Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of ...the human genome, we hypothesize that using a generic reference could lead to incorrectly mapped reads and bias downstream results.
We show that accounting for genetic variation using a modified reference genome or a de novo assembled genome can alter histone H3K4me1 and H3K27ac ChIP-seq peak calls either by creating new personal peaks or by the loss of reference peaks. Using permissive cutoffs, modified reference genomes are found to alter approximately 1% of peak calls while de novo assembled genomes alter up to 5% of peaks. We also show statistically significant differences in the amount of reads observed in regions associated with the new, altered, and unchanged peaks. We report that short insertions and deletions (indels), followed by single nucleotide variants (SNVs), have the highest probability of modifying peak calls. We show that using a graph personalized genome represents a reasonable compromise between modified reference genomes and de novo assembled genomes. We demonstrate that altered peaks have a genomic distribution typical of other peaks.
Analyzing epigenomic datasets with personalized and graph genomes allows the recovery of new peaks enriched for indels and SNVs. These altered peaks are more likely to differ between individuals and, as such, could be relevant in the study of various human phenotypes.
Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic ...contexts. Long-read, high fidelity genome sequencing (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal and graph genomes. We leverage standard reference genomes, public assemblies (n = 94) and a large collection of HiFi-GS data from a rare disease program (Genomic Answers for Kids, GA4K, n = 574 assemblies) to build a graph genome representing a unified SV callset in GA4K, identify common variation and prioritize SVs that are more likely to cause genetic disease (MAF < 0.01). Using graphs, we obtain a higher level of reproducibility than the standard reference approach. We observe over 200,000 SV alleles unique to GA4K, including nearly 1000 rare variants that impact coding sequence. With improved specificity for rare SVs, we isolate 30 candidate SVs in phenotypically prioritized genes, including known disease SVs. We isolate a novel diagnostic SV in KMT2E, demonstrating use of personal assemblies coupled with pangenome graphs for rare disease genomics. The community may interrogate our pangenome with additional assemblies to discover new SVs within the allele frequency spectrum relevant to genetic diseases.
Dogmatic discourse and institutionalized control build a totalitarian state on two main pillars: propaganda and indoctrination. Our study analyzes the phenomena of cultural mimesis and ideological ...transplantation inside the Romanian communist system. The periphery and centre represent concepts that help us in the process of constructing our cultural theory about the propaganda system and its evolution during the years before the abolition of the monarchy, 1946-1947. The study is based mainly on archive documents. Therefore, we followed up the chronological paths in which the propaganda was used as an external weapon, and also as an internal indoctrination.
The aim of the study is to show the evolution of the National Legionary State from its beginnings to its fi nal form of revolt (20-23rd January 1941). This type of state was created on 14th September ...1940 by the royal wish of Michael I of Romania, who was infl uenced by General Ion Antonescu. The study has the purpose to show how anti-Semitism can transform itself from a philosophy concept, through the ideas of Nae Ionescu, to a state ideology. The main documents which I studied are based on archives, the constitution of the state, during the period mentioned in the title, and the journals of general Ion Antonescu, or main political fi gures, and the notes written by Filip Browner, known better as Filip Brunea Fox, in his City of massacre. Journal of Legionary, Rebellion and Crime. This study is important because it analyzes a totalitarian regime that was made possible by the intervention of political arrangements alongside the help of the Legion of the Archangel Michael, founded by the Corneliu Zelea Codreanu in 1927.
A draft human pangenome reference Liao, Wen-Wei; Asri, Mobin; Ebler, Jana ...
Nature (London),
05/2023, Volume:
617, Issue:
7960
Journal Article
Peer reviewed
Open access
Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse ...individuals
. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.
Humans display remarkable interindividual variation in their immune response to identical challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation ...remains limited. Here we performed in-depth genetic, epigenetic and transcriptional profiling on primary macrophages derived from individuals of European and African ancestry before and after infection with influenza A virus. We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to influenza A virus across individuals. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation, with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape can be genetically controlled, even more than gene expression. Lastly, among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, while the remaining genetic variants impact epigenetic marks, stressing the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.
