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.
Highlights
Genome Wide Association (GWA) analysis is a powerful approach to study the genetic basis of complex traits in natural populations
Genome-wide association (GWA) studies have emerged as a powerful tool to address this challenge by dissecting the genetic architecture of trait variation into the contribution of individual genes
The variance-controlling locus was found to result from the contributions of multiple alleles at multiple loci that are closely linked on the chromosome and is a major contributor to the “missing heritability” for this trait identified in previous studies
Summary
Genome Wide Association (GWA) analysis is a powerful approach to study the genetic basis of complex traits in natural populations. To identify an individual locus that makes such direct contributions to the trait variance, a statistical test is used to identify significant differences in the phenotypic variance between the groups of individuals that carry alternative alleles at the locus. When such a variance difference exists between the genotypes at a locus, the locus displays a genetic variance-heterogeneity. By performing genome-wide analyses to identify such variance-heterogeneity loci, novel trait associations and alternative genetic mechanisms involved in shaping the total phenotypic variance in the analyzed populations can be identified [8,10]
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