Topologically associating domains (TADs) have been proposed to be the basic unit of chromosome folding and have been shown to play key roles in genome organization and gene regulation. Several different tools are available for TAD prediction, but their properties have never been thoroughly assessed. In this manuscript, we compare the output of seven different TAD prediction tools on two published Hi-C data sets. TAD predictions varied greatly between tools in number, size distribution and other biological properties. Assessed against a manual annotation of TADs, individual TAD boundary predictions were found to be quite reliable, but their assembly into complete TAD structures was much less so. In addition, many tools were sensitive to sequencing depth and resolution of the interaction frequency matrix. This manuscript provides users and designers of TAD prediction tools with information that will help guide the choice of tools and the interpretation of their predictions.
Background With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing. Findings Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for high-performance computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA sequencing, chromatin immunoprecipitation sequencing, DNA sequencing, methylation sequencing, Hi-C, capture Hi-C, metagenomics, and Pacific Biosciences long-read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has already been configured on several servers, and a Docker image is also available to facilitate additional installations. Conclusions GenPipes offers genomics researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.
Glioblastoma (GBM) is the most common and deadly malignant brain cancer, with a median survival of less than two years. GBM displays a cellular complexity that includes brain tumour-initiating cells (BTICs), which are considered as potential key targets for GBM therapies. Here we show that the transcription factors FOXG1 and Groucho/TLE are expressed in poorly differentiated astroglial cells in human GBM specimens and in primary cultures of GBM-derived BTICs, where they form a complex. FOXG1 knockdown in BTICs causes downregulation of neural stem/progenitor and proliferation markers, increased replicative senescence, upregulation of astroglial differentiation genes, and decreased BTIC-initiated tumour growth upon intracranial transplantation into host mice. These effects are phenocopied by Groucho/TLE knockdown or dominant-inhibition of the FOXG1:Groucho/TLE complex. These results provide evidence that transcriptional programs regulated by FOXG1 and Groucho/TLE are important for BTIC-initiated brain tumour growth, implicating FOXG1 and Groucho/TLE in GBM tumorigenesis.
Sex is a long-standing evolutionary enigma. Although the majority of eukaryotes reproduce sexually at least sometimes [1-3], the evolution of sex from an asexual ancestor has been difficult to explain because it requires sexually reproducing lineages to overcome the manifold costs of sex, including the destruction of favorable gene combinations created by selection [4, 5]. Conditions for the evolution of sex are much broader if individuals can reproduce either sexually or asexually (i.e., facultative sex) and allocate disproportionately more resources to sex when their fitness is low (fitness-associated-sex or FAS [6-10]). Although facultatively sexual organisms have been shown to engage in more sex when stressed [11], direct evidence for FAS is lacking. We provide evidence using 53 genotypes of the filamentous fungus Aspergillus nidulans in a reciprocal transplant experiment across three environments. Different genotypes achieved highest fitness in different environments and genotypes invested relatively more in sex in environments in which their fitness was lower, showing that allocation to sexual reproduction is a function of how well-adapted a genotype is to its environment. FAS in A. nidulans is unlikely to have evolved as a strategy to resist or avoid stress because asexual spores are more dispersive and equally resistant [12, 13].
Background Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene expression, open chromatin region, and 3D interactions in resting and TNFα-treated human endothelial cells. Results We show that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We identify physical loops by Hi-C and link open chromatin peaks that include CAD or BP SNPs with the promoters of genes expressed in endothelial cells. This analysis highlights 991 combinations of open chromatin regions and gene promoters that map to 38 CAD and 92 BP GWAS loci. We validate one CAD locus, by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measure the effect on the expression of the novel CAD candidate gene AIDA. Conclusions Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension. Electronic supplementary material The online version of this article (10.1186/s13059-019-1749-5) contains supplementary material, which is available to authorized users.
BackgroundBacteria excrete costly toxins to defend their ecological niche. The evolution of such antagonistic interactions between individuals is expected to depend on both the social environment and the strength of resource competition. Antagonism is expected to be weak among highly similar genotypes because most individuals are immune to antagonistic agents and among dissimilar genotypes because these are unlikely to be competing for the same resources and antagonism should not yield much benefit. The strength of antagonism is therefore expected to peak at intermediate genetic distance.ResultsWe studied the ability of laboratory strains of Pseudomonas aeruginosa to prevent growth of 55 different clinical P. aeruginosa isolates derived from cystic fibrosis patients. Genetic distance was determined using genetic fingerprints. We found that the strength of antagonism was maximal among genotypes of intermediate genetic distance and we show that genetic distance and resource use are linked.ConclusionsOur results suggest that the importance of social interactions like antagonism may be modulated by the strength of resource competition.
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