Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Jul 23

PMID 23870131

Citations 317

Authors

Jacqueline K White

Anna-Karin Gerdin

Natasha A Karp

Ed Ryder

Marija Buljan

James N Bussell

Jennifer Salisbury

Simon Clare

Neil J Ingham

Christine Podrini

Richard Houghton

Jeanne Estabel

Joanna R Bottomley

David G Melvin

David Sunter

Niels C Adams

David Tannahill

Darren W Logan

Daniel G MacArthur

Jonathan Flint

Vinit B Mahajan

Stephen H Tsang

Ian Smyth

Fiona M Watt

William C Skarnes

Gordon Dougan

David J Adams

Ramiro Ramirez-Solis

Allan Bradley

Karen P Steel

Affiliations

Soon will be listed here.

Abstract

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PAPERCLIP:

Citing Articles

MorPhiC Consortium: towards functional characterization of all human genes.

Adli M, Przybyla L, Burdett T, Burridge P, Cacheiro P, Chang H Nature. 2025; 638(8050):351-359.

PMID: 39939790 DOI: 10.1038/s41586-024-08243-w.

Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation.

Song W, Ovcharenko I iScience. 2025; 28(1):111658.

PMID: 39868043 PMC: 11761325. DOI: 10.1016/j.isci.2024.111658.

Role of TLR4 activation and signaling in bone remodeling, and afferent sprouting in serum transfer arthritis.

Dos Santos G, Jimenez-Andrade J, Munoz-Islas E, Candanedo-Quiroz M, Cardenas A, Drummond B Arthritis Res Ther. 2024; 26(1):212.

PMID: 39696684 PMC: 11654167. DOI: 10.1186/s13075-024-03424-4.

Deubiquitinase MYSM1: An Important Tissue Development and Function Regulator.

Qin Q, Ruan H, Zhang H, Xu Z, Pan W, Yan X Int J Mol Sci. 2024; 25(23).

PMID: 39684760 PMC: 11641604. DOI: 10.3390/ijms252313051.

Metabolic regulation in adult and aging skeletal muscle stem cells.

Sartorelli V, Ciuffoli V Genes Dev. 2024; 39(3-4):186-208.

PMID: 39662967 PMC: 11789647. DOI: 10.1101/gad.352277.124.

References

Berriz G, Beaver J, Cenik C, Tasan M, Roth F . Next generation software for functional trend analysis. Bioinformatics. 2009; 25(22):3043-4. PMC: 2800365. DOI: 10.1093/bioinformatics/btp498. View

Andreux P, Williams E, Koutnikova H, Houtkooper R, Champy M, Henry H . Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell. 2012; 150(6):1287-99. PMC: 3604687. DOI: 10.1016/j.cell.2012.08.012. View

Prosser H, Koike-Yusa H, Cooper J, Law F, Bradley A . A resource of vectors and ES cells for targeted deletion of microRNAs in mice. Nat Biotechnol. 2011; 29(9):840-5. PMC: 3242032. DOI: 10.1038/nbt.1929. View

Laughlin M, Lloyd K, Cline G, Wasserman D . NIH Mouse Metabolic Phenotyping Centers: the power of centralized phenotyping. Mamm Genome. 2012; 23(9-10):623-31. PMC: 3738176. DOI: 10.1007/s00335-012-9425-z. View

Flicek P, Amode M, Barrell D, Beal K, Brent S, Chen Y . Ensembl 2011. Nucleic Acids Res. 2010; 39(Database issue):D800-6. PMC: 3013672. DOI: 10.1093/nar/gkq1064. View

MacArthur D, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K . A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012; 335(6070):823-8. PMC: 3299548. DOI: 10.1126/science.1215040. View

Wilson D, Charoensawan V, Kummerfeld S, Teichmann S . DBD--taxonomically broad transcription factor predictions: new content and functionality. Nucleic Acids Res. 2007; 36(Database issue):D88-92. PMC: 2238844. DOI: 10.1093/nar/gkm964. View

Fischer H, Szabo S, Scherz J, Jaeger K, Rossiter H, Buchberger M . Essential role of the keratinocyte-specific endonuclease DNase1L2 in the removal of nuclear DNA from hair and nails. J Invest Dermatol. 2011; 131(6):1208-15. PMC: 3185332. DOI: 10.1038/jid.2011.13. View

Wakana S, Suzuki T, Furuse T, Kobayashi K, Miura I, Kaneda H . Introduction to the Japan Mouse Clinic at the RIKEN BioResource Center. Exp Anim. 2009; 58(5):443-50. DOI: 10.1538/expanim.58.443. View

10.

Fisher C, Pineault N, Brookes C, Helgason C, Ohta H, Bodner C . Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood. 2009; 115(1):38-46. PMC: 2803690. DOI: 10.1182/blood-2009-07-230698. View

11.

Ruepp A, Waegele B, Lechner M, Brauner B, Dunger-Kaltenbach I, Fobo G . CORUM: the comprehensive resource of mammalian protein complexes--2009. Nucleic Acids Res. 2009; 38(Database issue):D497-501. PMC: 2808912. DOI: 10.1093/nar/gkp914. View

12.

Miller L, Park K, Guo Q, Alkharouf N, Malek R, Lee N . Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation. Mol Cell Biol. 2001; 21(19):6626-39. PMC: 99808. DOI: 10.1128/MCB.21.19.6626-6639.2001. View

13.

Jimenez-Sanchez G, Childs B, Valle D . Human disease genes. Nature. 2001; 409(6822):853-5. DOI: 10.1038/35057050. View

14.

Gu Z, Steinmetz L, Gu X, Scharfe C, Davis R, Li W . Role of duplicate genes in genetic robustness against null mutations. Nature. 2003; 421(6918):63-6. DOI: 10.1038/nature01198. View

15.

Liang H, Li W . Gene essentiality, gene duplicability and protein connectivity in human and mouse. Trends Genet. 2007; 23(8):375-8. DOI: 10.1016/j.tig.2007.04.005. View

16.

Conant G, Wagner A . Duplicate genes and robustness to transient gene knock-downs in Caenorhabditis elegans. Proc Biol Sci. 2004; 271(1534):89-96. PMC: 1691561. DOI: 10.1098/rspb.2003.2560. View

17.

Park C, Jeker L, Carver-Moore K, Oh A, Liu H, Cameron R . A resource for the conditional ablation of microRNAs in the mouse. Cell Rep. 2012; 1(4):385-91. PMC: 3345170. DOI: 10.1016/j.celrep.2012.02.008. View

18.

Edwards A, Isserlin R, Bader G, Frye S, Willson T, Yu F . Too many roads not taken. Nature. 2011; 470(7333):163-5. DOI: 10.1038/470163a. View

19.

Deardorff M, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J . Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007; 80(3):485-94. PMC: 1821101. DOI: 10.1086/511888. View

20.

Flint J, Eskin E . Genome-wide association studies in mice. Nat Rev Genet. 2012; 13(11):807-17. PMC: 3625632. DOI: 10.1038/nrg3335. View