Identifying synonymous regulatory elements in vertebrate genomes

Synonymous gene regulation, defined by regulatory elements driving shared temporal and/or spatial aspects of gene expression, is most probably predicated on genomic elements that contain similar modules of certain transcription factor binding sites (TFBS). We have developed a method to scan vertebrate genomes for evolutionary conserved modules of TFBS in a predefined configuration, and created a tool, named SynoR that identifies synonymous regulatory elements (SREs) in vertebrate genomes. SynoR performs de novo identification of SREs utilizing known patterns of TFBS in active regulatory elements (REs) as seeds for genome scans. Layers of multiple-species conservation allow the use of differential phylogenetic sequence conservation filters in search of SREs and the results are displayed such as to provide an extensive annotation of the genes containing the detected REs. Gene Ontology categories are utilized to further functionally classify the identified genes, and integrated GNF Expression Atlas 2 data allow the cataloging of tissue-specificities of the predicted SREs. SynoR is publicly available at

Dcode.org anthology of comparative genomic tools

Comparative genomics provides the means to demarcate functional regions in anonymous DNA sequences. The successful application of this method to identifying novel genes is currently shifting to deciphering the non-coding encryption of gene regulation across genomes. To facilitate the practical application of comparative sequence analysis to genetics and genomics, we have developed several analytical and visualization tools for the analysis of arbitrary sequences and whole genomes. These tools include two alignment tools, zPicture and Mulan; a phylogenetic shadowing tool, eShadow for identifying lineage- and species-specific functional elements; two evolutionary conserved transcription factor analysis tools, rVista and multiTF; a tool for extracting cis-regulatory modules governing the expression of co-regulated genes, Creme 2.0; and a dynamic portal to multiple vertebrate and invertebrate genome alignments, the ECR Browser. Here, we briefly describe each one of these tools and provide specific examples on their practical applications. All the tools are publicly available at the website

Array2BIO: from microarray expression data to functional annotation of co-regulated genes

BACKGROUND: There are several isolated tools for partial analysis of microarray expression data. To provide an integrative, easy-to-use and automated toolkit for the analysis of Affymetrix microarray expression data we have developed Array2BIO, an application that couples several analytical methods into a single web based utility. RESULTS: Array2BIO converts raw intensities into probe expression values, automatically maps those to genes, and subsequently identifies groups of co-expressed genes using two complementary approaches: (1) comparative analysis of signal versus control and (2) clustering analysis of gene expression across different conditions. The identified genes are assigned to functional categories based on Gene Ontology classification and KEGG protein interaction pathways. Array2BIO reliably handles low-expressor genes and provides a set of statistical methods for quantifying expression levels, including Benjamini-Hochberg and Bonferroni multiple testing corrections. An automated interface with the ECR Browser provides evolutionary conservation analysis for the identified gene loci while the interconnection with Crème allows prediction of gene regulatory elements that underlie observed expression patterns. CONCLUSION: We have developed Array2BIO – a web based tool for rapid comprehensive analysis of Affymetrix microarray expression data, which also allows users to link expression data to Dcode.org comparative genomics tools and integrates a system for translating co-expression data into mechanisms of gene co-regulation. Array2BIO is publicly available a

Human-zebrafish non-coding conserved elements act in vivo to regulate transcription

Whole genome comparisons of distantly related species effectively predict biologically important sequences—core genes and cis-acting regulatory elements (REs)—but require experimentation to verify biological activity. To examine the efficacy of comparative genomics in identification of active REs from anonymous, non-coding (NC) sequences, we generated a novel alignment of the human and draft zebrafish genomes, and contrasted this set to existing human and fugu datasets. We tested the transcriptional regulatory potential of candidate sequences using two in vivo assays. Strict selection of non-genic elements which are deeply conserved in vertebrate evolution identifies 1744 core vertebrate REs in human and two fish genomes. We tested 16 elements in vivo for cis-acting gene regulatory properties using zebrafish transient transgenesis and found that 10 (63%) strongly modulate tissue-specific expression of a green fluorescent protein reporter vector. We also report a novel quantitative enhancer assay with potential for increased throughput based on normalized luciferase activity in vivo. This complementary system identified 11 (69%; including 9 of 10 GFP-confirmed elements) with cis-acting function. Together, these data support the utility of comparative genomics of distantly related vertebrate species to identify REs and provide a scaleable, in vivo quantitative assay to define functional activity of candidate REs

Independence of an advocate in disciplinary proceedings: a comparative approach with a focus on Ukrainian experience

This research brings a special focus on the notion of disciplinary liability of advocates, regarding their status in a legal system dedicated to universal standards of competitive fair trial. The article is based on experience of Ukraine in shaping an efficient system of the bar, with a wide comparative insight into the systems of disciplinary liability of lawyers in European counties. Universal standards of professional legal ethics are being peculiarly adverted. Safeguards of procedural independence of lawyers in disciplinary proceedings are presented regarding best European practices. It has been concluded that confidentiality is a cornerstone of professional status of a lawyer and limitations of this principal should be strictly envisaged by law. Otherwise, trustful relationships of a lawyer and his client would be challenged. Independence, due proceedings of investigation of disciplinary offences, proportionality are mentioned as basic principles on which the system of disciplinary liability of lawyers in a democratic society is being founded. Local bar associations play a leading role in protection of advocates’ professional rights and shielding them from unwanted attacks of any type, including infringements of procedural rights of lawyers, coming from law-enforcement authorities

Розробка алгоритму підбору жорстких упорів в сталебетонних балках при дії розподіленого навантаження

