Genetic Regulation of Bone Traits Is Influenced by Sex and Reciprocal Cross in F2 Progeny From GK and F344 Rats

Lagerholm, Sofia; Li, Luo-Sheng; Jiao, Hong; Park, Hee-Bok; Ohlsson, Claes; Åkesson, Kristina; Luthman, Holger

doi:10.1359/jbmr.081252

Cited by 6 publications

(21 citation statements)

References 47 publications

(87 reference statements)

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“…Given the importance of mitochondria in energy and metabolism processes, it was not surprising that such interactions were observed. Similarly, differential reciprocal cross effects have been documented in other QTL mapping studies (Smith Richards et al, 2002;Lagerholm et al, 2009). Another explanation of this reciprocal cross effect could be a result of some effects from the Y chromosome.…”

Section: Epistatic Qtl Interactions With Myostatin Genesupporting

confidence: 65%

Mapping genetic loci that interact with myostatin to affect growth traits

Cheng

Rachagani²,

Dekkers

et al. 2011

Heredity

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Myostatin, or GDF8, is an inhibitor of skeletal muscle growth. A non-functional myostatin mutation leads to a double muscling phenotype in some species, for example, mice, cattle and humans. Previous studies have indicated that there are loci in the genome that interact with myostatin to control backfat depth and other complex traits. We now report a quantitative trait loci (QTL) mapping study designed to identify loci that interact with myostatin to impact growth traits in mice. Body weight and average daily gain traits were collected on F2 progeny derived from a myostatin-null C57BL/6 strain by M16i cross. In all, 44 main effect QTL were detected above a 5% genome-wide significance threshold when an interval mapping method was used. An additional 37 QTL were identified to significantly interact with myostatin, sex or reciprocal cross. A total of 12 of these QTL interacted with myostatin genotype. These results provide a foundation for the further fine mapping of genome regions that harbor loci that interact with myostatin.

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Section: Epistatic Qtl Interactions With Myostatin Genesupporting

confidence: 65%

Mapping genetic loci that interact with myostatin to affect growth traits

Cheng

Rachagani²,

Dekkers

et al. 2011

Heredity

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“…Additionally, we previously reported that QTLs for trabecular and cortical tibial bone phenotypes measured by pQCT in (GK×F344) F2 crosses with divergent mtDNA are influenced by gender and reciprocal cross [24]. The more than 100 variant positions between GK and F344 mtDNA, including twelve non-synonymous amino acid changes in proteins required for ATP synthesis [25], support the involvement of mtDNA variants as a major factor behind the reciprocal cross effect.…”

Section: Introductionmentioning

confidence: 85%

“…A total of 192 genomewide microsatellite markers were genotyped and a genetic linkage map was generated as described previously [24]. Genetic linkage analysis was performed for each sex separately.…”

Section: Genotyping and Linkage Analysis Of Quantitative Traitsmentioning

confidence: 99%

“…Sex-and reciprocal cross-specific QTLs were identified using the method described previously [24]. To identify sex specific QTLs, the LOD score differences between males and females across the genome were assessed (∆LOD sex score).…”

Section: Evaluation Of Sex-and Reciprocal Cross-specific Qtlsmentioning

confidence: 99%

“…A statistical power calculation using the method of Lynch and Walsh et al [34] was conducted as described previously [24]. Using a LOD score of 2.4 to control false positive detection of linkage, a sample size of 52 is necessary to achieve 80% statistical power for detecting a QTL with R 2 value of 0.25.…”

Section: Evaluation Of Sex-and Reciprocal Cross-specific Qtlsmentioning

confidence: 99%

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Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat

