%0 Journal Article %J Nature %D 2021 %T Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Niroula, Abhishek %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Eric Boerwinkle %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %B Nature %V 591 %P E27 %8 2021 Mar %G eng %N 7851 %1 https://www.ncbi.nlm.nih.gov/pubmed/33707633?dopt=Abstract %R 10.1038/s41586-021-03280-1 %0 Journal Article %J Mol Psychiatry %D 2020 %T Correction: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. %A Bis, Joshua C %A Jian, Xueqiu %A Kunkle, Brian W %A Chen, Yuning %A Hamilton-Nelson, Kara L %A Bush, William S %A Salerno, William J %A Lancour, Daniel %A Ma, Yiyi %A Renton, Alan E %A Marcora, Edoardo %A Farrell, John J %A Zhao, Yi %A Qu, Liming %A Ahmad, Shahzad %A Amin, Najaf %A Amouyel, Philippe %A Beecham, Gary W %A Below, Jennifer E %A Campion, Dominique %A Cantwell, Laura %A Charbonnier, Camille %A Chung, Jaeyoon %A Crane, Paul K %A Cruchaga, Carlos %A Cupples, L Adrienne %A Dartigues, Jean-François %A Debette, Stephanie %A Deleuze, Jean-François %A Fulton, Lucinda %A Gabriel, Stacey B %A Genin, Emmanuelle %A Richard A Gibbs %A Goate, Alison %A Grenier-Boley, Benjamin %A Gupta, Namrata %A Haines, Jonathan L %A Havulinna, Aki S %A Helisalmi, Seppo %A Hiltunen, Mikko %A Howrigan, Daniel P %A Ikram, M Arfan %A Kaprio, Jaakko %A Konrad, Jan %A Kuzma, Amanda %A Lander, Eric S %A Lathrop, Mark %A Lehtimäki, Terho %A Lin, Honghuang %A Mattila, Kari %A Mayeux, Richard %A Donna M Muzny %A Nasser, Waleed %A Neale, Benjamin %A Nho, Kwangsik %A Nicolas, Gaël %A Patel, Devanshi %A Pericak-Vance, Margaret A %A Perola, Markus %A Psaty, Bruce M %A Quenez, Olivier %A Rajabli, Farid %A Redon, Richard %A Reitz, Christiane %A Remes, Anne M %A Salomaa, Veikko %A Sarnowski, Chloe %A Schmidt, Helena %A Schmidt, Michael %A Schmidt, Reinhold %A Soininen, Hilkka %A Thornton, Timothy A %A Tosto, Giuseppe %A Tzourio, Christophe %A van der Lee, Sven J %A van Duijn, Cornelia M %A Valladares, Otto %A Vardarajan, Badri %A Wang, Li-San %A Wang, Weixin %A Wijsman, Ellen %A Wilson, Richard K %A Witten, Daniela %A Kim C Worley %A Zhang, Xiaoling %A Bellenguez, Céline %A Lambert, Jean-Charles %A Kurki, Mitja I %A Palotie, Aarno %A Daly, Mark %A Eric Boerwinkle %A Lunetta, Kathryn L %A DeStefano, Anita L %A Dupuis, Josée %A Martin, Eden R %A Schellenberg, Gerard D %A Seshadri, Sudha %A Naj, Adam C %A Fornage, Myriam %A Farrer, Lindsay A %X

A correction to this paper has been published and can be accessed via a link at the top of the paper.

%B Mol Psychiatry %V 25 %P 1901-1903 %8 2020 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/31636380?dopt=Abstract %R 10.1038/s41380-019-0529-7 %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Eric Boerwinkle %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %K Adult %K Africa %K Aged %K Aged, 80 and over %K alpha Karyopherins %K Black People %K Cell Self Renewal %K Clonal Hematopoiesis %K Dioxygenases %K DNA-Binding Proteins %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Germ-Line Mutation %K Hematopoietic Stem Cells %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Precision Medicine %K Proto-Oncogene Proteins %K Tripartite Motif Proteins %K United States %K Whole Genome Sequencing %X

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

%B Nature %V 586 %P 763-768 %8 2020 Oct %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract %R 10.1038/s41586-020-2819-2 %0 Journal Article %J Nature %D 2020 %T Mapping and characterization of structural variation in 17,795 human genomes. %A Abel, Haley J %A Larson, David E %A Regier, Allison A %A Chiang, Colby %A Das, Indraniel %A Kanchi, Krishna L %A Layer, Ryan M %A Neale, Benjamin M %A Salerno, William J %A Reeves, Catherine %A Buyske, Steven %A Matise, Tara C %A Donna M Muzny %A Zody, Michael C %A Lander, Eric S %A Dutcher, Susan K %A Stitziel, Nathan O %A Hall, Ira M %K Alleles %K Case-Control Studies %K Epigenesis, Genetic %K Female %K Gene Dosage %K Genetic Variation %K Genetics, Population %K Genome, Human %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Molecular Sequence Annotation %K Quantitative Trait Loci %K Racial Groups %K Software %K Whole Genome Sequencing %X

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.

