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Summary
High-fat diets are associated with increased obesity and metabolic disease in mice and humans. Here we used analysis of variance (ANOVA) to scrutinize a microarray data set consisting of 10 inbred strains of mice from both sexes fed atherogenic high-fat and control chow diets. An overall F-test was applied to the 40 unique groups of strain-diet-sex to identify 15,288 genes with altered transcription. Bootstrapping k-means clustering separated these changes into four strain-dependent expression patterns, including two sex-related profiles and two diet-related profiles. Sex-induced effects correspond to secretion (males) or fat and energy metabolism (females), whereas diet-induced changes relate to neurological processes (chow) or immune response (high-fat). The full set of pairwise contrasts for differences between strains within sex (90 different statistical tests) uncovered 32,379 total changes. These differences were unevenly distributed across strains and between sexes, indicating that strain-specific responses to high-fat diet differ between sexes. Correlations between expression levels and 8 obesity-related traits identified 5,274 associations between transcript abundance and measured phenotypic endpoints. From this number, 2,678 genes are positively correlated with total cholesterol levels and associate with immune-related categories while 2,596 genes are negatively correlated with cholesterol and connect to cholesterol synthesis. Keywords: gene expression analysis, strain comparision, effect of dietary fat, sex-specific effects
Experiment design
Expression profiling by array.
One group of mice was fed an atherogenic high-fat (30% fat) diet containing cholic acid to increase fat uptake and another was fed a low-fat (6% fat) regular chow diet. Males and females from both diets were studied for mouse strains 129S1/SvImJ, A/J, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, I/LnJ, MRL/MpJ-Tnfrsf6lpr/J, NZB/BINJ, PERA/Ei, and SM/J. All strains were sacrificed between 11- and 13 weeks of age except for CAST and PERA, which were harvested after 50 weeks of age. CAST and PERA were subsequently removed from our analysis based on discrepant harvest age, but can be found in our database (see below). Three replicate animals were used for each combination of diet, strain, and sex, resulting in a total of 120 mice surveyed for gene expression.
About cases
Index Sample ID Strain ID HF=high-fat (30% fat)
