Brain-Region-Specific Genes Form the Major Pathways Featuring Their Basic Functional Role: Their Implication in Animal Chronic Stress Model.

The analysis of RNA-Sec data from murine bulk tissue samples taken from five brain regions associated with behavior and stress response was conducted. The focus was on the most contrasting brain region-specific genes (BRSG) sets in terms of their expression rates. These BRSGs are identified as genes with a distinct outlying (high) expression rate in a specific region compared to others used in the study. The analysis suggested that BRSG sets form non-randomly connected compact gene networks, which correspond to the major neuron-mediated functional processes or pathways in each brain region. The number of BRSGs and the connection rate were found to depend on the heterogeneity and coordinated firing rate of neuron types in each brain region. The most connected pathways, along with the highest BRSG number, were observed in the Striatum, referred to as Medium Spiny Neurons (MSNs), which make up 95% of neurons and exhibit synchronous firing upon dopamine influx. However, the Ventral Tegmental Area/Medial Raphe Nucleus (VTA/MRN) regions, although primarily composed of monoaminergic neurons, do not fire synchronously, leading to a smaller BRSG number. The Hippocampus (HPC) region, on the other hand, displays significant neuronal heterogeneity, with glutamatergic neurons being the most numerous and synchronized. Interestingly, the two monoaminergic regions involved in the study displayed a common BRSG subnetwork architecture, emphasizing their proximity in terms of axonal throughput specifics and high-energy metabolism rates. This finding suggests the concerted evolution of monoaminergic neurons, leading to unique adaptations at the genic repertoire scale. With BRSG sets, we were able to highlight the contrasting features of the three groups: control, depressive, and aggressive mice in the animal chronic stress model. Specifically, we observed a decrease in serotonergic turnover in both the depressed and aggressive groups, while dopaminergic emission was high in both groups. There was also a notable absence of dopaminoceptive receptors on the postsynaptic membranes in the striatum in the depressed group. Additionally, we confirmed that neurogenesis BRSGs are specific to HPC, with the aggressive group showing attenuated neurogenesis rates compared to the control/depressive groups. We also confirmed that immune-competent cells like microglia and astrocytes play a crucial role in depressed phenotypes, including mitophagy-related gene Prkcd. Based on this analysis, we propose the use of BRSG sets as a suitable framework for evaluating case-control group-wise assessments of specific brain region gene pathway responses.

Elucidation of the Landscape of Alternatively Spliced Genes and Features in the Dorsal Striatum of Aggressive/Aggression-Deprived Mice in the Model of Chronic Social Conflicts.

Both aggressive and aggression-deprived (AD) individuals represent pathological cases extensively studied in psychiatry and substance abuse disciplines. We employed the animal model of chronic social conflicts curated in our laboratory for over 30 years. In the study, we pursued the task of evaluation of the key events in the dorsal striatum transcriptomes of aggression-experienced mice and AD species, as compared with the controls, using RNA-seq profiling. We evaluated the alternative splicing-mediated transcriptome dynamics based on the RNA-seq data. We confined our attention to the exon skipping (ES) events as the major AS type for animals. We report the concurrent posttranscriptional and posttranslational regulation of the ES events observed in the phosphorylation cycles (in phosphoproteins and their targets) in the neuron-specific genes of the striatum. Strikingly, we found that major neurospecific splicing factors (Nova1, Ptbp1, 2, Mbnl1, 2, and Sam68) related to the alternative splicing regulation of cAMP genes (Darpp-32, Grin1, Ptpn5, Ppp3ca, Pde10a, Prkaca, Psd95, and Adora1) are upregulated specifically in aggressive individuals as compared with the controls and specifically AD animals, assuming intense switching between isoforms in the cAMP-mediated (de)phosphorylation signaling cascade. We found that the coding alternative splicing events were mostly attributed to synaptic plasticity and neural development-related proteins, while the nonsense-mediated decay-associated splicing events are mostly attributed to the mRNA processing of genes, including the spliceosome and splicing factors. In addition, considering the gene families, the transporter (Slc) gene family manifested most of the ES events. We found out that the major molecular systems employing AS for their plasticity are the 'spliceosome', 'chromatin rearrangement complex', 'synapse', and 'neural development/axonogenesis' GO categories. Finally, we state that approximately 35% of the exon skipping variants in gene coding regions manifest the noncoding variants subject to nonsense-mediated decay, employed as a homeostasis-mediated expression regulation layer and often associated with the corresponding gene expression alteration.