%B Nature %V 583 %P 83-89 %8 2020 Jul %G eng %N 7814 %1 https://www.ncbi.nlm.nih.gov/pubmed/32460305?dopt=Abstract %R 10.1038/s41586-020-2371-0 %0 Journal Article %J Mol Psychiatry %D 2020 %T Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. %A Bis, Joshua C %A Jian, Xueqiu %A Kunkle, Brian W %A Chen, Yuning %A Hamilton-Nelson, Kara L %A Bush, William S %A Salerno, William J %A Lancour, Daniel %A Ma, Yiyi %A Renton, Alan E %A Marcora, Edoardo %A Farrell, John J %A Zhao, Yi %A Qu, Liming %A Ahmad, Shahzad %A Amin, Najaf %A Amouyel, Philippe %A Beecham, Gary W %A Below, Jennifer E %A Campion, Dominique %A Cantwell, Laura %A Charbonnier, Camille %A Chung, Jaeyoon %A Crane, Paul K %A Cruchaga, Carlos %A Cupples, L Adrienne %A Dartigues, Jean-François %A Debette, Stephanie %A Deleuze, Jean-François %A Fulton, Lucinda %A Gabriel, Stacey B %A Genin, Emmanuelle %A Richard A Gibbs %A Goate, Alison %A Grenier-Boley, Benjamin %A Gupta, Namrata %A Haines, Jonathan L %A Havulinna, Aki S %A Helisalmi, Seppo %A Hiltunen, Mikko %A Howrigan, Daniel P %A Ikram, M Arfan %A Kaprio, Jaakko %A Konrad, Jan %A Kuzma, Amanda %A Lander, Eric S %A Lathrop, Mark %A Lehtimäki, Terho %A Lin, Honghuang %A Mattila, Kari %A Mayeux, Richard %A Donna M Muzny %A Nasser, Waleed %A Neale, Benjamin %A Nho, Kwangsik %A Nicolas, Gaël %A Patel, Devanshi %A Pericak-Vance, Margaret A %A Perola, Markus %A Psaty, Bruce M %A Quenez, Olivier %A Rajabli, Farid %A Redon, Richard %A Reitz, Christiane %A Remes, Anne M %A Salomaa, Veikko %A Sarnowski, Chloe %A Schmidt, Helena %A Schmidt, Michael %A Schmidt, Reinhold %A Soininen, Hilkka %A Thornton, Timothy A %A Tosto, Giuseppe %A Tzourio, Christophe %A van der Lee, Sven J %A van Duijn, Cornelia M %A Valladares, Otto %A Vardarajan, Badri %A Wang, Li-San %A Wang, Weixin %A Wijsman, Ellen %A Wilson, Richard K %A Witten, Daniela %A Kim C Worley %A Zhang, Xiaoling %A Bellenguez, Céline %A Lambert, Jean-Charles %A Kurki, Mitja I %A Palotie, Aarno %A Daly, Mark %A Eric Boerwinkle %A Lunetta, Kathryn L %A DeStefano, Anita L %A Dupuis, Josée %A Martin, Eden R %A Schellenberg, Gerard D %A Seshadri, Sudha %A Naj, Adam C %A Fornage, Myriam %A Farrer, Lindsay A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Exome Sequencing %K Female %K Gene Expression Regulation %K Haplotypes %K Humans %K Immunity %K Immunoglobulin G %K Kruppel-Like Transcription Factors %K Male %K Polymorphism, Genetic %K RNA, Long Noncoding %K Transcription, Genetic %X

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

%B Mol Psychiatry %V 25 %P 1859-1875 %8 2020 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/30108311?dopt=Abstract %R 10.1038/s41380-018-0112-7 %0 Journal Article %J Cancer Discov %D 2018 %T Genetic Mechanisms of Immune Evasion in Colorectal Cancer. %A Grasso, Catherine S %A Giannakis, Marios %A Wells, Daniel K %A Hamada, Tsuyoshi %A Mu, Xinmeng Jasmine %A Quist, Michael %A Nowak, Jonathan A %A Nishihara, Reiko %A Qian, Zhi Rong %A Inamura, Kentaro %A Morikawa, Teppei %A Nosho, Katsuhiko %A Abril-Rodriguez, Gabriel %A Connolly, Charles %A Escuin-Ordinas, Helena %A Geybels, Milan S %A Grady, William M %A Hsu, Li %A Hu-Lieskovan, Siwen %A Huyghe, Jeroen R %A Kim, Yeon Joo %A Krystofinski, Paige %A Leiserson, Mark D M %A Montoya, Dennis J %A Nadel, Brian B %A Pellegrini, Matteo %A Pritchard, Colin C %A Puig-Saus, Cristina %A Quist, Elleanor H %A Raphael, Ben J %A Salipante, Stephen J %A Shin, Daniel Sanghoon %A Shinbrot, Eve %A Shirts, Brian %A Shukla, Sachet %A Stanford, Janet L %A Sun, Wei %A Tsoi, Jennifer %A Upfill-Brown, Alexander %A Wheeler, David A %A Wu, Catherine J %A Yu, Ming %A Zaidi, Syed H %A Zaretsky, Jesse M %A Gabriel, Stacey B %A Lander, Eric S %A Garraway, Levi A %A Hudson, Thomas J %A Fuchs, Charles S %A Ribas, Antoni %A Ogino, Shuji %A Peters, Ulrike %K beta 2-Microglobulin %K Colorectal Neoplasms %K DNA Copy Number Variations %K DNA Methylation %K Germ-Line Mutation %K HLA Antigens %K Humans %K Loss of Heterozygosity %K Microsatellite Instability %K Tumor Escape %K Wnt Signaling Pathway %X

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of and genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. .

%B Cancer Discov %V 8 %P 730-749 %8 2018 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29510987?dopt=Abstract %R 10.1158/2159-8290.CD-17-1327 %0 Journal Article %J J Am Coll Cardiol %D 2017 %T ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. %A Stitziel, Nathan O %A Khera, Amit V %A Wang, Xiao %A Bierhals, Andrew J %A Vourakis, A Christina %A Sperry, Alexandra E %A Natarajan, Pradeep %A Klarin, Derek %A Emdin, Connor A %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Erdmann, Jeanette %A Schunkert, Heribert %A Samani, Nilesh J %A Kraus, William E %A Shah, Svati H %A Yu, Bing %A Eric Boerwinkle %A Rader, Daniel J %A Gupta, Namrata %A Frossard, Philippe M %A Rasheed, Asif %A Danesh, John %A Lander, Eric S %A Gabriel, Stacey %A Saleheen, Danish %A Musunuru, Kiran %A Kathiresan, Sekar %K Adult %K Angiopoietin-Like Protein 3 %K Angiopoietin-like Proteins %K Angiopoietins %K Animals %K Atherosclerosis %K Case-Control Studies %K Coronary Artery Disease %K Female %K Humans %K Lipids %K Male %K Mice, Inbred C57BL %K Mice, Knockout %K Middle Aged %K Mutation, Missense %K Myocardial Infarction %K Risk Factors %X

