ALBERT

Description: Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603574/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603574/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ley, Timothy J -- Mardis, Elaine R -- Ding, Li -- Fulton, Bob -- McLellan, Michael D -- Chen, Ken -- Dooling, David -- Dunford-Shore, Brian H -- McGrath, Sean -- Hickenbotham, Matthew -- Cook, Lisa -- Abbott, Rachel -- Larson, David E -- Koboldt, Dan C -- Pohl, Craig -- Smith, Scott -- Hawkins, Amy -- Abbott, Scott -- Locke, Devin -- Hillier, Ladeana W -- Miner, Tracie -- Fulton, Lucinda -- Magrini, Vincent -- Wylie, Todd -- Glasscock, Jarret -- Conyers, Joshua -- Sander, Nathan -- Shi, Xiaoqi -- Osborne, John R -- Minx, Patrick -- Gordon, David -- Chinwalla, Asif -- Zhao, Yu -- Ries, Rhonda E -- Payton, Jacqueline E -- Westervelt, Peter -- Tomasson, Michael H -- Watson, Mark -- Baty, Jack -- Ivanovich, Jennifer -- Heath, Sharon -- Shannon, William D -- Nagarajan, Rakesh -- Walter, Matthew J -- Link, Daniel C -- Graubert, Timothy A -- DiPersio, John F -- Wilson, Richard K -- U54 HG002042/HG/NHGRI NIH HHS/ -- U54 HG002042-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Nov 6;456(7218):66-72. doi: 10.1038/nature07485.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63108, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18987736" target="_blank"〉PubMed〈/a〉

Description: Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077050/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077050/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mills, Ryan E -- Walter, Klaudia -- Stewart, Chip -- Handsaker, Robert E -- Chen, Ken -- Alkan, Can -- Abyzov, Alexej -- Yoon, Seungtai Chris -- Ye, Kai -- Cheetham, R Keira -- Chinwalla, Asif -- Conrad, Donald F -- Fu, Yutao -- Grubert, Fabian -- Hajirasouliha, Iman -- Hormozdiari, Fereydoun -- Iakoucheva, Lilia M -- Iqbal, Zamin -- Kang, Shuli -- Kidd, Jeffrey M -- Konkel, Miriam K -- Korn, Joshua -- Khurana, Ekta -- Kural, Deniz -- Lam, Hugo Y K -- Leng, Jing -- Li, Ruiqiang -- Li, Yingrui -- Lin, Chang-Yun -- Luo, Ruibang -- Mu, Xinmeng Jasmine -- Nemesh, James -- Peckham, Heather E -- Rausch, Tobias -- Scally, Aylwyn -- Shi, Xinghua -- Stromberg, Michael P -- Stutz, Adrian M -- Urban, Alexander Eckehart -- Walker, Jerilyn A -- Wu, Jiantao -- Zhang, Yujun -- Zhang, Zhengdong D -- Batzer, Mark A -- Ding, Li -- Marth, Gabor T -- McVean, Gil -- Sebat, Jonathan -- Snyder, Michael -- Wang, Jun -- Ye, Kenny -- Eichler, Evan E -- Gerstein, Mark B -- Hurles, Matthew E -- Lee, Charles -- McCarroll, Steven A -- Korbel, Jan O -- 1000 Genomes Project -- 062023/Wellcome Trust/United Kingdom -- 077009/Wellcome Trust/United Kingdom -- 077014/Wellcome Trust/United Kingdom -- 077192/Wellcome Trust/United Kingdom -- 085532/Wellcome Trust/United Kingdom -- G0701805/Medical Research Council/United Kingdom -- G1000758/Medical Research Council/United Kingdom -- P01 HG004120/HG/NHGRI NIH HHS/ -- P41 HG004221/HG/NHGRI NIH HHS/ -- P41 HG004221-01/HG/NHGRI NIH HHS/ -- P41 HG004221-02/HG/NHGRI NIH HHS/ -- P41 HG004221-03/HG/NHGRI NIH HHS/ -- P41 HG004221-03S1/HG/NHGRI NIH HHS/ -- P41 HG004221-03S2/HG/NHGRI NIH HHS/ -- P41 HG004221-03S3/HG/NHGRI NIH HHS/ -- R01 GM059290/GM/NIGMS NIH HHS/ -- R01 GM081533/GM/NIGMS NIH HHS/ -- R01 GM081533-01A1/GM/NIGMS NIH HHS/ -- R01 GM081533-02/GM/NIGMS NIH HHS/ -- R01 GM081533-03/GM/NIGMS NIH HHS/ -- R01 GM081533-04/GM/NIGMS NIH HHS/ -- R01 GM59290/GM/NIGMS NIH HHS/ -- R01 HG004719/HG/NHGRI NIH HHS/ -- R01 HG004719-01/HG/NHGRI NIH HHS/ -- R01 HG004719-02/HG/NHGRI NIH HHS/ -- R01 HG004719-02S1/HG/NHGRI NIH HHS/ -- R01 HG004719-03/HG/NHGRI NIH HHS/ -- R01 HG004719-04/HG/NHGRI NIH HHS/ -- R01 MH091350/MH/NIMH NIH HHS/ -- RC2 HG005552/HG/NHGRI NIH HHS/ -- RC2 HG005552-01/HG/NHGRI NIH HHS/ -- RC2 HG005552-02/HG/NHGRI NIH HHS/ -- U01 HG005209/HG/NHGRI NIH HHS/ -- U01 HG005209-01/HG/NHGRI NIH HHS/ -- U01 HG005209-02/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 3;470(7332):59-65. doi: 10.1038/nature09708.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293372" target="_blank"〉PubMed〈/a〉