6C=low-fat (6% fat)Replicate Animal 1 GSM264767 129S1/SvImJ 6C Rep1 2 GSM264768 129S1/SvImJ 6C Rep2 3 GSM264769 129S1/SvImJ 6C Rep3 4 GSM264770 129S1/SvImJ HF Rep1 5 GSM264771 129S1/SvImJ HF Rep2 6 GSM264772 129S1/SvImJ HF Rep3 7 GSM264773 129S1/SvImJ 6C Rep1 8 GSM264774 129S1/SvImJ 6C Rep2 9 GSM264775 129S1/SvImJ 6C Rep3 10 GSM264776 129S1/SvImJ HF Rep1 11 GSM264777 129S1/SvImJ HF Rep2 12 GSM264778 129S1/SvImJ HF Rep3 13 GSM264779 A/J 6C Rep1 14 GSM264780 A/J 6C Rep2 15 GSM264781 A/J 6C Rep3 16 GSM264782 A/J HF Rep1 17 GSM264783 A/J HF Rep2 18 GSM264784 A/J HF Rep3 19 GSM264785 A/J 6C Rep1 20 GSM264786 A/J 6C Rep2 21 GSM264787 A/J 6C Rep3 22 GSM264788 A/J HF Rep1 23 GSM264789 A/J HF Rep2 24 GSM264790 A/J HF Rep3 25 GSM264791 C57BL/6J 6C Rep1 26 GSM264792 C57BL/6J 6C Rep2 27 GSM264793 C57BL/6J 6C Rep3 28 GSM264794 C57BL/6J HF Rep1 29 GSM264795 C57BL/6J HF Rep2 30 GSM264796 C57BL/6J HF Rep3 31 GSM264797 C57BL/6J 6C Rep1 32 GSM264798 C57BL/6J 6C Rep2 33 GSM264799 C57BL/6J 6C Rep3 34 GSM264800 C57BL/6J HF Rep1 35 GSM264801 C57BL/6J HF Rep2 36 GSM264802 C57BL/6J HF Rep3 37 GSM264803 BALB/cJ 6C Rep1 38 GSM264804 BALB/cJ 6C Rep2 39 GSM264805 BALB/cJ 6C Rep3 40 GSM264806 BALB/cJ HF Rep1 41 GSM264807 BALB/cJ HF Rep2 42 GSM264808 BALB/cJ HF Rep3 43 GSM264809 BALB/cJ 6C Rep1 44 GSM264810 BALB/cJ 6C Rep2 45 GSM264811 BALB/cJ 6C Rep3 46 GSM264813 BALB/cJ HF Rep1 47 GSM264814 BALB/cJ HF Rep2 48 GSM264815 BALB/cJ HF Rep3 49 GSM264845 C3H/HeJ 6C Rep1 50 GSM264846 C3H/HeJ 6C Rep2 51 GSM264847 C3H/HeJ 6C Rep3 52 GSM264848 C3H/HeJ HF Rep1 53 GSM264849 C3H/HeJ HF Rep2 54 GSM264850 C3H/HeJ HF Rep3 55 GSM264852 C3H/HeJ 6C Rep1 56 GSM264853 C3H/HeJ 6C Rep2 57 GSM264855 C3H/HeJ 6C Rep3 58 GSM264856 C3H/HeJ HF Rep1 59 GSM264857 C3H/HeJ HF Rep2 60 GSM264858 C3H/HeJ HF Rep3 61 GSM264859 CAST/EiJ 6C Rep1 62 GSM264861 CAST/EiJ 6C Rep2 63 GSM264862 CAST/EiJ 6C Rep3 64 GSM264863 CAST/EiJ HF Rep1 65 GSM264864 CAST/EiJ HF Rep2 66 GSM264865 CAST/EiJ HF Rep3 67 GSM264866 CAST/EiJ 6C Rep1 68 GSM264867 CAST/EiJ 6C Rep2 69 GSM264868 CAST/EiJ 6C Rep3 70 GSM264869 CAST/EiJ HF Rep1 71 GSM264870 CAST/EiJ HF Rep2 72 GSM264871 CAST/EiJ HF Rep3 73 GSM264872 DBA/2J 6C Rep1 74 GSM264873 DBA/2J 6C Rep2 75 GSM264874 DBA/2J 6C Rep3 76 GSM264875 DBA/2J HF Rep1 77 GSM264876 DBA/2J HF Rep2 78 GSM264877 DBA/2J HF Rep3 79 GSM264890 DBA/2J 6C Rep1 80 GSM264891 DBA/2J 6C Rep2 81 GSM264892 DBA/2J 6C Rep3 82 GSM264893 DBA/2J HF Rep1 83 GSM264894 DBA/2J HF Rep2 84 GSM264895 DBA/2J HF Rep3 85 GSM264896 I/LnJ 6C Rep1 86 GSM264897 I/LnJ 6C Rep2 87 GSM264898 I/LnJ 6C Rep3 88 GSM264899 I/LnJ HF Rep1 89 GSM264900 I/LnJ HF Rep2 90 GSM264901 I/LnJ HF Rep3 91 GSM264902 I/LnJ 6C Rep1 92 GSM264903 I/LnJ 6C Rep2 93 GSM264904 I/LnJ 6C Rep3 94 GSM264905 I/LnJ HF Rep1 95 GSM264906 I/LnJ HF Rep2 96 GSM264907 I/LnJ HF Rep3 97 GSM264908 MRL/MpJ-Fas/J 6C Rep1 98 GSM264909 MRL/MpJ-Fas/J 