An algorithm has been developed to select rigid stops in steel-concrete beams under the action of distributed load. Concrete is connected rigidly to a steel sheet in order to perform the joint operation of the concrete and steel sheet. Such a connection in the beam is provided by rigid stops that prevent shifting efforts in the concrete and steel contact area. The efforts are determined through the turning angles between the two adjacent sections of the beam. A graph-analytical method for determining movements is used to determine the turning angles. In determining the deformations of a steel-concrete beam, the calculation is based on the reduced rigidities of cross-sections.The purpose of this study is to optimize the structure of a steel-concrete beam by selecting the rational number and arrangement of rigid stops. This optimization would allow a more rational utilization of the structure's material ‒ concrete and steel. That would reduce the cost of operations and the quantity of materials required in the production, installation, and operation of the considered structures.An earlier proposed algorithm for the selection of rigid stops in steel-concrete beams under the action of a concentrated force has been expanded for the case of an evenly distributed load. When selecting the number of rigid stops, it is assumed that the magnitude of the distributed load acting on a beam, the mechanical characteristics of materials (steel and concrete), as well as the span of the beam and the size of its cross-section, are kNown. In contrast to the beams with a concentrated force in the middle, where the forces abide by a linear law, in the beams with an evenly distributed load the efforts in a steel strip change in line with a square parabola. Therefore, while the same step has been obtained for stops, it is not possible to achieve a situation at which efforts in all stops have the same valueРазработан алгоритм подбора жестких упоров в сталебетонных балках при действии распределенной нагрузки. Бетон со стальным листом соединяется жестко с целью достижения совместной работы бетона и стального листа. Такое соединение в балке обеспечивают жесткие упоры, которые препятствуют сдвиговым усилиям в зоне контакта бетона и стали. Усилия определяются через углы поворота между двумя соседними сечениями балки. Для определения углов поворота используется графо-аналитический метод определения перемещений. При определении деформаций сталебетонной балки расчет ведется по приведенным жесткостям поперечных сечений.Цель исследования заключается в оптимизации конструкции сталебетонной балки за счет подбора рационального количества и расположения жестких упоров. Такая оптимизация позволит более рационально использовать материал конструкции – бетон и сталь. Это приведет к снижению трудозатрат и количества требуемых материалов при производстве, монтаже и эксплуатации рассматриваемых конструкций.Ранее предложенный алгоритм подбора жестких упоров в сталебетонных балках при действии сосредоточенной силы распространён на случай действия равномерно распределенной нагрузки. При подборе количества жестких упоров предполагается, что величина действующей на балку распределенной нагрузки, механические характеристики материалов (стали и бетона), а также пролет балки и размеры ее поперечного сечения известны. В отличие от балок с сосредоточенной силой посередине, где усилия изменяются по линейному закону, в балках с равномерно распределенной нагрузкой усилия в стальной полосе изменяются по квадратной параболе. Поэтому, хотя и был получен одинаковый шаг упоров, невозможно добиться положения, при котором усилия во всех упорах принимают одинаковые значенияРозроблений алгоритм підбору жорстких упорів в сталебетонних балках при дії розподіленого навантаження. Бетон зі сталевою смугою з’єднується жорстко з метою досягнення сумісної роботи бетону та сталевої смуги. Таке з’єднання в балці забезпечують жорсткі упори, які перешкоджають зусиллям зсуву в зоні контакту бетону і сталі. Зусилля визначаються через кути повороту між двома сусідніми перерізами балки. Для визначення кутів повороту використовується графо-аналітичний метод визначення переміщень. При визначенні деформацій сталебетонної балки розрахунок ведеться за приведеними жорсткостями поперечних перерізів.Ціль дослідження полягає в оптимізації конструкції сталебетонної балки за рахунок підбору раціональної кількості і розташування жорстких упорів. Така оптимізація дозволяє більш раціонально використовувати матеріал конструкції – бетон і сталь. Це призведе до зниження працезатрат і кількості потрібних матеріалів при виробництві, монтажу та експлуатації розглянутих конструкцій.Запропонований раніше алгоритм підбору жорстких упорів в сталебетонних балках при дії зосередженої сили розвинуто на випадок дії рівномірно розподіленого навантаження. При підборі кількості жорстких упорів передбачається, що величина діючого на балку розподіленого навантаження, механічні характеристики матеріалів (сталі та бетону), а також проліт балки і розміри її поперечного перерізу відомі. На відміну від балок із зосередженою силою посередині, де зусилля змінюються за лінійним законом, в балках з рівномірно розподіленим навантаженням зусилля в сталевій смузі змінюються по квадратній параболі. Тому, хоча і було отримано однаковий крок упорів, неможливо знайти положення, при якому зусилля в усіх упорах приймають однакові значенн

Modeling islet enhancers using deep learning identifies candidate causal variants at loci associated with T2D and glycemic traits.

Genetic association studies have identified hundreds of independent signals associated with type 2 diabetes (T2D) and related traits. Despite these successes, the identification of specific causal variants underlying a genetic association signal remains challenging. In this study, we describe a deep learning (DL) method to analyze the impact of sequence variants on enhancers. Focusing on pancreatic islets, a T2D relevant tissue, we show that our model learns islet-specific transcription factor (TF) regulatory patterns and can be used to prioritize candidate causal variants. At 101 genetic signals associated with T2D and related glycemic traits where multiple variants occur in linkage disequilibrium, our method nominates a single causal variant for each association signal, including three variants previously shown to alter reporter activity in islet-relevant cell types. For another signal associated with blood glucose levels, we biochemically test all candidate causal variants from statistical fine-mapping using a pancreatic islet beta cell line and show biochemical evidence of allelic effects on TF binding for the model-prioritized variant. To aid in future research, we publicly distribute our model and islet enhancer perturbation scores across ~67 million genetic variants. We anticipate that DL methods like the one presented in this study will enhance the prioritization of candidate causal variants for functional studies

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms ( SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds ( a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines - in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases