title: Metabolomic profiles indicate distinct physiological pathways affected by two loci with major divergent effect on Bos taurus growth and lipid deposition.
abstract: Identifying trait-associated genetic variation offers new prospects to reveal novel physiological pathways modulating complex traits. Taking advantage of a unique animal model, we identified the I442M mutation in the non-SMC condensin I complex, subunit G (NCAPG) gene and the Q204X mutation in the growth differentiation factor 8 (GDF8) gene as substantial modulators of pre- and/or postnatal growth in cattle. In a combined metabolomic and genotype association approach, which is the first respective study in livestock, we surveyed the specific physiological background of the effects of both loci on body-mass gain and lipid deposition. Our data provided confirming evidence from two historically and geographically distant cattle populations that the onset of puberty is the key interval of divergent growth. The locus-specific metabolic patterns obtained from monitoring 201 plasma metabolites at puberty mirror the particular NCAPG I442M and GDF8 Q204X effects and represent biosignatures of divergent physiological pathways potentially modulating effects on proportional and disproportional growth, respectively. While the NCAPG I442M mutation affected the arginine metabolism, the 204X allele in the GDF8 gene predominantly raised the carnitine level and had concordant effects on glycerophosphatidylcholines and sphingomyelins. Our study provides a conclusive link between the well-described growth-regulating functions of arginine metabolism and the previously unknown specific physiological role of the NCAPG protein in mammalian metabolism. Owing to the confirmed effect of the NCAPG/LCORL locus on human height in genome-wide association studies, the results obtained for bovine NCAPG might add valuable, comparative information on the physiological background of genetically determined divergent mammalian growth.
authors.affiliation: Research Unit Molecular Biology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Weikard
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Altmaier
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Weinberger
authors.forename: Harald M
authors.initials: HM
authors.lastname: Hammon
authors.forename: Elke
authors.initials: E
authors.lastname: Albrecht
authors.forename: Kouji
authors.initials: K
authors.lastname: Setoguchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Takasuga
authors.forename: Christa
authors.initials: C
authors.lastname: Kühn
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000378:metabolism; D001823:Body Composition / Q000235:genetics; D002331:Carnitine / Q000378:metabolism; D002417:Cattle / Q000097:blood / Q000235:genetics* / Q000254:growth & development*; D018797:Cell Cycle Proteins / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D055432:Metabolomics; D009154:Mutation / Q000235:genetics; D055435:Myostatin / Q000235:genetics*; D010713:Phosphatidylcholines / Q000097:blood; D015203:Reproducibility of Results; D012741:Sexual Maturation / Q000502:physiology; D013109:Sphingomyelins / Q000097:blood
chemical_list: D018797:Cell Cycle Proteins; D055435:Myostatin; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D001120:Arginine; D002331:Carnitine