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Segregating variation in the transcriptome: Cis regulation and additivity of effects

School of Integraive Biology, University of Illinois, Urbana, Illinois 61801, USA.
Genetics (Impact Factor: 4.87). 08/2006; 173(3):1347-55. DOI: 10.1534/genetics.105.051474
Source: PubMed

ABSTRACT Properties of genes underlying variation in complex traits are largely unknown, especially for variation that segregates within populations. Here, we evaluate allelic effects, cis and trans regulation, and dominance patterns of transcripts that are genetically variable in a natural population of Drosophila melanogaster. Our results indicate that genetic variation due to the third chromosome causes mainly additive and nearly additive effects on gene expression, that cis and trans effects on gene expression are numerically about equal, and that cis effects account for more genetic variation than do trans effects. We also evaluated patterns of variation in different functional categories and determined that genes involved in metabolic processes are overrepresented among variable transcripts, but those involved in development, transcription regulation, and signal transduction are underrepresented. However, transcripts for proteins known to be involved in protein-protein interactions are proportionally represented among variable transcripts.

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Available from: Elizabeth Ruedi, Feb 27, 2014
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    • "There are greater contributions of cis than trans variants to interspecific divergence in expression regulation (Wittkopp et al. 2004; Lemos et al. 2008; Graze et al. 2009; Tirosh et al. 2009; Emerson et al. 2010; McManus et al. 2010). However, the story within species is less clear: although there is abundant regulatory variation (Townsend et al. 2003; Morley et al. 2004; Wayne et al. 2004), there are contradictory findings on the relative importance of cis versus trans variation (Brem et al. 2002; Schadt et al. 2003; Hughes et al. 2006; Genissel et al. 2008; Lemos et al. 2008; Wang et al. 2008; Wittkopp et al. 2008b). The lack of consensus may reflect differences between experimental designs: studies that use expression QTL (eQTL) designs or multiple chromosome substitutions have found many more transacting variants than cis-acting variants (Brem et al. 2002; Schadt et al. 2003; Genissel et al. 2008; Wang et al. 2008). "
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    ABSTRACT: The mechanistic basis of regulatory variation and the prevailing evolutionary forces shaping that variation are known to differ between sexes and between chromosomes. Regulatory variation of gene expression can be due to functional changes within a gene itself (cis), or in other genes elsewhere in the genome (trans). The evolutionary properties of cis mutations are expected to differ from mutations affecting gene expression in trans. We analyze allele-specific expression across a set of X substitution lines in intact adult Drosophila simulans to evaluate whether regulatory variation differs for cis and trans, for males and females, and for X-linked and autosomal genes. Regulatory variation is common (56% of genes), and patterns of variation within D. simulans are consistent with previous observations in Drosophila that there is more cis than trans variation within species (47% vs. 25%, respectively). The relationship between sex-bias and sex-limited variation is remarkably consistent across sexes. However, there are differences between cis and trans effects: cis variants show evidence of purifying selection in the sex towards which expression is biased, while trans variants do not. For female-biased genes, the X is depleted for trans variation in a manner consistent with a female-dominated selection regime on the X. Surprisingly, there is no evidence for depletion of trans variation for male-biased genes on the X. This is evidence for regulatory feminization of the X, trans acting factors controlling male-biased genes are more likely to be found on the autosomes than those controlling female-biased genes.
    Genome Biology and Evolution 04/2014; 6(4). DOI:10.1093/gbe/evu060 · 4.53 Impact Factor
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    • "Genetic differences which impact transcript abundance can arise from regulatory sequence variation occurring within regulatory regions of the gene itself (cis effects), in regulatory or coding regions of trans acting factors (trans effects), or through indirect or epistatic effects. Chromosome substitution , eQTL, and allele-specific expression (ASE) studies find abundant regulatory variation both in cis and in trans (Brem et al. 2002; Yan et al. 2002; Lo et al. 2003; Wittkopp et al. 2004; Kirst et al. 2005; Ronald et al. 2005; Hughes et al. 2006; Genissel et al. 2008; Guo et al. 2008; Lemos et al. 2008; Graze et al. 2009; Tirosh et al. 2009; Zhang and Borevitz 2009; McManus et al. 2010). However, there is still debate over the relative contribution of causal genetic differences in cis or trans to variation in gene regulation, with more cis than trans observed in some experiments (Wittkopp et al. 2004) and more trans than cis observed in others (Brem et al. 2002). "
