Studying the pharmacogenomic effect of cranberry extract on reducing body weight using collaborative cross mice

SummaryThe variation from spontaneous mutations for 6-week body weight in the mouse was estimated by selection from a cross of two inbred sublines, C57BL/6 and C57BL/10, separated about 50 years previously from the same inbred line. Selection was practised high and low for 12 generations from theF2, followed by one generation of relaxation. The lines diverged by approximately 1·7 g or 0·7 sd. The additive genetic variance was estimated in theF2by restricted maximum likelihood and from the selection response, and from this variance the mutational heritabilityhM2was estimated using the number of generations since divergence. Estimates ofhM2range from 0·08 to 0·10% depending on the method of analysis. These estimates are similar to those found for other species, but lower than other estimates for the mouse. It is concluded that substantial natural and, perhaps, artificial selection operated during the maintenance of the sublines.

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Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice

Scientific Reports ◽

10.1038/srep16247 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 19

Author(s):

Jian-Hua Mao ◽

Sasha A. Langley ◽

Yurong Huang ◽

Michael Hang ◽

Kristofer E. Bouchard ◽

...

Keyword(s):

Body Weight ◽

Motor Performance ◽

Genetic Factors ◽

Collaborative Cross

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Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.400975 ◽

2020 ◽

Vol 10 (9) ◽

pp. 3165-3177

Author(s):

Paola Giusti-Rodríguez ◽

James G Xenakis ◽

James J Crowley ◽

Randal J Nonneman ◽

Daniela M DeCristo ◽

...

Keyword(s):

Body Weight ◽

Recombinant Inbred ◽

Mixed Models ◽

Genetic Basis ◽

Collaborative Cross ◽

Typical Antipsychotic ◽

Therapeutic Approaches ◽

Orofacial Movements ◽

Almost All ◽

Vacuous Chewing

Abstract Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (P < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

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Opposite effects of alcohol in regulating stress-induced changes in body weight between the two mouse lines with enhanced or low opioid system activity

Physiology & Behavior ◽

10.1016/j.physbeh.2010.01.023 ◽

2010 ◽

Vol 99 (5) ◽

pp. 627-631 ◽

Cited By ~ 8

Author(s):

Mariusz Sacharczuk ◽

Bogdan Sadowski ◽

Kazimierz Jaszczak ◽

Andrzej W. Lipkowski ◽

Artur H. Swiergiel

Keyword(s):

Body Weight ◽

Opioid System ◽

System Activity ◽

Induced Changes ◽

Mouse Lines

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A Novel Leptin Receptor Variant with a Conservative Amino Acid Substitution (I359 V) in Body Weight Selected and Unselected Mouse Lines

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2003-41754 ◽

2003 ◽

Vol 111 (05) ◽

pp. 283-287 ◽

Cited By ~ 2

Author(s):

U. Reichart ◽

U. Renne ◽

B. Aigner ◽

J. Kratzsch ◽

G. Brockmann

Keyword(s):

Body Weight ◽

Amino Acid ◽

Amino Acid Substitution ◽

Leptin Receptor ◽

Mouse Lines

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Selection for increased adult body weight in mouse lines with and without the rat growth hormone transgene

Journal of Animal Breeding and Genetics ◽

10.1111/j.1439-0388.1993.tb00750.x ◽

1993 ◽

Vol 110 (1-6) ◽

pp. 374-384 ◽

Cited By ~ 5

Author(s):

J. Nagai ◽

C. Y. Lin ◽

P. Sabour

Keyword(s):

Growth Hormone ◽

Body Weight ◽

Adult Body ◽

Rat Growth ◽

Adult Body Weight ◽

Selection For ◽

Mouse Lines

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Architecture of energy balance traits in emerging lines of the Collaborative Cross

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00707.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. E1124-E1134 ◽

Cited By ~ 44

Author(s):

Wendy Foulds Mathes ◽

David L. Aylor ◽

Darla R. Miller ◽

Gary A. Churchill ◽

Elissa J. Chesler ◽

...

