ALBERT

Beschreibung: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P 〈 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955183/" 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/PMC2955183/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lango Allen, Hana -- Estrada, Karol -- Lettre, Guillaume -- Berndt, Sonja I -- Weedon, Michael N -- Rivadeneira, Fernando -- Willer, Cristen J -- Jackson, Anne U -- Vedantam, Sailaja -- Raychaudhuri, Soumya -- Ferreira, Teresa -- Wood, Andrew R -- Weyant, Robert J -- Segre, Ayellet V -- Speliotes, Elizabeth K -- Wheeler, Eleanor -- Soranzo, Nicole -- Park, Ju-Hyun -- Yang, Jian -- Gudbjartsson, Daniel -- Heard-Costa, Nancy L -- Randall, Joshua C -- Qi, Lu -- Vernon Smith, Albert -- Magi, Reedik -- Pastinen, Tomi -- Liang, Liming -- Heid, Iris M -- Luan, Jian'an -- Thorleifsson, Gudmar -- Winkler, Thomas W -- Goddard, Michael E -- Sin Lo, Ken -- Palmer, Cameron -- Workalemahu, Tsegaselassie -- Aulchenko, Yurii S -- Johansson, Asa -- Zillikens, M Carola -- Feitosa, Mary F -- Esko, Tonu -- Johnson, Toby -- Ketkar, Shamika -- Kraft, Peter -- Mangino, Massimo -- Prokopenko, Inga -- Absher, Devin -- Albrecht, Eva -- Ernst, Florian -- Glazer, Nicole L -- Hayward, Caroline -- Hottenga, Jouke-Jan -- Jacobs, Kevin B -- Knowles, Joshua W -- Kutalik, Zoltan -- Monda, Keri L -- Polasek, Ozren -- Preuss, Michael -- Rayner, Nigel W -- Robertson, Neil R -- Steinthorsdottir, Valgerdur -- Tyrer, Jonathan P -- Voight, Benjamin F -- Wiklund, Fredrik -- Xu, Jianfeng -- Zhao, Jing Hua -- Nyholt, Dale R -- Pellikka, Niina -- Perola, Markus -- Perry, John R B -- Surakka, Ida -- Tammesoo, Mari-Liis -- Altmaier, Elizabeth L -- Amin, Najaf -- Aspelund, Thor -- Bhangale, Tushar -- Boucher, Gabrielle -- Chasman, Daniel I -- Chen, Constance -- Coin, Lachlan -- Cooper, Matthew N -- Dixon, Anna L -- Gibson, Quince -- Grundberg, Elin -- Hao, Ke -- Juhani Junttila, M -- Kaplan, Lee M -- Kettunen, Johannes -- Konig, Inke R -- Kwan, Tony -- Lawrence, Robert W -- Levinson, Douglas F -- Lorentzon, Mattias -- McKnight, Barbara -- Morris, Andrew P -- Muller, Martina -- Suh Ngwa, Julius -- Purcell, Shaun -- Rafelt, Suzanne -- Salem, Rany M -- Salvi, Erika -- Sanna, Serena -- Shi, Jianxin -- Sovio, Ulla -- Thompson, John R -- Turchin, Michael C -- Vandenput, Liesbeth -- Verlaan, Dominique J -- Vitart, Veronique -- White, Charles C -- Ziegler, Andreas -- Almgren, Peter -- Balmforth, Anthony J -- Campbell, Harry -- Citterio, Lorena -- De Grandi, Alessandro -- Dominiczak, Anna -- Duan, Jubao -- Elliott, Paul -- Elosua, Roberto -- Eriksson, Johan G -- Freimer, Nelson B -- Geus, Eco J C -- Glorioso, Nicola -- Haiqing, Shen -- Hartikainen, Anna-Liisa -- Havulinna, Aki S -- Hicks, Andrew A -- Hui, Jennie -- Igl, Wilmar -- Illig, Thomas -- Jula, Antti -- Kajantie, Eero -- Kilpelainen, Tuomas O -- Koiranen, Markku -- Kolcic, Ivana -- Koskinen, Seppo -- Kovacs, Peter -- Laitinen, Jaana -- Liu, Jianjun -- Lokki, Marja-Liisa -- Marusic, Ana -- Maschio, Andrea -- Meitinger, Thomas -- Mulas, Antonella -- Pare, Guillaume -- Parker, Alex N -- Peden, John F -- Petersmann, Astrid -- Pichler, Irene -- Pietilainen, Kirsi H -- Pouta, Anneli -- Ridderstrale, Martin -- Rotter, Jerome I -- Sambrook, Jennifer G -- Sanders, Alan R -- Schmidt, Carsten Oliver -- Sinisalo, Juha -- Smit, Jan H -- Stringham, Heather M -- Bragi Walters, G -- Widen, Elisabeth -- Wild, Sarah H -- Willemsen, Gonneke -- Zagato, Laura -- Zgaga, Lina -- Zitting, Paavo -- Alavere, Helene -- Farrall, Martin -- McArdle, Wendy L -- Nelis, Mari -- Peters, Marjolein J -- Ripatti, Samuli -- van Meurs, Joyce B J -- Aben, Katja K -- Ardlie, Kristin G -- Beckmann, Jacques S -- Beilby, John P -- Bergman, Richard N -- Bergmann, Sven -- Collins, Francis S -- Cusi, Daniele -- den Heijer, Martin -- Eiriksdottir, Gudny -- Gejman, Pablo V -- Hall, Alistair S -- Hamsten, Anders -- Huikuri, Heikki V -- Iribarren, Carlos -- Kahonen, Mika -- Kaprio, Jaakko -- Kathiresan, Sekar -- Kiemeney, Lambertus -- Kocher, Thomas -- Launer, Lenore J -- Lehtimaki, Terho -- Melander, Olle -- Mosley, Tom H Jr -- Musk, Arthur W -- Nieminen, Markku S -- O'Donnell, Christopher J -- Ohlsson, Claes -- Oostra, Ben -- Palmer, Lyle J -- Raitakari, Olli -- Ridker, Paul M -- Rioux, John D -- Rissanen, Aila -- Rivolta, Carlo -- Schunkert, Heribert -- Shuldiner, Alan R -- Siscovick, David S -- Stumvoll, Michael -- Tonjes, Anke -- Tuomilehto, Jaakko -- van Ommen, Gert-Jan -- Viikari, Jorma -- Heath, Andrew C -- Martin, Nicholas G -- Montgomery, Grant W -- Province, Michael A -- Kayser, Manfred -- Arnold, Alice M -- Atwood, Larry D -- Boerwinkle, Eric -- Chanock, Stephen J -- Deloukas, Panos -- Gieger, Christian -- Gronberg, Henrik -- Hall, Per -- Hattersley, Andrew T -- Hengstenberg, Christian -- Hoffman, Wolfgang -- Lathrop, G Mark -- Salomaa, Veikko -- Schreiber, Stefan -- Uda, Manuela -- Waterworth, Dawn -- Wright, Alan F -- Assimes, Themistocles L -- Barroso, Ines -- Hofman, Albert -- Mohlke, Karen L -- Boomsma, Dorret I -- Caulfield, Mark J -- Cupples, L Adrienne -- Erdmann, Jeanette -- Fox, Caroline S -- Gudnason, Vilmundur -- Gyllensten, Ulf -- Harris, Tamara B -- Hayes, Richard B -- Jarvelin, Marjo-Riitta -- Mooser, Vincent -- Munroe, Patricia B -- Ouwehand, Willem H -- Penninx, Brenda W -- Pramstaller, Peter P -- Quertermous, Thomas -- Rudan, Igor -- Samani, Nilesh J -- Spector, Timothy D -- Volzke, Henry -- Watkins, Hugh -- Wilson, James F -- Groop, Leif C -- Haritunians, Talin -- Hu, Frank B -- Kaplan, Robert C -- Metspalu, Andres -- North, Kari E -- Schlessinger, David -- Wareham, Nicholas J -- Hunter, David J -- O'Connell, Jeffrey R -- Strachan, David P -- Wichmann, H-Erich -- Borecki, Ingrid B -- van Duijn, Cornelia M -- Schadt, Eric E -- Thorsteinsdottir, Unnur -- Peltonen, Leena -- Uitterlinden, Andre G -- Visscher, Peter M -- Chatterjee, Nilanjan -- Loos, Ruth J F -- Boehnke, Michael -- McCarthy, Mark I -- Ingelsson, Erik -- Lindgren, Cecilia M -- Abecasis, Goncalo R -- Stefansson, Kari -- Frayling, Timothy M -- Hirschhorn, Joel N -- 064890/Wellcome Trust/United Kingdom -- 068545/Wellcome Trust/United Kingdom -- 068545/Z/02/Wellcome Trust/United Kingdom -- 072856/Wellcome Trust/United Kingdom -- 072960/Wellcome Trust/United Kingdom -- 075491/Wellcome Trust/United Kingdom -- 076113/Wellcome Trust/United Kingdom -- 076113/B/04/Z/Wellcome Trust/United Kingdom -- 076113/C/04/Z/Wellcome Trust/United Kingdom -- 077016/Wellcome Trust/United Kingdom -- 077016/Z/05/Z/Wellcome Trust/United Kingdom -- 079557/Wellcome Trust/United Kingdom -- 079771/Wellcome Trust/United Kingdom -- 079895/Wellcome Trust/United Kingdom -- 081682/Wellcome Trust/United Kingdom -- 081682/Z/06/Z/Wellcome Trust/United Kingdom -- 083270/Wellcome Trust/United Kingdom -- 084183/Z/07/Z/Wellcome Trust/United Kingdom -- 085301/Wellcome Trust/United Kingdom -- 085301/Z/08/Z/Wellcome Trust/United Kingdom -- 086596/Wellcome Trust/United Kingdom -- 086596/Z/08/Z/Wellcome Trust/United Kingdom -- 088885/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 091746/Wellcome Trust/United Kingdom -- 091746/Z/10/Z/Wellcome Trust/United Kingdom -- 263-MA-410953/PHS HHS/ -- AA014041/AA/NIAAA NIH HHS/ -- AA07535/AA/NIAAA NIH HHS/ -- AA10248/AA/NIAAA NIH HHS/ -- AA13320/AA/NIAAA NIH HHS/ -- AA13321/AA/NIAAA NIH HHS/ -- AA13326/AA/NIAAA NIH HHS/ -- CA047988/CA/NCI NIH HHS/ -- CA49449/CA/NCI NIH HHS/ -- CA50385/CA/NCI NIH HHS/ -- CA65725/CA/NCI NIH HHS/ -- CA67262/CA/NCI NIH HHS/ -- CA87969/CA/NCI NIH HHS/ -- CZB/4/276/Chief Scientist Office/United Kingdom -- 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GM074518-05/GM/NIGMS NIH HHS/ -- U01 HG004399/HG/NHGRI NIH HHS/ -- U01 HG004399-02/HG/NHGRI NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HG004402-02/HG/NHGRI NIH HHS/ -- U01 HG005214/HG/NHGRI NIH HHS/ -- U01 HG005214-02/HG/NHGRI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL069757-10/HL/NHLBI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL072515-06/HL/NHLBI NIH HHS/ -- U01 HL080295/HL/NHLBI NIH HHS/ -- U01 HL080295-04/HL/NHLBI NIH HHS/ -- U01 HL084729/HL/NHLBI NIH HHS/ -- U01 HL084729-03/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U01 HL084756-03/HL/NHLBI NIH HHS/ -- U01 MH079469/MH/NIMH NIH HHS/ -- U01 MH079469-03/MH/NIMH NIH HHS/ -- U01 MH079470/MH/NIMH NIH HHS/ -- U01 MH079470-03/MH/NIMH NIH HHS/ -- U01-CA098233/CA/NCI NIH HHS/ -- U01-GM074518/GM/NIGMS NIH HHS/ -- U01-HG004399/HG/NHGRI NIH HHS/ -- U01-HG004402/HG/NHGRI NIH HHS/ -- U01-HL080295/HL/NHLBI NIH HHS/ -- U01-HL084756/HL/NHLBI NIH HHS/ -- U01-HL72515/HL/NHLBI NIH HHS/ -- U01-MH79469/MH/NIMH NIH HHS/ -- U01-MH79470/MH/NIMH NIH HHS/ -- U54-RR020278/RR/NCRR NIH HHS/ -- UL1-RR025005/RR/NCRR NIH HHS/ -- Z01-AG00675/AG/NIA NIH HHS/ -- Z01-AG007380/AG/NIA NIH HHS/ -- Z01-HG000024/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2010 Oct 14;467(7317):832-8. doi: 10.1038/nature09410. Epub 2010 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX1 2LU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881960" target="_blank"〉PubMed〈/a〉

Beschreibung: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in 〉100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P 〈 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039276/" 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/PMC3039276/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teslovich, Tanya M -- Musunuru, Kiran -- Smith, Albert V -- Edmondson, Andrew C -- Stylianou, Ioannis M -- Koseki, Masahiro -- Pirruccello, James P -- Ripatti, Samuli -- Chasman, Daniel I -- Willer, Cristen J -- Johansen, Christopher T -- Fouchier, Sigrid W -- Isaacs, Aaron -- Peloso, Gina M -- Barbalic, Maja -- Ricketts, Sally L -- Bis, Joshua C -- Aulchenko, Yurii S -- Thorleifsson, Gudmar -- Feitosa, Mary F -- Chambers, John -- Orho-Melander, Marju -- Melander, Olle -- Johnson, Toby -- Li, Xiaohui -- Guo, Xiuqing -- Li, Mingyao -- Shin Cho, Yoon -- Jin Go, Min -- Jin Kim, Young -- Lee, Jong-Young -- Park, Taesung -- Kim, Kyunga -- Sim, Xueling -- Twee-Hee Ong, Rick -- Croteau-Chonka, Damien C -- Lange, Leslie A -- Smith, Joshua D -- Song, Kijoung -- Hua Zhao, Jing -- Yuan, Xin -- Luan, Jian'an -- Lamina, Claudia -- Ziegler, Andreas -- Zhang, Weihua -- Zee, Robert Y L -- Wright, Alan F -- Witteman, Jacqueline C M -- Wilson, James F -- Willemsen, Gonneke -- Wichmann, H-Erich -- Whitfield, John B -- Waterworth, Dawn M -- Wareham, Nicholas J -- Waeber, Gerard -- Vollenweider, Peter -- Voight, Benjamin F -- Vitart, Veronique -- Uitterlinden, Andre G -- Uda, Manuela -- Tuomilehto, Jaakko -- Thompson, John R -- Tanaka, Toshiko -- Surakka, Ida -- Stringham, Heather M -- Spector, Tim D -- Soranzo, Nicole -- Smit, Johannes H -- Sinisalo, Juha -- Silander, Kaisa -- Sijbrands, Eric J G -- Scuteri, Angelo -- Scott, James -- Schlessinger, David -- Sanna, Serena -- Salomaa, Veikko -- Saharinen, Juha -- Sabatti, Chiara -- Ruokonen, Aimo -- Rudan, Igor -- Rose, Lynda M -- Roberts, Robert -- Rieder, Mark -- Psaty, Bruce M -- Pramstaller, Peter P -- Pichler, Irene -- Perola, Markus -- Penninx, Brenda W J H -- Pedersen, Nancy L -- Pattaro, Cristian -- Parker, Alex N -- Pare, Guillaume -- Oostra, Ben A -- O'Donnell, Christopher J -- Nieminen, Markku S -- Nickerson, Deborah A -- Montgomery, Grant W -- Meitinger, Thomas -- McPherson, Ruth -- McCarthy, Mark I -- McArdle, Wendy -- Masson, David -- Martin, Nicholas G -- Marroni, Fabio -- Mangino, Massimo -- Magnusson, Patrik K E -- Lucas, Gavin -- Luben, Robert -- Loos, Ruth J F -- Lokki, Marja-Liisa -- Lettre, Guillaume -- Langenberg, Claudia -- Launer, Lenore J -- Lakatta, Edward G -- Laaksonen, Reijo -- Kyvik, Kirsten O -- Kronenberg, Florian -- Konig, Inke R -- Khaw, Kay-Tee -- Kaprio, Jaakko -- Kaplan, Lee M -- Johansson, Asa -- Jarvelin, Marjo-Riitta -- Janssens, A Cecile J W -- Ingelsson, Erik -- Igl, Wilmar -- Kees Hovingh, G -- Hottenga, Jouke-Jan -- Hofman, Albert -- Hicks, Andrew A -- Hengstenberg, Christian -- Heid, Iris M -- Hayward, Caroline -- Havulinna, Aki S -- Hastie, Nicholas D -- Harris, Tamara B -- Haritunians, Talin -- Hall, Alistair S -- Gyllensten, Ulf -- Guiducci, Candace -- Groop, Leif C -- Gonzalez, Elena -- Gieger, Christian -- Freimer, Nelson B -- Ferrucci, Luigi -- Erdmann, Jeanette -- Elliott, Paul -- Ejebe, Kenechi G -- Doring, Angela -- Dominiczak, Anna F -- Demissie, Serkalem -- Deloukas, Panagiotis -- de Geus, Eco J C -- de Faire, Ulf -- Crawford, Gabriel -- Collins, Francis S -- Chen, Yii-der I -- Caulfield, Mark J -- Campbell, Harry -- Burtt, Noel P -- Bonnycastle, Lori L -- Boomsma, Dorret I -- Boekholdt, S Matthijs -- Bergman, Richard N -- Barroso, Ines -- Bandinelli, Stefania -- Ballantyne, Christie M -- Assimes, Themistocles L -- Quertermous, Thomas -- Altshuler, David -- Seielstad, Mark -- Wong, Tien Y -- Tai, E-Shyong -- Feranil, Alan B -- Kuzawa, Christopher W -- Adair, Linda S -- Taylor, Herman A Jr -- Borecki, Ingrid B -- Gabriel, Stacey B -- Wilson, James G -- Holm, Hilma -- Thorsteinsdottir, Unnur -- Gudnason, Vilmundur -- Krauss, Ronald M -- Mohlke, Karen L -- Ordovas, Jose M -- Munroe, Patricia B -- Kooner, Jaspal S -- Tall, Alan R -- Hegele, Robert A -- Kastelein, John J P -- Schadt, Eric E -- Rotter, Jerome I -- Boerwinkle, Eric -- Strachan, David P -- Mooser, Vincent -- Stefansson, Kari -- Reilly, Muredach P -- Samani, Nilesh J -- Schunkert, Heribert -- Cupples, L Adrienne -- Sandhu, Manjinder S -- Ridker, Paul M -- Rader, Daniel J -- van Duijn, Cornelia M -- Peltonen, Leena -- Abecasis, Goncalo R -- Boehnke, Michael -- Kathiresan, Sekar -- 068545/Z/02/Wellcome Trust/United Kingdom -- 076113/B/04/Z/Wellcome Trust/United Kingdom -- 077016/Z/05/Z/Wellcome Trust/United Kingdom -- 079895/Wellcome Trust/United Kingdom -- 1Z01 HG000024/HG/NHGRI NIH HHS/ -- 5R01DK06833603/DK/NIDDK NIH HHS/ -- 5R01DK07568102/DK/NIDDK NIH HHS/ -- 5R01HL087679-02/HL/NHLBI NIH HHS/ -- 5R01HL08770003/HL/NHLBI NIH HHS/ -- 5R01HL08821502/HL/NHLBI NIH HHS/ -- CA 047988/CA/NCI NIH HHS/ -- CZB/4/710/Chief Scientist Office/United Kingdom -- DK062370/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK072193/DK/NIDDK NIH HHS/ -- DK078150/DK/NIDDK NIH HHS/ -- DK56350/DK/NIDDK NIH HHS/ -- ES10126/ES/NIEHS NIH HHS/ -- G0000934/Medical Research Council/United Kingdom -- G0401527/Medical Research Council/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G0801566/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9521010D/Medical Research Council/United Kingdom -- HHSN268200625226C/PHS HHS/ -- HL 04381/HL/NHLBI NIH HHS/ -- HL 080467/HL/NHLBI NIH HHS/ -- HL-54776/HL/NHLBI NIH HHS/ -- HL085144/HL/NHLBI NIH HHS/ -- K99 HL098364/HL/NHLBI NIH HHS/ -- K99 HL098364-01/HL/NHLBI NIH HHS/ -- K99HL094535/HL/NHLBI NIH HHS/ -- M01-RR00425/RR/NCRR NIH HHS/ -- MC_QA137934/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- N01 HC-15103/HC/NHLBI NIH HHS/ -- N01 HC-55222/HC/NHLBI NIH HHS/ -- N01-AG-12100/AG/NIA NIH HHS/ -- N01-HC-25195/HC/NHLBI NIH HHS/ -- N01-HC-35129/HC/NHLBI NIH HHS/ -- N01-HC-45133/HC/NHLBI NIH HHS/ -- N01-HC-55015/HC/NHLBI NIH HHS/ -- N01-HC-55016/HC/NHLBI NIH HHS/ -- N01-HC-55018/HC/NHLBI NIH HHS/ -- N01-HC-55019/HC/NHLBI NIH HHS/ -- N01-HC-55020/HC/NHLBI NIH HHS/ -- N01-HC-55021/HC/NHLBI NIH HHS/ -- N01-HC-55022/HC/NHLBI NIH HHS/ -- N01-HC-75150/HC/NHLBI NIH HHS/ -- N01-HC-85079/HC/NHLBI NIH HHS/ -- N01-HC-85080/HC/NHLBI NIH HHS/ -- N01-HC-85081/HC/NHLBI NIH HHS/ -- N01-HC-85082/HC/NHLBI NIH HHS/ -- N01-HC-85083/HC/NHLBI NIH HHS/ -- N01-HC-85084/HC/NHLBI NIH HHS/ -- N01-HC-85085/HC/NHLBI NIH HHS/ -- N01-HC-85086/HC/NHLBI NIH HHS/ -- N01-HG-65403/HG/NHGRI NIH HHS/ -- N02-HL-6-4278/HL/NHLBI NIH HHS/ -- PG/02/128/British Heart Foundation/United Kingdom -- PG/08/094/British Heart Foundation/United Kingdom -- PG/08/094/26019/British Heart Foundation/United Kingdom -- R01 DK072193/DK/NIDDK NIH HHS/ -- R01 DK078150/DK/NIDDK NIH HHS/ -- R01 HL087647/HL/NHLBI NIH HHS/ -- R01 HL087676/HL/NHLBI NIH HHS/ -- R01 HL089650/HL/NHLBI NIH HHS/ -- R01HL086694/HL/NHLBI NIH HHS/ -- R01HL087641/HL/NHLBI NIH HHS/ -- R01HL087652/HL/NHLBI NIH HHS/ -- R01HL59367/HL/NHLBI NIH HHS/ -- R24 HD050924/HD/NICHD NIH HHS/ -- RC1 HL099634/HL/NHLBI NIH HHS/ -- RC1 HL099634-02/HL/NHLBI NIH HHS/ -- RC1 HL099793/HL/NHLBI NIH HHS/ -- RC2 HL101864,/HL/NHLBI NIH HHS/ -- RC2 HL102419/HL/NHLBI NIH HHS/ -- RG/07/005/23633/British Heart Foundation/United Kingdom -- RR20649/RR/NCRR NIH HHS/ -- SP/08/005/25115/British Heart Foundation/United Kingdom -- T32 GM007092/GM/NIGMS NIH HHS/ -- T32 HG00040/HG/NHGRI NIH HHS/ -- T32HL007208/HL/NHLBI NIH HHS/ -- TW05596/TW/FIC NIH HHS/ -- U01 DK062370/DK/NIDDK NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL080295/HL/NHLBI NIH HHS/ -- U01HG004402/HG/NHGRI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1RR025005/RR/NCRR NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):707-13. doi: 10.1038/nature09270.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686565" target="_blank"〉PubMed〈/a〉

Beschreibung: Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048781/" 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/PMC3048781/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Li-Jun -- van der Does, H Charlotte -- Borkovich, Katherine A -- Coleman, Jeffrey J -- Daboussi, Marie-Josee -- Di Pietro, Antonio -- Dufresne, Marie -- Freitag, Michael -- Grabherr, Manfred -- Henrissat, Bernard -- Houterman, Petra M -- Kang, Seogchan -- Shim, Won-Bo -- Woloshuk, Charles -- Xie, Xiaohui -- Xu, Jin-Rong -- Antoniw, John -- Baker, Scott E -- Bluhm, Burton H -- Breakspear, Andrew -- Brown, Daren W -- Butchko, Robert A E -- Chapman, Sinead -- Coulson, Richard -- Coutinho, Pedro M -- Danchin, Etienne G J -- Diener, Andrew -- Gale, Liane R -- Gardiner, Donald M -- Goff, Stephen -- Hammond-Kosack, Kim E -- Hilburn, Karen -- Hua-Van, Aurelie -- Jonkers, Wilfried -- Kazan, Kemal -- Kodira, Chinnappa D -- Koehrsen, Michael -- Kumar, Lokesh -- Lee, Yong-Hwan -- Li, Liande -- Manners, John M -- Miranda-Saavedra, Diego -- Mukherjee, Mala -- Park, Gyungsoon -- Park, Jongsun -- Park, Sook-Young -- Proctor, Robert H -- Regev, Aviv -- Ruiz-Roldan, M Carmen -- Sain, Divya -- Sakthikumar, Sharadha -- Sykes, Sean -- Schwartz, David C -- Turgeon, B Gillian -- Wapinski, Ilan -- Yoder, Olen -- Young, Sarah -- Zeng, Qiandong -- Zhou, Shiguo -- Galagan, James -- Cuomo, Christina A -- Kistler, H Corby -- Rep, Martijn -- BBS/E/C/00004973/Biotechnology and Biological Sciences Research Council/United Kingdom -- DP1 OD003958/OD/NIH HHS/ -- R01 GM086565/GM/NIGMS NIH HHS/ -- R01 GM086565-03/GM/NIGMS NIH HHS/ -- R01 HG000225/HG/NHGRI NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):367-73. doi: 10.1038/nature08850.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute, Cambridge, Massachusetts 02141, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20237561" target="_blank"〉PubMed〈/a〉

