Brief introduction in phenotypic and genetic differences of C57BL/6 and BALB/c mice substrains

Lan Zhao , Jie Wei , Bingfei Yue

Animal Models and Experimental Medicine ›› 2025, Vol. 8 ›› Issue (9) : 1628 -1634.

PDF
Animal Models and Experimental Medicine ›› 2025, Vol. 8 ›› Issue (9) : 1628 -1634. DOI: 10.1002/ame2.70067
REVIEW

Brief introduction in phenotypic and genetic differences of C57BL/6 and BALB/c mice substrains

Author information +
History +
PDF

Abstract

Experimental mice play a critical role in biomedical research. The phenotype and application of different substrains vary due to genetic differentiation and variation. To ensure validity and reliability of results, it is imperative to adhere to standardized experiments and controls. This paper objectively reviews the origin, differentiation, and phenotypic and genetic differences between the C57BL/6 and BALB/c mouse substrains. Furthermore, an optimal selection strategy is proposed based on the genetic quality control technology to facilitate the precise application of these two mouse substrains.

Keywords

BALB/c mice / C57BL/6 mice / genetic differences / phenotypic differences / substrains

Cite this article

Download citation ▾
Lan Zhao, Jie Wei, Bingfei Yue. Brief introduction in phenotypic and genetic differences of C57BL/6 and BALB/c mice substrains. Animal Models and Experimental Medicine, 2025, 8(9): 1628-1634 DOI:10.1002/ame2.70067

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Li Yinyin W, Shaoliang WH, Zhang S, et al. Genetic quality analysis of 24 domestic inbred mouse strains by microsatellite DNA. Chin J Comp Med. 2017; 27(8): 43-49.

[2]

Mekada K, Abe K, Murakami A, et al. Genetic differences among C57BL/6 substrains. Exp Anim. 2009; 58(2): 141-149.

[3]

Festing MF. Origins and characteristics of inbred strains of mice. In: Lyon MF, Rastan S, Brown SDM, eds. Genetic Variants and Strains of the Laboratory Mouse. Oxford University Press; 1996: 1537-1576.

[4]

Simon MM, Greenaway S, White JK, et al. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biol. 2013; 14(7): R82.

[5]

Altman PL, Kats DD. Inbred and genetically defined strains of laboratory animals, part 1 mouse and rat. Federation of American Societies for Experimental Biology; 1979.

[6]

Mekada K, Yoshiki A. Substrains matter in phenotyping of C57BL/6 mice. Exp Anim. 2021; 70(2): 145-160.

[7]

Potter M. History of the BALB/c family. In: Pottern M, ed. The BALB/c mouse: genetics and immunology, current topics in microbiology and immunology. Springer; 1985: 1-5.

[8]

Åhlgren J, Voikar V. Experiments done in Black-6 mice: what does it mean? Lab Anim. 2019; 48(6): 171-180.

[9]

Ashworth A, Bardgett ME, Fowler J, Garber H, Griffith M, Curran CP. Comparison of neurological function in males and females from two substrains of C57BL/6 mice. Toxics. 2015; 3(1): 1-17.

[10]

Stiedl O, Radulovic J, Lohmann R, et al. Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice. Behav Brain Res. 1999; 104(1-2): 1-12.

[11]

Matsuo N, Takao K, Nakanishi K, Yamasaki N, Tanda K, Miyakawa T. Behavioral profiles of three C57BL/6 substrains. Front Behav Neurosci. 2010; 4: 29.

[12]

Pinheiro BS, Seidl SS, Habazettl E, Gruber BE, Bregolin T, Zernig G. Dyadic social interaction of C57BL/6 mice versus interaction with a toy mouse: conditioned place preference/aversion, substrain differences, and no development of a hierarchy. Behav Pharmacol. 2016; 27: 279-288.

[13]

Blum K, Briggs AH, DeLallo L, Elston SF, Ochoa R. Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring c57BL mice. Experientia. 1982; 38(12): 1469-1470.

[14]

Khisti RT, Wolstenholme J, Shelton KL, Miles MF. Characterization of the ethanol-deprivation effect in substrains of C57BL/6 mice. Alcohol. 2006; 40(2): 119-126.

[15]

Ramachandra V, Phuc S, Franco AC, Gonzales RA. Ethanol preference is inversely correlated with ethanol-induced dopamine release in 2 substrains of C57BL/6 mice. Alcohol Clin Exp Res. 2007; 31(10): 1669-1676.

