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  • 1
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    The mutation spectrum revealed by paired genome sequences from a lung cancer patient (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-05-28
    Description: Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung carcinomas in smokers being the predominant form of the disease. Although previous studies have identified important common somatic mutations in lung cancers, they have primarily focused on a limited set of genes and have thus provided a constrained view of the mutational spectrum. Recent cancer sequencing efforts have used next-generation sequencing technologies to provide a genome-wide view of mutations in leukaemia, breast cancer and cancer cell lines. Here we present the complete sequences of a primary lung tumour (60x coverage) and adjacent normal tissue (46x). Comparing the two genomes, we identify a wide variety of somatic variations, including 〉50,000 high-confidence single nucleotide variants. We validated 530 somatic single nucleotide variants in this tumour, including one in the KRAS proto-oncogene and 391 others in coding regions, as well as 43 large-scale structural variations. These constitute a large set of new somatic mutations and yield an estimated 17.7 per megabase genome-wide somatic mutation rate. Notably, we observe a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes and in promoter regions up to 5 kilobases upstream of all protein-coding genes. Furthermore, we observe a higher rate of amino acid-changing mutations in kinase genes. We present a comprehensive view of somatic alterations in a single lung tumour, and provide the first evidence, to our knowledge, of distinct selective pressures present within the tumour environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, William -- Jiang, Zhaoshi -- Liu, Jinfeng -- Haverty, Peter M -- Guan, Yinghui -- Stinson, Jeremy -- Yue, Peng -- Zhang, Yan -- Pant, Krishna P -- Bhatt, Deepali -- Ha, Connie -- Johnson, Stephanie -- Kennemer, Michael I -- Mohan, Sankar -- Nazarenko, Igor -- Watanabe, Colin -- Sparks, Andrew B -- Shames, David S -- Gentleman, Robert -- de Sauvage, Frederic J -- Stern, Howard -- Pandita, Ajay -- Ballinger, Dennis G -- Drmanac, Radoje -- Modrusan, Zora -- Seshagiri, Somasekar -- Zhang, Zemin -- England -- Nature. 2010 May 27;465(7297):473-7. doi: 10.1038/nature09004.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20505728" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinoma, Non-Small-Cell Lung/*genetics ; DNA Mutational Analysis ; Genome, Human/*genetics ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; Models, Biological ; Point Mutation/*genetics ; Selection, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    A mechanically stabilized receptor-ligand flex-bond important in the vasculature (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-08-21
    Description: Haemostasis in the arteriolar circulation mediated by von Willebrand factor (VWF) binding to platelets is an example of an adhesive interaction that must withstand strong hydrodynamic forces acting on cells. VWF is a concatenated, multifunctional protein that has binding sites for platelets as well as subendothelial collagen. Binding of the A1 domain in VWF to the glycoprotein Ib alpha subunit (GPIbalpha) on the surface of platelets mediates crosslinking of platelets to one another and the formation of a platelet plug for arterioles. The importance of VWF is illustrated by its mutation in von Willebrand disease, a bleeding diathesis. Here, we describe a novel mechanochemical specialization of the A1-GPIbalpha bond for force-resistance. We have developed a method that enables, for the first time, repeated measurements of the binding and unbinding of a receptor and ligand in a single molecule (ReaLiSM). We demonstrate two states of the receptor-ligand bond, that is, a flex-bond. One state is seen at low force; a second state begins to engage at 10 pN with a approximately 20-fold longer lifetime and greater force resistance. The lifetimes of the two states, how force exponentiates lifetime, and the kinetics of switching between the two states are all measured. For the first time, single-molecule measurements on this system are in agreement with bulk phase measurements. The results have important implications not only for how platelets bound to VWF are able to resist force to plug arterioles, but also how increased flow activates platelet plug formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117310/" 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/PMC4117310/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jongseong -- Zhang, Cheng-Zhong -- Zhang, Xiaohui -- Springer, Timothy A -- HL-48675/HL/NHLBI NIH HHS/ -- P01 HL048675/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Aug 19;466(7309):992-5. doi: 10.1038/nature09295.