Functional Groups Of Genes Research Articles

Herpes Simplex Virus 1 Dramatically Alters Loading and Positioning of RNA Polymerase II on Host Genes Early in Infection.

Herpes simplex virus 1 (HSV-1) transcription is mediated by cellular RNA polymerase II (Pol II). Recent studies investigating how Pol II transcription of host genes is altered after HSV-1 are conflicting. Chromatin immunoprecipitation sequencing (ChIP-seq) studies suggest that Pol II is almost completely removed from host genes at 4 h postinfection (hpi), while 4-thiouridine (4SU) labeling experiments show that host transcription termination is extended at 7 hpi, implying that a significant amount of Pol II remains associated with host genes in infected cells. To address this discrepancy, we used precision nuclear run-on analysis (PRO-seq) to determine the location of Pol II to single-base-pair resolution in combination with quantitative reverse transcription-PCR (qRT-PCR) analysis at 3 hpi. HSV-1 decreased Pol II on approximately two-thirds of cellular genes but increased Pol II on others. For more than 85% of genes for which transcriptional termination could be statistically assessed, Pol II was displaced to positions downstream of the normal termination zone, suggesting extensive termination defects. Pol II amounts at the promoter, promoter-proximal pause site, and gene body were also modulated in a gene-specific manner. qRT-PCR of selected RNAs showed that HSV-1-induced extension of the termination zone strongly correlated with decreased RNA and mRNA accumulation. However, HSV-1-induced increases of Pol II occupancy on genes without termination zone extension correlated with increased cytoplasmic mRNA. Functional grouping of genes with increased Pol II occupancy suggested an upregulation of exosome secretion and downregulation of apoptosis, both of which are potentially beneficial to virus production.IMPORTANCE This study provides a map of RNA polymerase II location on host genes after infection with HSV-1 with greater detail than previous ChIP-seq studies and rectifies discrepancies between ChIP-seq data and 4SU labeling experiments with HSV-1. The data show the effects that a given change in RNA Pol II location on host genes has on the abundance of different RNA types, including nuclear, polyadenylated mRNA and cytoplasmic, polyadenylated mRNA. It gives a clearer understanding of how HSV-1 augments host transcription of some genes to provide an environment favorable to HSV-1 replication.

A Metagenome-Based Investigation of Gene Relationships for Non-Substrate-Associated Microbial Phosphorus Cycling in the Water Column of Streams and Rivers.

Phosphorus (P) is a nutrient of primary importance in all living systems, and it is especially important in streams and rivers which are sensitive to anthropogenic P inputs and eutrophication. Microbes are accepted as the primary mineralizers and solubilizers of P improving bioavailability for organisms at all trophic levels. Here, we use a genomics approach with metagenome sequencing of 24 temperate streams and rivers representing a total P (TP) gradient to identify relationships between functional genes, functional gene groupings, P, and organisms within the P biogeochemical cycle. Combining information from network analyses, functional groupings, and system P levels, we have constructed a System Relational Overview of Gene Groupings (SROGG) which is a cohesive system level representation of P cycle gene and nutrient relationships. Using SROGG analysis in concert with other statistical approaches, we found that the compositional makeup of P cycle genes is strongly correlated to environmental P whereas absolute abundance of P genes shows no significant correlation to environmental P. We also found orthophosphate (PO43-) to be the dominant factor correlating with system P cycle gene composition with little evidence of a strong organic phosphorous correlation present even in more oligotrophic streams.

Retinal genes are differentially expressed in areas of primary versus secondary degeneration following partial optic nerve injury.

