ORegAnno: an open-access community-driven resource for regulatory annotation

Griffith, Obi L.; Montgomery, Stephen B.; Bernier, Bridget; Chu, Bryan; Kasaian, Katayoon; Aerts, Stein; Mahony, Shaun; Sleumer, Monica C.; Bilenky, Mikhail; Haeussler, Maximilian; Griffith, Malachi; Gallo, Steven M.; Giardine, Belinda; Hooghe, Bart; Loo, Peter Van; Blanco, Enrique; Ticoll, Amy; Lithwick, Stuart; Portales-Casamar, Élodie; Donaldson, Ian J.; Robertson, Gordon; Wadelius, Claes; Bleser, Pieter De; Vlieghe, Dominique; Halfon, Marc S.; Wasserman, Wyeth W.; Hardison, Ross C.; Bergman, Casey M.; Jones, Steven J.M.

doi:10.1093/nar/gkm967

Cited by 216 publications

(188 citation statements)

References 29 publications

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“…One is the mammal most conserved (MMC) track of conserved sequences or elements based on whole-genome alignments of different mammalian species. The other is the track for open regulatory annotation (ORegAnno), which includes literaturecurated regulatory regions and transcription factor-binding sites (24). We reasoned that the sequences of these tracks could be used as probes that would allow us to follow the partitioning of regulatory sequences between the methylated regions and UMRs of the genome.…”

Section: Resultsmentioning

confidence: 99%

Expanded methyl-sensitive cut counting reveals hypomethylation as an epigenetic state that highlights functional sequences of the genome

Colaneri

Staffa

Fargo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Methyl-sensitive cut counting (MSCC) with the HpaII methylation-sensitive restriction enzyme is a cost-effective method to pinpoint unmethylated CpGs at single base-pair resolution. However, it has the drawback of addressing only CpGs in the context of the CCGG site, leaving out the remainder of the possible 16 XCGX tetranucleotides in which CpGs are found. We expanded MSCC to include three additional enzymes to address a total of 5 of the 16 XCGX combinations. This allowed us to survey methylation at about one-third of all a mammalian genome's CpGs. Applied to mouse liver DNA, we correctly confirmed data reported with other methods showing hypomethylation to be concentrated at promoters and in CpG islands (CGIs), with gene bodies and intergenic regions being mostly methylated. Grouping unmethylated CpGs, characterized by high MSCC scores (7% false discovery rate), we found a large number of unmethylated regions not qualifying as CGIs located in intergenic and intronic regions, which are highly enriched in functional DNA sequences (open regulatory annotation database) as well as in noncoding yet highly conserved mammalian sequences thought to be important but with as yet unknown function. About 50% of MSCC-defined unmethylated regions do not overlap algorithm-defined CGIs and offer a novel search space in which new functionalities of DNA may be found in health and disease.

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Section: Resultsmentioning

confidence: 99%

Expanded methyl-sensitive cut counting reveals hypomethylation as an epigenetic state that highlights functional sequences of the genome

Colaneri

Staffa

Fargo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, this region harbors several potential regulatory regions according to the Open Regulatory Annotation database (OregAnno; Figure 1a). 47 The most significant associations with BMI were observed with haplotypes Morphological and biochemical features of obesity M Korostishevsky et al (rs1353258-rs3006069 and rs3006069-rs863118) flanking the promoter region. In the ENPP1 gene, a significant association between the two adjacent haplotypes (rs7754561-rs9373000 and rs9373000-rs6569765) and BMI and leptin was observed.…”

Section: Resultsmentioning

confidence: 97%

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

et al. 2010

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Background: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. Aim: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. Subjects and methods: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. Results: Associations were observed between ENPP1 polymorphisms and BMI (P ¼ 0.0037) and leptin (P ¼ 0.0068). ALPL markers were associated with WHR (P ¼ 0.0026) and EGFR (P ¼ 0.0001). The ANKH gene was associated with all four studied obesity-related traits (Po0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. Conclusion: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

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“…Genome positions were annotated as coding sequence (CDS), 39-and 59-UTR, intron, regulatory, and ''other.'' Because regulatory regions are underrepresented in the FlyBase annotation, additional regulatory annotations were retrieved from the OregAnno database (Griffith et al 2008) and a recent genome-wide scan for transcription-factor binding sites (MacArthur et al 2009). Polymorphisms within coding sequence were additionally annotated as either nonsynonymous or synonymous.…”

Section: Methodsmentioning

confidence: 99%

Genomic Differentiation Between Temperate and Tropical Australian Populations ofDrosophila melanogaster

et al. 2011

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Determining the genetic basis of environmental adaptation is a central problem of evolutionary biology. This issue has been fruitfully addressed by examining genetic differentiation between populations that are recently separated and/or experience high rates of gene flow. A good example of this approach is the decades-long investigation of selection acting along latitudinal clines in Drosophila melanogaster. Here we use next-generation genome sequencing to reexamine the well-studied Australian D. melanogaster cline. We find evidence for extensive differentiation between temperate and tropical populations, with regulatory regions and unannotated regions showing particularly high levels of differentiation. Although the physical genomic scale of geographic differentiation is small-on the order of gene sized-we observed several larger highly differentiated regions. The region spanned by the cosmopolitan inversion polymorphism In(3R)P shows higher levels of differentiation, consistent with the major difference in allele frequencies of Standard and In(3R)P karyotypes in temperate vs. tropical Australian populations. Our analysis reveals evidence for spatially varying selection on a number of key biological processes, suggesting fundamental biological differences between flies from these two geographic regions.

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ORegAnno: an open-access community-driven resource for regulatory annotation

Cited by 216 publications

References 29 publications

Expanded methyl-sensitive cut counting reveals hypomethylation as an epigenetic state that highlights functional sequences of the genome

Expanded methyl-sensitive cut counting reveals hypomethylation as an epigenetic state that highlights functional sequences of the genome

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

Genomic Differentiation Between Temperate and Tropical Australian Populations ofDrosophila melanogaster

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