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The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.
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2015 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11Article in journal (Refereed) Published
Description
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 11, no 11
National Category
Natural Sciences
Research subject
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-294195DOI: 10.1371/journal.pgen.1005648PubMedID: 26599497OAI: oai:DiVA.org:uu-294195DiVA: diva2:929247
Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2016-11-30
In thesis
1. Complex Trait Genetics: Beyond Additivity
Open this publication in new window or tab >>Complex Trait Genetics: Beyond Additivity
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The link between the genotype and the phenotype of an organism is immensely complex. Despite this it can, to a great extent, be captured using models that assume that gene variants combine their effects in an additive manner. This thesis explores aspects of genetics that cannot be fully captured using such additive models. Using experimental data from three different model organisms, I study two phenomena that fall outside of the additive paradigm: genetic interactions and genetic variance heterogeneity.

Using the model plant Arabidopsis thaliana, we show how important biological insights can be reached by exploring loci that display genetic variance heterogeneity. In the first study, this approach identified alleles in the gene CMT2 associated with the climate at sampling locations, suggesting a role in climate adaption. These alleles affected the genome wide methylation pattern, and a complete knock down of this gene increased the plants heat tolerance. In the second study, we demonstrate how the observed genetic variance heterogeneity was the result of the partial linkage of many functional alleles near the gene MOT1, all contributing to Molybdenum levels in the leaves.

Further, we explore genetic interactions using data from dogs and budding yeast (Saccharomyces cerevisiae). In the dog population, two interacting loci were associated with fructosamine levels, a biomarker used to monitor blood glucose. One of the loci displayed the pattern of a selective sweep in some of the studied breeds, suggesting that the interaction is important for the phenotypic breed-differences.

In a cross between two strains of yeast, with the advantage of large population size and nearly equal allele frequencies, we identified large epistatic networks. The networks were largely centered on a number of hub-loci and altogether involved hundreds of genetic interactions. Most network hubs had the ability to either suppress or uncover the phenotypic effects of other loci. Many multi-locus allele combinations resulted in phenotypes that deviated significantly from the expectations, had the loci acted in an additive manner.

Critically, this thesis demonstrates that non-additive genetic mechanisms often need to be considered in order to fully understand the genetics of complex traits. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1278
Keyword
genetic interactions, epistasis, additivity, GWAS, vGWAS, Genetic mapping, yeast, Arabidopsis Thaliana, dog
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-307837 (URN)978-91-554-9754-5 (ISBN)
Public defence
2017-01-13, B22, BMC, Husarg. 3, Uppsala, 10:15 (English)
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Supervisors
Available from: 2016-12-22 Created: 2016-11-22 Last updated: 2016-12-28

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