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      Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

      research-article
      1 , 1 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , ICGC Prostate Cancer Working Group, ICGC Bone Cancer Working Group, ICGC Breast Cancer Working Group, 1 , 3 , 4 , 3 , 4 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 1 , 2 , 1 , 1 , 1
      Genome Research
      Cold Spring Harbor Laboratory Press

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          Abstract

          Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

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          Most cited references49

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            Fast and accurate short read alignment with Burrows–Wheeler transform

            Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
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              Tandem repeats finder: a program to analyze DNA sequences.

              G. Benson (1999)
              A tandem repeat in DNA is two or more contiguous, approximate copies of a pattern of nucleotides. Tandem repeats have been shown to cause human disease, may play a variety of regulatory and evolutionary roles and are important laboratory and analytic tools. Extensive knowledge about pattern size, copy number, mutational history, etc. for tandem repeats has been limited by the inability to easily detect them in genomic sequence data. In this paper, we present a new algorithm for finding tandem repeats which works without the need to specify either the pattern or pattern size. We model tandem repeats by percent identity and frequency of indels between adjacent pattern copies and use statistically based recognition criteria. We demonstrate the algorithm's speed and its ability to detect tandem repeats that have undergone extensive mutational change by analyzing four sequences: the human frataxin gene, the human beta T cellreceptor locus sequence and two yeast chromosomes. These sequences range in size from 3 kb up to 700 kb. A World Wide Web server interface atc3.biomath.mssm.edu/trf.html has been established for automated use of the program.
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                Author and article information

                Journal
                Genome Res
                Genome Res
                genome
                genome
                GENOME
                Genome Research
                Cold Spring Harbor Laboratory Press
                1088-9051
                1549-5469
                June 2015
                June 2015
                : 25
                : 6
                : 814-824
                Affiliations
                [1 ]Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
                [2 ]Cytogenetics Facility, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
                [3 ]Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom;
                [4 ]Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
                [5 ]Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom;
                [6 ]BioCare, Strategic Cancer Research Program, SE-223 81 Lund, Sweden;
                [7 ]CREATE Health, Strategic Centre for Translational Cancer Research, SE-221 00 Lund, Sweden;
                [8 ]Department of Oncology and Pathology, Lund University Cancer Center, SE-221 85 Lund, Sweden;
                [9 ]Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom;
                [10 ]Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, 230-0045 Yokohama, Japan;
                [11 ]National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan;
                [12 ]Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA;
                [13 ]Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands;
                [14 ]Department of General Surgery, Singapore General Hospital, Singapore 169608;
                [15 ]Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver V5Z 1L3, Canada;
                [16 ]Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, 6525 HP Nijmegen, Netherlands;
                [17 ]Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands;
                [18 ]Section of Oncology, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway;
                [19 ]Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway;
                [20 ]Institut Curie, INSERM U934 and Department of Tumor Biology, 75248 Paris cédex 05, France;
                [21 ]Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway;
                [22 ]The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway;
                [23 ]Cancer Research Laboratory, University of Iceland, 101 Reykjavik, Iceland;
                [24 ]Royal National Orthopaedic Hospital, Middlesex HA7 4LP, United Kingdom;
                [25 ]UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom;
                [26 ]University of Liverpool and HCA Pathology Laboratories, London WC1E 6JA, United Kingdom;
                [27 ]Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom;
                [28 ]Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom;
                [29 ]Institute of Cancer Research, Sutton, London SM2 5NG, United Kingdom;
                [30 ]Department of Biological Sciences and School of Medicine, University of East Anglia, Norwich NR4 7TJ, United Kingdom;
                [31 ]Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton SM2 5NG, United Kingdom;
                [32 ]Royal Marsden NHS Foundation Trust, London SW3 6JJ and Sutton SM2 5PT, United Kingdom;
                [33 ]University of Queensland, School of Medicine, Brisbane, QLD 4006, Australia;
                [34 ]Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia;
                [35 ]University of Queensland, UQ Centre for Clinical Research, Brisbane, QLD 4029, Australia;
                [36 ]Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, 1000 Brussels, Belgium;
                [37 ]Université Lyon 1, Institut National du Cancer (INCa)–Synergie, 69008 Lyon, France;
                [38 ]Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
                [39 ]Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
                [40 ]Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom;
                [41 ]Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
                Author notes
                [42]

                Deceased.

                [43]

                These authors contributed equally to this work.

                [44]

                A full list of members is provided in the Supplemental Material.

                Corresponding author: mrs@ 123456sanger.ac.uk
                Article
                9509184
                10.1101/gr.190470.115
                4448678
                25963125
                151abe72-d6cc-42fb-ac34-2dc4a051ee42
                © 2015 Ju et al.; Published by Cold Spring Harbor Laboratory Press

                This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 February 2015
                : 14 April 2015
                Page count
                Pages: 11
                Funding
                Funded by: European Molecular Biology Organization long-term fellowship (LTF) http://dx.doi.org/10.13039/100004410
                Award ID: 1203_2012
                Funded by: Marie Curie Fellowship
                Award ID: FP7-PEOPLE-2012-IEF
                Award ID: 328264
                Funded by: Wellcome Trust Senior Clinical Fellow http://dx.doi.org/10.13039/100004440
                Funded by: National Institute for Health Research (NIHR) UCLH Biomedical Research Centre http://dx.doi.org/10.13039/501100000272
                Funded by: Wellcome Trust http://dx.doi.org/10.13039/100004440
                Funded by: Dallaglio Foundation
                Award ID: C5047/A14835
                Funded by: National Institute for Health Research http://dx.doi.org/10.13039/501100000272
                Funded by: Biomedical Research Centre
                Funded by: The Institute of Cancer Research and Royal Marsden NHS Foundation Trust
                Funded by: National Cancer Research Prostate Cancer Mechanisms of Progression and Treatment (PROMPT)
                Award ID: G0500966/75466
                Funded by: National Institute for Health Research http://dx.doi.org/10.13039/501100000272
                Award ID: ICGC 08/09
                Award ID: KCL
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                Research

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