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Comparing phenotypic variation between inbred and outbred mice

Nature Methods volume 15, pages 994–996 (2018)Cite this article

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An Author Correction to this article was published on 29 July 2020

An Author Correction to this article was published on 21 December 2018

This article has been updated

Inbred mice are preferred over outbred mice because it is assumed that they display less trait variability. We compared coefficients of variation and did not find evidence of greater trait stability in inbred mice. We conclude that contrary to conventional wisdom, outbred mice might be better subjects for most biomedical research.

The laboratory mouse is the most commonly used nonhuman experimental subject in biomedical research1. For many decades, inbred mouse strains have been preferred over outbred stocks, with particular strains such as C57BL/6 and BALB/c used in wide-ranging biomedical applications2. Inbred mice are preferentially chosen for immunological studies (to prevent alloimmune responses), population genetic mapping (to allow diallele crosses for known genetic markers), and molecular genetic studies (to avoid background effects in mutagenesis and transgenics). The more general preference for inbred strains across biomedicine stems from the conventional wisdom that these animals should demonstrate less within-strain phenotypic variability than outbred animals, because in any given inbred strain phenotypic variability (Vp) equals environmental variability (Ve), whereas in outbred animals genetic variability (Vg) is present in addition to Ve and gene–environment interaction (Vge). If this assumption were valid, statistical power could be maintained with fewer inbred mice compared with the number needed in outbred-strain-based experiments, which would present practical and ethical advantages. However, the evidence for lower phenotypic variability among inbred mice is mixed, with some early (e.g., ref. 3) and more recent (e.g., ref. 4) studies explicitly suggesting otherwise. Nonetheless, the idea that genetic heterogeneity leads to greater phenotypic variability is compelling, and its proponents argue against the use of outbred stocks in biomedical research (e.g., refs 5,6,7).

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Fig. 1: Coefficients of variation of all available studies in which inbred and outbred mice were directly compared.
Fig. 2: CVs within each inbred strain and the average CV across 1,000 subsamples of the DO population.

Data availability

Data used in this paper are provided as Supplementary Information.

Change history

  • 29 July 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • 21 December 2018

    In the version of this Comment originally published, the authors omitted a funding source. Grant 5 P50 DA039841 (to E.J.C.) from the US National Institute on Drug Abuse has been added to the Acknowledgements in the HTML and PDF versions of the paper.

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Acknowledgements

This work was supported by funding from the Canadian Institutes for Health Research (FRN154281 to J.S.M.), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-03873 to J.S.M.), the Louise and Alan Edwards Foundation (J.S.M.), and the NIH National Institute on Drug Abuse (5 P50 DA039841 to E.J.C.).

Author information

Authors and Affiliations

  1. UNC Neuroscience Centre, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Alexander H. Tuttle

  2. The Jackson Laboratory, Bar Harbor, ME, USA

    Vivek M. Philip & Elissa J. Chesler

  3. Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada

    Jeffrey S. Mogil

Authors
  1. Alexander H. Tuttle
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  2. Vivek M. Philip
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  3. Elissa J. Chesler
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  4. Jeffrey S. Mogil
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Contributions

The study was conceived by J.S.M., designed by A.H.T. and J.S.M., carried out by A.H.T., and analyzed by V.M.P. and E.J.C.

Corresponding author

Correspondence to Jeffrey S. Mogil.

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Competing interests

The authors declare no competing interests.

Integrated supplementary information

Supplementary Figure 1

PRISMA diagram.

Supplementary Information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Table 2

Reporting Summary

Supplementary Table 1

Data from papers simultaneously testing inbred and outbred mouse strains.

Supplementary Table 3

DO versus inbred CVs.

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Tuttle, A.H., Philip, V.M., Chesler, E.J. et al. Comparing phenotypic variation between inbred and outbred mice. Nat Methods 15, 994–996 (2018). https://doi.org/10.1038/s41592-018-0224-7

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