Lagerholm

Park²,

Luthman³

et al. 2010

Bone

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The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344 x GK crosses well suited for the identification of genes related to bone size and allow for future investigation on the association with type-2 diabetes. The aim of this study was to identify quantitative trait loci (QTLs) for bone size phenotypes measured by a new application of three-dimensional computed tomography (3DCT) and to investigate the effects of sex-and reciprocal cross.Tibia from male and female GK and F344 rats, representing the parental, F1 and F2 generations, were examined with 3DCT and analyzed for: total and cortical volumetric BMD, straight and curved length, peri-and endosteal area at mid-shaft. F2 progeny (108 male and 98 female) were genotyped with 192 genome-wide microsatellite markers (average distance 10 cM). Sex-and reciprocal cross-separated QTL analyses were performed for the identification of QTLs linked to 3DCT phenotypes and true interactions were confirmed by likelihood ratio analysis in all F2 animals.Several genome-wide significant QTLs were found in the sex-and reciprocal cross-separated progeny on chromosomes (chr) 1, 3, 4, 9, 10, 14, and 17. Overlapping QTLs for both males and females in the (GK×F344)F2 progeny were located on chr 1 (39-67 cM). This region confirms previously reported pQCT QTLs and overlaps loci for fasting glucose. Sex separated linkage analysis confirmed a male specific QTL on chr 9 (67-82 cM) for endosteal area at the fibula site. Analyses separating the F2 population both by sex and reciprocal cross identified cross specific QTLs on chr 14 (males) and chr 3 and 4 (females). Two loci, chr 4 and 6, are unique to 3DCT and separate from pQCT generated loci.The 3DCT method was highly reproducible and provided high precision measurements of bone size in the rat enabling identification of new sex-and cross-specific loci. The QTLs on chr 1 indicate potential genetic association between bone-related phenotypes and traits affecting type-2 diabetes. The results illustrate the complexity of the genetic architecture of bone size phenotypes, and demonstrate the importance of complementary methods for bone analysis.

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Widespread Differential Maternal and Paternal Genome Effects on Fetal Bone Phenotype at Mid-Gestation

Xiang

Lee

Eindorf

et al. 2014

Journal of Bone and Mineral Research

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Parent-of-origin-dependent (epi)genetic factors are important determinants of prenatal development that program adult phenotype. However, data on magnitude and specificity of maternal and paternal genome effects on fetal bone are lacking. We used an outbred bovine model to dissect and quantify effects of parental genomes, fetal sex, and nongenetic maternal effects on the fetal skeleton and analyzed phenotypic and molecular relationships between fetal muscle and bone. Analysis of 51 bone morphometric and weight parameters from 72 fetuses recovered at day 153 gestation (54% term) identified six principal components (PC1-6) that explained 80% of the variation in skeletal parameters. Parental genomes accounted for most of the variation in bone wet weight (PC1, 72.1%), limb ossification (PC2, 99.8%), flat bone size (PC4, 99.7%), and axial skeletal growth (PC5, 96.9%). Limb length showed lesser effects of parental genomes (PC3, 40.8%) and a significant nongenetic maternal effect (gestational weight gain, 29%). Fetal sex affected bone wet weight (PC1, p < 0.0001) and limb length (PC3, p < 0.05). Partitioning of variation explained by parental genomes revealed strong maternal genome effects on bone wet weight (74.1%, p < 0.0001) and axial skeletal growth (93.5%, p < 0.001), whereas paternal genome controlled limb ossification (95.1%, p < 0.0001). Histomorphometric data revealed strong maternal genome effects on growth plate height (98.6%, p < 0.0001) and trabecular thickness (85.5%, p < 0.0001) in distal femur. Parental genome effects on fetal bone were mirrored by maternal genome effects on fetal serum 25-hydroxyvitamin D (96.9%, p < 0.001) and paternal genome effects on alkaline phosphatase (90.0%, p < 0.001) and their correlations with maternally controlled bone wet weight and paternally controlled limb ossification, respectively. Bone wet weight and flat bone size correlated positively with muscle weight (r ¼ 0.84 and 0.77, p < 0.0001) and negatively with muscle H19 expression (r ¼ -0.34 and -0.31, p < 0.01). Because imprinted maternally expressed H19 regulates growth factors by miRNA interference, this suggests muscle-bone interaction via epigenetic factors.

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Genetic Regulation of Bone Traits Is Influenced by Sex and Reciprocal Cross in F2 Progeny From GK and F344 Rats

Cited by 6 publications

References 47 publications

Mapping genetic loci that interact with myostatin to affect growth traits

Mapping genetic loci that interact with myostatin to affect growth traits

Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat

Widespread Differential Maternal and Paternal Genome Effects on Fetal Bone Phenotype at Mid-Gestation

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