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Search Results: 1 - 10 of 328277 matches for " Antigone S. Dimas equal contributor "
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Patterns of Cis Regulatory Variation in Diverse Human Populations
Barbara E. Stranger equal contributor,Stephen B. Montgomery equal contributor,Antigone S. Dimas equal contributor,Leopold Parts,Oliver Stegle,Catherine E. Ingle,Magda Sekowska,George Davey Smith,David Evans,Maria Gutierrez-Arcelus,Alkes Price,Towfique Raj,James Nisbett,Alexandra C. Nica,Claude Beazley,Richard Durbin,Panos Deloukas,Emmanouil T. Dermitzakis
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002639
Abstract: The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.
Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits
Joshua C. Randall equal contributor,Thomas W. Winkler equal contributor,Zoltán Kutalik equal contributor,Sonja I. Berndt equal contributor,Anne U. Jackson,Keri L. Monda,Tuomas O. Kilpel?inen,T?nu Esko,Reedik M?gi,Shengxu Li,Tsegaselassie Workalemahu,Mary F. Feitosa,Damien C. Croteau-Chonka,Felix R. Day,Tove Fall,Teresa Ferreira,Stefan Gustafsson,Adam E. Locke,Iain Mathieson,Andre Scherag,Sailaja Vedantam,Andrew R. Wood,Liming Liang,Valgerdur Steinthorsdottir,Gudmar Thorleifsson,Emmanouil T. Dermitzakis,Antigone S. Dimas,Fredrik Karpe,Josine L. Min,George Nicholson,Deborah J. Clegg,Thomas Person,Jon P. Krohn,Sabrina Bauer,Christa Buechler,Kristina Eisinger,DIAGRAM Consortium,Amélie Bonnefond,Philippe Froguel,MAGIC Investigators,Jouke-Jan Hottenga,Inga Prokopenko,Lindsay L. Waite,Tamara B. Harris,Albert Vernon Smith,Alan R. Shuldiner,Wendy L. McArdle,Mark J. Caulfield,Patricia B. Munroe,Henrik Gr?nberg,Yii-Der Ida Chen,Guo Li,Jacques S. Beckmann,Toby Johnson,Unnur Thorsteinsdottir,Maris Teder-Laving,Kay-Tee Khaw,Nicholas J. Wareham,Jing Hua Zhao,Najaf Amin,Ben A. Oostra,Aldi T. Kraja,Michael A. Province,L. Adrienne Cupples,Nancy L. Heard-Costa,Jaakko Kaprio,Samuli Ripatti,Ida Surakka,Francis S. Collins,Jouko Saramies,Jaakko Tuomilehto,Antti Jula,Veikko Salomaa,Jeanette Erdmann,Christian Hengstenberg,Christina Loley,Heribert Schunkert,Claudia Lamina,H. Erich Wichmann,Eva Albrecht,Christian Gieger,Andrew A. Hicks,?sa Johansson,Peter P. Pramstaller,Sekar Kathiresan
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003500
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10?8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations
Alexandra C. Nica,Stephen B. Montgomery,Antigone S. Dimas,Barbara E. Stranger,Claude Beazley,Inês Barroso,Emmanouil T. Dermitzakis
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000895
Abstract: The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases. Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants. In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r2) or historical (D'). Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex traits. We detect several potential disease-causing regulatory effects, with a strong enrichment for immunity-related conditions, consistent with the nature of the cell line tested (LCLs). Furthermore, we present an extension of the method in trans, where interrogating the whole genome for downstream effects of the disease variant can be informative regarding its unknown primary biological effect. We conclude that integrating cellular phenotype associations with organismal complex traits will facilitate the biological interpretation of the genetic effects on these traits.
Data analysis issues for allele-specific expression using Illumina's GoldenGate assay
Matthew E Ritchie, Matthew S Forrest, Antigone S Dimas, Caroline Daelemans, Emmanouil T Dermitzakis, Panagiotis Deloukas, Simon Tavaré
BMC Bioinformatics , 2010, DOI: 10.1186/1471-2105-11-280
Abstract: We analyze data from a mixture experiment where genomic DNA samples from pairs of individuals of known genotypes are pooled to create allelic imbalances at varying levels for the majority of SNPs on the array. We observe that GoldenGate has less sensitivity at detecting subtle allelic imbalances (around 1.3 fold) compared to extreme imbalances, and note the benefit of applying local background correction to the data. Analysis of data from a dye-swap control experiment allowed us to quantify dye-bias, which can be reduced considerably by careful normalization. The need to filter the data before carrying out further downstream analysis to remove non-responding probes, which show either weak, or non-specific signal for each allele, was also demonstrated. Throughout this paper, we find that a linear model analysis of the data from each SNP is a flexible modelling strategy that allows for testing of allelic imbalances in each sample when replicate hybridizations are available.Our analysis shows that local background correction carried out by Illumina's software, together with quantile normalization of the red and green channels within each array, provides optimal performance in terms of false positive rates. In addition, we strongly encourage intensity-based filtering to remove SNPs which only measure non-specific signal. We anticipate that a similar analysis strategy will prove useful when quantifying ASE on Illumina's higher density Infinium BeadChips.Preferential expression of one of the two alleles of a gene has been widely studied in the context of development, where key mechanisms such as genomic imprinting and X-inactivation lead to extreme allelic imbalances [1]. Allele-specific expression has been linked to the susceptibility of many human diseases [2-4].Various experimental techniques exist for measuring ASE [5], including microarray-based approaches that have been used in a number of studies to screen for ASE in a high-throughput manner [6-11]. With microarray
Tuning Curves, Neuronal Variability, and Sensory Coding
Daniel A Butts equal contributor ,Mark S Goldman equal contributor
PLOS Biology , 2006, DOI: 10.1371/journal.pbio.0040092
Abstract: Tuning curves are widely used to characterize the responses of sensory neurons to external stimuli, but there is an ongoing debate as to their role in sensory processing. Commonly, it is assumed that a neuron's role is to encode the stimulus at the tuning curve peak, because high firing rates are the neuron's most distinct responses. In contrast, many theoretical and empirical studies have noted that nearby stimuli are most easily discriminated in high-slope regions of the tuning curve. Here, we demonstrate that both intuitions are correct, but that their relative importance depends on the experimental context and the level of variability in the neuronal response. Using three different information-based measures of encoding applied to experimentally measured sensory neurons, we show how the best-encoded stimulus can transition from high-slope to high-firing-rate regions of the tuning curve with increasing noise level. We further show that our results are consistent with recent experimental findings that correlate neuronal sensitivities with perception and behavior. This study illustrates the importance of the noise level in determining the encoding properties of sensory neurons and provides a unified framework for interpreting how the tuning curve and neuronal variability relate to the overall role of the neuron in sensory encoding.
Maternal Expression Relaxes Constraint on Innovation of the Anterior Determinant, bicoid
Michael S Barker equal contributor,Jeffery P Demuth equal contributor ,Michael J Wade equal contributor
PLOS Genetics , 2005, DOI: 10.1371/journal.pgen.0010057
Abstract: The origin of evolutionary novelty is believed to involve both positive selection and relaxed developmental constraint. In flies, the redesign of anterior patterning during embryogenesis is a major developmental innovation and the rapidly evolving Hox gene, bicoid (bcd), plays a critical role. We report evidence for relaxation of selective constraint acting on bicoid as a result of its maternal pattern of gene expression. Evolutionary theory predicts 2-fold greater sequence diversity for maternal effect genes than for zygotically expressed genes, because natural selection is only half as effective acting on autosomal genes expressed in one sex as it is on genes expressed in both sexes. We sample an individual from ten populations of Drosophila melanogaster and nine populations of D. simulans for polymorphism in the tandem gene duplicates bcd, which is maternally expressed, and zerknüllt (zen), which is zygotically expressed. In both species, we find the ratio of bcd to zen nucleotide diversity to be two or more in the coding regions but one in the noncoding regions, providing the first quantitative support for the theoretical prediction of relaxed selective constraint on maternal-effect genes resulting from sex-limited expression. Our results suggest that the accelerated rate of evolution observed for bcd is owing, at least partly, to variation generated by relaxed selective constraint.