Effects of Positive Fighting Experience and Its Subsequent Deprivation on the Expression Profile of Mouse Hippocampal Genes Associated with Neurogenesis.

The hippocampus is known as the brain region implicated in visuospatial processes and processes associated with learning and short- and long-term memory. An important functional characteristic of the hippocampus is lifelong neurogenesis. A decrease or increase in adult hippocampal neurogenesis is associated with a wide range of neurological diseases. We have previously shown that in adult male mice with a chronic positive fighting experience in daily agonistic interactions, there is an increase in the proliferation of progenitor neurons and the production of young neurons in the dentate gyrus (in hippocampus), and these neurogenesis parameters remain modified during 2 weeks of deprivation of further fights. The aim of the present work was to identify hippocampal genes associated with neurogenesis and involved in the formation of behavioral features in mice with the chronic experience of wins in aggressive confrontations, as well as during the subsequent 2-week deprivation of agonistic interactions. Hippocampal gene expression profiles were compared among three groups of adult male mice: chronically winning for 20 days in the agonistic interactions, chronically victorious for 20 days followed by the 2-week deprivation of fights, and intact (control) mice. Neurogenesis-associated genes were identified whose transcription levels changed during the social confrontations and in the subsequent period of deprivation of fights. In the experimental males, some of these genes are associated with behavioral traits, including abnormal aggression-related behavior, an abnormal anxiety-related response, and others. Two genes encoding transcription factors (Nr1d1 and Fmr1) were likely to contribute the most to the between-group differences. It can be concluded that the chronic experience of wins in agonistic interactions alters hippocampal levels of transcription of multiple genes in adult male mice. The transcriptome changes get reversed only partially after the 2-week period of deprivation of fights. The identified differentially expressed genes associated with neurogenesis and involved in the control of a behavior/neurological phenotype can be used in further studies to identify targets for therapeutic correction of the neurological disturbances that develop in winners under the conditions of chronic social confrontations.

Advances of Brain Transcriptomics.

Advancements in RNA sequencing technology in past decade have underlined its power for elucidating the brain gene networks responsible for various stressful factors, as well as the pathologies associated with both genetically determined neurodegenerative diseases and those acquired during the lifespan [...].

The Dysfunction of Carcinogenesis- and Apoptosis-Associated Genes that Develops in the Hypothalamus under Chronic Social Defeat Stress in Male Mice.

Chronic social stress caused by daily agonistic interactions in male mice leads to a mixed anxiety/depression-like disorder that is accompanied by the development of psychogenic immunodeficiency and stimulation of oncogenic processes concurrently with many neurotranscriptomic changes in brain regions. The aim of the study was to identify carcinogenesis- and apoptosis-associated differentially expressed genes (DEGs) in the hypothalamus of male mice with depression-like symptoms and, for comparison, in aggressive male mice with positive social experience. To obtain two groups of animals with the opposite 20-day social experiences, a model of chronic social conflict was used. Analysis of RNA-Seq data revealed similar expression changes for many DEGs between the aggressive and depressed animals in comparison with the control group; however, the number of DEGs was significantly lower in the aggressive than in the depressed mice. It is likely that the observed unidirectional changes in the expression of carcinogenesis- and apoptosis-associated genes in the two experimental groups may be a result of prolonged social stress (of different severity) caused by the agonistic interactions. In addition, 26 DEGs were found that did not change expression in the aggressive animals and could be considered genes promoting carcinogenesis or inhibiting apoptosis. Akt1, Bag6, Foxp4, Mapk3, Mapk8, Nol3, Pdcd10, and Xiap were identified as genes whose expression most strongly correlated with the expression of other DEGs, suggesting that their protein products play a role in coordination of the neurotranscriptomic changes in the hypothalamus. Further research into functions of these genes may be useful for the development of pharmacotherapies for psychosomatic pathologies.

LPS Administration Impacts Glial Immune Programs by Alternative Splicing.

