The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation.
Violeta Muñoz-Fuentes,Pilar Cacheiro,Terrence F. Meehan,Juan Antonio Aguilar-Pimentel,Steve D.M. Brown,Ann M. Flenniken,Paul Flicek,Antonella Galli,Hamed Haseli Mashhadi,Martin Hrabě de Angelis,Jong Kyoung Kim,Kevin C K Lloyd,Colin McKerlie,Colin McKerlie,Hugh P. Morgan,Stephen A. Murray,Lauryl M. J. Nutter,Patrick T. Reilly,John R. Seavitt,Je Kyung Seong,Michelle Simon,Hannah Wardle-Jones,Ann-Marie Mallon,Damian Smedley,Helen Parkinson +24 more
Reads0
Chats0
TLDR
Using gorilla genomic data, it is shown how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species, and how these analyses can be routinely applied.Abstract:
The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied.read more
Citations
More filters
Journal ArticleDOI
The Monarch Initiative: an integrative data and analytic platform connecting phenotypes to genotypes across species.
Christopher J. Mungall,Julie A. McMurry,Sebastian Köhler,James P. Balhoff,Charles D. Borromeo,Matthew H. Brush,Seth Carbon,Tom Conlin,Nathan Dunn,Mark Engelstad,Erin D. Foster,Jean-Philippe F. Gourdine,Julius O.B. Jacobsen,Daniel Keith,Bryan Laraway,Suzanna E. Lewis,Jeremy Nguyen-Xuan,Kent Shefchek,Nicole Vasilevsky,Zhou Yuan,Nicole L. Washington,Harry Hochheiser,Tudor Groza,Damian Smedley,Peter N. Robinson,Melissa A. Haendel +25 more
TL;DR: The Monarch Initiative as discussed by the authors integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search, and develops many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery and diagnostics of Mendelian diseases.
A 660-Kb Deletion with Antagonistic Effects on Fertility and Milk Production Segregates at High Frequency in Nordic Red Cattle: Additional Evidence for the Common Occurrence of Balancing Selection in Livestock
Naveen Kumar Kadri,Goutam Sahana,Carole Charlier,Iso-Touru Terhi,Bernt Guldbrandtsen,Latifa Karim,U. S. Nielsen,Frank Panitz,Gert Pedersen Aamand,Nina Schulman,Michel Georges,Johanna Vilkki,Mogens Sandø Lund,Tom Druet +13 more
TL;DR: It is demonstrated that embryonic lethal mutations account for a non-negligible fraction of the decline in fertility of domestic cattle, and that associated positive effects on milk yield may account for part of the negative genetic correlation.
Journal ArticleDOI
The Collaborative Cross: A Systems Genetics Resource for Studying Host-Pathogen Interactions
TL;DR: Progress utilizing the Collaborative Cross as a platform to develop improved models of pathogen-induced disease and to map polymorphic host response loci associated with variation in susceptibility to pathogens is summarized.
Journal ArticleDOI
Transgenic and physiological mouse models give insights into different aspects of amyotrophic lateral sclerosis
TL;DR: Two key types of amyotrophic lateral sclerosis mouse models are compared: transgenic mice and those that express genes at physiological levels, exploring the advantages of each type for studying pathomechanisms and comparing the phenotypes for genes in which the two classes of model exist.
Journal ArticleDOI
Human and mouse essentiality screens as a resource for disease gene discovery.
Pilar Cacheiro,Violeta Muñoz-Fuentes,Stephen A. Murray,Mary E Dickinson,Maja Bucan,Lauryl M. J. Nutter,Kevin A. Peterson,Hamed Haselimashhadi,Ann M Flenniken,Hugh P. Morgan,Henrik Westerberg,Tomasz Konopka,Chih-Wei Hsu,Audrey E. Christiansen,Denise G. Lanza,Arthur L. Beaudet,Jason D. Heaney,Helmut Fuchs,Valerie Gailus-Durner,Tania Sorg,Jan Prochazka,Vendula Novosadova,Christopher J. Lelliott,Hannah Wardle-Jones,Sara Wells,Lydia Teboul,Heather Cater,Michelle Stewart,Tertius Hough,Wolfgang Wurst,Wolfgang Wurst,Radislav Sedlacek,David J. Adams,John R. Seavitt,Glauco P. Tocchini-Valentini,Fabio Mammano,Robert E. Braun,Colin McKerlie,Yann Herault,Martin Hrabě de Angelis,Ann-Marie Mallon,Kevin C K Lloyd,Steve D. M. Brown,Helen Parkinson,Terrence F. Meehan,Damian Smedley +45 more
TL;DR: A Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery is proposed.
References
More filters
Journal ArticleDOI
An integrated map of genetic variation from 1,092 human genomes
Gonçalo R. Abecasis,Adam Auton,Lisa D. Brooks,Mark A. DePristo,Richard Durbin,Robert E. Handsaker,Robert E. Handsaker,Hyun Min Kang,Gabor T. Marth,Gil McVean +9 more
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
Journal ArticleDOI
A conditional knockout resource for the genome-wide study of mouse gene function.