[16]

Cooper MA, O'Meara B, Jack MM, et al. Intrinsic activity of C57BL/6 substrains associates with high-fat diet-induced mechanical sensitivity in mice. J Pain. 2018; 19(11): 1285-1295.

[17]

Bryant CD, Bagdas D, Goldberg LR, et al. C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception. Mol Pain. 2019; 15: 1744806918825046.

[18]

Giles JM, Whitaker JW, Moy SS, Fletcher CA. Effect of environmental enrichment on aggression in BALB/cJ and BALB/cByJ mice monitored by using an automated system. J Am Assoc Lab Anim Sci. 2018; 57(3): 236-243.

[19]

Velez L, Sokoloff G, Miczek KA, Palmer AA, Dulawa SC. Differences in aggressive behavior and DNA copy number variants between BALB/cJ and BALB/cByJ substrains. Behav Genet. 2010; 40(2): 201-210.

[20]

Sittig LJ, Jeong C, Tixier E, Davis J, Barrios-Camacho CM, Palmer AA. Phenotypic instability between the near isogenic substrains BALB/cJ and BALB/cByJ. Mamm Genome. 2014; 25(11-12): 564-572.

[21]

Jager A, Dam SA, Van Der Mierden S, et al. Modulation of cognitive flexibility by reward and punishment in BALB/cJ and BALB/cByJ mice. Behav Brain Res. 2020; 378: 112294.

[22]

Beierle JA, Yao EJ, Goldstein SI, et al. Genetic basis of thermal nociceptive sensitivity and brain weight in a BALB/c reduced complexity cross. Mol Pain. 2022; 18: 17448069221079540.

[23]

Close AF, Chae H, Jonas JC. The lack of functional nicotinamide nucleotide transhydrogenase only moderately contributes to the impairment of glucose tolerance and glucose-stimulated insulin secretion in C57BL/6J vs C57BL/6N mice. Diabetologia. 2021; 64(11): 2550-2561.

[24]

Hull RL, Willard JR, Struck MD, et al. High fat feeding unmasks variable insulin responses in male C57BL/6 mouse substrains. J Endocrinol. 2017; 233(1): 53-64.

[25]

Fisher-Wellman KH, Ryan TE, Smith CD, et al. A direct comparison of metabolic responses to high-fat diet in C57BL/6J and C57BL/6NJ mice. Diabetes. 2016; 65(11): 3249-3261.

[26]

Vozenilek AE, Vetkoetter M, Green JM, et al. Absence of nicotinamide nucleotide transhydrogenase in C57BL/6J mice exacerbates experimental atherosclerosis. J Vasc Res. 2018; 55(2): 98-110.

[27]

Andersson KE, Immerstrand T, Swärd K, et al. Effects of oats on plasma cholesterol and lipoproteins in C57BL/6 mice are substrain specific. Br J Nutr. 2010; 103(4): 513-521.

[28]

Leskov I, Neville A, Shen X, et al. Nicotinamide nucleotide transhydrogenase activity impacts mitochondrial redox balance and the development of hypertension in mice. J Am Soc Hypertens. 2017; 11(2): 110-121.

[29]

Otto GP, Rathkolb B, Oestereicher MA, et al. Clinical chemistry reference intervals for C57BL/6J, C57BL/6N, and C3HeB/FeJ mice (Mus musculus). J Am Assoc Lab Anim Sci. 2016; 55: 375-386.

[30]

Marques O, Neves J, Horvat NK, Colucci S, Guida C, Muckenthaler MU. Iron-related parameters are altered between C57BL/6N and C57BL/6J Mus musculus wild-type substrains. HemaSphere. 2019; 3: e304.

[31]

Perincheri S, Peyton DK, Glenn M, Peterson ML, Spear BT. Characterization of the ETnII-alpha endogenous retroviral element in the BALB/cJ Zhx2 (Afr1) allele. Mamm Genome. 2008; 19(1): 26-31.

[32]

Clinkenbeard EL, Turpin C, Jiang J, Peterson ML, Spear BT. Liver size and lipid content differences between BALB/c and BALB/cJ mice on a high-fat diet are due, in part, to Zhx2. Mamm Genome. 2019; 30(7-8): 226-236.

[33]

Garifulin O, Qi Z, Shen H, Patnala S, Green MR, Boyartchuk V. Irf3 polymorphism alters induction of interferon beta in response to listeria monocytogenes infection. PLoS Genet. 2007; 3(9): 1587-1597.