BackgroundPartial transection (PT) of the optic nerve is an established experimental model of secondary degeneration in the central nervous system. After a dorsal transection, retinal ganglion cells (RGCs) with axons in ventral optic nerve are intact but vulnerable to secondary degeneration, whereas RGCs in dorsal retina with dorsal axons are affected by primary and secondary injuries. Using microarray, we quantified gene expression changes in dorsal and ventral retina at 1 and 7 days post PT, to characterize pathogenic pathways linked to primary and secondary degeneration.ResultsIn comparison to uninjured retina Cryba1, Cryba2 and Crygs, were significantly downregulated in injured dorsal retina at days 1 and 7. While Ecel1, Timp1, Mt2A and CD74, which are associated with reducing excitotoxicity, oxidative stress and inflammation, were significantly upregulated. Genes associated with oxygen binding pathways, immune responses, cytokine receptor activity and apoptosis were enriched in dorsal retina at day 1 after PT. Oxygen binding and apoptosis remained enriched at day 7, as were pathways involved in extracellular matrix modification. Fewer changes were observed in ventral retina at day 1 after PT, most associated with the regulation of protein homodimerization activity. By day 7, apoptosis, matrix organization and signal transduction pathways were enriched. Discriminant analysis was also performed for specific functional gene groups to compare expression intensities at each time point. Altered expression of selected genes (ATF3, GFAP, Ecel1, TIMP1, Tp53) and proteins (GFAP, ECEL1 and ATF3) were semi-quantitatively assessed by qRT-PCR and immunohistochemistry respectively.ConclusionThere was an acute and complex primary injury response in dorsal retina indicative of a dynamic interaction between neuroprotective and neurodegenerative events; ventral retina vulnerable to secondary degeneration showed a delayed injury response. Both primary and secondary injury resulted in the upregulation of numerous genes linked to RGC death, but differences in the nature of these changes strongly suggest that death occurred via different molecular mechanisms.

Developmental dynamics of the epigenome: A longitudinal study of three toddlers

Epigenetic regulation plays an important role in development, at the embryonic stages and later during the lifespan. Some epigenetic marks are highly conserved throughout the lifespan whereas others are closely associated with specific age periods and/or particular environmental factors. Little is known about the dynamics of epigenetic regulation during childhood, especially during the period of rapid early development. Our study was aimed to determine whether the developmental program at the early stages of human development is accompanied by significant changes in the systems of genome regulation, specifically, by genome-wide changes in DNA methylation. Using a sequencing approach (MBD-seq) we investigated genome-wide DNA methylation patterns in the T-lymphocytes of three healthy toddlers at two timepoints within the second year of life. Pairwise comparison of the methylation patterns across the individuals and time points was conducted to determine common longitudinal changes in the DNA methylation patterns. Despite relatively high interindividual variability in their epigenetic profiles and the dynamics of these profiles during the second year of life, all children showed consistent changes in the DNA methylation patterns of genes involved in the control of the immune system and genes related to the development of the CNS. Thereby, we provide evidence that early development might be accompanied by epigenetic changes in specific functional groups of genes; many such epigenetic changes appear to be related to the rapid development of the CNS.

Training the salmon\u2019s genes: influence of aerobic exercise, swimming performance and selection on gene expression in Atlantic salmon

BackgroundFarmed and wild Atlantic salmon are exposed to many infectious and non-infectious challenges that can cause mortality when they enter the sea. Exercise before transfer promotes growth, health and survival in the sea. Swimming performance in juveniles at the freshwater parr stage is positively associated with resistance to some diseases. Genetic variation is likely to affect response to exercise. In this study we map genetic differences associated with aerobic exercise, swimming performance and genetic origin.Eggs from the selectively bred Bolaks salmon and wild Lærdal River salmon strains were reared until parr in a common environment. Swimming performance was assessed by subjecting the fish to either continuous hard exercise or control conditions for 18 days. Heart was sampled for examination of gene expression using RNA-seq (~60 fish/treatment).ResultsLower expression of genes affecting immune function was found in domesticated than wild parr. Among wild parr under control exercise the expression of a large number of genes involved in general metabolism, stress and immune response was lower in superior swimmers suggesting that minimisation of energy expenditure during periods of low activity makes parr better able to sustain bursts of swimming for predator avoidance. A similar set of genes were down-regulated with training among wild parr with inferior swimming performance. These parr react to training in a way that their cardiac expression patterns become like the superior performing wild parr under control exercise conditions. Diversifying selection caused by breeding of domesticated stock, and adaptive pressures in wild stock, has affected the expression and frequency of single nucleotide polymorphisms (SNPs) for multiple functional groups of genes affecting diverse processes. SNPs associated with swimming performance in wild parr map to genes involved in energetic processes, coding for contractile filaments in the muscle and controlling cell proliferation.ConclusionsDomesticated parr have less phenotypic plasticity in response to training and lower expression of genes with functions affecting immune response. The genetic response to training is complex and depends on the background of parr and their swimming ability. Exercise should be tailored to the genetics and swimming performance of fish.

RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study

BackgroundMeasuring how gene expression changes in the course of an experiment assesses how an organism responds on a molecular level. Sequencing of RNA molecules, and their subsequent quantification, aims to assess global gene expression changes on the RNA level (transcriptome). While advances in high-throughput RNA-sequencing (RNA-seq) technologies allow for inexpensive data generation, accurate post-processing and normalization across samples is required to eliminate any systematic noise introduced by the biochemical and/or technical processes. Existing methods thus either normalize on selected known reference genes that are invariant in expression across the experiment, assume that the majority of genes are invariant, or that the effects of up- and down-regulated genes cancel each other out during the normalization.ResultsHere, we present a novel method, moose2, which predicts invariant genes in silico through a dynamic programming (DP) scheme and applies a quadratic normalization based on this subset. The method allows for specifying a set of known or experimentally validated invariant genes, which guides the DP. We experimentally verified the predictions of this method in the bacterium Escherichia coli, and show how moose2 is able to (i) estimate the expression value distances between RNA-seq samples, (ii) reduce the variation of expression values across all samples, and (iii) to subsequently reveal new functional groups of genes during the late stages of DNA damage. We further applied the method to three eukaryotic data sets, on which its performance compares favourably to other methods. The software is implemented in C++ and is publicly available from http://grabherr.github.io/moose2/.ConclusionsThe proposed RNA-seq normalization method, moose2, is a valuable alternative to existing methods, with two major advantages: (i) in silico prediction of invariant genes provides a list of potential reference genes for downstream analyses, and (ii) non-linear artefacts in RNA-seq data are handled adequately to minimize variations between replicates.

Dual RNA-seq reveals no plastic transcriptional response of the coccidian parasite Eimeria falciformis to host immune defenses

BackgroundParasites can either respond to differences in immune defenses that exist between individual hosts plastically or, alternatively, follow a genetically canalized (“hard wired”) program of infection. Assuming that large-scale functional plasticity would be discernible in the parasite transcriptome we have performed a dual RNA-seq study of the lifecycle of Eimeria falciformis using infected mice with different immune status as models for coccidian infections.ResultsWe compared parasite and host transcriptomes (dual transcriptome) between naïve and challenge infected mice, as well as between immune competent and immune deficient ones. Mice with different immune competence show transcriptional differences as well as differences in parasite reproduction (oocyst shedding). Broad gene categories represented by differently abundant host genes indicate enrichments for immune reaction and tissue repair functions. More specifically, TGF-beta, EGF, TNF and IL-1 and IL-6 are examples of functional annotations represented differently depending on host immune status. Much in contrast, parasite transcriptomes were neither different between Coccidia isolated from immune competent and immune deficient mice, nor between those harvested from naïve and challenge infected mice. Instead, parasite transcriptomes have distinct profiles early and late in infection, characterized largely by biosynthesis or motility associated functional gene groups, respectively. Extracellular sporozoite and oocyst stages showed distinct transcriptional profiles and sporozoite transcriptomes were found enriched for species specific genes and likely pathogenicity factors.ConclusionWe propose that the niche and host-specific parasite E. falciformis uses a genetically canalized program of infection. This program is likely fixed in an evolutionary process rather than employing phenotypic plasticity to interact with its host. This in turn might limit the potential of the parasite to adapt to new host species or niches, forcing it to coevolve with its host.

Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity.

