title: The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.
abstract: Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or "missing heritability". Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations.
authors.affiliation: Department of Clinical Sciences, Division of Computational Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Simon K G
authors.initials: SK
authors.lastname: Forsberg
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Andreatta
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Huang
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Danku
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Salt
authors.affiliation: Department of Clinical Sciences, Division of Computational Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Örjan
authors.initials: Ö
authors.lastname: Carlborg
mesh_terms: D000483:Alleles; D027321:Anion Transport Proteins / Q000235:genetics*; D017360:Arabidopsis / Q000235:genetics / Q000254:growth & development; D029681:Arabidopsis Proteins / Q000235:genetics* / Q000378:metabolism; D018740:Genetic Heterogeneity; D018745:Genome, Plant; D055106:Genome-Wide Association Study; D005838:Genotype; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008982:Molybdenum / Q000737:chemistry / Q000378:metabolism; D018515:Plant Leaves / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D000080083:SLC31 Proteins
chemical_list: D027321:Anion Transport Proteins; D029681:Arabidopsis Proteins; C576754:COPT6 protein, Arabidopsis; C525371:MOT1 protein, Arabidopsis; D026901:Membrane Transport Proteins; D000080083:SLC31 Proteins; D008982:Molybdenum