We performed transcriptome analysis in the hippocampus 24 h after lipopolysaccharide (LPS) administration. We observed glial-specific genes, comprised of two-thirds of all differentially expressed genes (DEGs). We found microglial DEGs that were the most numerous in LPS group. On the contrary, differential alternative splicing (DAS) analysis revealed the most numerous DAS events in astrocytes. Besides, we observed distinct major isoform switching in the Ptbp1 gene, with skipping of exon 8 in LPS group. Ptbp1 usually considered a pluripotency sustaining agent in brain embryonic development, according to the previous studies. Analyzing the splicing tune-up upon LPS exposure, we came to a supposition that the short Ptbp1 isoform de-represses immune-specific response by Ptbp1 adjusted splicing architecture. Additionally, the Ptbp3 (NOD1) immune-specific splicing factor has apparently been de-repressed by the Ptbp1 short isoform in glial cells. Notably, both the Ptbp1 and Ptbp3 genes express primarily in microglial/endothelial brain cells. We also report immune-related genes, altering their major isoforms upon LPS exposure. The results revealed immune modulating role of alternative splicing in brain.

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis.

Acute cerebral ischemia induces distant inflammation in the hippocampus; however, molecular mechanisms of this phenomenon remain obscure. Here, hippocampal gene expression profiles were compared in two experimental paradigms in rats: middle cerebral artery occlusion (MCAO) and intracerebral administration of lipopolysaccharide (LPS). The main finding is that 10 genes (Clec5a, CD14, Fgr, Hck, Anxa1, Lgals3, Irf1, Lbp, Ptx3, Serping1) may represent key molecular links underlying acute activation of immune cells in the hippocampus in response to experimental ischemia. Functional annotation clustering revealed that these genes built the same clusters related to innate immunity/immunity/innate immune response in all MCAO differentially expressed genes and responded to the direct pro-inflammatory stimulus group. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses also indicate that LPS-responding genes were the most abundant among the genes related to "positive regulation of tumor necrosis factor biosynthetic process", "cell adhesion", "TNF signaling pathway", and "phagosome" as compared with non-responding ones. In contrast, positive and negative "regulation of cell proliferation" and "HIF-1 signaling pathway" mostly enriched with genes that did not respond to LPS. These results contribute to understanding genomic mechanisms of the impact of immune/inflammatory activation on expression of hippocampal genes after focal brain ischemia.

Fitness Analysis and Transcriptome Profiling Following Repeated Mild Heat Stress of Varying Frequency in Drosophilamelanogaster Females.

Understanding how repeated stress affects metabolic and physiological functions in the long run is of crucial importance for evaluating anthropogenic pressure on the environment. We investigated fertility, longevity and metabolism in D. melanogaster females exposed to short-term heat stress (38 °C, 1 h) repeated daily or weekly. Daily stress was shown to cause a significant decrease in both fertility and longevity, as well as in body mass and triglyceride (fat) content, but a significant increase in trehalose and glucose content. Weekly stress did not affect longevity and carbohydrate metabolism but resulted in a significant decrease in body mass and fat content. Weekly stress did not affect the total level of fertility, despite sharp fertility drops on the exact days of stressing. However, stressing insects weekly, only in the first two weeks after eclosion, caused a significant increase in the total level of fertility. The analysis of differentially expressed genes in the fat bodies and adjacent tissues of researched groups with the use of RNA-Seq profiling revealed changes in signal pathways related to proteolysis/digestion, heat shock protein 23, and in the tightly linked stress-inducible humoral factor Turandot gene network.

Correlation of Expression Changes between Genes Controlling 5-HT Synthesis and Genes Crh and Trh in the Midbrain Raphe Nuclei of Chronically Aggressive and Defeated Male Mice.

