Fine mapping with epigenetic information and 3D structure

Since 2005, thousands of genome-wide association studies (GWAS) have been published, identifying hundreds of thousands of genetic variants that increase risk of complex traits such as autoimmune diseases. This wealth of data has the potential to improve patient care, through personalized medicine and the identification of novel drug targets. However, the potential of GWAS for clinical translation has not been fully achieved yet, due to the fact that the functional interpretation of risk variants and the identification of causal variants and genes are challenging. The past decade has seen the development of great advances that are facilitating the overcoming of these limitations, by utilizing a plethora of genomics and epigenomics tools to map and characterize regulatory elements and chromatin interactions, which can be used to fine map GWAS loci, and advance our understanding of the biological mechanisms that cause disease.

Neuromaps: structural and functional interpretation of brain maps

Imaging technologies are increasingly used to generate high-resolution reference maps of brain structure and function. Modern scientific discovery relies on making comparisons between new maps (e.g. task activations, group structural differences) and these reference maps. Although recent data sharing initiatives have increased the accessibility of such brain maps, data are often shared in disparate coordinate systems (or ``spaces''), precluding systematic and accurate comparisons among them. Here we introduce the neuromaps toolbox, an open-access software package for accessing, transforming, and analyzing structural and functional brain annotations. We implement two registration frameworks to generate high-quality transformations between four standard coordinate systems commonly used in neuroimaging research. The initial release of the toolbox features >40 curated reference maps and biological ontologies of the human brain, including maps of gene expression, neurotransmitter receptors, metabolism, neurophysiological oscillations, developmental and evolutionary expansion, functional hierarchy, individual functional variability, and cognitive specialization. Robust quantitative assessment of map-to-map similarity is enabled via a suite of spatial autocorrelation-preserving null models. By combining open-access data with transparent functionality for standardizing and comparing brain maps, the neuromaps software package provides a systematic workflow for comprehensive structural and functional annotation enrichment analysis of the human brain.

Canonical EEG Microstates Transitions Reflect Switching Among BOLD Resting State Networks and Predict fMRI Signal

Objective. Electroencephalography microstates (EEG-ms), which reflect a large topographical representation of coherent electrophysiological brain activity, are widely adopted to study cognitive processes mechanisms and aberrant alterations in brain disorders. EEG-ms topographies are quasi-stable lasting between 60-120 milliseconds. Some evidence suggests that EEG-ms are the electrophysiological signature of resting-state networks (RSNs). However, the spatial and functional interpretation of EEG-ms and their association with functional MRI (fMRI) remains unclear. Approach. In a large cohort of healthy subjects (n = 52), we conducted several statistical and machine learning approaches analyses on the association among EEG-ms spatio-temporal dynamics and the blood-oxygenation-level dependent (BOLD) simultaneous EEG-fMRI data using statistical and machine learning approaches. Main results. Our results using a generalized linear model unraveled that EEG-ms transitions were largely and negatively associated with blood-oxygenation-level dependent (BOLD) signals in the somatomotor, visual, dorsal attention, and ventral attention fMRI networks with limited association within the default mode network. Additionally, a novel recurrent neural network (RNN) confirmed the association between EEG-ms transitioning and fMRI signal while revealing that EEG-ms dynamics can predict BOLD signals and vice versa. Significance. Results suggest that EEG-ms transitions may represent the deactivation of fMRI RSNs and provide evidence that both modalities can measure common aspects of undergoing brain neuronal activities. Moreover, our results may help to better understand the electrophysiological interpretation of EEG-ms and solve several contradicting findings in the literature.

A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples

Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n=120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (False Discovery Rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.

Gloss to the Resolution of the Supreme Court of 26 February 2021, III CZP 24/20 [on the Interpretation of the Will]

The resolution with gloss concerns the rules for interpreting a will. The Supreme Court stated in it that an interpretation of a will should be performed taking into account all circumstances, including those external to the will and using all means of evidence. The Supreme Court decided that it is the court adjudicating in the case for inheritance acquisition, assessing the evidence gathered in a specific case, that should assess whether it is actually possible to establish the will of the testator. The author of the gloss accepts the thesis of the resolution, but argues with the position of the Supreme Court contained in its justification that only the rules for evidence assessment constitute an instrument allowing one to establish the testator’s will. In the opinion of the author of the gloss the functional interpretation of Art. 948 of the Polish Civil Code (k.c.) indicates limits to the interpretation of the will. After all this is a process that renders it possible to determine the testator’s will in a manner that does not raise any doubts. Therefore, if the interpretation of the will of such fails to secure such a degree of certainty, even despite a positive assessment of the evidence gathered in the case, the court should state that the inheritance has been acquired under the Act.

