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

Abstract

Evidence has emerged that suggests a link between motor deficits, obesity and many neurological disorders. However, the contributing genetic risk factors are poorly understood. Here we used the Collaborative Cross (CC), a large panel of newly inbred mice that captures 90% of the known variation among laboratory mice, to identify the genetic loci controlling rotarod performance and its relationship with body weight in a cohort of 365 mice across 16 CC strains. Body weight and rotarod performance varied widely across CC strains and were significantly negatively correlated. Genetic linkage analysis identified 14 loci that were associated with body weight. However, 45 loci affected rotarod performance, seven of which were also associated with body weight, suggesting a strong link at the genetic level. As a result, we show that genes identified in this study overlap significantly with those related to neurological disorders and obesity found in human GWA studies. In conclusion, our results provide a genetic framework for studies of the connection between body weight, the central nervous system and behavior.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1243256
Alternate Identifier(s):
OSTI ID: 1378638
Report Number(s):
PNNL-SA-115429
Journal ID: ISSN 2045-2322
Grant/Contract Number:
AC05-76RL01830; AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; behavioural genetics

Citation Formats

Mao, Jian -Hua, Langley, Sasha A., Huang, Yurong, Hang, Michael, Bouchard, Kristofer E., Celniker, Susan E., Brown, James B., Jansson, Janet K., Karpen, Gary H., and Snijders, Antoine M. Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice. United States: N. p., 2015. Web. doi:10.1038/srep16247.
Mao, Jian -Hua, Langley, Sasha A., Huang, Yurong, Hang, Michael, Bouchard, Kristofer E., Celniker, Susan E., Brown, James B., Jansson, Janet K., Karpen, Gary H., & Snijders, Antoine M. Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice. United States. doi:10.1038/srep16247.
Mao, Jian -Hua, Langley, Sasha A., Huang, Yurong, Hang, Michael, Bouchard, Kristofer E., Celniker, Susan E., Brown, James B., Jansson, Janet K., Karpen, Gary H., and Snijders, Antoine M. Mon . "Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice". United States. doi:10.1038/srep16247. https://www.osti.gov/servlets/purl/1243256.
@article{osti_1243256,
title = {Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice},
author = {Mao, Jian -Hua and Langley, Sasha A. and Huang, Yurong and Hang, Michael and Bouchard, Kristofer E. and Celniker, Susan E. and Brown, James B. and Jansson, Janet K. and Karpen, Gary H. and Snijders, Antoine M.},
abstractNote = {Evidence has emerged that suggests a link between motor deficits, obesity and many neurological disorders. However, the contributing genetic risk factors are poorly understood. Here we used the Collaborative Cross (CC), a large panel of newly inbred mice that captures 90% of the known variation among laboratory mice, to identify the genetic loci controlling rotarod performance and its relationship with body weight in a cohort of 365 mice across 16 CC strains. Body weight and rotarod performance varied widely across CC strains and were significantly negatively correlated. Genetic linkage analysis identified 14 loci that were associated with body weight. However, 45 loci affected rotarod performance, seven of which were also associated with body weight, suggesting a strong link at the genetic level. As a result, we show that genes identified in this study overlap significantly with those related to neurological disorders and obesity found in human GWA studies. In conclusion, our results provide a genetic framework for studies of the connection between body weight, the central nervous system and behavior.},
doi = {10.1038/srep16247},
journal = {Scientific Reports},
number = ,
volume = 5,
place = {United States},
year = {Mon Nov 09 00:00:00 EST 2015},
month = {Mon Nov 09 00:00:00 EST 2015}
}

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  • Evidence has emerged that suggests a link between motor deficits, obesity and many neurological disorders. However, the contributing genetic risk factors are poorly understood. Here we used the Collaborative Cross (CC), a large panel of newly inbred mice that captures 90% of the known variation among laboratory mice, to identify the genetic loci controlling rotarod performance and its relationship with body weight in a cohort of 365 mice across 16 CC strains. Body weight and rotarod performance varied widely across CC strains and were significantly negatively correlated. Genetic linkage analysis identified 14 loci that were associated with body weight. However,more » 45 loci affected rotarod performance, seven of which were also associated with body weight, suggesting a strong link at the genetic level. Lastly, we show that genes identified in this study overlap significantly with those related to neurological disorders and obesity found in human GWA studies. In conclusion, our results provide a genetic framework for studies of the connection between body weight, the central nervous system and behavior.« less
  • Genetic reference populations in model organisms are critical resources for systems genetic analysis of disease related phenotypes. The breeding history of these inbred panels may influence detectable allelic and phenotypic diversity. The existing panel of common inbred strains reflects historical selection biases, and existing recombinant inbred panels have low allelic diversity. All such populations may be subject to consequences of inbreeding depression. The Collaborative Cross (CC) is a mouse reference population with high allelic diversity that is being constructed using a randomized breeding design that systematically outcrosses eight founder strains, followed by inbreeding to obtain new recombinant inbred strains. Fivemore » of the eight founders are common laboratory strains, and three are wild-derived. Since its inception, the partially inbred CC has been characterized for physiological, morphological, and behavioral traits. The construction of this population provided a unique opportunity to observe phenotypic variation as new allelic combinations arose through intercrossing and inbreeding to create new stable genetic combinations. Processes including inbreeding depression and its impact on allelic and phenotypic diversity were assessed. Phenotypic variation in the CC breeding population exceeds that of existing mouse genetic reference populations due to both high founder genetic diversity and novel epistatic combinations. However, some focal evidence of allele purging was detected including a suggestive QTL for litter size in a location of changing allele frequency. Despite these inescapable pressures, high diversity and precision for genetic mapping remain. These results demonstrate the potential of the CC population once completed and highlight implications for development of related populations. Supplementary material consists of Supplementary Table 1 Phenotypic means, variances, ranges and heritabilities for all traits and generations, Supplementary Table 2, all phenotypic values, Supplementary Table 3, multiple QTL mapping.« less