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

%B J Am Coll Cardiol %V 69 %P 2054-2063 %8 2017 Apr 25 %G eng %N 16 %1 https://www.ncbi.nlm.nih.gov/pubmed/28385496?dopt=Abstract %R 10.1016/j.jacc.2017.02.030 %0 Journal Article %J Nature %D 2015 %T Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. %A Do, Ron %A Stitziel, Nathan O %A Won, Hong-Hee %A Jørgensen, Anders Berg %A Duga, Stefano %A Angelica Merlini, Pier %A Kiezun, Adam %A Farrall, Martin %A Goel, Anuj %A Zuk, Or %A Guella, Illaria %A Asselta, Rosanna %A Lange, Leslie A %A Peloso, Gina M %A Auer, Paul L %A Girelli, Domenico %A Martinelli, Nicola %A Farlow, Deborah N %A DePristo, Mark A %A Roberts, Robert %A Stewart, Alexander F R %A Saleheen, Danish %A Danesh, John %A Epstein, Stephen E %A Sivapalaratnam, Suthesh %A Hovingh, G Kees %A Kastelein, John J %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Shah, Svati H %A Kraus, William E %A Davies, Robert %A Nikpay, Majid %A Johansen, Christopher T %A Wang, Jian %A Hegele, Robert A %A Hechter, Eliana %A Marz, Winfried %A Kleber, Marcus E %A Huang, Jie %A Johnson, Andrew D %A Li, Mingyao %A Burke, Greg L %A Gross, Myron %A Liu, Yongmei %A Assimes, Themistocles L %A Heiss, Gerardo %A Lange, Ethan M %A Folsom, Aaron R %A Taylor, Herman A %A Olivieri, Oliviero %A Hamsten, Anders %A Clarke, Robert %A Reilly, Dermot F %A Yin, Wu %A Rivas, Manuel A %A Donnelly, Peter %A Rossouw, Jacques E %A Psaty, Bruce M %A Herrington, David M %A Wilson, James G %A Rich, Stephen S %A Bamshad, Michael J %A Tracy, Russell P %A Cupples, L Adrienne %A Rader, Daniel J %A Reilly, Muredach P %A Spertus, John A %A Cresci, Sharon %A Hartiala, Jaana %A Tang, W H Wilson %A Hazen, Stanley L %A Allayee, Hooman %A Reiner, Alex P %A Carlson, Christopher S %A Kooperberg, Charles %A Jackson, Rebecca D %A Eric Boerwinkle %A Lander, Eric S %A Schwartz, Stephen M %A Siscovick, David S %A McPherson, Ruth %A Tybjaerg-Hansen, Anne %A Abecasis, Gonçalo R %A Watkins, Hugh %A Nickerson, Deborah A %A Ardissino, Diego %A Sunyaev, Shamil R %A O'Donnell, Christopher J %A Altshuler, David %A Gabriel, Stacey %A Kathiresan, Sekar %K Age Factors %K Age of Onset %K Alleles %K Apolipoprotein A-V %K Apolipoproteins A %K Case-Control Studies %K Cholesterol, LDL %K Coronary Artery Disease %K Exome %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation %K Myocardial Infarction %K National Heart, Lung, and Blood Institute (U.S.) %K Receptors, LDL %K Triglycerides %K United States %X

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

%B Nature %V 518 %P 102-6 %8 2015 Feb 05 %G eng %N 7537 %1 https://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract %R 10.1038/nature13917 %0 Journal Article %J Nature %D 2011 %T A high-resolution map of human evolutionary constraint using 29 mammals. %A Lindblad-Toh, Kerstin %A Garber, Manuel %A Zuk, Or %A Lin, Michael F %A Parker, Brian J %A Washietl, Stefan %A Kheradpour, Pouya %A Ernst, Jason %A Jordan, Gregory %A Mauceli, Evan %A Ward, Lucas D %A Lowe, Craig B %A Holloway, Alisha K %A Clamp, Michele %A Gnerre, Sante %A Alföldi, Jessica %A Beal, Kathryn %A Chang, Jean %A Clawson, Hiram %A Cuff, James %A Di Palma, Federica %A Fitzgerald, Stephen %A Flicek, Paul %A Guttman, Mitchell %A Hubisz, Melissa J %A Jaffe, David B %A Jungreis, Irwin %A Kent, W James %A Kostka, Dennis %A Lara, Marcia %A Martins, André L %A Massingham, Tim %A Moltke, Ida %A Raney, Brian J %A Rasmussen, Matthew D %A Robinson, Jim %A Stark, Alexander %A Vilella, Albert J %A Wen, Jiayu %A Xie, Xiaohui %A Zody, Michael C %A Baldwin, Jen %A Bloom, Toby %A Chin, Chee Whye %A Heiman, Dave %A Nicol, Robert %A Nusbaum, Chad %A Young, Sarah %A Wilkinson, Jane %A Worley, Kim C %A Kovar, Christie L %A Muzny, Donna M %A Gibbs, Richard A %A Cree, Andrew %A Dihn, Huyen H %A Fowler, Gerald %A Jhangiani, Shalili %A Joshi, Vandita %A Lee, Sandra %A Lewis, Lora R %A Nazareth, Lynne V %A Okwuonu, Geoffrey %A Santibanez, Jireh %A Warren, Wesley C %A Mardis, Elaine R %A Weinstock, George M %A Wilson, Richard K %A Delehaunty, Kim %A Dooling, David %A Fronik, Catrina %A Fulton, Lucinda %A Fulton, Bob %A Graves, Tina %A Minx, Patrick %A Sodergren, Erica %A Birney, Ewan %A Margulies, Elliott H %A Herrero, Javier %A Green, Eric D %A Haussler, David %A Siepel, Adam %A Goldman, Nick %A Pollard, Katherine S %A Pedersen, Jakob S %A Lander, Eric S %A Kellis, Manolis %K Animals %K Disease %K Evolution, Molecular %K Exons %K Genome %K Genome, Human %K Genomics %K Health %K Humans %K Mammals %K Molecular Sequence Annotation %K Phylogeny %K RNA %K Selection, Genetic %K Sequence Alignment %K Sequence Analysis, DNA %X

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

%B Nature %V 478 %P 476-82 %8 2011 Oct 12 %G eng %N 7370 %1 https://www.ncbi.nlm.nih.gov/pubmed/21993624?dopt=Abstract %R 10.1038/nature10530 %0 Journal Article %J Nature %D 2008 %T Somatic mutations affect key pathways in lung adenocarcinoma. %A Ding, Li %A Getz, Gad %A Wheeler, David A %A Mardis, Elaine R %A McLellan, Michael D %A Cibulskis, Kristian %A Sougnez, Carrie %A Greulich, Heidi %A Donna M Muzny %A Morgan, Margaret B %A Fulton, Lucinda %A Fulton, Robert S %A Zhang, Qunyuan %A Wendl, Michael C %A Lawrence, Michael S %A Larson, David E %A Chen, Ken %A Dooling, David J %A Aniko Sabo %A Hawes, Alicia C %A Shen, Hua %A Jhangiani, Shalini N %A Lewis, Lora R %A Hall, Otis %A Zhu, Yiming %A Mathew, Tittu %A Ren, Yanru %A Yao, Jiqiang %A Steven E Scherer %A Clerc, Kerstin %A Ginger A Metcalf %A Ng, Brian %A Milosavljevic, Aleksandar %A Gonzalez-Garay, Manuel L %A Osborne, John R %A Meyer, Rick %A Shi, Xiaoqi %A Tang, Yuzhu %A Koboldt, Daniel C %A Lin, Ling %A Abbott, Rachel %A Miner, Tracie L %A Pohl, Craig %A Fewell, Ginger %A Haipek, Carrie %A Schmidt, Heather %A Dunford-Shore, Brian H %A Kraja, Aldi %A Crosby, Seth D %A Sawyer, Christopher S %A Vickery, Tammi %A Sander, Sacha %A Robinson, Jody %A Winckler, Wendy %A Baldwin, Jennifer %A Chirieac, Lucian R %A Dutt, Amit %A Fennell, Tim %A Hanna, Megan %A Johnson, Bruce E %A Onofrio, Robert C %A Thomas, Roman K %A Tonon, Giovanni %A Weir, Barbara A %A Zhao, Xiaojun %A Ziaugra, Liuda %A Zody, Michael C %A Giordano, Thomas %A Orringer, Mark B %A Roth, Jack A %A Spitz, Margaret R %A Wistuba, Ignacio I %A Ozenberger, Bradley %A Good, Peter J %A Chang, Andrew C %A Beer, David G %A Watson, Mark A %A Ladanyi, Marc %A Broderick, Stephen %A Yoshizawa, Akihiko %A Travis, William D %A Pao, William %A Province, Michael A %A Weinstock, George M %A Varmus, Harold E %A Gabriel, Stacey B %A Lander, Eric S %A Richard A Gibbs %A Meyerson, Matthew %A Wilson, Richard K %K Adenocarcinoma, Bronchiolo-Alveolar %K Female %K Gene Dosage %K Gene Expression Regulation, Neoplastic %K Genes, Tumor Suppressor %K Humans %K Lung Neoplasms %K Male %K Mutation %K Proto-Oncogenes %X