Midbrain raphe nuclei (MRNs) contain a large number of serotonergic neurons associated with the regulation of numerous types of psychoemotional states and physiological processes. The aim of this work was to study alterations of the MRN transcriptome in mice with prolonged positive or negative fighting experience and to identify key gene networks associated with the regulation of serotonergic system functioning. Numerous genes underwent alterations of transcription in the MRNs of male mice that either manifested aggression or experienced social defeat in daily agonistic interactions. The expression of the Tph2 gene encoding the rate-limiting enzyme of the serotonin synthesis pathway correlated with the expression of many genes, 31 of which were common between aggressive and defeated mice and were downregulated in the MRNs of mice of both experimental groups. Among these common differentially expressed genes (DEGs), there were genes associated with behavior, learning, memory, and synaptic signaling. These results suggested that, in the MRNs of the mice, the transcriptome changes associated with serotonergic regulation of various processes are similar between the two groups (aggressive and defeated). In the MRNs, more DEGs correlating with Tph2 expression were found in defeated mice than in the winners, which is probably a consequence of deeper Tph2 downregulation in the losers. It was shown for the first time that, in both groups of experimental mice, the changes in the transcription of genes controlling the synthesis and transport of serotonin directly correlate with the expression of genes Crh and Trh, which control the synthesis of corticotrophin- and thyrotropin-releasing hormones. Our findings indicate that CRH and TRH locally produced in MRNs are related to serotonergic regulation of brain processes during a chronic social conflict.

Reduced Expression of Slc Genes in the VTA and NAcc of Male Mice with Positive Fighting Experience.

A range of several psychiatric medications targeting the activity of solute carrier (SLC) transporters have proved effective for treatment. Therefore, further research is needed to elucidate the expression profiles of the Slc genes, which may serve as markers of altered brain metabolic processes and neurotransmitter activities in psychoneurological disorders. We studied the Slc differentially expressed genes (DEGs) using transcriptomic profiles in the ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of control and aggressive male mice with psychosis-like behavior induced by repeated experience of aggression accompanied with wins in daily agonistic interactions. The majority of the Slc DEGs were shown to have brain region-specific expression profiles. Most of these genes in the VTA and NAcc (12 of 17 and 25 of 26, respectively) were downregulated, which was not the case in the PFC (6 and 5, up- and downregulated, respectively). In the VTA and NAcc, altered expression was observed for the genes encoding the transporters of neurotransmitters as well as inorganic and organic ions, amino acids, metals, glucose, etc. This indicates an alteration in transport functions for many substrates, which can lead to the downregulation or even disruption of cellular and neurotransmitter processes in the VTA and NAcc, which are attributable to chronic stimulation of the reward systems induced by positive fighting experience. There is not a single Slc DEG common to all three brain regions. Our findings show that in male mice with repeated experience of aggression, altered activity of neurotransmitter systems leads to a restructuring of metabolic and neurotransmitter processes in a way specific for each brain region. We assume that the scoring of Slc DEGs by the largest instances of significant expression co-variation with other genes may outline a candidate for new prognostic drug targets. Thus, we propose that the Slc genes set may be treated as a sensitive genes marker scaffold in brain RNA-Seq studies.

Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation.

Both aggressive and aggression-deprived (AD) species represent pathologic cases intensely addressed in psychiatry and substance abuse disciplines. Previously, we reported that AD mice displayed a higher aggressive behavior score than the aggressive group, implying the manifestation of a withdrawal effect. We employed an animal model of chronic social conflicts, curated in our lab for more than 30 years. In the study, we pursued the task of evaluating key events in the dorsal striatum transcriptome of aggression experienced mice and AD species compared to controls using RNA-Seq profiling. Aggressive species were subjected to repeated social conflict encounters (fights) with regular positive (winners) experience in the course of 20 consecutive days (A20 group). This led to a profoundly shifted transcriptome expression profile relative to the control group, outlined by more than 1000 differentially expressed genes (DEGs). RNA-Seq cluster analysis revealed that elevated cyclic AMP (cAMP) signaling cascade and associated genes comprising 170 differentially expressed genes (DEGs) in aggressive (A20) species were accompanied by a downturn in the majority of other metabolic/signaling gene networks (839 DEGs) via the activation of transcriptional repressor DEGs. Fourteen days of a consecutive fighting deprivation period (AD group) featured the basic restoration of the normal (control) transcriptome expression profile yielding only 62 DEGs against the control. Notably, we observed a network of 12 coordinated DEG Transcription Factor (TF) activators from 62 DEGs in total that were distinctly altered in AD compared to control group, underlining the distinct transcription programs featuring AD group, partly retained from the aggressive encounters and not restored to normal in 14 days. We found circadian clock TFs among them, reported previously as a withdrawal effect factor. We conclude that the aggressive phenotype selection with positive reward effect (winning) manifests an addiction model featuring a distinct opioid-related withdrawal effect in AD group. Along with reporting profound transcriptome alteration in A20 group and gaining some insight on its specifics, we outline specific TF activator gene networks associated with transcriptional repression in affected species compared to controls, outlining Nr1d1 as a primary candidate, thus offering putative therapeutic targets in opioid-induced withdrawal treatment.