Uncoupling Transcription from Covalent Histone Modification
Hesheng Zhang equal contributor,Lu Gao equal contributor,Jayamani Anandhakumar equal contributor,David S. Gross
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004202
Abstract: It is widely accepted that transcriptional regulation of eukaryotic genes is intimately coupled to covalent modifications of the underlying chromatin template, and in certain cases the functional consequences of these modifications have been characterized. Here we present evidence that gene activation in the silent heterochromatin of the yeast Saccharomyces cerevisiae can occur in the context of little, if any, covalent histone modification. Using a SIR-regulated heat shock-inducible transgene, hsp82-2001, and a natural drug-inducible subtelomeric gene, YFR057w, as models we demonstrate that substantial transcriptional induction (>200-fold) can occur in the context of restricted histone loss and negligible levels of H3K4 trimethylation, H3K36 trimethylation and H3K79 dimethylation, modifications commonly linked to transcription initiation and elongation. Heterochromatic gene activation can also occur with minimal H3 and H4 lysine acetylation and without replacement of H2A with the transcription-linked variant H2A.Z. Importantly, absence of histone modification does not stem from reduced transcriptional output, since hsp82-ΔTATA, a euchromatic promoter mutant lacking a TATA box and with threefold lower induced transcription than heterochromatic hsp82-2001, is strongly hyperacetylated in response to heat shock. Consistent with negligible H3K79 dimethylation, dot1Δ cells lacking H3K79 methylase activity show unimpeded occupancy of RNA polymerase II within activated heterochromatic promoter and coding regions. Our results indicate that large increases in transcription can be observed in the virtual absence of histone modifications often thought necessary for gene activation.
Modifier Effects between Regulatory and Protein-Coding Variation
Antigone S. Dimas,Barbara E. Stranger,Claude Beazley,Robert D. Finn,Catherine E. Ingle,Matthew S. Forrest,Matthew E. Ritchie,Panos Deloukas,Simon Tavaré,Emmanouil T. Dermitzakis
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000244
Abstract: Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis. Furthermore, we show that such interactions in cis can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a cis interaction between regulatory and protein-coding variants has a trans impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.
CPAF: A Chlamydial Protease in Search of an Authentic Substrate
Allan L. Chen equal contributor,Kirsten A. Johnson equal contributor,Jennifer K. Lee equal contributor,Christine Sütterlin ,Ming Tan
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002842
Abstract: Bacteria in the genus Chlamydia are major human pathogens that cause an intracellular infection. A chlamydial protease, CPAF, has been proposed as an important virulence factor that cleaves or degrades at least 16 host proteins, thereby altering multiple cellular processes. We examined 11 published CPAF substrates and found that there was no detectable proteolysis when CPAF activity was inhibited during cell processing. We show that the reported proteolysis of these putative CPAF substrates was due to enzymatic activity in cell lysates rather than in intact cells. Nevertheless, Chlamydia-infected cells displayed Chlamydia-host interactions, such as Golgi reorganization, apoptosis resistance, and host cytoskeletal remodeling, that have been attributed to CPAF-dependent proteolysis of host proteins. Our findings suggest that other mechanisms may be responsible for these Chlamydia-host interactions, and raise concerns about all published CPAF substrates and the proposed roles of CPAF in chlamydial pathogenesis.
DNA Display III. Solid-Phase Organic Synthesis on Unprotected DNA
David R Halpin equal contributor,Juanghae A Lee equal contributor,S. Jarrett Wrenn equal contributor,Pehr B Harbury
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020175
Abstract: DNA-directed synthesis represents a powerful new tool for molecular discovery. Its ultimate utility, however, hinges upon the diversity of chemical reactions that can be executed in the presence of unprotected DNA. We present a solid-phase reaction format that makes possible the use of standard organic reaction conditions and common reagents to facilitate chemical transformations on unprotected DNA supports. We demonstrate the feasibility of this strategy by comprehensively adapting solid-phase 9-fluorenylmethyoxycarbonyl–based peptide synthesis to be DNA-compatible, and we describe a set of tools for the adaptation of other chemistries. Efficient peptide coupling to DNA was observed for all 33 amino acids tested, and polypeptides as long as 12 amino acids were synthesized on DNA supports. Beyond the direct implications for synthesis of peptide–DNA conjugates, the methods described offer a general strategy for organic synthesis on unprotected DNA. Their employment can facilitate the generation of chemically diverse DNA-encoded molecular populations amenable to in vitro evolution and genetic manipulation.
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