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PubMed2005

Putting microarrays in a context: integrated analysis of diverse biological data.

In recent years, multiple types of high-throughput functional genomic data that facilitate rapid functional annotation of sequenced genomes have become available. Gene expression microarrays are the most commonly available source of such data. However, genomic data often sacrifice specificity for scale, yielding very large quantities of relatively lower-quality data than traditional experimental methods. Thus sophisticated analysis methods are necessary to make accurate functional interpretation of these large-scale data sets. This review presents an overview of recently developed methods that integrate the analysis of microarray data with sequence, interaction, localisation and literature data, and further outlines current challenges in the field. The focus of this review is on the use of such methods for gene function prediction, understanding of protein regulation and modelling of biological networks.

Algorithms↗
PubMed2006

Comparative genomics of Brassica oleracea and Arabidopsis thaliana reveal gene loss, fragmentation, and dispersal after polyploidy.

We sequenced 2.2 Mb representing triplicated genome segments of Brassica oleracea, which are each paralogous with one another and homologous with a segmentally duplicated region of the Arabidopsis thaliana genome. Sequence annotation identified 177 conserved collinear genes in the B. oleracea genome segments. Analysis of synonymous base substitution rates indicated that the triplicated Brassica genome segments diverged from a common ancestor soon after divergence of the Arabidopsis and Brassica lineages. This conclusion was corroborated by phylogenetic analysis of protein families. Using A. thaliana as an outgroup, 35% of the genes inferred to be present when genome triplication occurred in the Brassica lineage have been lost, most likely via a deletion mechanism, in an interspersed pattern. Genes encoding proteins involved in signal transduction or transcription were not found to be significantly more extensively retained than those encoding proteins classified with other functions, but putative proteins predicted in the A. thaliana genome were underrepresented in B. oleracea. We identified one example of gene loss from the Arabidopsis lineage. We found evidence for the frequent insertion of gene fragments of nuclear genomic origin and identified four apparently intact genes in noncollinear positions in the B. oleracea and A. thaliana genomes.

Arabidopsis↗
PubMed1993

FISH: a guide to protein-coding DNA sequences in the GenBank database.

FISH (Fast Index Search for Homologous coding sequences) consists of a database and associated software and is intended to function as a directory of protein-coding gene sequences. The FISH index contains descriptions of 22,361 DNA sequences from release 69.0 of the GenBank genetic sequence database. Complete coding sequences are represented numerically with counts of nucleotides and synonymous codons, and with GenBank LOCUS names and short descriptions. The software permits the database to be queried by GenBank LOCUS name, sequence length (expressed as total number of codons), or by comparison with a DNA sequence. In the latter case, the numerical descriptions are compared with simple distance measures in place of actual DNA sequences. The FISH package can be used to rapidly assemble lists of similar coding sequences, without regard to functional annotation or sequence alignments. Typical search times are well under a minute on widely available IBM-compatible microcomputers.

Algorithms↗
PubMed2026

Identification and characterization of G protein-coupled receptors in the nocturnal halictid bee Megalopta genalis.

G protein-coupled receptors (GPCRs) are one of the largest families of membrane proteins in insects, regulating vision, neural signal transduction, and various physiological behaviors. Megalopta genalis exhibits a unique facultatively eusocial lifestyle and possesses adaptations for nocturnal activity; however, its GPCR family has not yet been systematically characterized. In this study, we performed genome-wide identification, phylogenetic analysis, and expression profiling of GPCRs in M. genalis by integrating genomic annotation and transcriptomic analysis. The results showed that a total of 99 GPCRs were identified in the genome of M. genalis, which were classified into four major families. Here, we show that M. genalis has undergone lineage-specific GPCR repertoire remodeling, marked by the expansion of novel orphan receptors and the systematic loss of multiple receptor subtypes, such as the neuropeptide receptors MIP-R and NPFR. Moreover, opsins have formed a diverse array of combinations and non-GPCR odorant receptors have undergone significant expansion via tandem duplication. Together, these features may represent part of the molecular repertoire associated with the adaptation of M. genalis to a nocturnal lifestyle. Furthermore, transcriptomic analysis revealed distinct spatiotemporal expression divergence within each of the Mth/Mthl and Fz GPCR families, suggesting functional specialization across development and adult tissues. This study provides the first systematic identification and initial functional characterization of GPCRs in M. genalis, revealing an evolutionary pattern characterized by the coexistence of contraction and expansion within the GPCR family. These findings lay a foundation for further studies aimed at elucidating the roles of these GPCRs in regulating M. genalis physiology and behavior.

Animals↗
PubMed2004

Genes transcribed in the salivary glands of female Rhipicephalus appendiculatus ticks infected with Theileria parva.

We describe the generation of an auto-annotated index of genes that are expressed in the salivary glands of four-day fed female adult Rhipicephalus appendiculatus ticks. A total of 9162 EST sequences were derived from an uninfected tick cDNA library and 9844 ESTs were from a cDNA library from ticks infected with Theileria parva, which develop in type III salivary gland acini. There were no major differences between abundantly expressed ESTs from the two cDNA libraries, although there was evidence for an up-regulation in the expression of some glycine-rich proteins in infected salivary glands. Gene ontology terms were also assigned to sequences in the index and those with potential enzyme function were linked to the Kyoto encyclopedia of genes and genomes database, allowing reconstruction of metabolic pathways. Several genes code for previously characterized tick proteins such as receptors for myokinin or ecdysteroid and an immunosuppressive protein. cDNAs coding for homologs of heme-lipoproteins which are major components of tick hemolymph were identified by searching the database with published N-terminal peptide sequence data derived from biochemically purified Boophilus microplus proteins. The EST data will be a useful resource for construction of microarrays to probe vector biology, vector-host and vector-pathogen interactions and to underpin gene identification via proteomics approaches.