Doxorubicin (DOX), a potent and broad-spectrum antineoplastic agent, causes an irreversible, cumulative and dose-dependent cardiomyopathy that ultimately leads to congestive heart failure. The mechanisms responsible for DOX cardiotoxicity remain poorly understood, but seem to involve mitochondrial dysfunction on several levels. Epigenetics may explain a portion of this effect. Since mitochondrial dysfunction may affect the epigenetic landscape, we hypothesize that this cardiac toxicity may result from epigenetic changes related to disruption of mitochondrial function. To test this hypothesis, eight-week-old male Wistar rats (n=6/group) were administered 7 weekly injections with DOX (2mgkg-1) or saline, and sacrificed two weeks after the last injection. We assessed gene expression patterns by qPCR, global DNA methylation by ELISA, and proteome lysine acetylation status by Western blot in cardiac tissue from saline and DOX-treated rats. We show for the first time that DOX treatment decreases global DNA methylation in heart but not in liver. These differences were accompanied by alterations in mRNA expression of multiple functional gene groups. DOX disrupted cardiac mitochondrial biogenesis, as demonstrated by decreased mtDNA levels and altered transcript levels for multiple mitochondrial genes encoded by both nuclear and mitochondrial genomes. Transcription of genes involved in lipid metabolism and epigenetic modulation were also affected. Western blotting analyses indicated a differential protein acetylation pattern in cardiac mitochondrial fractions of DOX-treated rats compared to controls. Additionally, DOX treatment increased the activity of histone deacetylases. These results suggest an interplay between mitochondrial dysfunction and epigenetic alterations, which may be a primary determinant of DOX-induced cardiotoxicity.

Contrasting Patterns of Nucleotide Substitution Rates Provide Insight into Dynamic Evolution of Plastid and Mitochondrial Genomes of Geranium.

Geraniaceae have emerged as a model system for investigating the causes and consequences of variation in plastid and mitochondrial genomes. Incredible structural variation in plastid genomes (plastomes) and highly accelerated evolutionary rates have been reported in selected lineages and functional groups of genes in both plastomes and mitochondrial genomes (mitogenomes), and these phenomena have been implicated in cytonuclear incompatibility. Previous organelle genome studies have included limited sampling of Geranium, the largest genus in the family with over 400 species. This study reports on rates and patterns of nucleotide substitutions in plastomes and mitogenomes of 17 species of Geranium and representatives of other Geraniaceae. As detected across other angiosperms, substitution rates in the plastome are 3.5 times higher than the mitogenome in most Geranium. However, in the branch leading to Geranium brycei/Geranium incanum mitochondrial genes experienced significantly higher dN and dS than plastid genes, a pattern that has only been detected in one other angiosperm. Furthermore, rate accelerations differ in the two organelle genomes with plastomes having increased dN and mitogenomes with increased dS. In the Geranium phaeum/Geranium reflexum clade, duplicate copies of clpP and rpoA genes that experienced asymmetric rate divergence were detected in the single copy region of the plastome. In the case of rpoA, the branch leading to G. phaeum/G. reflexum experienced positive selection or relaxation of purifying selection. Finally, the evolution of acetyl-CoA carboxylase is unusual in Geraniaceae because it is only the second angiosperm family where both prokaryotic and eukaryotic ACCases functionally coexist in the plastid.

Nuclear Pores Regulate Muscle Development and Maintenance by Assembling a Localized Mef2C Complex

Nuclear pore complexes (NPCs) are multiprotein channels connecting the nucleus with the cytoplasm. NPCs have been shown to have tissue-specific composition, suggesting that their function can be specialized. However, the physiological roles of NPC composition changes and their impacts on cellular processes remain unclear. Here we show that the addition of the Nup210 nucleoporin to NPCs during myoblast differentiation results in assembly of an Mef2C transcriptional complex required for efficient expression of muscle structural genes and microRNAs. We show that this NPC-localized complex is essential for muscle growth, myofiber maturation, and muscle cell survival and that alterations in its activity result in muscle degeneration. Our findings suggest that NPCs regulate the activity of functional gene groups by acting as scaffolds that promote the local assembly of tissue-specific transcription complexes and show how nuclear pore composition changes can be exploited to regulate gene expression at the nuclear periphery.

Auxin regulates functional gene groups in a fold-change-specific manner in Arabidopsis thaliana roots

Auxin plays a pivotal role in virtually every aspect of plant morphogenesis. It simultaneously orchestrates a diverse variety of processes such as cell wall biogenesis, transition through the cell cycle, or metabolism of a wide range of chemical substances. The coordination principles for such a complex orchestration are poorly understood at the systems level. Here, we perform an RNA-seq experiment to study the transcriptional response to auxin treatment within gene groups of different biological processes, molecular functions, or cell components in a quantitative fold-change-specific manner. We find for Arabidopsis thaliana roots treated with auxin for 6 h that (i) there are functional groups within which genes respond to auxin with a surprisingly similar fold changes and that (ii) these fold changes vary from one group to another. These findings make it tempting to conjecture the existence of some transcriptional logic orchestrating the coordinated expression of genes within functional groups in a fold-change-specific manner. To obtain some initial insight about this coordinated expression, we performed a motif enrichment analysis and found cis-regulatory elements TBX1-3, SBX, REG, and TCP/site2 as the candidates conferring fold-change-specific responses to auxin in Arabidopsis thaliana.

