964
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2016

                Genetics
                Genetics

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