High-throughput discovery of novel developmental phenotypes

被引：823

作者：

Dickinson, Mary E. ^{[1
]}

Flenniken, Ann M. ^{[2
,3
]}

Ji, Xiao ^{[4
]}

Teboul, Lydia ^{[5
,6
]}

Wong, Michael D. ^{[2
,7
]}

White, Jacqueline K. ^{[8
]}

Meehan, Terrence F. ^{[9
]}

Weninger, Wolfgang J. ^{[10
]}

Westerberg, Henrik ^{[5
,6
]}

Adissu, Hibret ^{[2
,11
]}

Baker, Candice N. ^{[12
]}

Bower, Lynette ^{[13
]}

Brown, James M. ^{[5
,6
]}

Caddle, L. Brianna ^{[12
]}

Chiani, Francesco ^{[14
]}

Clary, Dave ^{[9
,13
]}

Cleak, James ^{[5
,6
]}

Daly, Mark J. ^{[15
,16
]}

Denegre, James M. ^{[12
]}

Doe, Brendan ^{[8
]}

Dolan, Mary E. ^{[12
]}

Edie, Sarah M. ^{[12
]}

Fuchs, Helmut ^{[17
,18
]}

Gailus-Durner, Valerie ^{[17
,18
]}

Galli, Antonella ^{[8
]}

Gambadoro, Alessia ^{[14
]}

Gallegos, Juan ^{[19
]}

Guo, Shiying ^{[20
]}

Horner, Neil R. ^{[5
,6
]}

Hsu, Chih-Wei ^{[1
]}

Johnson, Sara J. ^{[5
,6
]}

Kalaga, Sowmya ^{[1
]}

Keith, Lance C. ^{[1
]}

Lanoue, Louise ^{[13
]}

Lawson, Thomas N. ^{[5
,6
]}

Lek, Monkol ^{[15
,16
]}

Mark, Manuel ^{[21
,22
]}

Arschall, Susan M. ^{[17
,18
]}

Mason, Jeremy ^{[9
]}

McElwee, Melissa L. ^{[1
]}

Newbigging, Susan ^{[2
,11
]}

Nutter, Lauryl M. J. ^{[2
,11
]}

Peterson, Kevin A. ^{[12
]}

Ramirez-Solis, Ramiro ^{[8
]}

Rowland, Douglas J. ^{[13
]}

Ryder, Edward ^{[8
]}

Samocha, Kaitlin E. ^{[15
,16
]}

Seavitt, John R. ^{[19
]}

Selloum, Mohammed ^{[21
,22
]}

Szoke-Kovacs, Zsombor ^{[5
,6
]}

机构：

[1] Dept Mol Physiol & Biophys, Houston, TX 77030 USA

[2] Toronto Ctr Phenogen, Toronto, ON M5T 3H7, Canada

[3] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada

[4] Univ Penn, Perelman Sch Med, Genom & Computat Biol Program, Philadelphia, PA 19104 USA

[5] Med Res Council Harwell, Mammalian Genet Unit, Harwell OX11 0RD, Oxon, England

[6] Mary Lyon Ctr, Harwell OX11 0RD, Oxon, England

[7] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON M5T 3H7, Canada

[8] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England

[9] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[10] Med Univ Vienna, Ctr Anat & Cell Biol, A-1090 Vienna, Austria

[11] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada

[12] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA

[13] Univ Calif Davis, Mouse Biol Program, Davis, CA 95618 USA

[14] Italian Natl Res Council CNR, Inst Cell Biol & Neurobiol, Monterotondo Mouse Clin, I-00015 Monterotondo, Italy

[15] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[16] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[17] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, D-85764 Neuherberg, Germany

[18] German Mouse Clin, D-85764 Neuherberg, Germany

[19] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[20] Nanjing Univ, Nanjing Biomed Res Inst, Collaborat Innovat Ctr Genet & Dev, SKL Pharmaceut Biotechnol & Model Anim Res Ctr, Nanjing 210061, Jiangsu, Peoples R China

[21] Univ Strasbourg, ICS, Infrastruct Natl PHENOMIN, F-67404 Illkirch Graffenstaden, France

[22] Univ Strasbourg, INSERM, CNRS, IGBMC, F-67404 Illkirch Graffenstaden, France

[23] RIKEN, BioResource Ctr, Tsukuba, Ibaraki 3050074, Japan

[24] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA

[25] IMPC, San Anselmo, CA 94960 USA

[26] Tech Univ Munich, Sch Life Sci Weihenstephan, Chair Expt Genet, D-81675 Freising Weihenstephan, Germany

[27] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany

[28] Francis Crick Inst, Mill Hill Lab, Mill Hill, London NW1 1AT, England

[29] Univ Penn, Perlman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[30] Univ Penn, Dept Psychiat, Perlman Sch Med, Philadelphia, PA 19104 USA

来源：

NATURE | 2016年 / 537卷 / 7621期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

MAMMALIAN GENE-FUNCTION; MOUSE EMBRYO; GLYCOGENIN-1; DEFICIENCY; GENOME-WIDE; MICRO-CT; SCREENS; DISEASE; EXPRESSION; RESOURCE; IDENTIFICATION;

D O I：

10.1038/nature19356

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

引用

页码：508 / +

页数：20

共 59 条

[31] DIFFERENT PHENOTYPES FOR MICE DEFICIENT IN EITHER ACTIVINS OR ACTIVIN RECEPTOR-TYPE-II [J].

