Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations

Svenson, Karen L.; Smith, R. V.; Magnani, Phyllis A.; Suetin, Heather R.; Paigen, Beverly; Naggert, Jürgen Κ.; Li, Renhua; Churchill, Gary A.; Peters, Luanne L.

doi:10.1152/japplphysiol.01077.2006

Cited by 169 publications

(168 citation statements)

References 27 publications

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“…In contrast to most other mouse lines, in which males express a higher phenotype than females, 28,29 BFMI860 females accumulated the same high amount of total fat mass and single adipose tissues as the males. Taking body weight into account, females had a higher total fat mass percentage than males.…”

Section: Phenotypes Of Parental Lines F 1 and F 2 Animalscontrasting

confidence: 65%

A unique genetic defect on chromosome 3 is responsible for juvenile obesity in the Berlin Fat Mouse

et al. 2010

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Objective: This study aimed at the mapping and estimation of genetic and sex effects contributing to the obese phenotype of the Berlin Fat Mouse Inbred line 860 (BFMI860). This mouse line is predisposed for juvenile obesity. BFMI860 mice accumulate 24% total fat mass at 10 weeks of age under a standard maintenance diet. Design: A total of 471 mice of a (BFMI860 Â C57BL/6NCrl) F 2 intercross population were fed a standard maintenance diet and were analysed for body composition at 10 weeks when they finished their rapid growth phase. Results: The most striking result was the identification of a novel obesity locus on chromosome 3 (Chr 3) at 40 Mb, explaining 39% of the variance of total fat mass in the F 2 population under a standard diet. This locus was named jObes1 (juvenile obesity 1). The BFMI860 allele effect was recessive. Males and females homozygous at jObes1 had on average 3.0 and 3.3 g more total fat mass at 10 weeks than the other two genotype classes, respectively. The effect was evident in all white adipose tissues, brown adipose tissue and also in liver. The position of the Chr 3 effect is syntenic to an obesity locus in humans. Additional loci for total fat mass and different white adipose tissue weights with minor effects were detected on mouse Chr 5 and 6. Another locus on Chr 4 had influence especially on liver weight. Many loci including jObes1 affected males and females to a different extent. Conclusion:The major locus on Chr 3 for juvenile obesity and its interaction with sex is unique and makes the BFMI860 mice an interesting resource for the discovery of novel genetic factors predisposing obesity, which might also contribute to obesity in humans. The results suggested that metabolic and regulatory pathways differed between the sexes.

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Section: Phenotypes Of Parental Lines F 1 and F 2 Animalscontrasting

confidence: 65%

A unique genetic defect on chromosome 3 is responsible for juvenile obesity in the Berlin Fat Mouse

et al. 2010

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“…Additional strain selection: Using the Paigen2 mouse strain set (Svenson et al 2007) from the Mouse Phenome Database as a starting point, we determined a new set of 33 inbred strains that would provide an increase in power when compared with the Paigen2 set. Our strain set was selected by first removing both wild-type and some genetically similar strains from the original Paigen2 strain set of 42 strains [for high-density lipoprotein (HDL) cholesterol].…”

Section: Imputation Of Missing Genotypesmentioning

confidence: 99%

Fine Mapping in 94 Inbred Mouse Strains Using a High-Density Haplotype Resource

et al. 2010

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The genetics of phenotypic variation in inbred mice has for nearly a century provided a primary weapon in the medical research arsenal. A catalog of the genetic variation among inbred mouse strains, however, is required to enable powerful positional cloning and association techniques. A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, yet the common use of hundreds of inbred strains in medical research motivates the need for a high-density variation map of a larger set of strains. Here we report a dense set of genotypes from 94 inbred mouse strains containing 10.77 million genotypes over 121,433 single nucleotide polymorphisms (SNPs), dispersed at 20-kb intervals on average across the genome, with an average concordance of 99.94% with previous SNP sets. Through pairwise comparisons of the strains, we identified an average of 4.70 distinct segments over 73 classical inbred strains in each region of the genome, suggesting limited genetic diversity between the strains. Combining these data with genotypes of 7570 gap-filling SNPs, we further imputed the untyped or missing genotypes of 94 strains over 8.27 million Perlegen SNPs. The imputation accuracy among classical inbred strains is estimated at 99.7% for the genotypes imputed with high confidence. We demonstrated the utility of these data in high-resolution linkage mapping through power simulations and statistical power analysis and provide guidelines for developing such studies. We also provide a resource of in silico association mapping between the complex traits deposited in the Mouse Phenome Database with our genotypes. We expect that these resources will facilitate effective designs of both human and mouse studies for dissecting the genetic basis of complex traits.

