trackViewer: a Bioconductor package for interactive and integrative visualization of multi-omics data

Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF < 0.1%) variants against 4264 phenotypes in 49,960 exome-sequenced individuals from the UK Biobank and 1934 phenotypes (1821 overlapping with UK Biobank) in 21,866 members of the Healthy Nevada Project (HNP) cohort who underwent Exome + sequencing at Helix. After using our rare-variant-tailored methodology to reduce test statistic inflation, we identify 64 statistically significant gene-based associations in our meta-analysis of the two cohorts and 37 for phenotypes available in only one cohort. Singletons make significant contributions to our results, and the vast majority of the associations could not have been identified with a genotyping chip. Our results are available for interactive browsing in a webapp (https://ukb.research.helix.com). This comprehensive analysis illustrates the biological value of large, deeply phenotyped cohorts of unselected populations coupled with NGS data.

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“…Gene plots were made using trackViewer and Protter and annotated with Pfam domains v. 32.0 [60][61][62] .…”

Section: Methodsmentioning

confidence: 99%

Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts

et al. 2020

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“…One advantage of deploying our software in the Bioconductor framework is that we can leverage the rich genomic annotation data and borrow functionalities already implemented in other R/Bioconductor packages. For example, we used the ATACseqQC package (Ou et al 2018) to efficiently read in the alignments, the baseline package for baseline correction (https://cran.r-project .org/web/packages/baseline/index.html), the signal package for smoothing (http://r-forge.r-project.org/projects/signal/), the trackViewer package (Ou and Zhu 2019) for visualizing the signals, the limma package (Ritchie et al 2015) for statistical analysis of the signal noise ratios across multiple replicates, and the ChIPpea-kAnno package (Zhu et al 2010;Zhu 2013) for annotating NADs with other genomic features of interest and for GO enrichment analyses. NADfinder is freely available (https://bioconductor.org/ packages/release/bioc/html/NADfinder.html).…”

Section: Nadfinder a New Bioconductor Package For Large Domain Analysismentioning

confidence: 99%

Two contrasting classes of nucleolus-associated domains in mouse fibroblast heterochromatin

Vertii

et al. 2019

Genome Res.

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In interphase eukaryotic cells, almost all heterochromatin is located adjacent to the nucleolus or to the nuclear lamina, thus defining nucleolus-associated domains (NADs) and lamina-associated domains (LADs), respectively. Here, we determined the first genome-scale map of murine NADs in mouse embryonic fibroblasts (MEFs) via deep sequencing of chromatin associated with purified nucleoli. We developed a Bioconductor package called NADfinder and demonstrated that it identifies NADs more accurately than other peak-calling tools, owing to its critical feature of chromosome-level local baseline correction. We detected two distinct classes of NADs. Type I NADs associate frequently with both the nucleolar periphery and the nuclear lamina, and generally display characteristics of constitutive heterochromatin, including late DNA replication, enrichment of H3K9me3, and little gene expression. In contrast, Type II NADs associate with nucleoli but do not overlap with LADs. Type II NADs tend to replicate earlier, display greater gene expression, and are more often enriched in H3K27me3 than Type I NADs. The nucleolar associations of both classes of NADs were confirmed via DNA-FISH, which also detected Type I but not Type II probes enriched at the nuclear lamina. Type II NADs are enriched in distinct gene classes, including factors important for differentiation and development. In keeping with this, we observed that a Type II NAD is developmentally regulated, and present in MEFs but not in undifferentiated embryonic stem (ES) cells.

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“…signal package for smoothing, the trackViewer package(Ou et al 2018b) for visualizing the signals, the limma package(Ritchie et al 2015) for statistical analysis of the signal noise ratios across multiple replicates, and the ChIPpeakAnno package(Zhu et al 2010;Zhu 2013) for annotating NADs with other genomic features of interest and for GO enrichment analyses. bioconductor.org/packages/release/bioc/html/NADfinder.html.…”

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confidence: 99%

Two Contrasting Classes of Nucleolus-Associated Domains in Mouse Fibroblast Heterochromatin

Vertii

et al. 2018

Preprint

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In interphase eukaryotic cells, almost all heterochromatin is located adjacent to the nucleolus or to the nuclear lamina, thus defining Nucleolus-Associated Domains (NADs) and Lamina-Associated Domains (LADs), respectively. Here, we determined the first genome-scale map of murine NADs in mouse embryonic fibroblasts (MEFs) via deep sequencing of chromatin associated with purified nucleoli. We developed a Bioconductor package called NADfinder and demonstrated that it identifies NADs more accurately than other peak-calling tools, due to its critical feature of chromosome-level local baseline correction. We detected two distinct classes of NADs. Type I NADs associate frequently with both the nucleolar periphery and with the nuclear lamina, and generally display characteristics of constitutive heterochromatin, including late DNA replication, enrichment of H3K9me3 and little gene expression. In contrast, Type II NADs associate with nucleoli but do not overlap with LADs. Type II NADs tend to replicate earlier, display greater gene expression, and are more often enriched in H3K27me3 than Type I NADs. The nucleolar associations of both classes of NADs were confirmed via DNA-FISH, which also detected Type I but not Type II probes enriched at the nuclear lamina. Interestingly, Type II NADs are enriched in distinct gene classes, notably factors important for differentiation and development. In keeping with this, we observed that a Type II NAD is developmentally regulated, present in MEFs but not in undifferentiated embryonic stem (ES) cells. microscopy images (Supplemental Fig. 1B; see also the "NAD-seq" QC files at the NIH 4DN Data Portal (data.4dnucleome.org)). Quantitative PCR suggested that rDNA sequences were enriched relative to the input total genomic DNA > 20-fold in the non-crosslinked preparations, and > 7-fold in crosslinked preparations ( Supplemental Fig. 1C). Immunoblot analyses showed enrichment of nucleolar protein fibrillarin relative to non-nucleolar proteins such as actin, a nucleoporin (Nup62), or lamin A/C (Supplemental Fig.1D). Additionally, we characterized the small RNAs present in the non-crosslinked preparation, observing that the nucleoli were highly enriched for the nucleolar U3 RNA (Supplemental Fig.1E). Small RNAs could not be recovered from crosslinked samples (data not shown).Bioinformatic analysis of nucleolar-associated DNA. We performed three biological replicate experiments for both the crosslinked and non-crosslinked protocols. For each experiment, we purified DNA from the isolated nucleoli, alongside genomic DNA from a sample of whole, unfractionated cells from the same population for normalization of the nucleolar sequencing data. These DNAs were used to generate sequencing libraries via PCR-free protocols, yielding genome-scale maps. Visual inspection of these "NAD-seq" data showed that the total genomic DNA was largely evenly distributed across the genome (Fig. 1B, C), occasionally interspersed with short, poorly represented regions. The nucleolar DNA was distributed with distinct pea...

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trackViewer: a Bioconductor package for interactive and integrative visualization of multi-omics data

Cited by 171 publications

References 6 publications

Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts

Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts

Two contrasting classes of nucleolus-associated domains in mouse fibroblast heterochromatin

Two Contrasting Classes of Nucleolus-Associated Domains in Mouse Fibroblast Heterochromatin

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