Description: Sequencing studies of breast tumour cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumours. Here we developed a whole-genome and exome single cell sequencing approach called nuc-seq that uses G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumour nuclei from an oestrogen-receptor-positive (ER(+)) breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumour evolution and remained highly stable as the tumour masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Using targeted single-molecule sequencing, many of the diverse mutations were shown to occur at low frequencies (〈10%) in the tumour mass. Using mathematical modelling we found that the triple-negative tumour cells had an increased mutation rate (13.3x), whereas the ER(+) tumour cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158312/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158312/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yong -- Waters, Jill -- Leung, Marco L -- Unruh, Anna -- Roh, Whijae -- Shi, Xiuqing -- Chen, Ken -- Scheet, Paul -- Vattathil, Selina -- Liang, Han -- Multani, Asha -- Zhang, Hong -- Zhao, Rui -- Michor, Franziska -- Meric-Bernstam, Funda -- Navin, Nicholas E -- 1R01CA169244-01/CA/NCI NIH HHS/ -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA098258/CA/NCI NIH HHS/ -- R01 CA169244/CA/NCI NIH HHS/ -- R01 CA172652/CA/NCI NIH HHS/ -- R01CA172652/CA/NCI NIH HHS/ -- R21 CA174397/CA/NCI NIH HHS/ -- R21CA174397-01/CA/NCI NIH HHS/ -- U24CA143883/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- UL1 TR000371/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Aug 14;512(7513):155-60. doi: 10.1038/nature13600. Epub 2014 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, Texas 77030, USA. ; 1] The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA. ; The University of Texas MD Anderson Cancer Center, Department of Bioinformatics and Computational Biology, Houston, Texas 77030, USA. ; 1] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA [2] The University of Texas MD Anderson Cancer Center, Department of Epidemiology, Houston, Texas 77030, USA. ; The University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, Texas 77030, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02215, USA. ; The University of Texas MD Anderson Cancer Center Department of Investigational Cancer Therapeutics, Houston, Texas 77030, USA. ; 1] The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA [3] The University of Texas MD Anderson Cancer Center, Department of Bioinformatics and Computational Biology, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079324" target="_blank"〉PubMed〈/a〉

Description: Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617611/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617611/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sudmant, Peter H -- Rausch, Tobias -- Gardner, Eugene J -- Handsaker, Robert E -- Abyzov, Alexej -- Huddleston, John -- Zhang, Yan -- Ye, Kai -- Jun, Goo -- Hsi-Yang Fritz, Markus -- Konkel, Miriam K -- Malhotra, Ankit -- Stutz, Adrian M -- Shi, Xinghua -- Paolo Casale, Francesco -- Chen, Jieming -- Hormozdiari, Fereydoun -- Dayama, Gargi -- Chen, Ken -- Malig, Maika -- Chaisson, Mark J P -- Walter, Klaudia -- Meiers, Sascha -- Kashin, Seva -- Garrison, Erik -- Auton, Adam -- Lam, Hugo Y K -- Jasmine Mu, Xinmeng -- Alkan, Can -- Antaki, Danny -- Bae, Taejeong -- Cerveira, Eliza -- Chines, Peter -- Chong, Zechen -- Clarke, Laura -- Dal, Elif -- Ding, Li -- Emery, Sarah -- Fan, Xian -- Gujral, Madhusudan -- Kahveci, Fatma -- Kidd, Jeffrey M -- Kong, Yu -- Lameijer, Eric-Wubbo -- McCarthy, Shane -- Flicek, Paul -- Gibbs, Richard A -- Marth, Gabor -- Mason, Christopher E -- Menelaou, Androniki -- Muzny, Donna M -- Nelson, Bradley J -- Noor, Amina -- Parrish, Nicholas F -- Pendleton, Matthew -- Quitadamo, Andrew -- Raeder, Benjamin -- Schadt, Eric E -- Romanovitch, Mallory -- Schlattl, Andreas -- Sebra, Robert -- Shabalin, Andrey A -- Untergasser, Andreas -- Walker, Jerilyn A -- Wang, Min -- Yu, Fuli -- Zhang, Chengsheng -- Zhang, Jing -- Zheng-Bradley, Xiangqun -- Zhou, Wanding -- Zichner, Thomas -- Sebat, Jonathan -- Batzer, Mark A -- McCarroll, Steven A -- 1000 Genomes Project Consortium -- Mills, Ryan E -- Gerstein, Mark B -- Bashir, Ali -- Stegle, Oliver -- Devine, Scott E -- Lee, Charles -- Eichler, Evan E -- Korbel, Jan O -- P01HG007497/HG/NHGRI NIH HHS/ -- R01 CA166661/CA/NCI NIH HHS/ -- R01 HG002385/HG/NHGRI NIH HHS/ -- R01 HG002898/HG/NHGRI NIH HHS/ -- R01CA166661/CA/NCI NIH HHS/ -- R01GM59290/GM/NIGMS NIH HHS/ -- R01HG002898/HG/NHGRI NIH HHS/ -- R01HG007068/HG/NHGRI NIH HHS/ -- RR029676-01/RR/NCRR NIH HHS/ -- RR19895/RR/NCRR NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U41 HG007497/HG/NHGRI NIH HHS/ -- U41HG007497/HG/NHGRI NIH HHS/ -- WT085532/Z/08/Z/Wellcome Trust/United Kingdom -- WT104947/Z/14/Z/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Oct 1;526(7571):75-81. doi: 10.1038/nature15394.