Molecular landscape of arthrofibrosis: Microarray and bioinformatic analysis of the temporal expression of 380 genes during contracture genesis

PurposeInflammatory changes are suspected in the pathophysiology of arthrofibrosis formation and require early molecular examination. Here, we assessed the hypothesis that early inflammatory genes are related to arthrofibrosis by ascertaining gene expression during the early stages of contracture genesis in an animal model. MethodsJoint trauma was incited surgically in a cohort of rabbits (n=36) knees followed by immobilization in a model of contracture. Six groups of 6 rabbits were sacrificed at multiple time points (0, 6, 12, 24, 72h and 2weeks). Microarray expression and RT-qPCR profiling were performed to determine genes that are significantly up or downregulated. Bioinformatic analysis was carried out to understand which biological programs and functional groups of genes are modulated in arthrofibrosis. ResultsGene expression profiling revealed a large number biologically relevant genes (>100) that are either upregulated or downregulated by at least a 1.5 fold (log2) during the first two weeks after joint injury during contracture development. Gene ontology analysis identified molecular pathways and programs that act during the course of fibrosis and joint contracture. Our main finding is that the development of contractures occur concomitant with modulation of genes mediating inflammatory responses, ECM remodeling and the epithelial-to-mesenchymal transition. ConclusionThe genesis of joint contracture reflects an imbalance between pro- and anti-fibrotic expression. Our study indicates that inflammatory genes may be involved in the process of contracture genesis and initiated at relatively early stages. Our findings also may inform clinical practice in the future by suggesting potential therapeutic targets in preventing the long-term development of arthrofibrosis.

TTCA: an R package for the identification of differentially expressed genes in time course microarray data

BackgroundThe analysis of microarray time series promises a deeper insight into the dynamics of the cellular response following stimulation. A common observation in this type of data is that some genes respond with quick, transient dynamics, while other genes change their expression slowly over time. The existing methods for detecting significant expression dynamics often fail when the expression dynamics show a large heterogeneity. Moreover, these methods often cannot cope with irregular and sparse measurements.ResultsThe method proposed here is specifically designed for the analysis of perturbation responses. It combines different scores to capture fast and transient dynamics as well as slow expression changes, and performs well in the presence of low replicate numbers and irregular sampling times. The results are given in the form of tables including links to figures showing the expression dynamics of the respective transcript. These allow to quickly recognise the relevance of detection, to identify possible false positives and to discriminate early and late changes in gene expression. An extension of the method allows the analysis of the expression dynamics of functional groups of genes, providing a quick overview of the cellular response. The performance of this package was tested on microarray data derived from lung cancer cells stimulated with epidermal growth factor (EGF).ConclusionHere we describe a new, efficient method for the analysis of sparse and heterogeneous time course data with high detection sensitivity and transparency. It is implemented as R package TTCA (transcript time course analysis) and can be installed from the Comprehensive R Archive Network, CRAN. The source code is provided with the Additional file 1.

Zinc concentration affects the functional groups of microbial communities in sugarcane-cultivated soil

The addition of zinc (Zn) to the soil has significant gains in sugarcane productivity. The understanding of the consequences of zinc application requires insight into ecological aspects of changes in soil microbial communities. Here, we evaluated the effects of zinc application on richness, diversity, evenness and structure of microbial functional genes in sugarcane-cultivated soil, and response thresholds of abundance for groups of microbial functional genes on different zinc concentrations added to the soil (0, 5, 10 and 20kg Zn ha−1) in two sugarcane fields in the Northeastern São Paulo state, Brazil. Using a high-density functional gene array termed GeoChip 5.0, which contains 101,796 distinct probes belonging to gene categories involved in zinc transport, secondary metabolism, stress, virulence and nutrient cycling, differences were observed in the functional gene structure of microbial communities and abundance of specific gene families with a threshold between 5 and 10kg Zn ha−1. However, the richness, diversity and evenness of functional genes did not differ across the zinc gradients in soil. Cluster analysis based on microbial functional subcategories revealed variation in abundances across the gradient of zinc concentrations in soil mainly for virulence, stress, secondary metabolism, and carbon- and phosphorus-cycling-related gene families. A threshold in abundance was observed between 5 and 10kg Zn ha−1 with high abundance of microbial gene families associated with zinc transporter proteins, antioxidant enzymes, exoenzymes associated with infection, secretion proteins, virulence regulatory genes, carbon fixation, and phosphorus utilization in soils supplemented with up to 5kg Zn ha−1. In these same soils, reduced abundance was observed for gene families associated with methanogenesis, metabolism of halogen and carotenoid, and antiphagocytosis compared with soil supplements with 10 or 20kg Zn ha−1. The results suggest that changes in microbial functional gene structure and abundance could be used to evaluate the impact of soil management practices on soil microbial communities in sugarcane production fields.

