Inbred lab mice are not isogenic: genetic variation within inbred strains used to infer the mutation rate per nucleotide site

Chebib, Jobran; Jackson, Benjamin C.; López‐Cortegano, Eugenio; Tautz, Diethard; Keightley, Peter D.

doi:10.1038/s41437-020-00361-1

Cited by 29 publications

(20 citation statements)

References 37 publications

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“…6). The male mice used here were delivered by two different vendors and should be considered sub-strains of the C57BL/6 strain which may differ in several respects [55][56][57][58][59][60] . However, our main finding of an infraradian rhythmicity in activity was evident and similar in all three groups of cages with mice studied suggesting that this trait is not overtly vendor or sex sensitive.…”

Section: Discussionmentioning

confidence: 99%

Major oscillations in spontaneous home-cage activity in C57BL/6 mice housed under constant conditions

Pernold

Rullman

Ulfhake

2021

Sci Rep

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The mouse is the most important mammalian model in life science research and the behavior of the mouse is a key read-out of experimental interventions and genetic manipulations. To serve this purpose a solid understanding of the mouse normal behavior is a prerequisite. Using 14–19 months of cumulative 24/7 home-cage activity recorded with a non-intrusive technique, evidence is here provided for a highly significant circannual oscillation in spontaneous activity (1–2 SD of the mean, on average 65% higher during peak of highs than lows; P = 7E−50) of male and female C57BL/6 mice held under constant conditions. The periodicity of this hitherto not recognized oscillation is in the range of 2–4 months (average estimate was 97 days across cohorts of cages). It off-sets responses to environmental stimuli and co-varies with the feeding behavior but does not significantly alter the preference for being active during the dark hours. The absence of coordination of this rhythmicity between cages with mice or seasons of the year suggest that the oscillation of physical activity is generated by a free-running intrinsic oscillator devoid of external timer. Due to the magnitude of this rhythmic variation it may be a serious confounder in experiments on mice if left unrecognized.

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Section: Discussionmentioning

confidence: 99%

Major oscillations in spontaneous home-cage activity in C57BL/6 mice housed under constant conditions

Pernold

Rullman

Ulfhake

2021

Sci Rep

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“…Strains AKR/J and PL/J showed a different distribution pattern. Perhaps in these two strains, spontaneous mutations arose in some of their generations after genotyping, as described for C3H/HeN, BL6, BALBc, and FVB [ 29 ]. A suggestive association threshold (blue line) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2A ) p ≤ 4.1x10 −6 was calculated in Ref. [ [17] , [29] ] and ii) a Bonferroni correction, which resulted in a much stricter p -value of 1.28x10 −8 , denoted by the red line in Fig. 2A .…”

Section: Resultsmentioning

confidence: 99%

Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

Durán

Rebolledo‐Jaramillo

Olguín

et al. 2021

Biochemistry and Biophysics Reports

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The acid β-glucocerebrosidase (GCase) enzyme cleaves glucosylceramide into glucose and ceramide. Loss of function variants in the gene encoding for GCase can lead to Gaucher disease and Parkinson's disease. Therapeutic strategies aimed at increasing GCase activity by targeting a modulating factor are attractive and poorly explored. To identify genetic modifiers, we measured hepatic GCase activity in 27 inbred mouse strains. A genome-wide association study (GWAS) using GCase activity as a trait identified several candidate modifier genes, including Dmrtc2 and Arhgef1 (p=2.1x10 −7 ), and Grik5 (p=2.1x10 −7 ). Bayesian integration of the gene mapping with transcriptomics was used to build integrative networks. The analysis uncovered additional candidate GCase regulators, highlighting modules of the acute phase response (p=1.01x10 −8 ), acute inflammatory response (p=1.01x10 −8 ), fatty acid beta-oxidation (p=7.43x10 −5 ), among others. Our study revealed previously unknown candidate modulators of GCase activity, which may facilitate the design of therapies for diseases with GCase dysfunction.

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“…This discrepancy might be explained by previous research showing that inbred mouse strains are not always isogenic. Factors such as genetic drift, spontaneous mutations and epigenetic changes may all influence the behavior of experimental animals (Chebib, Jackson, López-Cortegano, Tautz, & Keightley, 2021; Loos et al, 2015; Oey, Isbel, Hickey, Ebaid, & Whitelaw, 2015; Stiedl et al, 1999). We tried to control for this variability by ordering animals from a well-established breeder (Charles River laboratories, France) that has robust genetic monitoring programs in place.…”

Section: Discussionmentioning

confidence: 99%

Interfering with contextual fear memories by post-reactivation administration of propranolol in mice: a series of null findings

Cox

Faliagkas

Besseling

et al. 2021

Preprint

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Post-reactivation amnesia of contextual fear memories by blockade of noradrenergic signaling has been shown to have limited replicability in rodents. This is usually attributed to several boundary conditions that gate the destabilization of memory during its retrieval. However, how these boundary conditions can be overcome, and what neural mechanisms underlie post-reactivation changes in contextual fear memory remain largely unknown. Here, we report a series of experiments in a contextual fear conditioning paradigm in mice, that were aimed at elucidating these matters. Towards this overarching goal, we first attempted to obtain a training paradigm that would consistently result in a contextual fear memory that could be destabilized upon reactivation, enabling robust amnesia by administration of propranolol. Unexpectedly, our attempts were unsuccessful to this end. Specifically, over a series of 11 experiments (including replicates) in which we varied different parameters of the fear acquisition procedure and administered propranolol or anisomycin, at best small and inconsistent effects were observed. These null findings are surprising, given that the training paradigms we implemented were previously shown to be vulnerable to post-reactivation amnestic agents. Additionally, we found that propranolol did not alter memory retrieval-induced neural activity, as measured by the number of c-Fos+ cells in the hippocampal dentate gyrus. Together, our findings illustrate the elusive nature of reactivation-dependent changes of non-human fear memory and underscore the need for better control over genetic and environmental factors that may influence behavioral outcomes of commonly used mouse strains.

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Inbred lab mice are not isogenic: genetic variation within inbred strains used to infer the mutation rate per nucleotide site

Cited by 29 publications

References 37 publications

Major oscillations in spontaneous home-cage activity in C57BL/6 mice housed under constant conditions

Major oscillations in spontaneous home-cage activity in C57BL/6 mice housed under constant conditions

Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

Interfering with contextual fear memories by post-reactivation administration of propranolol in mice: a series of null findings

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