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

%B Nature %V 455 %P 1069-75 %8 2008 Oct 23 %G eng %N 7216 %1 https://www.ncbi.nlm.nih.gov/pubmed/18948947?dopt=Abstract %R 10.1038/nature07423 %0 Journal Article %J Genome Res %D 2007 %T 28-way vertebrate alignment and conservation track in the UCSC Genome Browser. %A Miller, Webb %A Rosenbloom, Kate %A Hardison, Ross C %A Hou, Minmei %A Taylor, James %A Raney, Brian %A Burhans, Richard %A King, David C %A Baertsch, Robert %A Blankenberg, Daniel %A Kosakovsky Pond, Sergei L %A Nekrutenko, Anton %A Giardine, Belinda %A Harris, Robert S %A Tyekucheva, Svitlana %A Diekhans, Mark %A Pringle, Thomas H %A Murphy, William J %A Lesk, Arthur %A Weinstock, George M %A Lindblad-Toh, Kerstin %A Richard A Gibbs %A Lander, Eric S %A Siepel, Adam %A Haussler, David %A Kent, W James %K Animals %K Base Sequence %K Cats %K Cattle %K Codon, Initiator %K Codon, Terminator %K Conserved Sequence %K Databases, Genetic %K Dogs %K Genome, Human %K Guinea Pigs %K Humans %K Mice %K Molecular Sequence Data %K Mutagenesis, Insertional %K Rabbits %K Rats %K Sequence Alignment %K Sequence Deletion %X

This article describes a set of alignments of 28 vertebrate genome sequences that is provided by the UCSC Genome Browser. The alignments can be viewed on the Human Genome Browser (March 2006 assembly) at http://genome.ucsc.edu, downloaded in bulk by anonymous FTP from http://hgdownload.cse.ucsc.edu/goldenPath/hg18/multiz28way, or analyzed with the Galaxy server at http://g2.bx.psu.edu. This article illustrates the power of this resource for exploring vertebrate and mammalian evolution, using three examples. First, we present several vignettes involving insertions and deletions within protein-coding regions, including a look at some human-specific indels. Then we study the extent to which start codons and stop codons in the human sequence are conserved in other species, showing that start codons are in general more poorly conserved than stop codons. Finally, an investigation of the phylogenetic depth of conservation for several classes of functional elements in the human genome reveals striking differences in the rates and modes of decay in alignability. Each functional class has a distinctive period of stringent constraint, followed by decays that allow (for the case of regulatory regions) or reject (for coding regions and ultraconserved elements) insertions and deletions.

%B Genome Res %V 17 %P 1797-808 %8 2007 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/17984227?dopt=Abstract %R 10.1101/gr.6761107 %0 Journal Article %J Genome Res %D 2007 %T Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome. %A Margulies, Elliott H %A Cooper, Gregory M %A Asimenos, George %A Thomas, Daryl J %A Dewey, Colin N %A Siepel, Adam %A Birney, Ewan %A Keefe, Damian %A Schwartz, Ariel S %A Hou, Minmei %A Taylor, James %A Nikolaev, Sergey %A Montoya-Burgos, Juan I %A Löytynoja, Ari %A Whelan, Simon %A Pardi, Fabio %A Massingham, Tim %A Brown, James B %A Bickel, Peter %A Holmes, Ian %A Mullikin, James C %A Ureta-Vidal, Abel %A Paten, Benedict %A Stone, Eric A %A Rosenbloom, Kate R %A Kent, W James %A Bouffard, Gerard G %A Guan, Xiaobin %A Hansen, Nancy F %A Idol, Jacquelyn R %A Maduro, Valerie V B %A Maskeri, Baishali %A McDowell, Jennifer C %A Park, Morgan %A Thomas, Pamela J %A Young, Alice C %A Blakesley, Robert W %A Donna M Muzny %A Sodergren, Erica %A David A Wheeler %A Kim C Worley %A Jiang, Huaiyang %A Weinstock, George M %A Richard A Gibbs %A Graves, Tina %A Fulton, Robert %A Mardis, Elaine R %A Wilson, Richard K %A Clamp, Michele %A Cuff, James %A Gnerre, Sante %A Jaffe, David B %A Chang, Jean L %A Lindblad-Toh, Kerstin %A Lander, Eric S %A Hinrichs, Angie %A Trumbower, Heather %A Clawson, Hiram %A Zweig, Ann %A Kuhn, Robert M %A Barber, Galt %A Harte, Rachel %A Karolchik, Donna %A Field, Matthew A %A Moore, Richard A %A Matthewson, Carrie A %A Schein, Jacqueline E %A Marra, Marco A %A Antonarakis, Stylianos E %A Batzoglou, Serafim %A Goldman, Nick %A Hardison, Ross %A Haussler, David %A Miller, Webb %A Pachter, Lior %A Green, Eric D %A Sidow, Arend %K Animals %K Evolution, Molecular %K Genome, Human %K Human Genome Project %K Humans %K Mammals %K Open Reading Frames %K Phylogeny %K Sequence Alignment %X

A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.