A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network.

BackgroundObesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation.ResultsThe compendium of genes controlling FB or BW includes 578 human genes. Candidate genes were identified from various sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man). All genes were ranked according to knowledge about their biological role in body weight regulation and classified according to expression patterns or functional characteristics. Substantial and overrepresented numbers of genes from the compendium encoded cell surface receptors, signaling molecules (hormones, neuropeptides, cytokines), transcription factors, signal transduction proteins, cilium and BBSome components, and lipid binding proteins or were present in the brain-specific list of tissue-enriched genes identified with TSEA tool. We identified 27 pathways from KEGG, REACTOME and BIOCARTA whose genes were overrepresented in the compendium. Networks formed by physical interactions or homological relationships between proteins or interactions between proteins involved in biochemical/signaling pathways were reconstructed and analyzed. Subnetworks and clusters identified by the MCODE tool included genes/proteins associated with cilium morphogenesis, signal transduction proteins (particularly, G protein–coupled receptors, kinases or proteins involved in response to insulin stimulus) and transcription regulation (particularly nuclear receptors). We ranked GWAS genes according to the number of neighbors in three networks and revealed 22 GWAS genes involved in the brain-specific PPI network. On the base of the most reliable PPIs functioning in the brain tissue, new regulatory schemes interpreting relevance to BW regulation are proposed for three GWAS genes (ETV5, LRP1B, and NDUFS3). ConclusionsA compendium comprising 578 human genes controlling FB or BW was designed, and the most significant functional groups of genes, biological processes/pathways, and tissues/organs involved in BW regulation were revealed. We ranked genes from the GWAS meta-analysis set according to the number and quality of associations in the networks and then according to their involvement in the brain-specific PPI network and proposed new regulatory schemes involving three GWAS genes (ETV5, LRP1B, and NDUFS3) in BW regulation. The compendium is expected to be useful for pathology risk estimation and for design of new pharmacological approaches in the treatment of human obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0466-2) contains supplementary material, which is available to authorized users.

Pre- and post-weaning diet alters the faecal metagenome in the cat with differences in vitamin and carbohydrate metabolism gene abundances.

Dietary format, and its role in pet nutrition, is of interest to pet food manufacturers and pet owners alike. The aim of the present study was to investigate the effects of pre- and post-weaning diets (kibbled or canned) on the composition and function of faecal microbiota in the domestic cat by shotgun metagenomic sequencing and gene taxonomic and functional assignment using MG-RAST. Post-weaning diet had a dramatic effect on community composition; 147 of the 195 bacterial species identified had significantly different mean relative abundances between kittens fed kibbled and canned diets. The kittens fed kibbled diets had relatively higher abundances of Lactobacillus (>100-fold), Bifidobacterium (>100-fold), and Collinsella (>9-fold) than kittens fed canned diets. There were relatively few differences in the predicted microbiome functions associated with the pre-weaning diet. Post-weaning diet affected the abundance of functional gene groups. Genes involved in vitamin biosynthesis, metabolism, and transport, were significantly enriched in the metagenomes of kittens fed the canned diet. The impact of post-weaning diet on the metagenome in terms of vitamin biosynthesis functions suggests that modulation of the microbiome function through diet may be an important avenue for improving the nutrition of companion animals.

The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort.

The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at ∼164Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes.

Integrative analysis of somatic mutations and transcriptomic data to functionally stratify breast cancer patients.

