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A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains

Michelle M Simon1, Simon Greenaway1, Jacqueline K White2, Helmut Fuchs3, Valérie Gailus-Durner3, Sara Wells1, Tania Sorg6, Kim Wong2, Elodie Bedu6, Elizabeth J Cartwright7, Romain Dacquin9, Sophia Djebali9, Jeanne Estabel2, Jochen Graw4, Neil J Ingham2, Ian J Jackson10, Andreas Lengeling11, Silvia Mandillo12, Jacqueline Marvel9, Hamid Meziane6, Frédéric Preitner13, Oliver Puk4, Michel Roux6, David J Adams2, Sarah Atkins1, Abdel Ayadi6, Lore Becker3, Andrew Blake1, Debra Brooker1, Heather Cater1, Marie-France Champy6, Roy Combe6, Petr Danecek2, Armida di Fenza1, Hilary Gates1, Anna-Karin Gerdin2, Elisabetta Golini12, John M Hancock1, Wolfgang Hans3, Sabine M Hölter3, Tertius Hough1, Pierre Jurdic9, Thomas M Keane2, Hugh Morgan1, Werner Müller8, Frauke Neff5, George Nicholson1, Bastian Pasche14, Laura-Anne Roberson2, Jan Rozman3, Mark Sanderson2, Luis Santos1, Mohammed Selloum6, Carl Shannon2, Anne Southwell1, Glauco P Tocchini-Valentini12, Valerie E Vancollie2, Henrik Westerberg1, Wolfgang Wurst1617184, Min Zi7, Binnaz Yalcin156, Ramiro Ramirez-Solis2, Karen P Steel2, Ann-Marie Mallon1, Martin Hrabě de Angelis3, Yann Herault6 and Steve DM Brown1*

Author affiliations

1 Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell Science Campus, OX11 0RD, UK

2 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK

3 Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Ingolstädter Landstraße 1, Neuherberg, D-85764, Germany

4 Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstraße 1, Neuherberg, D-85764, Germany

5 Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Pathology, Ingolstädter Landstraße 1, Neuherberg, D-85764, Germany

6 Institut Clinique de la Souris, ICS/MCI, PHENOMIN, GIE CERBM, IGBMC, CNRS, INSERM, 1 Rue Laurent Fries, 67404 Illkirch-Graffenstaden Cedex, France

7 Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, MN13 9PT, UK

8 Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, MN13 9PT, UK

9 AniRA ImmOs phenotyping facility- SFR Biosciences Lyon Gerland- UMS3444/US8, 21 avenue Tony Garnier F-69007 Lyon, France

10 Medical Research Council Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK

11 Infection and Immunity Division, Roslin Institute, University of Edinburgh, Easter Bush Veterinary Campus, Midlothian, EH25 9RG, UK

12 Consiglio Nazionale delle Ricerche- Cell Biology and Neurobiology Institute, Via E.Ramarini 32, 00015 Monterotondo Scala, Italy

13 Department of Infection Genetics, Helmholtz Centre for Infection Research, Inhoffenstraße 7, Braunschweig, 38124, Germany

14 Mouse Metabolic Facility of the Cardiomet Center, University Hospital, and Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland

15 Center for Integrative Genomics, University of Lausanne, Lausanne, CH-1015, Switzerland

16 Chair for Developmental Genetics, Technische Universität München, Arcisstr. 21, Munich, 80333, Germany

17 Max Planck Institute of Psychiatry, Kraepelinstrasse 2, Munich, 80804, Germany

18 Deutsches Zentrum für Neurodegenerative Erkrankungen, Schillerstrasse 44, Munich, 80336, Germany

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Citation and License

Genome Biology 2013, 14:R82  doi:10.1186/gb-2013-14-7-r82

Published: 31 July 2013

Abstract

Background

The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms.

Results

We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems.

Conclusions

Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.

Keywords:
Mouse inbred lines; sequence variation; mouse phenotyping; gene knockout; C57BL/6