%B Genome Res %V 17 %P 760-74 %8 2007 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17567995?dopt=Abstract %R 10.1101/gr.6034307 %0 Journal Article %J Nature %D 2007 %T Characterizing the cancer genome in lung adenocarcinoma. %A Weir, Barbara A %A Woo, Michele S %A Getz, Gad %A Perner, Sven %A Ding, Li %A Beroukhim, Rameen %A Lin, William M %A Province, Michael A %A Kraja, Aldi %A Johnson, Laura A %A Shah, Kinjal %A Sato, Mitsuo %A Thomas, Roman K %A Barletta, Justine A %A Borecki, Ingrid B %A Broderick, Stephen %A Chang, Andrew C %A Chiang, Derek Y %A Chirieac, Lucian R %A Cho, Jeonghee %A Fujii, Yoshitaka %A Gazdar, Adi F %A Giordano, Thomas %A Greulich, Heidi %A Hanna, Megan %A Johnson, Bruce E %A Kris, Mark G %A Lash, Alex %A Lin, Ling %A Lindeman, Neal %A Mardis, Elaine R %A McPherson, John D %A Minna, John D %A Morgan, Margaret B %A Nadel, Mark %A Orringer, Mark B %A Osborne, John R %A Ozenberger, Brad %A Ramos, Alex H %A Robinson, James %A Roth, Jack A %A Rusch, Valerie %A Sasaki, Hidefumi %A Shepherd, Frances %A Sougnez, Carrie %A Spitz, Margaret R %A Tsao, Ming-Sound %A Twomey, David %A Verhaak, Roel G W %A Weinstock, George M %A David A Wheeler %A Winckler, Wendy %A Yoshizawa, Akihiko %A Yu, Soyoung %A Zakowski, Maureen F %A Zhang, Qunyuan %A Beer, David G %A Wistuba, Ignacio I %A Watson, Mark A %A Garraway, Levi A %A Ladanyi, Marc %A Travis, William D %A Pao, William %A Rubin, Mark A %A Gabriel, Stacey B %A Richard A Gibbs %A Varmus, Harold E %A Wilson, Richard K %A Lander, Eric S %A Meyerson, Matthew %K Adenocarcinoma %K Cell Line, Tumor %K Chromosome Deletion %K Chromosomes, Human, Pair 14 %K Gene Amplification %K Genome, Human %K Genomics %K Genotype %K Humans %K Intracellular Signaling Peptides and Proteins %K Loss of Heterozygosity %K Lung Neoplasms %K Neoplasms %K Nuclear Proteins %K Polymorphism, Single Nucleotide %K Proto-Oncogene Mas %K RNA Interference %K Thyroid Nuclear Factor 1 %K Transcription Factors %X

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

%B Nature %V 450 %P 893-8 %8 2007 Dec 06 %G eng %N 7171 %1 https://www.ncbi.nlm.nih.gov/pubmed/17982442?dopt=Abstract %R 10.1038/nature06358 %0 Journal Article %J Nature %D 2007 %T Genome-wide detection and characterization of positive selection in human populations. %A Sabeti, Pardis C %A Varilly, Patrick %A Fry, Ben %A Lohmueller, Jason %A Hostetter, Elizabeth %A Cotsapas, Chris %A Xie, Xiaohui %A Byrne, Elizabeth H %A McCarroll, Steven A %A Gaudet, Rachelle %A Schaffner, Stephen F %A Lander, Eric S %A Frazer, Kelly A %A Ballinger, Dennis G %A Cox, David R %A Hinds, David A %A Stuve, Laura L %A Richard A Gibbs %A Belmont, John W %A Boudreau, Andrew %A Hardenbol, Paul %A Leal, Suzanne M %A Pasternak, Shiran %A David A Wheeler %A Willis, Thomas D %A Fuli Yu %A Yang, Huanming %A Zeng, Changqing %A Gao, Yang %A Hu, Haoran %A Hu, Weitao %A Li, Chaohua %A Lin, Wei %A Liu, Siqi %A Pan, Hao %A Tang, Xiaoli %A Wang, Jian %A Wang, Wei %A Yu, Jun %A Zhang, Bo %A Zhang, Qingrun %A Zhao, Hongbin %A Zhao, Hui %A Zhou, Jun %A Gabriel, Stacey B %A Barry, Rachel %A Blumenstiel, Brendan %A Camargo, Amy %A Defelice, Matthew %A Faggart, Maura %A Goyette, Mary %A Gupta, Supriya %A Moore, Jamie %A Nguyen, Huy %A Onofrio, Robert C %A Parkin, Melissa %A Roy, Jessica %A Stahl, Erich %A Winchester, Ellen %A Ziaugra, Liuda %A Altshuler, David %A Shen, Yan %A Yao, Zhijian %A Huang, Wei %A Chu, Xun %A He, Yungang %A Jin, Li %A Liu, Yangfan %A Shen, Yayun %A Sun, Weiwei %A Wang, Haifeng %A Wang, Yi %A Wang, Ying %A Xiong, Xiaoyan %A Xu, Liang %A Waye, Mary M Y %A Tsui, Stephen K W %A Xue, Hong %A Wong, J Tze-Fei %A Galver, Luana M %A Fan, Jian-Bing %A Gunderson, Kevin %A Murray, Sarah S %A Oliphant, Arnold R %A Chee, Mark S %A Montpetit, Alexandre %A Chagnon, Fanny %A Ferretti, Vincent %A Leboeuf, Martin %A Olivier, Jean-François %A Phillips, Michael S %A Roumy, Stéphanie %A Sallée, Clémentine %A Verner, Andrei %A Hudson, Thomas J %A Kwok, Pui-Yan %A Cai, Dongmei %A Koboldt, Daniel C %A Miller, Raymond D %A Pawlikowska, Ludmila %A Taillon-Miller, Patricia %A Xiao, Ming %A Tsui, Lap-Chee %A Mak, William %A Song, You Qiang %A Tam, Paul K H %A Nakamura, Yusuke %A Kawaguchi, Takahisa %A Kitamoto, Takuya %A Morizono, Takashi %A Nagashima, Atsushi %A Ohnishi, Yozo %A Sekine, Akihiro %A Tanaka, Toshihiro %A Tsunoda, Tatsuhiko %A Deloukas, Panos %A Bird, Christine P %A Delgado, Marcos %A Dermitzakis, Emmanouil T %A Gwilliam, Rhian %A Hunt, Sarah %A Morrison, Jonathan %A Powell, Don %A Stranger, Barbara E %A Whittaker, Pamela %A Bentley, David R %A Daly, Mark J %A de Bakker, Paul I W %A Barrett, Jeff %A Chretien, Yves R %A Maller, Julian %A McCarroll, Steve %A Patterson, Nick %A Pe'er, Itsik %A Price, Alkes %A Purcell, Shaun %A Richter, Daniel J %A Sabeti, Pardis %A Saxena, Richa %A Schaffner, Stephen F %A Sham, Pak C %A Varilly, Patrick %A Altshuler, David %A Stein, Lincoln D %A Krishnan, Lalitha %A Smith, Albert Vernon %A Tello-Ruiz, Marcela K %A Thorisson, Gudmundur A %A Chakravarti, Aravinda %A Chen, Peter E %A Cutler, David J %A Kashuk, Carl S %A Lin, Shin %A Abecasis, Gonçalo R %A Guan, Weihua %A Li, Yun %A Munro, Heather M %A Qin, Zhaohui Steve %A Thomas, Daryl J %A McVean, Gilean %A Auton, Adam %A Bottolo, Leonardo %A Cardin, Niall %A Eyheramendy, Susana %A Freeman, Colin %A Marchini, Jonathan %A Myers, Simon %A Spencer, Chris %A Stephens, Matthew %A Donnelly, Peter %A Cardon, Lon R %A Clarke, Geraldine %A Evans, David M %A Morris, Andrew P %A Weir, Bruce S %A Tsunoda, Tatsuhiko %A Johnson, Todd A %A Mullikin, James C %A Sherry, Stephen T %A Feolo, Michael %A Skol, Andrew %A Zhang, Houcan %A Zeng, Changqing %A Zhao, Hui %A Matsuda, Ichiro %A Fukushima, Yoshimitsu %A Macer, Darryl R %A Suda, Eiko %A Rotimi, Charles N %A Adebamowo, Clement A %A Ajayi, Ike %A Aniagwu, Toyin %A Marshall, Patricia A %A Nkwodimmah, Chibuzor %A Royal, Charmaine D M %A Leppert, Mark F %A Dixon, Missy %A Peiffer, Andy %A Qiu, Renzong %A Kent, Alastair %A Kato, Kazuto %A Niikawa, Norio %A Adewole, Isaac F %A Knoppers, Bartha M %A Foster, Morris W %A Clayton, Ellen Wright %A Watkin, Jessica %A Richard A Gibbs %A Belmont, John W %A Donna M Muzny %A Nazareth, Lynne %A Sodergren, Erica %A Weinstock, George M %A David A Wheeler %A Yakub, Imtaz %A Gabriel, Stacey B %A Onofrio, Robert C %A Richter, Daniel J %A Ziaugra, Liuda %A Birren, Bruce W %A Daly, Mark J %A Altshuler, David %A Wilson, Richard K %A Fulton, Lucinda L %A Rogers, Jane %A Burton, John %A Carter, Nigel P %A Clee, Christopher M %A Griffiths, Mark %A Jones, Matthew C %A McLay, Kirsten %A Plumb, Robert W %A Ross, Mark T %A Sims, Sarah K %A Willey, David L %A Chen, Zhu %A Han, Hua %A Kang, Le %A Godbout, Martin %A Wallenburg, John C %A L'Archevêque, Paul %A Bellemare, Guy %A Saeki, Koji %A Wang, Hongguang %A An, Daochang %A Fu, Hongbo %A Li, Qing %A Wang, Zhen %A Wang, Renwu %A Holden, Arthur L %A Brooks, Lisa D %A McEwen, Jean E %A Guyer, Mark S %A Wang, Vivian Ota %A Peterson, Jane L %A Shi, Michael %A Spiegel, Jack %A Sung, Lawrence M %A Zacharia, Lynn F %A Collins, Francis S %A Kennedy, Karen %A Jamieson, Ruth %A Stewart, John %K Antiporters %K Edar Receptor %K Gene Frequency %K Genetics, Population %K Genome, Human %K Geography %K Haplotypes %K Humans %K Models, Molecular %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Selection, Genetic %X

