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- De Koning, Dirk-Jan
(author)
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Why Breeding Values Estimated Using Familial Data Should Not Be Used for Genome-Wide Association Studies
- 2014
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In: G3. - : Oxford University Press (OUP). - 2160-1836. ; 19, s. 341-347
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Journal article (peer-reviewed)abstract
- In animal breeding, the genetic potential of an animal is summarized as its estimated breeding value, which is derived from its own performance as well as the performance of related individuals. Here, we illustrate why estimated breeding values are not suitable as a phenotype for genome-wide association studies. We simulated human-type and pig-type pedigrees with a range of quantitative trait loci (QTL) effects (0.5-3% of phenotypic variance) and heritabilities (0.3-0.8). We analyzed 1000 replicates of each scenario with four models: (a) a full mixed model including a polygenic effect, (b) a regression analysis using the residual of a mixed model as a trait score (so called GRAMMAR approach), (c) a regression analysis using the estimated breeding value as a trait score, and (d) a regression analysis that uses the raw phenotype as a trait score. We show that using breeding values as a trait score gives very high false-positive rates (up 14% in human pedigrees and >60% in pig pedigrees). Simulations based on a real pedigree show that additional generations of pedigree increase the type I error. Including the family relationship as a random effect provides the greatest power to detect QTL while controlling for type I error at the desired level and providing the most accurate estimates of the QTL effect. Both the use of residuals and the use of breeding values result in deflated estimates of the QTL effect. We derive the contributions of QTL effects to the breeding value and residual and show how this affects the estimates.
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- Hallingbäck, Henrik, et al.
(author)
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Functional Multi-Locus QTL Mapping of Temporal Trends in Scots Pine Wood Traits
- 2014
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In: G3. - : Oxford University Press (OUP). - 2160-1836. ; 4, s. 2365-2379
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Journal article (peer-reviewed)abstract
- Quantitative trait loci (QTL) mapping of wood properties in conifer species has focused on single time point measurements or on trait means based on heterogeneous wood samples (e.g., increment cores), thus ignoring systematic within-tree trends. In this study, functional QTL mapping was performed for a set of important wood properties in increment cores from a 17-yr-old Scots pine (Pinus sylvestris L.) full-sib family with the aim of detecting wood trait QTL for general intercepts (means) and for linear slopes by increasing cambial age. Two multi-locus functional QTL analysis approaches were proposed and their performances were compared on trait datasets comprising 2 to 9 time points, 91 to 455 individual tree measurements and genotype datasets of amplified length polymorphisms (AFLP), and single nucleotide polymorphism (SNP) markers. The first method was a multilevel LASSO analysis whereby trend parameter estimation and QTL mapping were conducted consecutively; the second method was our Bayesian linear mixed model whereby trends and underlying genetic effects were estimated simultaneously. We also compared several different hypothesis testing methods under either the LASSO or the Bayesian framework to perform QTL inference. In total, five and four significant QTL were observed for the intercepts and slopes, respectively, across wood traits such as earlywood percentage, wood density, radial fiberwidth, and spiral grain angle. Four of these QTL were represented by candidate gene SNPs, thus providing promising targets for future research in QTL mapping and molecular function. Bayesian and LASSO methods both detected similar sets of QTL given datasets that comprised large numbers of individuals.
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- Jiu, YM, et al.
(author)
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par-1, atypical pkc, and PP2A/B55 sur-6 are implicated in the regulation of exocyst-mediated membrane trafficking in Caenorhabditis elegans
- 2014
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In: G3 (Bethesda, Md.). - : Oxford University Press (OUP). - 2160-1836. ; 4:1, s. 173-183
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Journal article (peer-reviewed)abstract
- The exocyst is a conserved protein complex that is involved in tethering secretory vesicles to the plasma membrane and regulating cell polarity. Despite a large body of work, little is known how exocyst function is controlled. To identify regulators for exocyst function, we performed a targeted RNA interference (RNAi) screen in Caenorhabditis elegans to uncover kinases and phosphatases that genetically interact with the exocyst. We identified seven kinase and seven phosphatase genes that display enhanced phenotypes when combined with hypomorphic alleles of exoc-7 (exo70), exoc-8 (exo84), or an exoc-7;exoc-8 double mutant. We show that in line with its reported role in exocytotic membrane trafficking, a defective exoc-8 caused accumulation of exocytotic soluble NSF attachment protein receptor (SNARE) proteins in both intestinal and neuronal cells in C. elegans. Down-regulation of the phosphatase protein phosphatase 2A (PP2A) phosphatase regulatory subunit sur-6/B55 gene resulted in accumulation of exocytic SNARE proteins SNB-1 and SNAP-29 in wild-type and in exoc-8 mutant animals. In contrast, RNAi of the kinase par-1 caused reduced intracellular green fluorescent protein signal for the same proteins. Double RNAi experiments for par-1, pkc-3, and sur-6/B55 in C. elegans suggest a possible cooperation and involvement in postembryo lethality, developmental timing, as well as SNARE protein trafficking. Functional analysis of the homologous kinases and phosphatases in Drosophila median neurosecretory cells showed that atypical protein kinase C kinase and phosphatase PP2A regulate exocyst-dependent, insulin-like peptide secretion. Collectively, these results characterize kinases and phosphatases implicated in the regulation of exocyst function, and suggest the possibility for interplay between the par-1 and pkc-3 kinases and the PP2A phosphatase regulatory subunit sur-6 in this process.
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- Lockwood, Sarah H, et al.
(author)
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The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors
- 2014
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In: G3. - : Oxford University Press (OUP). - 2160-1836. ; 4, s. 1647-1655
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Journal article (peer-reviewed)abstract
- Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared to non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on ZNF DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions, nor evidence of a difference selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity, and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factors binding sites.
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