![Heat maps illustrating significant differences in phenotype parameters between C57BL/6N and C57BL/6J male and female mice. Parameters were assessed from each of the four centers: Helmholtz Zentrum Munchen (HMGU), Institut Clinique Souris (ICS), MRC Harwell, and the Wellcome Trust Sanger Institute (WTSI). Parameter designations and parameter descriptions are from EMPReSSslim [37]. Significance levels and the direction of the effect (red and green) are defined in the key. Significant differences for categorical data are illustrated in blue. (A, B) Phenotype parameters showing a significant difference between N and J in (A) three or more centers, and (B) in two centers but no evidence of trends in the other centers.](https://www.researchgate.net/profile/Wolfgang-Hans/publication/254260446/figure/fig1/AS:214035967549447@1428041559978/Heat-maps-illustrating-significant-differences-in-phenotype-parameters-between-C57BL-6N_Q320.jpg)
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A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N
mouse strains
Genome Biology 2013, 14:R82 doi:10.1186/gb-2013-14-7-r82
Michelle M Simon (m.simon@har.mrc.ac.uk)
Simon Greenaway (s.greenaway@har.mrc.ac.uk)
Jacqueline K White (jkw@sanger.ac.uk)
Helmut Fuchs (hfuchs@helmholtz-muenchen.de)
Valérie Gailus-Durner (gailus@helmholtz-muenchen.de)
Tania Sorg (tsorg@igbmc.fr)
Kim Wong (kw10@sanger.ac.uk)
Elodie Bedu (bedu@igbmc.fr)
Elizabeth J Cartwright (elizabeth.j.cartwright@manchester.ac.uk)
Romain Dacquin (romain.dacquin@etu.univ-lyon1.fr)
Sophia Djebali (sophia.djebali@inserm.fr)
Jeanne Estabel (je2@sanger.ac.uk)
Jochen Graw (graw@helmholtz-muenchen.de)
Neil J Ingham (neil.ingham@kcl.ac.uk)
Ian J Jackson (ian.jackson@igmm.ed.ac.uk)
Andreas Lengeling (andreas.lengeling@roslin.ed.ac.uk)
Silvia Mandillo (smandillo@ibc.cnr.it)
Jacqueline Marvel (jacqueline.marvel@inserm.fr)
Hamid Meziane (meziane@igbmc.fr)
Frédéric Preitner (Frederic.Preitner@unil.ch)
Oliver Puk (oliver.puk@helmholtz-muenchen.de)
Michel Roux (mjroux@igbmc.fr)
David J Adams (da1@sanger.ac.uk)
Sarah Atkins (s.atkins@har.mrc.ac.uk)
Abdel Ayadi (ayadi@igbmc.fr)
Lore Becker (lore.becker@helmholtz-muenchen.de)
Andrew Blake (a.blake@har.mrc.ac.uk)
Debra Brooker (d.brooker@har.mrc.ac.uk)
Heather Cater (h.cater@har.mrc.ac.uk)
Marie-France Champy (champy@igbmc.fr)
Roy Combe (combe@igbmc.fr)
Petr Danecek (pd3@sanger.ac.uk)
Armida di Fenza (a.difenza@har.mrc.ac.uk)
Hilary Gates (h.gates@har.mrc.ac.uk)
Anna-Karin Gerdin (akg@sanger.ac.uk)
Elisabetta Golini (egolini@ibc.cnr.it)
John M Hancock (jmhancock@gmail.com)
Wolfgang Hans (wolfgang.hans@helmholtz-muenchen.de)
Sabine M Hölter (hoelter@helmholtz-muenchen.de)
Genome Biology
© 2013 Simon et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Tertius Hough (t.hough@har.mrc.ac.uk)
Pierre Jurdic (pjurdic@ens-lyon.fr)
Thomas M Keane (tk2@sanger.ac.uk)
Hugh Morgan (h.morgan@har.mrc.ac.uk)
Werner Müller (werner.muller@manchester.ac.uk)
Frauke Neff (frauke.neff@helmholtz-muenchen.de)
George Nicholson (george.nicholson@stats.ox.ac.uk)
Bastian Pasche (Bastian.Pasche@helmholtz-hzi.de)
Laura-Anne Roberson (lr4@sanger.ac.uk)
Jan Rozman (jan.rozman@helmholtz-muenchen.de)
Mark Sanderson (ms14@sanger.ac.uk)
Luis Santos (l.santos@har.mrc.ac.uk)
Mohammed Selloum (selloum@igbmc.fr)
Carl Shannon (cs7@sanger.ac.uk)
Anne Southwell (a.southwell@har.mrc.ac.uk)
Glauco P Tocchini-Valentini (tocchini@ibc.cnr.it)
Valerie E Vancollie (vv2@sanger.ac.uk)
Sara Wells (s.wells@har.mr.ac.uk)
Henrik Westerberg (h.westerberg@har.mrc.ac.uk)
Wolfgang Wurst (wurst@helmholtz-muenchen.de)
Min Zi (min.zi@manchester.ac.uk)
Binnaz Yalcin (Binnaz.Yalcin@well.ox.ac.uk)
Ramiro Ramirez-Solis (rrs@sanger.ac.uk)
Karen P Steel (karen.steel@kcl.ac.uk)
Ann-Marie Mallon (a.mallon@har.mrc.ac.uk)
Martin Hrabě de Angelis (hrabe@helmholtz-muenchen.de)
Yann Herault (herault@igbmc.fr)
Steve DM Brown (s.brown@har.mrc.ac.uk)
ISSN 1465-6906
Article type Research
Submission date 18 March 2013
Acceptance date 28 June 2013
Publication date 31 July 2013
Article URL http://genomebiology.com/2013/14/7/R82
This peer-reviewed article can be downloaded, printed and distributed freely for any purposes (see
copyright notice below).
