Transcriptome and epigenome landscape of human cortical development modeled in organoids

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Abstract

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.

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Fast R Functions for Robust Correlations and Hierarchical Clustering.

Peter Langfelder, Steve Horvath, José Pereira (2012)

Many high-throughput biological data analyses require the calculation of large correlation matrices and/or clustering of a large number of objects. The standard R function for calculating Pearson correlation can handle calculations without missing values efficiently, but is inefficient when applied to data sets with a relatively small number of missing data. We present an implementation of Pearson correlation calculation that can lead to substantial speedup on data with relatively small number of missing entries. Further, we parallelize all calculations and thus achieve further speedup on systems where parallel processing is available. A robust correlation measure, the biweight midcorrelation, is implemented in a similar manner and provides comparable speed. The functions cor and bicor for fast Pearson and biweight midcorrelation, respectively, are part of the updated, freely available R package WGCNA.The hierarchical clustering algorithm implemented in R function hclust is an order n(3) (n is the number of clustered objects) version of a publicly available clustering algorithm (Murtagh 2012). We present the package flashClust that implements the original algorithm which in practice achieves order approximately n(2), leading to substantial time savings when clustering large data sets.

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FQC Dashboard: integrates FastQC results into a web-based, interactive, and extensible FASTQ quality control tool

Joseph Brown, Meg Pirrung, Lee McCue (2017)

Abstract Summary FQC is software that facilitates quality control of FASTQ files by carrying out a QC protocol using FastQC, parsing results, and aggregating quality metrics into an interactive dashboard designed to richly summarize individual sequencing runs. The dashboard groups samples in dropdowns for navigation among the data sets, utilizes human-readable configuration files to manipulate the pages and tabs, and is extensible with CSV data. Availability and implementation FQC is implemented in Python 3 and Javascript, and is maintained under an MIT license. Documentation and source code is available at: https://github.com/pnnl/fqc. Contact joseph.brown@pnnl.gov

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Temporal dynamics and genetic control of transcription in the human prefrontal cortex.

Carlo Colantuoni, Barbara K. Lipska, Tianzhang Ye … (2011)

Previous investigations have combined transcriptional and genetic analyses in human cell lines, but few have applied these techniques to human neural tissue. To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of post-mortem brains from fetal development through ageing. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half-century later in life, this pattern of reversals is mirrored in ageing and in neurodegeneration. Although we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire data set is freely available (from Gene Expression Omnibus: accession GSE30272; and dbGaP: accession phs000417.v1.p1) and can also be interrogated via a biologist-friendly stand-alone application (http://www.libd.org/braincloud).