The article presents the social, diplomatic, and military evolution of the ideological conflict known as The Prague Spring. The analysis focuses on the aspects which created a context suitable for ...the reforms generated by the think-tank surrounding Alexander Dubček, Zdenek Mlynar, and the war veteran Ludvíc Svoboda. Our historical journey starts from the 5th of January 1968, when the former leadership, represented by Antonin Novotny, failed to bring Czechoslovakia out from the socio-economic crisis. Moscow was not prepared for the social reform initiated by Dubček and the citizens. We follow up the main events that brought the conflict between The Warsaw Pact and The Prague Spring.The radiography of the legal initiatives is needed because of the complexity of the thesis, in which we can find two hypotheses that create a mirror image of the Czechoslovakian events of 1968: political opposition vs. a new type of communism. Those two aspects are mingled because of the dynamic of the diplomatic relations between Prague and Moscow from January to August 1968. The consequence of the invasion initiated by the Warsaw Pact troops spread the signal that unreformed Marxist-Leninist doctrine obeyed the rules of political evolution as any type of ideology.
The aim of the study is to show the evolution of the National Legionary State from its beginnings to its final form of revolt (20-23rd January 1941). This type of state was created on 14thSeptember ...1940 by the royal wish of Michael I of Romania, who was influenced by General Ion Antonescu. The study has the purpose to show how anti-Semitism can transform itself from a philosophy concept, through the ideas of Nae Ionescu, to a state ideology. The main documents which I studied are based on archives, the constitution of the state, during the period mentioned in the title, and the journals of general Ion Antonescu, or main political figures, and the notes written by Filip Browner, known better as Filip Brunea Fox, in his City of massacre. Journal of Legionary, Rebellion and Crime. This study is important because it analyzes a totalitarian regime that was made possible by the intervention of political arrangements alongside the help of the Legion of the Archangel Michael, founded by the Corneliu Zelea Codreanu in 1927.
Genetic variants, including mobile element insertions (MEIs), are known to impact the epigenome. We hypothesized that genome graphs, which encapsulate genetic diversity, could reveal missing ...epigenomic signals. To test this, we sequenced the epigenome of monocyte-derived macrophages from 35 ancestrally diverse individuals before and after influenza infection, allowing us to investigate the role of MEIs in immunity. We characterized genetic variants and MEIs using linked reads and built a genome graph. Mapping epigenetic data revealed 2.3%–3% novel peaks for H3K4me1, H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq), and ATAC-seq. Additionally, the use of a genome graph modified some quantitative trait loci estimates and revealed 375 polymorphic MEIs in an active epigenomic state. Among these is an AluYh3 polymorphism whose chromatin state changed after infection and was associated with the expression of TRIM25, a gene that restricts influenza RNA synthesis. Our results demonstrate that graph genomes can reveal regulatory regions that would have been overlooked by other approaches.
Display omitted
•We built a genome graph for 35 individuals with transposable element polymorphisms•Mapping epigenomic data to the genome graph revealed between 2% and 3% novel peaks•Some new peaks were near immune genes and impacted quantitative trait loci estimates•We found peaks within reconstructed polymorphisms such as in an AluYh3 near TRIM25
Groza et al. created a cohort genome graph that represents the genetic variation in 35 ancestrally diverse individuals. They used the genome graph to reveal novel peaks that were hidden by reference bias and to find the epigenomic state of mobile element insertions that are eQTLs for genes that regulate antiviral innate immunity. Their finding also suggests that genome graphs may improve hQTL and caQTL discovery.
Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the ...variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.
Display omitted
•Several TE families had enhanced accessibility and variability following infection•Basal TE transcripts level was inversely correlated with viral load post-infection•Motif analysis revealed potential host regulatory factors, including KRAB-ZNFs•TEs and associated host factors were predictive of viral load post-infection
Using multi-omics data from monocyte-derived macrophages before and after influenza infection, Chen et al. characterize transcriptional and epigenetic changes in transposable elements (TEs). They identify epigenetically variable TE families with binding sites for novel host factors. Their findings suggest a role for TEs and KRAB-ZNFs in inter-individual variation in immunity.
PDF