Articles in Genome Biology are listed in PubMed and archived at PubMed Central.
Genome Biology
© 2013 Simon et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
For information about publishing your research in Genome Biology go to
http://genomebiology.com/authors/instructions/
Genome Biology
© 2013 Simon et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1
A comparative phenotypic and genomic analysis of
C57BL/6J and C57BL/6N mouse strains
Michelle M Simon
1
, Simon Greenaway
1
, Jacqueline K White
2
, Helmut Fuchs
3a
,
Valérie Gailus-Durner
3a
, Tania Sorg
4
, Kim Wong
2
, Elodie Bedu
4
, Elizabeth J
Cartwright
5a
, Romain Dacquin
6
, Sophia Djebali
7
, Jeanne Estabel
2
, Jochen
Graw
3b
, Neil J Ingham
2
, Ian J Jackson
8
, Andreas Lengeling
9
, Silvia
Mandillo
10
, Jacqueline Marvel
6
, Hamid Meziane
4
, Frédéric Preitner
11
, Oliver
Puk
3b
, Michel Roux
4
, David J Adams
2
, Sarah Atkins
1
, Abdel Ayadi
4
, Lore
Becker
3a
, Andrew Blake
1
, Debra Brooker
1
, Heather Cater
1
, Marie-France
Champy
4
, Roy Combe
4
, Petr Danecek
2
, Armida di Fenza
1
, Hilary Gates, Anna-
Karin Gerdin
2
, Elisabetta Golini
10
, John M Hancock
1
, Wolfgang Hans
3a
, Sabine
M Hölter
3a
, Tertius Hough
1
, Pierre Jurdic
6
, Thomas M Keane
2
, Hugh Morgan
1
,
Werner Müller
5b
, Frauke Neff
3c
, George Nicholson
1
, Bastian Pasche
12
, Laura-
Anne Roberson
2
, Jan Rozman
3a
, Mark Sanderson
2
, Luis Santos
1
, Mohammed
Selloum
4
, Carl Shannon
2
, Anne Southwell
1
,Glauco P Tocchini-Valentini
10
,
Valerie E Vancollie
2
, Sara Wells
1
, Henrik Westerberg
1
, Wolfgang
Wurst
3b,15,16,17
, Min Zi
5a
, Binnaz Yalcin
13, 14
, Ramiro Ramirez-Solis
2
, Karen P
Steel
2
, Ann-Marie Mallon
1
, Martin Hrabě de Angelis
3a
, Yann Herault
4
and
Steve DM Brown
1
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26
Materials and Methods
Sequencing and genomic analyses
=67*<8H67*<830;'
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29
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32
'2'0C%0'
$4='4'2440!C5,
42!C5C
Abbreviations
1:E1:'0G1E
14G1E1'IG
=+E=?+2'G(#E(#>
G(:E(:'G(:%%E
(%%G#:E#>:IG:E
:G3:E'3:G:E
':
Competing interests
%200C
Authors’ contributions
H#&=B?"%#&1*1H"H1H3H((HH+H
=:::H*K?#:+?+K"*4;
2')C
"H+*:H#&=B?"%1*1H"H1H3H((HH+H=::
:H#:K"+++*"*?=+=+?#1&%
&=3?+H+%?BB1B&&&.0
)C
33
"H+*:+?"*+*:"H%#3&0
C
+20C
Description of additional data files
+0E%43:24
+0$E='1:'C
+0,E='$?''
004'C
Acknowledgements
%1"(I0414
?%?$!!8?!,755?%?$!!7?!,79964
&%'4!@5!6C&'0>'4
041"(IG40N@OC&>
?2'&%0
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34
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ELL
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Database (MGD): comprehensive resource for genetics and genomics of the
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mouse phenotyping resource. Nucleic Acids Res 2008, 36:D715-718.
38. Europhenome Java Library:
http://sourceforge.net/projects/europhenome/
39. Phenotype Data: http://www.har.mrc.ac.uk/nj
40. Efron B: 1977 Rietz Lecture - Bootstrap Methods - Another Look at the
Jackknife. Ann Stat 1979, 7:1-26.
38
Figure 1. ''000
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43
Table 1. Coding SNPs and small indels identified between C57BL/6N and
C57BL/6J
Chr
Position
B6J
Base
B6N
Base
Strain
Gene Name
B6J
Amino Acid
B
6N
Amino Acid
Nonsense Polymorphism
13 65023280 C T B6N
Spata31
Arginine * (STOP)
Missense Polymorphisms
1 59904011 G A B6N
Bmpr2
Arginine Glutamine
3 95538799 T C B6J
Ecm1
Isoleucine Valine
3 96658480 A G B6J
Pdzk1
Asparagine Aspartic acid
4 21800831 C G B6J
Sfrs18
Arginine Glycine
4 137777588 C T B6N
Hp1bp3
Leucine Phenylalanine
4 140354038 A G B6N
Padi3
Leucine Proline
4 148318468 T C B6J
Casz1
Leucine Proline
5 90204376 C T B6N
Adamts3
Valine Isoleucine
5 97187161 T C B6J
Fras1
Leucine Proline
5 113191741 C T B6N
Myo18b
Arginine Histidine
6 39350455 T A B6J
Mkrn1
Asparagine Tyrosine
7 3222538 T C B6J
Nlrp12
Lysine Arginine
7 63386662 G A B6J
Herc2
Glycine Aspartic acid
7 86256240 A C B6J
Acan
Histidine Proline
7 110121823 C T B6N
Olfr577
Valine Isoleucine
7 127278693 G A B6N+Spretus
Zp2
Alanine Valine
7 129311164 C T B6N
Plk1
Arginine Tryptophan
9 24935069 C G B6N
Herpud2
Valine Leucine
10 66700922 T C B6J
Jmjd1c
Leucine Proline
10 78632222 A G B6N
Vmn2r80
Asparagine Serine
10 87554578 T C B6N
Pmch
Isoleucine Threonine
11 46036117 G A B6N
Cyfip2
Serine Phenylalanine
11 90341985 C T B6N
Stxb4
Alanine Threonine
13 21560172 A G B6J
Nkapl
Glycine Arginine
13 73465884 A G B6J
Ndufs6
Valine Alanine
13 93833534 C G B6J
Cmya5
Alanine Proline
14 70986011 G T B6N
Fam160b2
Serine Arginine
15 11266138 G T B6N
Adamts12
Cysteine Phenylalanine
15 77468437 A C B6J
Apol11b
Isoleucine Arginine
16 35291630 G A B6N
Adcy5
Valine Methionine
17 47537359 T C B6J
Guca1a
Isoleucine Valine
X 131227581 C A B6N
Armcx4
Alanine Aspartic acid
Splice Site Polymorphism
5 54280548 A G
B6J
Tbc1d19
- -
Frameshift
1bp
-
D
eletions
1 141133664 G -
B6N
Crb1
- -
9 65127938 G -
B6J
Cilp
- -
44
Table 2. Structural variants between C57BL/6N and C57BL/6J
Chr SV start SV stop Ancestral event Strain Gene Overlap
1 149518394 149524878 LINE Ins B6J
2 7325700 7330977 IAP Ins B6J
2 70619835 70620080 SINE Ins B6J
Tlk1
intron
3 77975065 77977953 Del B6N
3 5049018 5055845 LINE Ins B6J
3 60336036 60336037 Del (large) B6J
Mbnl1
intron
3 41885819 41887255 LINE Ins B6J
3 18484710 18484889 Del B6N
4 101954274 101954395 Del B6N
Pde4b
intron
4 116051393 116051799 MaLR Ins B6J
Mast2
intron
5 46376307 46377852 LINE Ins B6J
5 90356490 90356491 Del (~300 bp) B6J
5 146248861 146261885 Ins B6J+others
6 18112291 18119019 LINE Ins B6J
6 62964974 62972907 LINE Ins B6J
6 86478779 86479400 Ins B6J
6 103669536 103676487 LINE Ins B6J
Chl1
intron
6 104207081 104214434 LINE Ins B6J
7 92095990 92096149 Del B6N
Vmn2r65
exon
7 27636128 27748456 Ins B6J
Cyp2a22
entire
7 100892501 100899058 LINE Ins B6J
7 139306094 139307981 MaLR Ins B6J
Cpxm2
intron
8 16716381 16716382 Del (large) B6J
