Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Transpositional landscape of the rice genome revealed by paired-end mapping of high-throughput re-sequencing data.

Transposable elements (TEs) are mobile entities that densely populate most eukaryotic genomes and contribute to both their structural and functional dynamics. However, most TE-related sequences in both plant and animal genomes correspond to inactive, degenerated elements, due to the combined effect of silencing pathways and elimination through deletions. One of the major difficulties in fully characterizing the molecular basis of genetic diversity of a given species lies in establishing its genome-wide transpositional activity. Here, we provide an extensive survey of the transpositional landscape of a plant genome using a deep sequencing strategy. This was achieved through paired-end mapping of a fourfold coverage of the genome of rice mutant line derived from an in vitro callus culture using Illumina technology. Our study shows that at least 13 TE families are active in this genotype, causing 34 new insertions. This next-generation sequencing-based strategy provides new opportunities to quantify the impact of TEs on the genome dynamics of the species.

Alta-Cyclic: a self-optimizing base caller for next-generation sequencing.

Next-generation sequencing is limited to short read lengths and by high error rates. We systematically analyzed sources of noise in the Illumina Genome Analyzer that contribute to these high error rates and developed a base caller, Alta-Cyclic, that uses machine learning to compensate for noise factors. Alta-Cyclic substantially improved the number of accurate reads for sequencing runs up to 78 bases and reduced systematic biases, facilitating confident identification of sequence variants.

Management, Analyses, and Distribution of the MaizeCODE Data on the Cloud.

MaizeCODE is a project aimed at identifying and analyzing functional elements in the maize genome. In its initial phase, MaizeCODE assayed up to five tissues from four maize strains (B73, NC350, W22, TIL11) by RNA-Seq, Chip-Seq, RAMPAGE, and small RNA sequencing. To facilitate reproducible science and provide both human and machine access to the MaizeCODE data, we enhanced SciApps, a cloud-based portal, for analysis and distribution of both raw data and analysis results. Based on the SciApps workflow platform, we generated new components to support the complete cycle of MaizeCODE data management. These include publicly accessible scientific workflows for the reproducible and shareable analysis of various functional data, a RESTful API for batch processing and distribution of data and metadata, a searchable data page that lists each MaizeCODE experiment as a reproducible workflow, and integrated JBrowse genome browser tracks linked with workflows and metadata. The SciApps portal is a flexible platform that allows the integration of new analysis tools, workflows, and genomic data from multiple projects. Through metadata and a ready-to-compute cloud-based platform, the portal experience improves access to the MaizeCODE data and facilitates its analysis.