Beschreibung: Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (gamma-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057962/" 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/PMC3057962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chao, Hsiao-Tuan -- Chen, Hongmei -- Samaco, Rodney C -- Xue, Mingshan -- Chahrour, Maria -- Yoo, Jong -- Neul, Jeffrey L -- Gong, Shiaoching -- Lu, Hui-Chen -- Heintz, Nathaniel -- Ekker, Marc -- Rubenstein, John L R -- Noebels, Jeffrey L -- Rosenmund, Christian -- Zoghbi, Huda Y -- 29709/PHS HHS/ -- F31MH078678/MH/NIMH NIH HHS/ -- HD024064/HD/NICHD NIH HHS/ -- HD053862/HD/NICHD NIH HHS/ -- K08 NS052240/NS/NINDS NIH HHS/ -- K08 NS052240-01/NS/NINDS NIH HHS/ -- K08 NS052240-02/NS/NINDS NIH HHS/ -- K08 NS052240-03/NS/NINDS NIH HHS/ -- K08 NS052240-04/NS/NINDS NIH HHS/ -- K08 NS052240-05/NS/NINDS NIH HHS/ -- P30 HD024064/HD/NICHD NIH HHS/ -- P30 HD024064-22/HD/NICHD NIH HHS/ -- R01 HD062553/HD/NICHD NIH HHS/ -- R01 NS048884/NS/NINDS NIH HHS/ -- R01 NS057819/NS/NINDS NIH HHS/ -- R01 NS057819-04/NS/NINDS NIH HHS/ -- R01 NS057819-05/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Nov 11;468(7321):263-9. doi: 10.1038/nature09582.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉]Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068835" target="_blank"〉PubMed〈/a〉

Beschreibung: We report here the genome sequence of an ancient human. Obtained from approximately 4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20x, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951495/" 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/PMC3951495/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rasmussen, Morten -- Li, Yingrui -- Lindgreen, Stinus -- Pedersen, Jakob Skou -- Albrechtsen, Anders -- Moltke, Ida -- Metspalu, Mait -- Metspalu, Ene -- Kivisild, Toomas -- Gupta, Ramneek -- Bertalan, Marcelo -- Nielsen, Kasper -- Gilbert, M Thomas P -- Wang, Yong -- Raghavan, Maanasa -- Campos, Paula F -- Kamp, Hanne Munkholm -- Wilson, Andrew S -- Gledhill, Andrew -- Tridico, Silvana -- Bunce, Michael -- Lorenzen, Eline D -- Binladen, Jonas -- Guo, Xiaosen -- Zhao, Jing -- Zhang, Xiuqing -- Zhang, Hao -- Li, Zhuo -- Chen, Minfeng -- Orlando, Ludovic -- Kristiansen, Karsten -- Bak, Mads -- Tommerup, Niels -- Bendixen, Christian -- Pierre, Tracey L -- Gronnow, Bjarne -- Meldgaard, Morten -- Andreasen, Claus -- Fedorova, Sardana A -- Osipova, Ludmila P -- Higham, Thomas F G -- Ramsey, Christopher Bronk -- Hansen, Thomas V O -- Nielsen, Finn C -- Crawford, Michael H -- Brunak, Soren -- Sicheritz-Ponten, Thomas -- Villems, Richard -- Nielsen, Rasmus -- Krogh, Anders -- Wang, Jun -- Willerslev, Eske -- R01 HG003229/HG/NHGRI NIH HHS/ -- R01 HG003229-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2010 Feb 11;463(7282):757-62. doi: 10.1038/nature08835.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for GeoGenetics, Natural History Museum of Denmark and Department of Biology, University of Copenhagen, Universitetsparken 15, DK-2100 Copenhagen, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20148029" target="_blank"〉PubMed〈/a〉