6C Rep2 99 GSM264910 MRL/MpJ-Fas/J 6C Rep3 100 GSM264912 MRL/MpJ-Fas/J HF Rep1 101 GSM264913 MRL/MpJ-Fas/J HF Rep2 102 GSM264914 MRL/MpJ-Fas/J HF Rep3 103 GSM264915 MRL/MpJ-Fas/J 6C Rep1 104 GSM264916 MRL/MpJ-Fas/J 6C Rep2 105 GSM264917 MRL/MpJ-Fas/J 6C Rep3 106 GSM264918 MRL/MpJ-Fas/J HF Rep1 107 GSM264920 MRL/MpJ-Fas/J HF Rep2 108 GSM264921 MRL/MpJ-Fas/J HF Rep3 109 GSM264922 NZB/BlNJ 6C Rep1 110 GSM264924 NZB/BlNJ 6C Rep2 111 GSM264925 NZB/BlNJ 6C Rep3 112 GSM264926 NZB/BlNJ HF Rep1 113 GSM264928 NZB/BlNJ HF Rep2 114 GSM264929 NZB/BlNJ HF Rep3 115 GSM264930 NZB/BlNJ 6C Rep1 116 GSM264931 NZB/BlNJ 6C Rep2 117 GSM264932 NZB/BlNJ 6C Rep3 118 GSM264933 NZB/BlNJ HF Rep1 119 GSM264935 NZB/BlNJ HF Rep2 120 GSM264936 NZB/BlNJ HF Rep3 121 GSM265061 PERA/EiJ 6C Rep1 122 GSM265062 PERA/EiJ 6C Rep2 123 GSM265063 PERA/EiJ 6C Rep3 124 GSM265064 PERA/EiJ HF Rep1 125 GSM265065 PERA/EiJ HF Rep2 126 GSM265066 PERA/EiJ HF Rep3 127 GSM265067 PERA/EiJ 6C Rep1 128 GSM265068 PERA/EiJ 6C Rep2 129 GSM265069 PERA/EiJ 6C Rep3 130 GSM265070 PERA/EiJ HF Rep1 131 GSM265071 PERA/EiJ HF Rep2 132 GSM265072 PERA/EiJ HF Rep3 133 GSM265074 SM/J 6C Rep1 134 GSM265075 SM/J 6C Rep2 135 GSM265105 SM/J 6C Rep3 136 GSM265217 SM/J HF Rep1 137 GSM265248 SM/J HF Rep2 138 GSM265275 SM/J HF Rep3 139 GSM265324 SM/J 6C Rep1 140 GSM265331 SM/J 6C Rep2 141 GSM265357 SM/J 6C Rep3 142 GSM265358 SM/J HF Rep1 143 GSM265359 SM/J HF Rep2 144 GSM265360 SM/J HF Rep3
About tissue
Liver
About platform
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array. Affymetrix submissions are typically submitted to GEO using the GEOarchive method described at http://www.ncbi.nlm.nih.gov/projects/geo/info/geo_affy.html All probe sets represented on the GeneChip Mouse Expression Set 430 are included on the GeneChip Mouse Genome 430 2.0 Array. The sequences from which these probe sets were derived were selected from GenBank«, dbEST, and RefSeq. The sequence clusters were created from the UniGene database (Build 107, June 2002) and then refined by analysis and comparison with the publicly available draft assembly of the mouse genome from the Whitehead Institute for Genome Research (MGSC, April 2002).
Contributors
Churchill GA, Paigen B, Shockley KR, Witmer D
Citation
Burgess-Herbert SL, Cox A, Tsaih SW, Paigen B. Practical applications of the bioinformatics toolbox for narrowing quantitative trait loci. Genetics 2008 Dec;180(4):2227-35. PMID: 18845850 Shockley KR, Witmer D, Burgess-Herbert SL, Paigen B et al. Effects of atherogenic diet on hepatic gene expression across mouse strains. Physiol Genomics 2009 Nov 6;39(3):172-82. PMID: 19671657
Acknowledgment
Churchill GA, Paigen B, Shockley KR, Witmer D