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

%B Nature %V 449 %P 913-8 %8 2007 Oct 18 %G eng %N 7164 %1 https://www.ncbi.nlm.nih.gov/pubmed/17943131?dopt=Abstract %R 10.1038/nature06250 %0 Journal Article %J Nature %D 2007 %T Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. %A Birney, Ewan %A Stamatoyannopoulos, John A %A Dutta, Anindya %A Guigó, Roderic %A Gingeras, Thomas R %A Margulies, Elliott H %A Weng, Zhiping %A Snyder, Michael %A Dermitzakis, Emmanouil T %A Thurman, Robert E %A Kuehn, Michael S %A Taylor, Christopher M %A Neph, Shane %A Koch, Christoph M %A Asthana, Saurabh %A Malhotra, Ankit %A Adzhubei, Ivan %A Greenbaum, Jason A %A Andrews, Robert M %A Flicek, Paul %A Boyle, Patrick J %A Cao, Hua %A Carter, Nigel P %A Clelland, Gayle K %A Davis, Sean %A Day, Nathan %A Dhami, Pawandeep %A Dillon, Shane C %A Dorschner, Michael O %A Fiegler, Heike %A Giresi, Paul G %A Goldy, Jeff %A Hawrylycz, Michael %A Haydock, Andrew %A Humbert, Richard %A James, Keith D %A Johnson, Brett E %A Johnson, Ericka M %A Frum, Tristan T %A Rosenzweig, Elizabeth R %A Karnani, Neerja %A Lee, Kirsten %A Lefebvre, Gregory C %A Navas, Patrick A %A Neri, Fidencio %A Parker, Stephen C J %A Sabo, Peter J %A Sandstrom, Richard %A Shafer, Anthony %A Vetrie, David %A Weaver, Molly %A Wilcox, Sarah %A Yu, Man %A Collins, Francis S %A Dekker, Job %A Lieb, Jason D %A Tullius, Thomas D %A Crawford, Gregory E %A Sunyaev, Shamil %A Noble, William S %A Dunham, Ian %A Denoeud, France %A Reymond, Alexandre %A Kapranov, Philipp %A Rozowsky, Joel %A Zheng, Deyou %A Castelo, Robert %A Frankish, Adam %A Harrow, Jennifer %A Ghosh, Srinka %A Sandelin, Albin %A Hofacker, Ivo L %A Baertsch, Robert %A Keefe, Damian %A Dike, Sujit %A Cheng, Jill %A Hirsch, Heather A %A Sekinger, Edward A %A Lagarde, Julien %A Abril, Josep F %A Shahab, Atif %A Flamm, Christoph %A Fried, Claudia %A Hackermüller, Jörg %A Hertel, Jana %A Lindemeyer, Manja %A Missal, Kristin %A Tanzer, Andrea %A Washietl, Stefan %A Korbel, Jan %A Emanuelsson, Olof %A Pedersen, Jakob S %A Holroyd, Nancy %A Taylor, Ruth %A Swarbreck, David %A Matthews, Nicholas %A Dickson, Mark C %A Thomas, Daryl J %A Weirauch, Matthew T %A Gilbert, James %A Drenkow, Jorg %A Bell, Ian %A Zhao, XiaoDong %A Srinivasan, K G %A Sung, Wing-Kin %A Ooi, Hong Sain %A Chiu, Kuo Ping %A Foissac, Sylvain %A Alioto, Tyler %A Brent, Michael %A Pachter, Lior %A Tress, Michael L %A Valencia, Alfonso %A Choo, Siew Woh %A Choo, Chiou Yu %A Ucla, Catherine %A Manzano, Caroline %A Wyss, Carine %A Cheung, Evelyn %A Clark, Taane G %A Brown, James B %A Ganesh, Madhavan %A Patel, Sandeep %A Tammana, Hari %A Chrast, Jacqueline %A Henrichsen, Charlotte N %A Kai, Chikatoshi %A Kawai, Jun %A Nagalakshmi, Ugrappa %A Wu, Jiaqian %A Lian, Zheng %A Lian, Jin %A Newburger, Peter %A Zhang, Xueqing %A Bickel, Peter %A Mattick, John S %A Carninci, Piero %A Hayashizaki, Yoshihide %A Weissman, Sherman %A Hubbard, Tim %A Myers, Richard M %A Rogers, Jane %A Stadler, Peter F %A Lowe, Todd M %A Wei, Chia-Lin %A Ruan, Yijun %A Struhl, Kevin %A Gerstein, Mark %A Antonarakis, Stylianos E %A Fu, Yutao %A Green, Eric D %A Karaöz, Ulaş %A Siepel, Adam %A Taylor, James %A Liefer, Laura A %A Wetterstrand, Kris A %A Good, Peter J %A Feingold, Elise A %A Guyer, Mark S %A Cooper, Gregory M %A Asimenos, George %A Dewey, Colin N %A Hou, Minmei %A Nikolaev, Sergey %A Montoya-Burgos, Juan I %A Löytynoja, Ari %A Whelan, Simon %A Pardi, Fabio %A Massingham, Tim %A Huang, Haiyan %A Zhang, Nancy R %A Holmes, Ian %A Mullikin, James C %A Ureta-Vidal, Abel %A Paten, Benedict %A Seringhaus, Michael %A Church, Deanna %A Rosenbloom, Kate %A Kent, W James %A Stone, Eric A %A Batzoglou, Serafim %A Goldman, Nick %A Hardison, Ross C %A Haussler, David %A Miller, Webb %A Sidow, Arend %A Trinklein, Nathan D %A Zhang, Zhengdong D %A Barrera, Leah %A Stuart, Rhona %A King, David C %A Ameur, Adam %A Enroth, Stefan %A Bieda, Mark C %A Kim, Jonghwan %A Bhinge, Akshay A %A Jiang, Nan %A Liu, Jun %A Yao, Fei %A Vega, Vinsensius B %A Lee, Charlie W H %A Ng, Patrick %A Shahab, Atif %A Yang, Annie %A Moqtaderi, Zarmik %A Zhu, Zhou %A Xu, Xiaoqin %A Squazzo, Sharon %A Oberley, Matthew J %A Inman, David %A Singer, Michael A %A Richmond, Todd A %A Munn, Kyle J %A Rada-Iglesias, Alvaro %A Wallerman, Ola %A Komorowski, Jan %A Fowler, Joanna C %A Couttet, Phillippe %A Bruce, Alexander W %A Dovey, Oliver M %A Ellis, Peter D %A Langford, Cordelia F %A Nix, David A %A Euskirchen, Ghia %A Hartman, Stephen %A Urban, Alexander E %A Kraus, Peter %A Van Calcar, Sara %A Heintzman, Nate %A Kim, Tae Hoon %A Wang, Kun %A Qu, Chunxu %A Hon, Gary %A Luna, Rosa %A Glass, Christopher K %A Rosenfeld, M Geoff %A Aldred, Shelley Force %A Cooper, Sara J %A Halees, Anason %A Lin, Jane M %A Shulha, Hennady P %A Zhang, Xiaoling %A Xu, Mousheng %A Haidar, Jaafar N S %A Yu, Yong %A Ruan, Yijun %A Iyer, Vishwanath R %A Green, Roland D %A Wadelius, Claes %A Farnham, Peggy J %A Ren, Bing %A Harte, Rachel A %A Hinrichs, Angie S %A Trumbower, Heather %A Clawson, Hiram %A Hillman-Jackson, Jennifer %A Zweig, Ann S %A Smith, Kayla %A Thakkapallayil, Archana %A Barber, Galt %A Kuhn, Robert M %A Karolchik, Donna %A Armengol, Lluis %A Bird, Christine P %A de Bakker, Paul I W %A Kern, Andrew D %A Lopez-Bigas, Nuria %A Martin, Joel D %A Stranger, Barbara E %A Woodroffe, Abigail %A Davydov, Eugene %A Dimas, Antigone %A Eyras, Eduardo %A Hallgrímsdóttir, Ingileif B %A Huppert, Julian %A Zody, Michael C %A Abecasis, Gonçalo R %A Estivill, Xavier %A Bouffard, Gerard G %A Guan, Xiaobin %A Hansen, Nancy F %A Idol, Jacquelyn R %A Maduro, Valerie V B %A Maskeri, Baishali %A McDowell, Jennifer C %A Park, Morgan %A Thomas, Pamela J %A Young, Alice C %A Blakesley, Robert W %A Donna M Muzny %A Sodergren, Erica %A Wheeler, David A %A Worley, Kim C %A Jiang, Huaiyang %A Weinstock, George M %A Richard A Gibbs %A Graves, Tina %A Fulton, Robert %A Mardis, Elaine R %A Wilson, Richard K %A Clamp, Michele %A Cuff, James %A Gnerre, Sante %A Jaffe, David B %A Chang, Jean L %A Lindblad-Toh, Kerstin %A Lander, Eric S %A Koriabine, Maxim %A Nefedov, Mikhail %A Osoegawa, Kazutoyo %A Yoshinaga, Yuko %A Zhu, Baoli %A De Jong, Pieter J %K Chromatin %K Chromatin Immunoprecipitation %K Conserved Sequence %K DNA Replication %K Evolution, Molecular %K Exons %K Genetic Variation %K Genome, Human %K Genomics %K Heterozygote %K Histones %K Humans %K Pilot Projects %K Protein Binding %K Regulatory Sequences, Nucleic Acid %K RNA, Messenger %K RNA, Untranslated %K Transcription Factors %K Transcription Initiation Site %K Transcription, Genetic %X