MATZUK, MM ;

KUMAR, TR ;

BRADLEY, A .

NATURE, 1995, 374 (6520) :356-360

[32] Brief Report: Glycogenin-1 Deficiency and Inactivated Priming of Glycogen Synthesis. [J].

Moslemi, Ali-Reza ;

Lindberg, Christopher ;

Nilsson, Johanna ;

Tajsharghi, Homa ;

Andersson, Bert ;

Oldfors, Anders .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (13) :1203-1210

[33] Health and population effects of rare gene knockouts in adult humans with related parents [J].

Narasimhan, Vagheesh M. ;

Hunt, Karen A. ;

Mason, Dan ;

Baker, Christopher L. ;

Karczewski, Konrad J. ;

Barnes, Mi El R. ;

Barnett, Anthony H. ;

Bates, Chris ;

Bellary, Srikanth ;

Bockett, Nicholas A. ;

Giorda, Kristina ;

Griffiths, Christopher J. ;

Hemingway, Harry ;

Jia, Zhilong ;

Kelly, M. Ann ;

Khawaja, Hajrah A. ;

Lek, Monkol ;

McCarthy, Shane ;

McEachan, Rosie ;

O'Donnell-Luria, Anne ;

Paigen, Kenneth ;

Parisinos, Constantinos A. ;

Sheridan, Eamonn ;

Southgate, Laura ;

Tee, Louise ;

Thomas, Mark ;

Xue, Yali ;

Schnall-Levin, Michael ;

Petkov, Petko M. ;

-Smith, Chris Tyler ;

Maher, Eamonn R. ;

Trembath, Richard C. ;

MacArthur, Daniel G. ;

Wright, John ;

Durbin, Richard ;

van Heel, David A. .

SCIENCE, 2016, 352 (6284) :474-477

[34] Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography [J].

Nieman, BJ ;

Flenniken, AM ;

Adamson, SL ;

Henkelman, RM ;

Sled, JG .

PHYSIOLOGICAL GENOMICS, 2006, 24 (02) :154-162

[35] Mouse behavioral mutants have neuroimaging abnormalities [J].

Nieman, Brian J. ;

Lerch, Jason P. ;

Bock, Nicholas A. ;

Chen, X. Josette ;

Sled, John G. ;

Henkelman, R. Mark .

HUMAN BRAIN MAPPING, 2007, 28 (06) :567-575

[36] Make mouse studies work [J].

Perrin, Steve .

NATURE, 2014, 507 (7493) :423-425

[37] Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes [J].

Petrovski, Slave ;

Wang, Quanli ;

Heinzen, Erin L. ;

Allen, Andrew S. ;

Goldstein, David B. .

PLOS GENETICS, 2013, 9 (08)

[38] Recurrent SETBP1 mutations in atypical chronic myeloid leukemia [J].

Piazza, Rocco ;

Valletta, Simona ;

Winkelmann, Nils ;

Redaelli, Sara ;

Spinelli, Roberta ;

Pirola, Alessandra ;

Antolini, Laura ;

Mologni, Luca ;

Donadoni, Carla ;

Papaemmanuil, Elli ;

Schnittger, Susanne ;

Kim, Dong-Wook ;

Boultwood, Jacqueline ;

Rossi, Fabio ;

Gaipa, Giuseppe ;

De Martini, Greta P. ;

Di Celle, Paola Francia ;

Jang, Hyun Gyung ;

Fantin, Valeria ;

Bignell, Graham R. ;

Magistroni, Vera ;

Haferlach, Torsten ;

Pogliani, Enrico Maria ;

Campbell, Peter J. ;

Chase, Andrew J. ;

Tapper, William J. ;

Cross, Nicholas C. P. ;

Gambacorti-Passerini, Carlo .

NATURE GENETICS, 2013, 45 (01) :18-U41

[39] Believe it or not: how much can we rely on published data on potential drug targets? [J].

Prinz, Florian ;

Schlange, Thomas ;

Asadullah, Khusru .

NATURE REVIEWS DRUG DISCOVERY, 2011, 10 (09) :712-U81

[40] Variability in gene expression underlies incomplete penetrance [J].

Raj, Arjun ;

Rifkin, Scott A. ;

Andersen, Erik ;

van Oudenaarden, Alexander .

NATURE, 2010, 463 (7283) :913-U84

← 1 2 3 4 5 6 →