CHiCP: a web-based tool for the integrative and interactive visualization of promoter capture Hi-C datasets.

UNLABELLED: Promoter capture Hi-C (PCHi-C) allows the genome-wide interrogation of physical interactions between distal DNA regulatory elements and gene promoters in multiple tissue contexts. Visual integration of the resultant chromosome interaction maps with other sources of genomic annotations can provide insight into underlying regulatory mechanisms. We have developed Capture HiC Plotter (CHiCP), a web-based tool that allows interactive exploration of PCHi-C interaction maps and integration with both public and user-defined genomic datasets. AVAILABILITY AND IMPLEMENTATION: CHiCP is freely accessible from www.chicp.org and supports most major HTML5 compliant web browsers. Full source code and installation instructions are available from http://github.com/D-I-L/django-chicp CONTACT: [email protected] is the published version. It first appeared at http://bioinformatics.oxfordjournals.org/content/early/2016/04/26/bioinformatics.btw173

Prioritisation of candidate genes underpinning COVID-19 host genetic traits based on high-resolution 3D chromosomal topology

Genetic variants showing associations with specific biological traits and diseases detected by genome-wide association studies (GWAS) commonly map to non-coding DNA regulatory regions. Many of these regions are located considerable distances away from the genes they regulate and come into their proximity through 3D chromosomal interactions. We previously developed COGS, a statistical pipeline for linking GWAS variants with their putative target genes based on 3D chromosomal interaction data arising from high-resolution assays such as Promoter Capture Hi-C (PCHi-C). Here, we applied COGS to COVID-19 Host Genetic Consortium (HGI) GWAS meta-analysis data on COVID-19 susceptibility and severity using our previously generated PCHi-C results in 17 human primary cell types and SARS-CoV-2-infected lung carcinoma cells. We prioritise 251 genes putatively associated with these traits,including 16 out of 47 genes highlighted by the GWAS meta-analysis authors. The prioritised genes are expressed in a broad arrayof tissues, including, but not limited to, blood and brain cells, and are enriched for genes involved in the inflammatory response to viral infection. Our prioritised genes and pathways, in conjunction with results from other prioritisation approaches and targeted validation experiments, will aid in the understanding of COVID-19 pathology, paving the way for novel treatments

Approaches and advances in the genetic causes of autoimmune disease and their implications

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Despite the field being just over ten years old, advances in understanding the underlying mechanistic pathways of these conditions, which are the result of a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights in therapeutic possibilities. Nevertheless, the challenge to identify the actual causal genes and pathways and their biological effects in altering disease risk for many identified susceptibility regions remains. It is this fundamental knowledge that will underpin a revolution in patient stratification, therapeutic target discovery and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardised gene expression data and other phenotypic data that are fuelling a bounty of discovery and improved understanding of human physiology

Approaches and advances in the genetic causes of autoimmune disease and their implications

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Despite the field being just over ten years old, advances in understanding the underlying mechanistic pathways of these conditions, which are the result of a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights in therapeutic possibilities. Nevertheless, the challenge to identify the actual causal genes and pathways and their biological effects in altering disease risk for many identified susceptibility regions remains. It is this fundamental knowledge that will underpin a revolution in patient stratification, therapeutic target discovery and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardised gene expression data and other phenotypic data that are fuelling a bounty of discovery and improved understanding of human physiology

Approaches and advances in the genetic causes of autoimmune disease and their implications

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology

Prevalence of CFTR variants in PID patients with bronchiectasis - an important modifying co-factor

Background Cystic fibrosis (CF) is one of the most common life limiting autosomal recessive disorders and is caused by genetic defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID). Objective We hypothesized that a ‘carrier’ CFTR status might be associated with worse outcome regarding structural lung disease in patients with PID. Methods A within-cohort and population level statistical genomic analysis of a large European cohort of PID patients was performed using genome sequence data. Genomic analysis of variant pathogenicity was performed. Results Compared to the general population, p.Phe508del carriage was enriched in lung-related PID. Additionally, carriage of several pathogenic CFTR gene variants were increased in PID associated with structural lung damage, compared to PID patients without the structural lung damage. We identified three additional biallelic cases including several variants not traditionally considered as CF-causing. Conclusion Genome sequencing identified cases of CFTR dysfunction in PID, driving an increased susceptibility to infection. Large national genomics services provide an opportunity for precision medicine by interpreting subtle features of genomic diversity when treating traditional Mendelian disorders

Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters

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