Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models.
Characterizing the relationships between genomic and phenotypic variation is essential to understanding disease etiology. Information-dense data sets derived from pathophysiological, proteomic and transcriptomic profiling have been applied to map quantitative trait loci (QTLs). Metabolic traits, already used in QTL studies in plants, are essential phenotypes in mammalian genetics to define disease biomarkers. Using a complex mammalian system, here we show chromosomal mapping of untargeted plasma metabolic fingerprints derived from NMR spectroscopic analysis in a cross between diabetic and control rats. We propose candidate metabolites for the most significant QTLs. Metabolite profiling in congenic strains provided evidence of QTL replication. Linkage to a gut microbial metabolite (benzoate) can be explained by deletion of a uridine diphosphate glucuronosyltransferase. Mapping metabotypic QTLs provides a practical approach to understanding genome-phenotype relationships in mammals and may uncover deeper biological complexity, as extended genome (microbiome) perturbations that affect disease processes through transgenomic effects may influence QTL detection.
Dumas
Marc-Emmanuel
ME
Imperial College London, Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, UK.
Wilder
Steven P
SP
Bihoreau
Marie-Thérèse
MT
Barton
Richard H
RH
Fearnside
Jane F
JF
Argoud
Karène
K
D'Amato
Lisa
L
Wallis
Robert H
RH
Blancher
Christine
C
Keun
Hector C
HC
Baunsgaard
Dorrit
D
Scott
James
J
Sidelmann
Ulla Grove
UG
Nicholson
Jeremy K
JK
Gauguier
Dominique
D
D000818:Animals; D001483:Base Sequence; D001565:Benzoates / Q000737:chemistry; D015415:Biomarkers / Q000032:analysis; D003920:Diabetes Mellitus / Q000235:genetics*; D008040:Genetic Linkage; D016678:Genome / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics; D008126:Lod Score; D008660:Metabolism / Q000235:genetics*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010641:Phenotype; D040641:Quantitative Trait Loci; D051381:Rats; D017422:Sequence Analysis, DNA
D001565:Benzoates; D015415:Biomarkers; D014453:Glucuronosyltransferase