Analyzing a putative enhancer of optic disc morphology.

BACKGROUND: Genome-wide association studies have identified the CDC7-TGFBR3 intergenic region on chromosome 1 to be strongly associated with optic disc area size. The mechanism of its function remained unclear until new data on eQTL markers emerged from the Genotype-Tissue Expression project. The target region was found to contain a strong silencer of the distal (800 kb) Transcription Factor (TF) gene GFI1 (Growth Factor Independent Transcription Repressor 1) specifically in neuroendocrine cells (pituitary gland). GFI1 has also been reported to be involved in the development of sensory neurons and hematopoiesis. Therefore, GFI1, being a developmental gene, is likely to affect optic disc area size by altering the expression of the associated genes via long-range interactions. RESULTS: Distribution of haplotypes in the putative enhancer region has been assessed using the data on four continental supergroups generated by the 1000 Genomes Project. The East Asian (EAS) populations were shown to manifest a highly homogenous unimodal haplotype distribution pattern within the region with the major haplotype occurring with the frequency of 0.9. Another European specific haplotype was observed with the frequency of 0.21. The major haplotype appears to be involved in silencing GFI1repressor gene expression, which might be the cause of increased optic disc area characteristic of the EAS populations. The enhancer/eQTL region overlaps AluJo element, which implies that this particular regulatory element is primate-specific and confined to few tissues. CONCLUSION: Population specific distribution of GFI1 enhancer alleles may predispose certain ethnic groups to glaucoma.

Gene Expression Changes in the Ventral Tegmental Area of Male Mice with Alternative Social Behavior Experience in Chronic Agonistic Interactions.

Daily agonistic interactions of mice are an effective experimental approach to elucidate the molecular mechanisms underlying the excitation of the brain neurons and the formation of alternative social behavior patterns. An RNA-Seq analysis was used to compare the ventral tegmental area (VTA) transcriptome profiles for three groups of male C57BL/6J mice: winners, a group of chronically winning mice, losers, a group of chronically defeated mice, and controls. The data obtained show that both winners and defeated mice experience stress, which however, has a more drastic effect on defeated animals causing more significant changes in the levels of gene transcription. Four genes (Nrgn, Ercc2, Otx2, and Six3) changed their VTA expression profiles in opposite directions in winners and defeated mice. It was first shown that Nrgn (neurogranin) expression was highly correlated with the expression of the genes involved in dopamine synthesis and transport (Th, Ddc, Slc6a3, and Drd2) in the VTA of defeated mice but not in winners. The obtained network of 31 coregulated genes, encoding proteins associated with nervous system development (including 24 genes associated with the generation of neurons), may be potentially useful for studying their role in the VTA dopaminergic neurons maturation under the influence of social stress.

Frequent Recombination Events in Leishmania donovani: Mining Population Data.

The Leishmania donovani species complex consists of all L. donovani and L. infantum strains mainly responsible for visceral leishmaniasis (VL). It was suggested that genome rearrangements in Leishmania spp. occur very often, thus enabling parasites to adapt to the different environmental conditions. Some of these rearrangements may be directly linked to the virulence or explain the reduced efficacy of antimonial drugs in some isolates. In the current study, we focused on a large-scale analysis of putative gene conversion events using publicly available datasets. Previous population study of L. donovani suggested that population variability of L. donovani is relatively low, however the authors used masking procedures and strict read selection criteria. We decided to re-analyze DNA-seq data without masking sequences, because we were interested in the most dynamic fraction of the genome. The majority of samples have an excess of putative gene conversion/recombination events in the noncoding regions, however we found an overall excess of putative intrachromosomal gene conversion/recombination in the protein coding genes, compared to putative interchromosomal gene conversion/recombination events.

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks.

BACKGROUND: Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)-mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. RESULTS: A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. CONCLUSION: Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.

