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The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics.

ABSTRACT: There is growing evidence that genetic risk factors for common disease are caused by hereditary changes of gene regulation acting in complex pathways. Clearly understanding the molecular genetic relationships between genetic control of gene expression and its effect on complex diseases is essential. Here we describe the Brisbane Systems Genetics Study (BSGS), a family-based study that will be used to elucidate the genetic factors affecting gene expression and the role of gene regulation in mediating endophenotypes and complex diseases.BSGS comprises of a total of 962 individuals from 314 families, for which we have high-density genotype, gene expression and phenotypic data. Families consist of combinations of both monozygotic and dizygotic twin pairs, their siblings, and, for 72 families, both parents. A significant advantage of the inclusion of parents is improved power to disentangle environmental, additive genetic and non-additive genetic effects of gene expression and measured phenotypes. Furthermore, it allows for the estimation of parent-of-origin effects, something that has not previously been systematically investigated in human genetical genomics studies. Measured phenotypes available within the BSGS include blood phenotypes and biochemical traits measured from components of the tissue sample in which transcription levels are determined, providing an ideal test case for systems genetics approaches.We report results from an expression quantitative trait loci (eQTL) analysis using 862 individuals from BSGS to test for associations between expression levels of 17,926 probes and 528,509 SNP genotypes. At a study wide significance level approximately 15,000 associations were observed between expression levels and SNP genotypes. These associations corresponded to a total of 2,081 expression quantitative trait loci (eQTL) involving 1,503 probes. The majority of identified eQTL (87%) were located within cis-regions.

SUBMITTER: Powell JE

PROVIDER: S-EPMC3338511 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics.

Powell Joseph E JE Henders Anjali K AK McRae Allan F AF Caracella Anthony A Smith Sara S Wright Margaret J MJ Whitfield John B JB Dermitzakis Emmanouil T ET Martin Nicholas G NG Visscher Peter M PM Montgomery Grant W GW

PloS one 20120426 4

There is growing evidence that genetic risk factors for common disease are caused by hereditary changes of gene regulation acting in complex pathways. Clearly understanding the molecular genetic relationships between genetic control of gene expression and its effect on complex diseases is essential. Here we describe the Brisbane Systems Genetics Study (BSGS), a family-based study that will be used to elucidate the genetic factors affecting gene expression and the role of gene regulation in media ...[more]

PMID: 22563384

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Project description:BackgroundLeaf morphology varies extensively among plant species and is under strong genetic control. Mutagenic screens in model systems have identified genes and established molecular mechanisms regulating leaf initiation, development, and shape. However, it is not known whether this diversity across plant species is related to naturally occurring variation at these genes. Quantitative trait locus (QTL) analysis has revealed a polygenic control for leaf shape variation in different species suggesting that loci discovered by mutagenesis may only explain part of the naturally occurring variation in leaf shape. Here we undertook a genetical genomics study in a poplar intersectional pseudo-backcross pedigree to identify genetic factors controlling leaf shape. The approach combined QTL discovery in a genetic linkage map anchored to the Populus trichocarpa reference genome sequence and transcriptome analysis.ResultsA major QTL for leaf lamina width and length:width ratio was identified in multiple experiments that confirmed its stability. A transcriptome analysis of expanding leaf tissue contrasted gene expression between individuals with alternative QTL alleles, and identified an ADP-ribosylation factor (ARF) GTPase (PtARF1) as a candidate gene for regulating leaf morphology in this pedigree. ARF GTPases are critical elements in the vesicular trafficking machinery. Disruption of the vesicular trafficking function of ARF by the pharmacological agent Brefeldin A (BFA) altered leaf lateral growth in the narrow-leaf P. trichocarpa suggesting a molecular mechanism of leaf shape determination. Inhibition of the vesicular trafficking processes by BFA interferes with cycling of PIN proteins and causes their accumulation in intercellular compartments abolishing polar localization and disrupting normal auxin flux with potential effects on leaf expansion.ConclusionsIn other model systems, ARF proteins have been shown to control the localization of auxin efflux carriers, which function to establish auxin gradients and apical-basal cell polarity in developing plant organs. Our results support a model where PtARF1 transcript abundance changes the dynamics of endocytosis-mediated PIN localization in leaf cells, thus affecting lateral auxin flux and subsequently lamina leaf expansion. This suggests that evolution of differential cellular polarity plays a significant role in leaf morphological variation observed in subgenera of genus Populus.

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The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics.

Publications

The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics.

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