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, 3720 15th Avenue NE, Seattle, Washington 98195-5065, USA. ; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. ; Institute for Genome Sciences, University of Maryland School of Medicine, 801 W Baltimore Street, Baltimore, Maryland 21201, USA. ; Department of Genetics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, Massachusetts 02115, USA. ; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA. ; Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. ; Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA. ; Program in Computational Biology and Bioinformatics, Yale University, BASS 432 &437, 266 Whitney Avenue, New Haven, Connecticut 06520, USA. ; Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520, USA. ; The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; Department of Genetics, Washington University in St Louis, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, 1415 Washington Heights, Ann Arbor, Michigan 48109, USA. ; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler St., Houston, Texas 77030, USA. ; Department of Biological Sciences, Louisiana State University, 202 Life Sciences Building, Baton Rouge, Louisiana 70803, USA. ; The Jackson Laboratory for Genomic Medicine, 10 Discovery 263 Farmington Avenue, Farmington, Connecticut 06030, USA. ; Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, North Carolina 28223, USA. ; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut 06520, USA. ; Department of Computational Medicine &Bioinformatics, University of Michigan, 500 S. State Street, Ann Arbor, Michigan 48109, USA. ; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Department of Biology, Boston College, 355 Higgins Hall, 140 Commonwealth Avenue, Chestnut Hill, Massachusetts 02467, USA. ; Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA. ; Bina Technologies, Roche Sequencing, 555 Twin Dolphin Drive, Redwood City, California 94065, USA. ; Cancer Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA. ; Department of Computer Engineering, Bilkent University, 06800 Ankara, Turkey. ; University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA. ; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892 USA. ; Department of Medicine, Washington University in St Louis, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; Siteman Cancer Center, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; Department of Human Genetics, University of Michigan, 1241 Catherine Street, Ann Arbor, Michigan 48109, USA. ; Molecular Epidemiology, Leiden University Medical Center, Leiden 2300RA, The Netherlands. ; Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA. ; The Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, 1305 York Avenue, Weill Cornell Medical College, New York, New York 10065, USA. ; The Feil Family Brain and Mind Research Institute, 413 East 69th St, Weill Cornell Medical College, New York, New York 10065, USA. ; University of Oxford, 1 South Parks Road, Oxford OX3 9DS, UK. ; Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. ; Department of Genetics and Genomic Sciences, Icahn School of Medicine, New York School of Natural Sciences, 1428 Madison Avenue, New York, New York 10029, USA. ; Institute for Virus Research, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. ; Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, McGuire Hall, Richmond, Virginia 23298-0581, USA. ; Zentrum fur Molekulare Biologie, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. ; Department of Computer Science, Yale University, 51 Prospect Street, New Haven, Connecticut 06511, USA. ; Department of Graduate Studies - Life Sciences, Ewha Womans University, Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, South Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26432246" target="_blank"〉PubMed〈/a〉