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immune Disease Institute, Children's Hospital Boston and Department of Pathology, Harvard Medical School, 3 Blackfan Circle, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725043" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arterioles/cytology/*physiology ; Blood Coagulation/*physiology ; Blood Platelets/chemistry/cytology/*metabolism ; Cell Line ; Hemorheology ; Humans ; Kinetics ; Ligands ; Membrane Glycoproteins/chemistry/*metabolism ; Mice ; Models, Chemical ; Models, Molecular ; Platelet Glycoprotein GPIb-IX Complex ; Protein Binding ; Protein Structure, Tertiary ; Tensile Strength ; von Willebrand Factor/chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Complete Khoisan and Bantu genomes from southern Africa (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-19
    Description: The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890430/" 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/PMC3890430/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schuster, Stephan C -- Miller, Webb -- Ratan, Aakrosh -- Tomsho, Lynn P -- Giardine, Belinda -- Kasson, Lindsay R -- Harris, Robert S -- Petersen, Desiree C -- Zhao, Fangqing -- Qi, Ji -- Alkan, Can -- Kidd, Jeffrey M -- Sun, Yazhou -- Drautz, Daniela I -- Bouffard, Pascal -- Muzny, Donna M -- Reid, Jeffrey G -- Nazareth, Lynne V -- Wang, Qingyu -- Burhans, Richard -- Riemer, Cathy -- Wittekindt, Nicola E -- Moorjani, Priya -- Tindall, Elizabeth A -- Danko, Charles G -- Teo, Wee Siang -- Buboltz, Anne M -- Zhang, Zhenhai -- Ma, Qianyi -- Oosthuysen, Arno -- Steenkamp, Abraham W -- Oostuisen, Hermann -- Venter, Philippus -- Gajewski, John -- Zhang, Yu -- Pugh, B Franklin -- Makova, Kateryna D -- Nekrutenko, Anton -- Mardis, Elaine R -- Patterson, Nick -- Pringle, Tom H -- Chiaromonte, Francesca -- Mullikin, James C -- Eichler, Evan E -- Hardison, Ross C -- Gibbs, Richard A -- Harkins, Timothy T -- Hayes, Vanessa M -- R01 GM087472/GM/NIGMS NIH HHS/ -- R01 HG004909/HG/NHGRI NIH HHS/ -- R01GM087472/GM/NIGMS NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):943-7. doi: 10.1038/nature08795.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Pennsylvania State University, Center for Comparative Genomics and Bioinformatics, 310 Wartik Lab, University Park, Pennsylvania 16802, USA. scs@bx.psu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164927" target="_blank"〉PubMed〈/a〉
    Keywords: African Continental Ancestry Group/*genetics ; Asian Continental Ancestry Group/genetics ; Ethnic Groups/*genetics ; European Continental Ancestry Group/genetics ; Exons/genetics ; Genetics, Medical ; Genome, Human/*genetics ; Humans ; Phylogeny ; Polymorphism, Single Nucleotide/genetics ; South Africa/ethnology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Diverse somatic mutation patterns and pathway alterations in human cancers (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-30
    Description: The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kan, Zhengyan -- Jaiswal, Bijay S -- Stinson, Jeremy -- Janakiraman, Vasantharajan -- Bhatt, Deepali -- Stern, Howard M -- Yue, Peng -- Haverty, Peter M -- Bourgon, Richard -- Zheng, Jianbiao -- Moorhead, Martin -- Chaudhuri, Subhra -- Tomsho, Lynn P -- Peters, Brock A -- Pujara, Kanan -- Cordes, Shaun -- Davis, David P -- Carlton, Victoria E H -- Yuan, Wenlin -- Li, Li -- Wang, Weiru -- Eigenbrot, Charles -- Kaminker, Joshua S -- Eberhard, David A -- Waring, Paul -- Schuster, Stephan C -- Modrusan, Zora -- Zhang, Zemin -- Stokoe, David -- de Sauvage, Frederic J -- Faham, Malek -- Seshagiri, Somasekar -- England -- Nature. 2010 Aug 12;466(7308):869-73. doi: 10.1038/nature09208. Epub 2010 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20668451" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/classification/genetics ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; Female ; GTP-Binding Protein alpha Subunits/genetics ; Genes, Neoplasm/*genetics ; Humans ; Lung Neoplasms/classification/genetics ; MAP Kinase Kinase 4/genetics ; Male ; Mutation/*genetics ; Neoplasms/enzymology/*genetics/*metabolism/pathology ; Ovarian Neoplasms/classification/genetics ; Prostatic Neoplasms/classification/genetics ; Protein Kinases/genetics ; Receptors, G-Protein-Coupled/genetics ; Signal Transduction/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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