Mechanism of Rad26-assisted rescue of stalled RNA polymerase II in transcription-coupled repair

Transcription-coupled repair is essential for the removal of DNA lesions from the transcribed genome. The pathway is initiated by CSB protein binding to stalled RNA polymerase II. Mutations impairing CSB function cause severe genetic disease. Yet, the ATP-dependent mechanism by which CSB powers RNA polymerase to bypass certain lesions while triggering excision of others is incompletely understood. Here we build structural models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in nucleotide-free and bound states. This enables simulations and graph-theoretical analyses to define partitioning of this complex into dynamic communities and delineate how its structural elements function together to remodel DNA. We identify an allosteric pathway coupling motions of the Rad26 ATPase modules to changes in RNA polymerase and DNA to unveil a structural mechanism for CSB-assisted progression past less bulky lesions. Our models allow functional interpretation of the effects of Cockayne syndrome disease mutations.

Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

The quest for palaeolithic art in the Neris river valley, Central-Eastern Lithuania

Only a few artifacts discovered in Lithuania can be considered as examples of portable art from the Final Palaeolithic period. Three of them were found in the Neris river valley in central-eastern Lithuania: an engraved slate pebble from the Eiguliai 1А site, a notched blade from the Skaruliai 1 site, and a flint “figurine” from the Vilnius 1 site. Discovered by Rimutė Rimantienė and her father Konstantinas Jablonskis, these three finds were the first and for many years the only artifacts underpinning the discussion of art from the Lithuanian Final Palaeolithic. The debate on the tentative function of these items, initiated by Rimantienė, is reviewed in this study before presenting the results of the latest research on the subject between 2012 and 2017, carried out using a range of methods: visual examination, comparative analysis with other archaeological finds and reconstructed prehistoric tools, surface analysis under a microscope. The functional interpretation proposed as a result of these investigations in two cases disproves the identification of these artifacts as portable art.

Development of a bioinformatics platform for analysis of quantitative transcriptomics and proteomics data: the OMnalysis

Background In the past decade, RNA sequencing and mass spectrometry based quantitative approaches are being used commonly to identify the differentially expressed biomarkers in different biological conditions. Data generated from these approaches come in different sizes (e.g., count matrix, normalized list of differentially expressed biomarkers, etc.) and shapes (e.g., sequences, spectral data, etc.). The list of differentially expressed biomarkers is used for functional interpretation and retrieve biological meaning, however, it requires moderate computational skills. Thus, researchers with no programming expertise find difficulty in data interpretation. Several bioinformatics tools are available to analyze such data; however, they are less flexible for performing the multiple steps of visualization and functional interpretation. Implementation We developed an easy-to-use Shiny based web application (named as OMnalysis) that provides users with a single platform to analyze and visualize the differentially expressed data. The OMnalysis accepts the data in tabular form from edgeR, DESeq2, MaxQuant Perseus, R packages, and other similar software, which typically contains the list of differentially expressed genes or proteins, log of the fold change, log of the count per million, the P value, q-value, etc. The key features of the OMnalysis are multiple image type visualization and their dimension customization options, seven multiple hypothesis testing correction methods to get more significant gene ontology, network topology-based pathway analysis, and multiple databases support (KEGG, Reactome, PANTHER, biocarta, NCI-Nature Pathway Interaction Database PharmGKB and STRINGdb) for extensive pathway enrichment analysis. OMnalysis also fetches the literature information from PubMed to provide supportive evidence to the biomarkers identified in the analysis. In a nutshell, we present the OMnalysis as a well-organized user interface, supported by peer-reviewed R packages with updated databases for quick interpretation of the differential transcriptomics and proteomics data to biological meaning. Availability The OMnalysis codes are entirely written in R language and freely available at https://github.com/Punit201016/OMnalysis. OMnalysis can also be accessed from - http://lbmi.uvlf.sk/omnalysis.html. OMnalysis is hosted on a Shiny server at https://omnalysis.shinyapps.io/OMnalysis/. The minimum system requirements are: 4 gigabytes of RAM, i3 processor (or equivalent). It is compatible with any operating system (windows, Linux or Mac). The OMnalysis is heavily tested on Chrome web browsers; thus, Chrome is the preferred browser. OMnalysis works on Firefox and Safari.

Massively parallel identification of functionally consequential noncoding genetic variants in undiagnosed rare disease patients

Clinical whole genome sequencing has enabled the discovery of potentially pathogenic noncoding variants in the genomes of rare disease patients with a prior history of negative genetic testing. However, interpreting the functional consequences of noncoding variants and distinguishing those that contribute to disease etiology remains a challenge. Here we address this challenge by experimentally profiling the functional consequences of rare noncoding variants detected in a cohort of undiagnosed rare disease patients at scale using a massively parallel reporter assay. We demonstrate that this approach successfully identifies rare noncoding variants that alter the regulatory capacity of genomic sequences. In addition, we describe an integrative analysis that utilizes genomic features alongside patient clinical data to further prioritize candidate variants with an increased likelihood of pathogenicity. This work represents an important step towards establishing a framework for the functional interpretation of clinically detected noncoding variants.