Beschreibung: The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases. Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058342/" 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/PMC3058342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gan, Boyi -- Hu, Jian -- Jiang, Shan -- Liu, Yingchun -- Sahin, Ergun -- Zhuang, Li -- Fletcher-Sananikone, Eliot -- Colla, Simona -- Wang, Y Alan -- Chin, Lynda -- Depinho, Ronald A -- 01CA141508/CA/NCI NIH HHS/ -- R21 CA135057/CA/NCI NIH HHS/ -- R21 CA135057-01/CA/NCI NIH HHS/ -- R21CA135057/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 2;468(7324):701-4. doi: 10.1038/nature09595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124456" target="_blank"〉PubMed〈/a〉

Beschreibung: The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock and Bmal1 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective beta-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the beta-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920067/" 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/PMC2920067/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marcheva, Biliana -- Ramsey, Kathryn Moynihan -- Buhr, Ethan D -- Kobayashi, Yumiko -- Su, Hong -- Ko, Caroline H -- Ivanova, Ganka -- Omura, Chiaki -- Mo, Shelley -- Vitaterna, Martha H -- Lopez, James P -- Philipson, Louis H -- Bradfield, Christopher A -- Crosby, Seth D -- JeBailey, Lellean -- Wang, Xiaozhong -- Takahashi, Joseph S -- Bass, Joseph -- P01 AG011412/AG/NIA NIH HHS/ -- P01 AG011412-080011/AG/NIA NIH HHS/ -- R01 HL097817/HL/NHLBI NIH HHS/ -- R01 HL097817-01/HL/NHLBI NIH HHS/ -- R37 ES005703/ES/NIEHS NIH HHS/ -- R37-ES-005703/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 29;466(7306):627-31. doi: 10.1038/nature09253.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20562852" target="_blank"〉PubMed〈/a〉

Beschreibung: Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062476/" 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/PMC3062476/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Musunuru, Kiran -- Strong, Alanna -- Frank-Kamenetsky, Maria -- Lee, Noemi E -- Ahfeldt, Tim -- Sachs, Katherine V -- Li, Xiaoyu -- Li, Hui -- Kuperwasser, Nicolas -- Ruda, Vera M -- Pirruccello, James P -- Muchmore, Brian -- Prokunina-Olsson, Ludmila -- Hall, Jennifer L -- Schadt, Eric E -- Morales, Carlos R -- Lund-Katz, Sissel -- Phillips, Michael C -- Wong, Jamie -- Cantley, William -- Racie, Timothy -- Ejebe, Kenechi G -- Orho-Melander, Marju -- Melander, Olle -- Koteliansky, Victor -- Fitzgerald, Kevin -- Krauss, Ronald M -- Cowan, Chad A -- Kathiresan, Sekar -- Rader, Daniel J -- K99 HL098364/HL/NHLBI NIH HHS/ -- K99 HL098364-01/HL/NHLBI NIH HHS/ -- K99 HL098364-02/HL/NHLBI NIH HHS/ -- K99-HL098364/HL/NHLBI NIH HHS/ -- P01 HL059407/HL/NHLBI NIH HHS/ -- P01 HL059407-13/HL/NHLBI NIH HHS/ -- P01-HL059407/HL/NHLBI NIH HHS/ -- RC2 HL101864/HL/NHLBI NIH HHS/ -- RC2 HL101864-02/HL/NHLBI NIH HHS/ -- RC2-HL101864/HL/NHLBI NIH HHS/ -- T32 HL007954/HL/NHLBI NIH HHS/ -- T32 HL007954-10/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL069757-09/HL/NHLBI NIH HHS/ -- U01-HL069757/HL/NHLBI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):714-9. doi: 10.1038/nature09266.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686566" target="_blank"〉PubMed〈/a〉

