Person: Stranger, Barbara Elaine
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Stranger
First Name
Barbara Elaine
Name
Stranger, Barbara Elaine
5 results
Search Results
Now showing 1 - 5 of 5
Publication Extensive Genetic Diversity and Substructuring Among Zebrafish Strains Revealed through Copy Number Variant Analysis(Proceedings of the National Academy of Sciences, 2012) Brown, Kim H.; Dobrinski, Kimberly P.; Lee, Arthur S.; Gokcumen, Omer; Mills, Ryan Edward; Shi, Xinghua; Chong, Wilson W. S.; Chen, Jin Yun Helen; Yoo, Paulo; David, Sthuthi; Peterson, Samuel M.; Raj, Towfique; Choy, Kwong Wai; Stranger, Barbara Elaine; Williamson, Robin E.; Zon, Leonard; Freeman, Jennifer L.; Lee, CharlesCopy number variants (CNVs) represent a substantial source of genomic variation in vertebrates and have been associated with numerous human diseases. Despite this, the extent of CNVs in the zebrafish, an important model for human disease, remains unknown. Using 80 zebrafish genomes, representing three commonly used laboratory strains and one native population, we constructed a genome-wide, high-resolution CNV map for the zebrafish comprising 6,080 CNV elements and encompassing 14.6% of the zebrafish reference genome. This amount of copy number variation is four times that previously observed in other vertebrates, including humans. Moreover, 69% of the CNV elements exhibited strain specificity, with the highest number observed for Tubingen. This variation likely arose, in part, from Tubingen's large founding size and composite population origin. Additional population genetic studies also provided important insight into the origins and substructure of these commonly used laboratory strains. This extensive variation among and within zebrafish strains may have functional effects that impact phenotype and, if not properly addressed, such extensive levels of germ-line variation and population substructure in this commonly used model organism can potentially confound studies intended for translation to human diseases.Publication Patterns of \(Cis\) Regulatory Variation in Diverse Human Populations(Public Library of Science, 2012) Montgomery, Stephen B.; Dimas, Antigone S.; Parts, Leopold; Stegle, Oliver; Ingle, Catherine E.; Sekowska, Magda; Gutierrez-Arcelus, Maria; Nisbett, James; Nica, Alexandra C.; Beazley, Claude; Durbin, Richard; Deloukas, Panos; Dermitzakis, Emmanouil T.; Stranger, Barbara Elaine; Smith, George; Price, Alkes; Raj, TowfiqueThe 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.Publication Genevar: A Database and Java Application for the Analysis and Visualization of SNP-Gene Associations in eQTL Studies(Oxford University Press, 2010) Yang, Tsun-Po; Beazley, Claude; Montgomery, Stephen B.; Dimas, Antigone S.; Gutierrez-Arcelus, Maria; Stranger, Barbara Elaine; Deloukas, Panos; Dermitzakis, Emmanouil T.Summary: Genevar (GENe Expression VARiation) is a database and Java tool designed to integrate multiple datasets, and provides analysis and visualization of associations between sequence variation and gene expression. Genevar allows researchers to investigate expression quantitative trait loci (eQTL) associations within a gene locus of interest in real time. The database and application can be installed on a standard computer in database mode and, in addition, on a server to share discoveries among affiliations or the broader community over the Internet via web services protocols.Publication Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations(Public Library of Science, 2010) Nica, Alexandra C.; Montgomery, Stephen B.; Dimas, Antigone S.; Beazley, Claude; Barroso, Inês; Dermitzakis, Emmanouil T.; Gibson, Greg; Stranger, Barbara ElaineThe 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.Publication Independent and Population-Specific Association of Risk Variants at the IRGM Locus with Crohn's Disease(Oxford University Press, 2010) Prescott, Natalie J.; Dominy, Katherine M.; Kubo, Michiaki; Lewis, Cathryn M.; Fisher, Sheila A.; Redon, Richard; Blaszczyk, Katarzyna; Hudspith, Barry; Parkes, Gareth; Hosono, Naoya; Yamazaki, Keiko; Onnie, Clive M.; Forbes, Alastair; Dermitzakis, Emmanouil T.; Nakamura, Yusuke; Sanderson, Jeremy; Hurles, Matthew E.; Roberts, Roland G.; Mathew, Christopher G.; Huang, Ni; Stranger, Barbara Elaine; Mansfield, John C.DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10−5 to 1.40 × 10−9), and that the CNV and the 5′-untranslated region variant −308(GTTT)5 contribute independently to CD susceptibility (P = 2.6 × 10−7 and P = 2 × 10−5, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10−12) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case–control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene–gene or gene–environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European–Asian split.