title: Widespread differential maternal and paternal genome effects on fetal bone phenotype at mid-gestation.
abstract: 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 = 0.84 and 0.77, p < 0.0001) and negatively with muscle H19 expression (r = -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.
authors.affiliation: Robinson Research Institute, The University of Adelaide, Adelaide, Australia; JS Davies Epigenetics and Genetics Group, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Adelaide, Australia.
authors.forename: Ruidong
authors.initials: R
authors.lastname: Xiang
authors.forename: Alice M C
authors.initials: AM
authors.lastname: Lee
authors.forename: Tanja
authors.initials: T
authors.lastname: Eindorf
authors.forename: Ali
authors.initials: A
authors.lastname: Javadmanesh
authors.forename: Mani
authors.initials: M
authors.lastname: Ghanipoor-Samami
authors.forename: Madeleine
authors.initials: M
authors.lastname: Gugger
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Fitzsimmons
authors.forename: Zbigniew A
authors.initials: ZA
authors.lastname: Kruk
authors.forename: Wayne S
authors.initials: WS
authors.lastname: Pitchford
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Leviton
authors.forename: Dana A
authors.initials: DA
authors.lastname: Thomsen
authors.forename: Ian
authors.initials: I
authors.lastname: Beckman
authors.forename: Gail I
authors.initials: GI
authors.lastname: Anderson
authors.forename: Brian M
authors.initials: BM
authors.lastname: Burns
authors.forename: David L
authors.initials: DL
authors.lastname: Rutley
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
authors.forename: Stefan
authors.initials: S
authors.lastname: Hiendleder
mesh_terms: D000818:Animals; D002417:Cattle; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D016678:Genome / Q000502:physiology*; D018392:Genomic Imprinting / Q000502:physiology*; D006132:Growth Plate / Q000196:embryology*; D008297:Male; D010012:Osteogenesis / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy
keywords: EPIGENETICS; GENETIC ANIMAL MODELS; STATISTICAL METHODS