Aberrant Expression of Collagen Gene Family in the Brain Regions of Male Mice with Behavioral Psychopathologies Induced by Chronic Agonistic Interactions.

Chronic agonistic interactions promote the development of experimental psychopathologies in animals: a depression-like state in chronically defeated mice and the pathology of aggressive behavior in the mice with repeated wins. The abundant research data indicate that such psychopathological states are associated with significant molecular and cellular changes in the brain. This paper aims to study the influence of a 20-day period of agonistic interactions on the expression patterns of collagen family genes encoding the proteins which are basic components of extracellular matrix (ECM) in different brain regions of mice using the RNA-Seq database. Most of differentially expressed collagen genes were shown to be upregulated in the hypothalamus and striatum of chronically aggressive and defeated mice and in the hippocampus of defeated mice, whereas downregulation of collagen genes was demonstrated in the ventral tegmental areas in both experimental groups. Aberrant expression of collagen genes induced by chronic agonistic interactions may be indicative of specific ECM defects in the brain regions of mice with alternative social experience. This is the first study demonstrating remodeling of ECM under the development of experimental disorders.

FTO haplotyping underlines high obesity risk for European populations.

BACKGROUND: Fat mass and obesity-associated (FTO) gene has been under close investigation since the discovery of its high impact on the obesity status in 2007 by a range of publications. Recent report on its implication in adipocytes underscored its molecular and functional mechanics in pathology. Still, the population specific features of the locus structure have not been approached in detail. METHODS: We analyzed the population specific haplotype profiles of FTO genomic locus identified by Genome Wide Association Studies (GWAS) for the high obesity risk by examining eighteen 1000G populations from 4 continental groups. The GWAS SNPs cluster is located in the FTO gene intron 1 spanning around 70 kb. RESULTS: We reconstructed the ancestral state of the locus, which comprised low-risk major allele found in all populations, and two minor risk-associated alleles, each one specific for African and European populations, correspondingly. The locus structure and its allele frequency distribution underscore the high risk allele frequency specifically for the European population. South Asian populations have the second highest frequency of risk alleles, while East Asian populations have the lowest. African population-specific minor allele was only partially risk-associated. All of the GWAS SNPs considered are manifested by low risk alleles as reference (major) ones (p > 0.5) in each of the continental groups. Strikingly, rs1421085, recently reported as a causal SNP, was found to be monomorphic in ancestral (African) populations, implying possible selection sweep in the course of its rapid fixation, as reported previously. CONCLUSION: The observations underscore varying FTO -linked risk in the manifestation of population specific epidemiology of genetically bound obesity. The results imply that the FTO locus is one of the major genetic determinants for obesity risk from GWAS SNPs set.

Volatile Evolution of Long Non-Coding RNA Repertoire in Retinal Pigment Epithelium: Insights from Comparison of Bovine and Human RNA Expression Profiles.

Currently, several long non-coding RNAs (lncRNAs) (TUG1, MALAT1, MEG3 and others) have been discovered to regulate normal visual function and may potentially contribute to dysfunction of the retina. We decided to extend these analyses of lncRNA genes to the retinal pigment epithelium (RPE) to determine whether there is conservation of RPE-expressed lncRNA between human and bovine genomes. We reconstructed bovine RPE lncRNAs based on genome-guided assembly. Next, we predicted homologous human transcripts based on whole genome alignment. We found a small set of conserved lncRNAs that could be involved in signature RPE functions that are conserved across mammals. However, the fraction of conserved lncRNAs in the overall pool of lncRNA found in RPE appeared to be very small (less than 5%), perhaps reflecting a fast and flexible adaptation of the mammalian eye to various environmental conditions.

Nucleotide Weight Matrices Reveal Ubiquitous Mutational Footprints of AID/APOBEC Deaminases in Human Cancer Genomes.

Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type. The conventional method used for the analysis of mutable motifs is the consensus approach. Here, for the first time, we have adopted the frequently used weight matrix (sequence profile) approach for the analysis of mutagenesis and provide evidence for this method being a more precise descriptor of mutations than the sequence consensus approach. We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of somatic mutation spectra attributable to deaminases in cancer genomes. Overall, the weight matrix approach reveals that somatic mutations are significantly associated with at least one AID/APOBEC mutable motif in all studied cancers.