William C. Skarnes,Barry Rosen,Anthony P. West,Manousos Koutsourakis,Wendy Bushell,Vivek Iyer,Alejandro O. Mujica,Alejandro O. Mujica,Mark G. Thomas,Jennifer Harrow,Tony Cox,David A. Jackson,Jessica Severin,Jessica Severin,Patrick J. Biggs,Patrick J. Biggs,Jun Fu,Michael Nefedov,Pieter J. de Jong,A. Francis Stewart,Allan Bradley +20 more
TL;DR: High-throughput genome engineering highlighted by this study is broadly applicable to rat and human stem cells and provides a foundation for future genome-wide efforts aimed at deciphering the function of all genes encoded by the mammalian genome.
Journal ArticleDOI
Identification and characterization of essential genes in the human genome
Timothy C. Wang,Kıvanç Birsoy,Nicholas W. Hughes,Kevin M. Krupczak,Yorick Post,Yorick Post,Jenny J. Wei,Eric S. Lander,Eric S. Lander,Eric S. Lander,David M. Sabatini +10 more
TL;DR: Using the bacterial clustered regularly interspaced short palindromic repeats (CRISPR) system, this article constructed a genome-wide single-guide RNA library to screen for genes required for proliferation and survival in a human cancer cell line.
Journal ArticleDOI
High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities
Traver Hart,Megha Chandrashekhar,Michael Aregger,Zachary Steinhart,Kevin R. Brown,Graham MacLeod,Monika Mis,Michal Zimmermann,Amélie Fradet-Turcotte,Song Sun,Patricia Mero,Peter B. Dirks,Sachdev S. Sidhu,Frederick P. Roth,Olivia S. Rissland,Daniel Durocher,Daniel Durocher,Stephane Angers,Jason Moffat,Jason Moffat +19 more
TL;DR: It is demonstrated that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds.
Journal ArticleDOI
A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes
Daniel G. MacArthur,Daniel G. MacArthur,Suganthi Balasubramanian,Adam Frankish,Ni Huang,James Morris,Klaudia Walter,Luke Jostins,Lukas Habegger,Joseph K. Pickrell,Stephen B. Montgomery,Stephen B. Montgomery,Cornelis A. Albers,Cornelis A. Albers,Zhengdong D. Zhang,Donald F. Conrad,Gerton Lunter,Hancheng Zheng,Qasim Ayub,Mark A. DePristo,Eric Banks,Min Hu,Robert E. Handsaker,Robert E. Handsaker,Jeffrey A. Rosenfeld,Menachem Fromer,Mike Jin,Xinmeng Jasmine Mu,Ekta Khurana,Kai Ye,M. Kay,Gary Saunders,Marie-Marthe Suner,Toby Hunt,If H. A. Barnes,Clara Amid,Denise Carvalho-Silva,Alexandra Bignell,Catherine E. Snow,Bryndis Yngvadottir,Suzannah Bumpstead,David Neil Cooper,Yali Xue,Irene Gallego Romero,Irene Gallego Romero,Jun Wang,Yingrui Li,Richard A. Gibbs,Steven A. McCarroll,Steven A. McCarroll,Emmanouil T. Dermitzakis,Jonathan K. Pritchard,Jeffrey C. Barrett,Jennifer Harrow,Matthew E. Hurles,Mark Gerstein,Chris Tyler-Smith +56 more
TL;DR: Functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies are described.