Keyword(s):

Body Weight ◽

Energy Balance ◽

Complex Traits ◽

Wheel Running ◽

Phenotypic Diversity ◽

Inbred Strains ◽

Collaborative Cross ◽

Voluntary Exercise ◽

Shared Ancestry ◽

Primary Focus

The potential utility of the Collaborative Cross (CC) mouse resource was evaluated to better understand complex traits related to energy balance. A primary focus was to examine if genetic diversity in emerging CC lines (pre-CC) would translate into equivalent phenotypic diversity. Second, we mapped quantitative trait loci (QTL) for 15 metabolism- and exercise-related phenotypes in this population. We evaluated metabolic and voluntary exercise traits in 176 pre-CC lines, revealing phenotypic variation often exceeding that seen across the eight founder strains from which the pre-CC was derived. Many phenotypic correlations existing within the founder strains were no longer significant in the pre-CC population, potentially representing reduced linkage disequilibrium (LD) of regions harboring multiple genes with effects on energy balance or disruption of genetic structure of extant inbred strains with substantial shared ancestry. QTL mapping revealed five significant and eight suggestive QTL for body weight (Chr 4, 7.54 Mb; CI 3.32–10.34 Mb; Bwq14), body composition, wheel running (Chr 16, 33.2 Mb; CI 32.5–38.3 Mb), body weight change in response to exercise (1: Chr 6, 77.7Mb; CI 72.2–83.4 Mb and 2: Chr 6, 42.8 Mb; CI 39.4–48.1 Mb), and food intake during exercise (Chr 12, 85.1 Mb; CI 82.9–89.0 Mb). Some QTL overlapped with previously mapped QTL for similar traits, whereas other QTL appear to represent novel loci. These results suggest that the CC will be a powerful, high-precision tool for examining the genetic architecture of complex traits such as those involved in regulation of energy balance.

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Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

10.1101/761353 ◽

2019 ◽

Cited By ~ 1

Author(s):

Paola Giusti-Rodríguez ◽

James G. Xenakis ◽

James J. Crowley ◽

Randal J. Nonneman ◽

Daniela M. DeCristo ◽

...

Keyword(s):

Body Weight ◽

Recombinant Inbred ◽

Mixed Models ◽

Genetic Basis ◽

Collaborative Cross ◽

Typical Antipsychotic ◽

Therapeutic Approaches ◽

Orofacial Movements ◽

Almost All ◽

Vacuous Chewing

ABSTRACTSchizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

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The genetic basis of response in mouse lines divergently selected for body weight or fat content. I. The relative contributions of autosomal and sex-linked genes

Genetics Research ◽

10.1017/s0016672300031876 ◽

1993 ◽

Vol 62 (3) ◽

pp. 169-175 ◽

Cited By ~ 9

Author(s):

Ian M. Hastings ◽

Roel F. Veerkamp

Keyword(s):

Body Weight ◽

Y Chromosome ◽

Genetic Basis ◽

Gene Action ◽

Fat Content ◽

Reciprocal Crosses ◽

Relative Contribution ◽

Cytoplasmic Effects ◽

Parental Lines ◽

Mouse Lines

SummaryLines of mice have been divergently selected for over forty generations on either body weight or fat content. Reciprocal crosses were made between the divergent lines and the offspring backcrossed to the parental lines. The resulting data allowed us to investigate the genetic basis of response, including two features of particular interest: (i) the relative contribution of autosomal and sex-linked genes and whether any significant Y chromosome or cytoplasmic effects were present (ii) the mechanism of gene action, whether predominantly additive or whether significant dominance effects were present. A large additive sex-linked effect was observed in lines selected on body weight which accounted for approximately 25% of the divergence. The remaining 75% of the divergence appeared to be autosomal. There was no apparent sex-linked effect in lines selected on fat content and the response appeared to be entirely autosomal and additive.

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