[34]

Ulland TK, Jain N, Hornick EE, et al. Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun. 2016; 7: 13180.

[35]

Eisfeld AJ, Gasper DJ, Suresh M, Kawaoka Y. C57BL/6J and C57BL/6NJ mice are differentially susceptible to inflammation-associated disease caused by influenza a virus. Front Microbiol. 2019; 9: 3307.

[36]

Treger RS, Pope SD, Kong Y, Tokuyama M, Taura M, Iwasaki A. The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV. Immunity. 2019; 50: 334-347.e9.

[37]

Nicholson SM, Peterson JD, Miller SD, Wang K, Dal Canto MC, Melvold RW. BALB/c substrain differences in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease. J Neuroimmunol. 1994; 52(1): 19-24.

[38]

Kaushansky A, Austin LS, Mikolajczak SA, et al. Susceptibility to plasmodium yoelii preerythrocytic infection in BALB/c substrains is determined at the point of hepatocyte invasion. Infect Immun. 2015; 83(1): 39-47.

[39]

Farkas B, Boldizsar F, Tarjanyi O, et al. BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance. Arthritis Res Ther. 2009; 11(1): R21.

[40]

Seetharamaiah GS, Land KJ. Differential susceptibility of BALB/c and BALB/cBy mice to graves' hyperthyroidism. Thyroid. 2006; 16(7): 651-658.

[41]

Poyntz HC, Jones A, Jauregui R, et al. Genetic regulation of antibody responsiveness to immunization in substrains of BALB/c mice. Immunol Cell Biol. 2019; 97(1): 39-53.

[42]

Stevens JC, Banks GT, Festing MF, Fisher EM. Quiet mutations in inbred strains of mice. Trends Mol Med. 2007; 13(12): 512-519.

[43]

Toye AA, Lippiat JD, Proks P, et al. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia. 2005; 48: 675-686.

[44]

Mortazavi M, Ren Y, Saini S, et al. SNPs, short tandem repeats, and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains. Cell Genom. 2022; 2(3): 100102.

[45]

Mellor AL, Antoniou J, Robinson PJ. Structure and expression of genes encoding murine Qa-2 class I antigens. Proc Natl Acad Sci USA. 1985; 82(17): 5920-5924.

[46]

Miura I, Kikkawa Y, Yasuda SP, et al. Characterization of single nucleotide polymorphisms for a forward genetics approach using genetic crosses in C57BL/6 and BALB/c substrains of mice. Exp Anim. 2022; 71(2): 240-251.

[47]

Festing MF. Genetic reliability of commercially-bred laboratory mice. Lab Anim. 1974; 8(3): 265-270.

[48]

Roderick TH, Ruddle FH, Chapman VM, Shows TB. Biochemical polymorphisms in feral and inbred mice (mus musculus). Biochem Genet. 1971; 5(5): 457-466.

[49]

Strobel MC, Reinholdt LG, Malcolm RD, Pritchett-Corning K. Chapter 31 - genetic monitoring of laboratory mice and rats. In: Fox JG, Anderson LC, Otto GM, Pritchett-Corning KR, Whary MT, eds. Laboratory Animal Medicine. 3rd ed. Academic Press; 2015: 1403-1416.

[50]

Sun Fangyuan WY, Cluping YW, Xiaoke SLW. Advances of microsatellite and single nucleotide polymorphism analysis for genetic monitoring in mouse and rat. Lab Anim Sci. 2014; 31(3): 60-65.

[51]

Laboratory animal - genetic quality control of mammalian laboratory animals: GB 14923-2010. 2010.

[52]

Yinyin L, Zhenwen C, Lijun L, et al. Genetic mornitoring for inbred mice with single nucleotide polymorphisms. Lab Anim Comp Med. 2018; 1: 16-21.

[53]

Zhao L, Zhang R, Zhao Y, Zheng-hong XI, Guo-qiang CH. Application of single nucleotide polymorphism genotyping panel in genetic monitoring of laboratory mice. Lab Anim Comp Med. 2016; 36(1): 24-31.

[54]

Laboratory animal - methods for microsateltlie markers of laboratory mice & rats:T/CALAS 21-2017[S]. 2017.

[55]

Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020; 18: e3000410.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences

AI Summary AI Mindmap
PDF

27

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/