Csmd1
intron
9 25674550 25674770 SINE Ins B6J
9 58544415 58546304 MaLR Ins B6J
2410076I21Rik
intron
10 3039196 3039197 Del (large) B6J
10 29339441 29345955 LINE Ins B6J
10 32536420 32543464 LINE Ins B6J
Nkain2
intron
10 49543303 49550645 LINE Ins B6J
11 104906390 104906621 Del B6N
11 119560391 119566827 MTA Ins B6J
Rptor
intron
12 42023964 42032747 Del B6N
Immp2l
intron
13 71224557 71231011 MTA Ins B6J
13 120164268 120164269 Del (large) B6J
Nnt
exon
14 112825585 112832341 LINE Ins B6J
15 49554596 49554597 Ins (large) B6N
15 31106173 31106382 VNTR
16 6115804 6138105 Del B6N
17 60286367 60286368 Ins (~2000 bp) B6N
18 4809271 4809272 Del (~1200 bp) B6J
19 12863187 12863188 Del (~1800 bp) B6J
Zfp91
intron
X 15697909 15697910 Del (~400 bp) B6J
X 95155499 95163160 LINE Ins B6J
Start and stop coordinates are given for MGSCv37 of the mouse reference genome. Del, deletion; IAP,
intracisternal A particle; Ins, insertion; LINE, long interspersed nuclear elements; MaLR, mammalian
apparent LTR-retrotransposon; MTA, member of transcript retrotransposon; SINE, short interspersed
nuclear elements; VNTR, variable number tandem repeat.
45
Table 3. Comparison of predicted effects of SNPs and SVs that might contribute to the phenotypic
differences between C57BL/6N and C57BL/6J (see text). We have identified variant genes that show
homozygote knockout phenotypes with associated MP terms that were assessed in the phenotyping
pipeline, and compared these phenotypes to those observed between N and J.
Protein
coding
gene
C57BL/6J
Amino
Acid
C57BL/6N
Amino Acid
SNP is
Private
to
PROVEAN
Prediction
1
MP Terms
B6J
vs
B6N
2
B6N vs
B6J
2
Adcy5 Valine (V) Methionine
(M)
B6N TOLERATED
(-1.712)
impaired
coordination_MP:0001405
NR P
hypoactivity_MP:0001402 NR P
Pmch Isoleucine
(I)
Threonine
(T)
B6N TOLERATED
(0.493)
decreased circulating glucose
level_MP:0005560
NR A
abnormal glucose
tolerance_MP:0005291
NR A
increased oxygen
consumption_MP:0005289
NR P
Pdzk1 Asparagine
(N)
Aspartic Acid
(D)
B6J TOLERATED
(0.95)
increased circulating
cholesterol level_MP:0001556
A NR
Nlrp12 Lysine
(K)
Arginine
(A)
B6J TOLERATED
(0.781)
abnormal type IV
hypersensitivity
reaction_MP:0002534
P NR
Crb1 - - B6N - photosensitivity_MP:0001999 NR P
abnormal ocular fundus
morphology_MP:0002864
NR P
retinal
degeneration_MP:0001326
NR P
abnormal retina
morphology_MP:0001325
NR P
abnormal retinal photoreceptor
layer_MP:0003728
NR P
Chl1 - - B6J - abnormal learning/ memory_
MP:0001449
A NR
abnormal spatial working
memory_MP:0008428
A NR
Rptor - - B6J - increased lean body
mass_MP:0003960
P NR
increased oxygen
consumption_MP:0005289
A NR
hypoactivity_MP:0001402 A NR
decreased circulating glucose
level_MP:0005560
P NR
improved glucose
tolerance_MP:0005292
A NR
Nnt - - B6J - impaired glucose
tolerance_MP:0005293
P NR
1
Threshold for intolerance is -2.3
2
These columns indicate the direction of the phenotype effect that might be observed given the assignment of a SNP or SV as
private to B6J or B6N. Only one direction will be relevant and comparable to the effects of the knockout mutation.
Key:
NR
Not relevant
P
Phenotype present
A
Phenotype ant
46
Figure 1
Figure 2
Figure 3
Figure 5
Figure 6
Figure 7
Additional files provided with this submission:
Additional file 1: TableS1.pdf, 225K
http://genomebiology.com/imedia/8046326471045638/supp1.pdf
Additional file 2: Supplementary_Figure_1.pdf, 544K
http://genomebiology.com/imedia/1086014387104073/supp2.pdf
Additional file 3: Supplementary_Figure_2.pdf, 2994K
http://genomebiology.com/imedia/1777967506104073/supp3.pdf