Beschreibung: Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874979/" 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/PMC2874979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guiguemde, W Armand -- Shelat, Anang A -- Bouck, David -- Duffy, Sandra -- Crowther, Gregory J -- Davis, Paul H -- Smithson, David C -- Connelly, Michele -- Clark, Julie -- Zhu, Fangyi -- Jimenez-Diaz, Maria B -- Martinez, Maria S -- Wilson, Emily B -- Tripathi, Abhai K -- Gut, Jiri -- Sharlow, Elizabeth R -- Bathurst, Ian -- El Mazouni, Farah -- Fowble, Joseph W -- Forquer, Isaac -- McGinley, Paula L -- Castro, Steve -- Angulo-Barturen, Inigo -- Ferrer, Santiago -- Rosenthal, Philip J -- Derisi, Joseph L -- Sullivan, David J -- Lazo, John S -- Roos, David S -- Riscoe, Michael K -- Phillips, Margaret A -- Rathod, Pradipsinh K -- Van Voorhis, Wesley C -- Avery, Vicky M -- Guy, R Kiplin -- AI045774/AI/NIAID NIH HHS/ -- AI053680/AI/NIAID NIH HHS/ -- AI067921/AI/NIAID NIH HHS/ -- AI075517/AI/NIAID NIH HHS/ -- AI075594/AI/NIAID NIH HHS/ -- AI080625/AI/NIAID NIH HHS/ -- AI082617/AI/NIAID NIH HHS/ -- AI28724/AI/NIAID NIH HHS/ -- AI35707/AI/NIAID NIH HHS/ -- AI53862/AI/NIAID NIH HHS/ -- AI772682/AI/NIAID NIH HHS/ -- CA78039/CA/NCI NIH HHS/ -- F32 AI077268/AI/NIAID NIH HHS/ -- F32 AI077268-03/AI/NIAID NIH HHS/ -- P01 AI035707/AI/NIAID NIH HHS/ -- P01 AI035707-140007/AI/NIAID NIH HHS/ -- P01 CA078039-10/CA/NCI NIH HHS/ -- P41 RR001614/RR/NCRR NIH HHS/ -- P41 RR001614-246970/RR/NCRR NIH HHS/ -- R01 AI045774/AI/NIAID NIH HHS/ -- R01 AI045774-09/AI/NIAID NIH HHS/ -- R37 AI028724/AI/NIAID NIH HHS/ -- R37 AI028724-17/AI/NIAID NIH HHS/ -- R56 AI082617/AI/NIAID NIH HHS/ -- R56 AI082617-01/AI/NIAID NIH HHS/ -- U01 AI053862/AI/NIAID NIH HHS/ -- U01 AI053862-05/AI/NIAID NIH HHS/ -- U01 AI075594-03/AI/NIAID NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 May 20;465(7296):311-5. doi: 10.1038/nature09099.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485428" target="_blank"〉PubMed〈/a〉

Beschreibung: The canalization concept describes the resistance of a developmental process to phenotypic variation, regardless of genetic and environmental perturbations, owing to the existence of buffering mechanisms. Severe perturbations, which overcome such buffering mechanisms, produce altered phenotypes that can be heritable and can themselves be canalized by a genetic assimilation process. An important implication of this concept is that the buffering mechanism could be genetically controlled. Recent studies on Hsp90, a protein involved in several cellular processes and development pathways, indicate that it is a possible molecular mechanism for canalization and genetic assimilation. In both flies and plants, mutations in the Hsp90-encoding gene induce a wide range of phenotypic abnormalities, which have been interpreted as an increased sensitivity of different developmental pathways to hidden genetic variability. Thus, Hsp90 chaperone machinery may be an evolutionarily conserved buffering mechanism of phenotypic variance, which provides the genetic material for natural selection. Here we offer an additional, perhaps alternative, explanation for proposals of a concrete mechanism underlying canalization. We show that, in Drosophila, functional alterations of Hsp90 affect the Piwi-interacting RNA (piRNA; a class of germ-line-specific small RNAs) silencing mechanism leading to transposon activation and the induction of morphological mutants. This indicates that Hsp90 mutations can generate new variation by transposon-mediated 'canonical' mutagenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Specchia, Valeria -- Piacentini, Lucia -- Tritto, Patrizia -- Fanti, Laura -- D'Alessandro, Rosalba -- Palumbo, Gioacchino -- Pimpinelli, Sergio -- Bozzetti, Maria P -- England -- Nature. 2010 Feb 4;463(7281):662-5. doi: 10.1038/nature08739. Epub 2010 Jan 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), University of Salento, 73100 Lecce, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20062045" target="_blank"〉PubMed〈/a〉