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

%B Nature %V 447 %P 799-816 %8 2007 Jun 14 %G eng %N 7146 %1 https://www.ncbi.nlm.nih.gov/pubmed/17571346?dopt=Abstract %R 10.1038/nature05874 %0 Journal Article %J Nature %D 2002 %T Initial sequencing and comparative analysis of the mouse genome. %A Waterston, Robert H %A Lindblad-Toh, Kerstin %A Birney, Ewan %A Rogers, Jane %A Abril, Josep F %A Agarwal, Pankaj %A Agarwala, Richa %A Ainscough, Rachel %A Alexandersson, Marina %A An, Peter %A Antonarakis, Stylianos E %A Attwood, John %A Baertsch, Robert %A Bailey, Jonathon %A Barlow, Karen %A Beck, Stephan %A Berry, Eric %A Birren, Bruce %A Bloom, Toby %A Bork, Peer %A Botcherby, Marc %A Bray, Nicolas %A Brent, Michael R %A Brown, Daniel G %A Brown, Stephen D %A Bult, Carol %A Burton, John %A Butler, Jonathan %A Campbell, Robert D %A Carninci, Piero %A Cawley, Simon %A Chiaromonte, Francesca %A Chinwalla, Asif T %A Church, Deanna M %A Clamp, Michele %A Clee, Christopher %A Collins, Francis S %A Cook, Lisa L %A Copley, Richard R %A Coulson, Alan %A Couronne, Olivier %A Cuff, James %A Curwen, Val %A Cutts, Tim %A Daly, Mark %A David, Robert %A Davies, Joy %A Delehaunty, Kimberly D %A Deri, Justin %A Dermitzakis, Emmanouil T %A Dewey, Colin %A Dickens, Nicholas J %A Diekhans, Mark %A Dodge, Sheila %A Dubchak, Inna %A Dunn, Diane M %A Eddy, Sean R %A Elnitski, Laura %A Emes, Richard D %A Eswara, Pallavi %A Eyras, Eduardo %A Felsenfeld, Adam %A Fewell, Ginger A %A Flicek, Paul %A Foley, Karen %A Frankel, Wayne N %A Fulton, Lucinda A %A Fulton, Robert S %A Furey, Terrence S %A Gage, Diane %A Gibbs, Richard A %A Glusman, Gustavo %A Gnerre, Sante %A Goldman, Nick %A Goodstadt, Leo %A Grafham, Darren %A Graves, Tina A %A Green, Eric D %A Gregory, Simon %A Guigó, Roderic %A Guyer, Mark %A Hardison, Ross C %A Haussler, David %A Hayashizaki, Yoshihide %A Hillier, LaDeana W %A Hinrichs, Angela %A Hlavina, Wratko %A Holzer, Timothy %A Hsu, Fan %A Hua, Axin %A Hubbard, Tim %A Hunt, Adrienne %A Jackson, Ian %A Jaffe, David B %A Johnson, L Steven %A Jones, Matthew %A Jones, Thomas A %A Joy, Ann %A Kamal, Michael %A Karlsson, Elinor K %A Karolchik, Donna %A Kasprzyk, Arkadiusz %A Kawai, Jun %A Keibler, Evan %A Kells, Cristyn %A Kent, W James %A Kirby, Andrew %A Kolbe, Diana L %A Korf, Ian %A Kucherlapati, Raju S %A Kulbokas, Edward J %A Kulp, David %A Landers, Tom %A Leger, J P %A Leonard, Steven %A Letunic, Ivica %A Levine, Rosie %A Li, Jia %A Li, Ming %A Lloyd, Christine %A Lucas, Susan %A Ma, Bin %A Maglott, Donna R %A Mardis, Elaine R %A Matthews, Lucy %A Mauceli, Evan %A Mayer, John H %A McCarthy, Megan %A McCombie, W Richard %A McLaren, Stuart %A McLay, Kirsten %A McPherson, John D %A Meldrim, Jim %A Meredith, Beverley %A Mesirov, Jill P %A Miller, Webb %A Miner, Tracie L %A Mongin, Emmanuel %A Montgomery, Kate T %A Morgan, Michael %A Mott, Richard %A Mullikin, James C %A Muzny, Donna M %A Nash, William E %A Nelson, Joanne O %A Nhan, Michael N %A Nicol, Robert %A Ning, Zemin %A Nusbaum, Chad %A O'Connor, Michael J %A Okazaki, Yasushi %A Oliver, Karen %A Overton-Larty, Emma %A Pachter, Lior %A Parra, Genís %A Pepin, Kymberlie H %A Peterson, Jane %A Pevzner, Pavel %A Plumb, Robert %A Pohl, Craig S %A Poliakov, Alex %A Ponce, Tracy C %A Ponting, Chris P %A Potter, Simon %A Quail, Michael %A Reymond, Alexandre %A Roe, Bruce A %A Roskin, Krishna M %A Rubin, Edward M %A Rust, Alistair G %A Santos, Ralph %A Sapojnikov, Victor %A Schultz, Brian %A Schultz, Jörg %A Schwartz, Matthias S %A Schwartz, Scott %A Scott, Carol %A Seaman, Steven %A Searle, Steve %A Sharpe, Ted %A Sheridan, Andrew %A Shownkeen, Ratna %A Sims, Sarah %A Singer, Jonathan B %A Slater, Guy %A Smit, Arian %A Smith, Douglas R %A Spencer, Brian %A Stabenau, Arne %A Stange-Thomann, Nicole %A Sugnet, Charles %A Suyama, Mikita %A Tesler, Glenn %A Thompson, Johanna %A Torrents, David %A Trevaskis, Evanne %A Tromp, John %A Ucla, Catherine %A Ureta-Vidal, Abel %A Vinson, Jade P %A Von Niederhausern, Andrew C %A Wade, Claire M %A Wall, Melanie %A Weber, Ryan J %A Weiss, Robert B %A Wendl, Michael C %A West, Anthony P %A Wetterstrand, Kris %A Wheeler, Raymond %A Whelan, Simon %A Wierzbowski, Jamey %A Willey, David %A Williams, Sophie %A Wilson, Richard K %A Winter, Eitan %A Worley, Kim C %A Wyman, Dudley %A Yang, Shan %A Yang, Shiaw-Pyng %A Zdobnov, Evgeny M %A Zody, Michael C %A Lander, Eric S %K Animals %K Base Composition %K Chromosomes, Mammalian %K Conserved Sequence %K CpG Islands %K Evolution, Molecular %K Gene Expression Regulation %K Genes %K Genetic Variation %K Genome %K Genome, Human %K Genomics %K Humans %K Mice %K Mice, Knockout %K Mice, Transgenic %K Models, Animal %K Multigene Family %K Mutagenesis %K Neoplasms %K Physical Chromosome Mapping %K Proteome %K Pseudogenes %K Quantitative Trait Loci %K Repetitive Sequences, Nucleic Acid %K RNA, Untranslated %K Selection, Genetic %K Sequence Analysis, DNA %K Sex Chromosomes %K Species Specificity %K Synteny %X

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

%B Nature %V 420 %P 520-62 %8 2002 Dec 05 %G eng %N 6915 %1 https://www.ncbi.nlm.nih.gov/pubmed/12466850?dopt=Abstract %R 10.1038/nature01262