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    ABSTRACT: Unraveling how regulatory divergence contributes to species differences and adaptation requires identifying functional variants from among millions of genetic differences. Analysis of allelic imbalance (AI) reveals functional genetic differences in cis regulation and has demonstrated differences in cis regulation within and between species. Regulatory mechanisms are often highly conserved, yet differences between species in gene expression are extensive. What evolutionary forces explain widespread divergence in cis regulation? AI was assessed in Drosophila melanogaster-Drosophila simulans hybrid female heads using RNA-seq technology. Mapping bias was virtually eliminated by using genotype-specific references. Allele representation in DNA sequencing was used as a prior in a novel Bayesian model for the estimation of AI in RNA. Cis regulatory divergence was common in the organs and tissues of the head with 41% of genes analyzed showing significant AI. Using existing population genomic data, the relationship between AI and patterns of sequence evolution was examined. Evidence of positive selection was found in 30% of cis regulatory divergent genes. Genes involved in defense, RNAi/RISC complex genes, and those that are sex regulated are enriched among adaptively evolving cis regulatory divergent genes. For genes in these groups, adaptive evolution may play a role in regulatory divergence between species. However, there is no evidence that adaptive evolution drives most of the cis regulatory divergence that is observed. The majority of genes showed patterns consistent with stabilizing selection and neutral evolutionary processes.
    Molecular Biology and Evolution 02/2012; 29(6):1521-32. DOI:10.1093/molbev/msr318 · 14.31 Impact Factor
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    • "Classifications of expression QTLs as cis-or trans-acting based solely on their proximity to the affected gene are therefore only an approximation – and one that comes with many caveats (Rockman & Kruglyak 2006). Nevertheless, studies mapping expression QTLs suggest that both cis-and trans-regulatory mutations contribute to transcriptional variation, with a preponderance of expression QTLs appearing to be cis-acting (Wayne et al. 2004; Hughes et al. 2006; Osada et al. 2006; Bergen et al. 2007; Genissel et al. 2008; Gilad et al. 2008; Price et al. 2008; Lemos et al. 2008; but see Morley et al. 2004), although this methodology generally has less statistical power to detect trans-acting than cis-acting variants (Cookson et al. 2009). In addition, QTL mapping studies of variable gene expression require microarrays suitable for studying the species of interest, molecular markers that cover its complete genome, and resources for genotyping these markers in a segregating population. "
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    ABSTRACT: Differences in gene expression are thought to be an important source of phenotypic diversity, so dissecting the genetic components of natural variation in gene expression is important for understanding the evolutionary mechanisms that lead to adaptation. Gene expression is a complex trait that, in diploid organisms, results from transcription of both maternal and paternal alleles. Directly measuring allelic expression rather than total gene expression offers greater insight into regulatory variation. The recent emergence of high-throughput sequencing offers an unprecedented opportunity to study allelic transcription at a genomic scale for virtually any species. By sequencing transcript pools derived from heterozygous individuals, estimates of allelic expression can be directly obtained. The statistical power of this approach is influenced by the number of transcripts sequenced and the ability to unambiguously assign individual sequence fragments to specific alleles on the basis of transcribed nucleotide polymorphisms. Here, using mathematical modelling and computer simulations, we determine the minimum sequencing depth required to accurately measure relative allelic expression and detect allelic imbalance via high-throughput sequencing under a variety of conditions. We conclude that, within a species, a minimum of 500-1000 sequencing reads per gene are needed to test for allelic imbalance, and consequently, at least five to 10 millions reads are required for studying a genome expressing 10 000 genes. Finally, using 454 sequencing, we illustrate an application of allelic expression by testing for cis-regulatory divergence between closely related Drosophila species.
    Molecular Ecology 03/2010; 19 Suppl 1:212-27. DOI:10.1111/j.1365-294X.2010.04472.x · 6.49 Impact Factor
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