BackgroundSomatic mutations can be used as potential biomarkers for subtyping and predicting outcomes for cancer patients. However, cancer patients often carry many somatic mutations, which do not always concentrate on specific genomic loci, suggesting that the mutations may affect common pathways or gene interaction networks instead of common genes. The challenge is thus to identify the functional relationships among the mutations using multi-modal data. We developed a novel approach for integrating patient somatic mutation, transcriptome and clinical data to mine underlying functional gene groups that can be used to stratify cancer patients into groups with different clinical outcomes. Specifically, we use distance correlation metric to mine the correlations between expression profiles of mutated genes from different patients.ResultsWith this approach, we were able to cluster patients based on the functional relationships between the affected genes using their expression profiles, and to visualize the results using multi-dimensional scaling. Interestingly, we identified a stable subgroup of breast cancer patients that are highly enriched with ER-negative and triple-negative subtypes, and the somatic mutation genes they harbor were capable of acting as potential biomarkers to predict patient survival in several different breast cancer datasets, especially in ER-negative cohorts which has lacked reliable biomarkers.ConclusionsOur method provides a novel and promising approach for integrating genotyping and gene expression data in patient stratification in complex diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2902-0) contains supplementary material, which is available to authorized users.

Sex, Scavengers, and Chaperones: Transcriptome Secrets of Divergent Symbiodinium Thermal Tolerances.

Corals rely on photosynthesis by their endosymbiotic dinoflagellates (Symbiodinium spp.) to form the basis of tropical coral reefs. High sea surface temperatures driven by climate change can trigger the loss of Symbiodinium from corals (coral bleaching), leading to declines in coral health. Different putative species (genetically distinct types) as well as conspecific populations of Symbiodinium can confer differing levels of thermal tolerance to their coral host, but the genes that govern dinoflagellate thermal tolerance are unknown. Here we show physiological and transcriptional responses to heat stress by a thermo-sensitive (physiologically susceptible at 32 °C) type C1 Symbiodinium population and a thermo-tolerant (physiologically healthy at 32 °C) type C1 Symbiodinium population. After nine days at 32 °C, neither population exhibited physiological stress, but both displayed up-regulation of meiosis genes by ≥ 4-fold and enrichment of meiosis functional gene groups, which promote adaptation. After 13 days at 32 °C, the thermo-sensitive population suffered a significant decrease in photosynthetic efficiency and increase in reactive oxygen species (ROS) leakage from its cells, whereas the thermo-tolerant population showed no signs of physiological stress. Correspondingly, only the thermo-tolerant population demonstrated up-regulation of a range of ROS scavenging and molecular chaperone genes by ≥ 4-fold and enrichment of ROS scavenging and protein-folding functional gene groups. The physiological and transcriptional responses of the Symbiodinium populations to heat stress directly correlate with the bleaching susceptibilities of corals that harbored these same Symbiodinium populations. Thus, our study provides novel, foundational insights into the molecular basis of dinoflagellate thermal tolerance and coral bleaching.

Systems-level analysis of human aging genes shed new light on mechanisms of aging.

Although studies over the last decades have firmly connected a number of genes and molecular pathways to aging, the aging process as a whole still remains poorly understood. To gain novel insights into the mechanisms underlying aging, instead of considering aging genes individually, we studied their characteristics at the systems level in the context of biological networks. We calculated a comprehensive set of network characteristics for human aging-related genes from the GenAge database. By comparing them with other functional groups of genes, we identified a robust group of aging-specific network characteristics. To find the structural basis and the molecular mechanisms underlying this aging-related network specificity, we also analyzed protein domain interactions and gene expression patterns across different tissues. Our study revealed that aging genes not only tend to be network hubs, playing important roles in communication among different functional modules or pathways, but also are more likely to physically interact and be co-expressed with essential genes. The high expression of aging genes across a large number of tissue types also points to a high level of connectivity among aging genes. Unexpectedly, contrary to the depletion of interactions among hub genes in biological networks, we observed close interactions among aging hubs, which renders the aging subnetworks vulnerable to random attacks and thus may contribute to the aging process. Comparison across species reveals the evolution process of the aging subnetwork. As the organisms become more complex, the complexity of its aging mechanisms increases and their aging hub genes are more functionally connected.