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“…This suggested that the LDLR directs apoB to degradation through an ER-associated pathway. To test this result in a more physiological system, we used a newly generated hypercholesterolemic mouse obtained from an ethyl-nitrosourea mutagenesis screen with high throughput phenotyping (24). The hypercholesterolemia in this mouse results from a mutation in the Ldlr gene leading to a C678Y amino acid substitution (numbering excludes the 21-amino-acid signal peptide).…”

Section: The Ldlr Regulates Apob Secretion Through a Post-ermentioning

confidence: 99%

Regulation of ApoB Secretion by the Low Density Lipoprotein Receptor Requires Exit from the Endoplasmic Reticulum and Interaction with ApoE or ApoB

Blasiole¹,

Oler

Attie

2008

Journal of Biological Chemistry

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Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. We investigated the trafficking pathways and ligand requirements for the LDLR to promote degradation of apoB. We first tested whether the LDLR drives apoB degradation in an endoplasmic reticulum (ER)-associated pathway. Primary mouse hepatocytes harboring an ethyl-nitrosourea-induced, ER-retained mutant LDLR secreted comparable levels of apoB with LDLR-null hepatocytes, despite reduced secretion from cells expressing the wild-type LDLR. Additionally, treatment of cells with brefeldin A inhibited LDLR-dependent degradation. However, this rescue was reversible, and degradation of apoB occurred upon removal of brefeldin A. To characterize the lipoprotein reuptake pathway of degradation, we employed an LDLR mutant defective in constitutive endocytosis and internalization of apoB. This mutant was as effective in reducing apoB secretion as the wild-type LDLR. However, the effect was dependent on apolipoprotein E (apoE) as only the wild-type LDLR, and not the endocytic mutant, reduced apoB secretion in apoE-null cells. Treatment with heparin rescued a pool of apoB in cells expressing the endocytic mutant, indicating that reuptake of VLDL via apoE still occurs with this mutant. Finally, an LDLR mutant defective in binding apoB but not apoE reduced apoB secretion in an apoE-dependent manner. Together, these data suggest that the LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. Apolipoprotein B (apoB)3 is the major protein component of very low density lipoprotein (VLDL), the triglyceride-enriched lipoprotein particle produced by the liver. apoB is essential for the assembly and secretion of nascent VLDL particles (1-3). apoB is constitutively expressed, and its stability is regulated through co-and post-translational degradation (4). Therefore, the number of VLDL particles secreted is a function of the proportion of apoB that escapes degradation.The LDL receptor (LDLR) is a ubiquitously expressed protein responsible for the clearance of cholesterol-rich lipoproteins from the bloodstream through its ligands, apoB and apolipoprotein E (apoE). A loss in LDLR activity, as occurs in humans with familial hypercholesterolemia (FH), results in a defect in LDL clearance (5). In addition to its role in mediating lipoprotein clearance, the LDLR also regulates VLDL secretion. Studies in humans (6 -8), mice (9 -11), primary hepatocytes (12-15), and human hepatoma cells (16) have revealed that the loss of LDLR activity leads to increased secretion of VLDL particles, due to a decrease in the degradation of apoB. The particles secreted from livers lacking LDLR activity are small (6, 10, 14) and have decreased triglyceride content ...

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Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations

Cited by 169 publications

References 27 publications

A unique genetic defect on chromosome 3 is responsible for juvenile obesity in the Berlin Fat Mouse

A unique genetic defect on chromosome 3 is responsible for juvenile obesity in the Berlin Fat Mouse

Fine Mapping in 94 Inbred Mouse Strains Using a High-Density Haplotype Resource

Regulation of ApoB Secretion by the Low Density Lipoprotein Receptor Requires Exit from the Endoplasmic Reticulum and Interaction with ApoE or ApoB

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