title: Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver.
abstract: Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients.
authors.affiliation: †These authors contributed equally to this work. ‡Deceased October 23, 2015. Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain Department of Evolutionary Genetics, Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Johannes
authors.initials: J
authors.lastname: Engelken
authors.affiliation: †These authors contributed equally to this work. Proteomics Unit, Center of Genomics Regulation, Barcelona, Spain Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Espadas
authors.affiliation: Proteomics Unit, Center of Genomics Regulation, Barcelona, Spain Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Mancuso
authors.affiliation: Genomics Core Facility, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Nuria
authors.initials: N
authors.lastname: Bonet
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Scherr
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Victoria
authors.initials: V
authors.lastname: Jímenez-Álvarez
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Codina-Solà
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina-Stacey
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Nino
authors.initials: N
authors.lastname: Spataro
authors.affiliation: Department of Evolutionary Genetics, Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Stoneking
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Francesc
authors.initials: F
authors.lastname: Calafell
authors.affiliation: Proteomics Unit, Center of Genomics Regulation, Barcelona, Spain Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sabidó
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain eduard.sabido@crg.cat elena.bosch@upf.edu.
authors.forename: Elena
authors.initials: E
authors.lastname: Bosch
mesh_terms: D000220:Adaptation, Biological; D000328:Adult; D000483:Alleles; D005075:Biological Evolution; D016000:Cluster Analysis; D019143:Evolution, Molecular; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008670:Metals / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020543:Proteome; D040901:Proteomics; D040641:Quantitative Trait Loci; D012641:Selection, Genetic; D014131:Trace Elements / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D008670:Metals; D020543:Proteome; D014131:Trace Elements
keywords: micronutrient homeostasis; positive selection; proteomics; quantitative trait loci; trace elements