Related Papers (5)
High-throughput discovery of novel developmental phenotypes
Mary E. Dickinson,Ann M. Flenniken,Xiao Ji,Lydia Teboul,Michael D. Wong,Jacqueline K. White,Terrence F. Meehan,Wolfgang Weninger,Henrik Westerberg,Hibret A. Adissu,Candice N. Baker,Lynette Bower,James M. Brown,L. Brianna Caddle,Francesco Chiani,Dave Clary,James Cleak,Mark J. Daly,James M. Denegre,Brendan Doe,Mary E. Dolan,Sarah M. Edie,Helmut Fuchs,Valerie Gailus-Durner,Antonella Galli,Alessia Gambadoro,Juan Gallegos,Shiying Guo,Neil R. Horner,Chih-Wei Hsu,Sara Johnson,Sowmya Kalaga,Lance C. Keith,Louise Lanoue,Thomas N. Lawson,Monkol Lek,Monkol Lek,Manuel Mark,Susan Marschall,Jeremy Mason,Melissa L. McElwee,Susan Newbigging,Lauryl M. J. Nutter,Kevin A. Peterson,Ramiro Ramirez-Solis,Douglas J. Rowland,Edward Ryder,Kaitlin E. Samocha,Kaitlin E. Samocha,John R. Seavitt,Mohammed Selloum,Zsombor Szoke-Kovacs,Masaru Tamura,Amanda G. Trainor,Ilinca Tudose,Shigeharu Wakana,Jonathan Warren,Olivia Wendling,David B. West,Leeyean Wong,Atsushi Yoshiki,Daniel G. MacArthur,Daniel G. MacArthur,Glauco P. Tocchini-Valentini,Xiang Gao,Paul Flicek,Allan Bradley,William C. Skarnes,Monica J. Justice,Helen Parkinson,Mark W. Moore,Sara Wells,Robert E. Braun,Karen L. Svenson,Martin Hrabé de Angelis,Yann Herault,Timothy J. Mohun,Ann-Marie Mallon,R. Mark Henkelman,Steve D.M. Brown,David J. Adams,Kevin C K Lloyd,Colin McKerlie,Arthur L. Beaudet,Maja Bucan,Stephen A. Murray +85 more
Analysis of protein-coding genetic variation in 60,706 humans
Monkol Lek,Konrad J. Karczewski,Konrad J. Karczewski,Eric Vallabh Minikel,Eric Vallabh Minikel,Kaitlin E. Samocha,Eric Banks,Timothy Fennell,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,James S. Ware,Andrew J. Hill,Andrew J. Hill,Andrew J. Hill,Beryl B. Cummings,Beryl B. Cummings,Taru Tukiainen,Taru Tukiainen,Daniel P. Birnbaum,Jack A. Kosmicki,Laramie E. Duncan,Laramie E. Duncan,Karol Estrada,Karol Estrada,Fengmei Zhao,Fengmei Zhao,James Zou,Emma Pierce-Hoffman,Emma Pierce-Hoffman,Joanne Berghout,David Neil Cooper,Nicole A. Deflaux,Mark A. DePristo,Ron Do,Jason Flannick,Jason Flannick,Menachem Fromer,Laura D. Gauthier,Jackie Goldstein,Jackie Goldstein,Namrata Gupta,Daniel P. Howrigan,Daniel P. Howrigan,Adam Kiezun,Mitja I. Kurki,Mitja I. Kurki,Ami Levy Moonshine,Pradeep Natarajan,Lorena Orozco,Gina M. Peloso,Gina M. Peloso,Ryan Poplin,Manuel A. Rivas,Valentin Ruano-Rubio,Samuel A. Rose,Douglas M. Ruderfer,Khalid Shakir,Peter D. Stenson,Christine Stevens,Brett Thomas,Brett Thomas,Grace Tiao,María Teresa Tusié-Luna,Ben Weisburd,Hong-Hee Won,Dongmei Yu,David Altshuler,David Altshuler,Diego Ardissino,Michael Boehnke,John Danesh,Stacey Donnelly,Roberto Elosua,Jose C. Florez,Jose C. Florez,Stacey Gabriel,Gad Getz,Gad Getz,Stephen J. Glatt,Christina M. Hultman,Sekar Kathiresan,Markku Laakso,Steven A. McCarroll,Steven A. McCarroll,Mark I. McCarthy,Mark I. McCarthy,Dermot P.B. McGovern,Ruth McPherson,Benjamin M. Neale,Benjamin M. Neale,Aarno Palotie,Shaun Purcell,Danish Saleheen,Jeremiah M. Scharf,Pamela Sklar,Patrick F. Sullivan,Patrick F. Sullivan,Jaakko Tuomilehto,Ming T. Tsuang,Hugh Watkins,Hugh Watkins,James G. Wilson,Mark J. Daly,Mark J. Daly,Daniel G. MacArthur,Daniel G. MacArthur +106 more
Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes
Jacqueline K. White,Anna-Karin Gerdin,Natasha A. Karp,Edward Ryder,Marija Buljan,James Bussell,Jennifer Salisbury,Simon Clare,Neil J. Ingham,Christine Podrini,Richard Houghton,Jeanne Estabel,Joanna Bottomley,David Melvin,David Sunter,Niels C. Adams,David Tannahill,Darren W. Logan,Daniel G. MacArthur,Jonathan Flint,Vinit B. Mahajan,Stephen H. Tsang,Ian M. Smyth,Fiona M. Watt,William C. Skarnes,Gordon Dougan,David J. Adams,Ramiro Ramirez-Solis,Allan Bradley,Karen P. Steel +29 more
The Monarch Initiative: an integrative data and analytic platform connecting phenotypes to genotypes across species.
Christopher J. Mungall,Julie A. McMurry,Sebastian Köhler,James P. Balhoff,Charles D. Borromeo,Matthew H. Brush,Seth Carbon,Tom Conlin,Nathan Dunn,Mark Engelstad,Erin D. Foster,Jean-Philippe F. Gourdine,Julius O.B. Jacobsen,Daniel Keith,Bryan Laraway,Suzanna E. Lewis,Jeremy Nguyen-Xuan,Kent Shefchek,Nicole Vasilevsky,Zhou Yuan,Nicole L. Washington,Harry Hochheiser,Tudor Groza,Damian Smedley,Peter N. Robinson,Melissa A. Haendel +25 more