Amino Acid Sequence↗
PubMed2000

Representing and reasoning about protein families using generative and discriminative methods.

This work addresses the issues of data representation and incorporation of domain knowledge into the design of learning systems for reasoning about protein families. Given the limited expressive capacity of a particular method, a mixture of protein annotation and fold recognition experts, each implementing a different underlying representation, should provide a robust method for assigning sequences to families. These ideas are illustrated using two data-driven learning methods that make use of different prior information and employ independent, yet complementary, projections of a family: hidden Markov models (HMMs) based on a multiple sequence alignment and neural networks (NNs) based on global sequence descriptors of proteins. Examination of seven protein families indicates that combining a generative (HMM) and a discriminative (NN) method is better than either method on its own. Biologically, human 4-hydroxyphenylpyruvic acid dioxygenase, involved in tyrosinemia type 3, is predicted to be structurally and functionally related to the glyoxalase I family.

Amino Acid Sequence↗
PubMed2005

A semantic analysis of the annotations of the human genome.

The correct interpretation of any biological experiment depends in an essential way on the accuracy and consistency of the existing annotation databases. Such databases are ubiquitous and used by all life scientists in most experiments. However, it is well known that such databases are incomplete and many annotations may also be incorrect. In this paper we describe a technique that can be used to analyze the semantic content of such annotation databases. Our approach is able to extract implicit semantic relationships between genes and functions. This ability allows us to discover novel functions for known genes. This approach is able to identify missing and inaccurate annotations in existing annotation databases, and thus help improve their accuracy. We used our technique to analyze the current annotations of the human genome. From this body of annotations, we were able to predict 212 additional gene-function assignments. A subsequent literature search found that 138 of these gene-functions assignments are supported by existing peer-reviewed papers. An additional 23 assignments have been confirmed in the meantime by the addition of the respective annotations in later releases of the Gene Ontology database. Overall, the 161 confirmed assignments represent 75.95% of the proposed gene-function assignments. Only one of our predictions (0.4%) was contradicted by the existing literature. We could not find any relevant articles for 50 of our predictions (23.58%). The method is independent of the organism and can be used to analyze and improve the quality of the data of any public or private annotation database.

Chromosome Mapping↗
PubMed2026

Annotated genome assemblies of two temperate North American dung beetles, Canthon chalcites and Phanaeus vindex.

Dung beetles serve as cultivators of their natural habitats, improving soil health and functions in both natural and anthropogenic environments. Despite their ecological importance, whole genome sequences for Scarabaeinae are limited. Here, we present the draft annotated genome assemblies for 2 temperate species of North American dung beetles collected from eastern Tennessee: Canthon chalcites and Phanaeus vindex. Both genome assemblies were generated from PacBio long reads and have high completeness, with BUSCO scores of 98.1% and 98.6% for C. chalcites and P. vindex, respectively. For C. chalcites, the BRAKER3 pipeline predicted 12,799 genes, and the gene set was 93.7% complete. For P. vindex, the BRAKER3 predicted 12,252 genes, and the gene set was 94.9% complete. From the annotated gene sets, orthologous protein sequence analyses among C. chalcites, P. vindex, the dung beetle species Onthophagus taurus, and the more evolutionarily distant beetle Tribolium castaneum indicated that there are 260 unique protein clusters for C. chalcites and 210 unique protein clusters for P. vindex. These 2 draft genomes provide valuable data for comparative genomics, evolution, and phylogenic studies for dung beetle species.

Animals↗
PubMed2026

The effect of sex and endurance exercise training on the incretin signaling pathway in 17 rat tissues.

Incretin-based pharmacotherapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists, have transformed the treatment of type 2 diabetes, with demonstrated benefits across multiple organ systems. Their success has driven the investigation of related gut-derived hormones, most prominently dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, but extend to other targets with similar metabolic functions. For this class of drugs, the extent to which organ health improvements are secondary to improved systemic glycemic control versus direct tissue signaling remains unclear, partly because receptor availability across tissues is poorly annotated. We leveraged data from the Molecular Transducers of Physical Activity Consortium to annotate incretin receptor expression across 17 tissues in Fischer 344 rats and the Genotype-Tissue Expression Portal for human-level receptor expression. Furthermore, given the role of exercise in the preservation of muscle mass during weight loss, we analyzed the effects of 1, 2, 4, or 8 wk of treadmill exercise training on incretin-related signaling at the epigenetic, transcript, and protein levels. Endurance training elicited sex- and tissue-specific changes in incretin receptor expression, including downregulation of Gcgr across brown adipose, adrenal glands, and white adipose tissue (WAT). Training-induced Gipr regulation occurred in the adrenal glands, brain cortex, and hippocampus. Collectively, these findings contribute to the map of incretin receptor biology and identify exercise-responsive regulatory axes that may underlie synergistic effects of exercise and incretin-based therapies on weight management and metabolic health.NEW & NOTEWORTHY This study provides the first multiomic, multitissue description of incretin signaling receptor expression and regulation in response to endurance exercise training. We identify time point and sex-specific changes in incretin signaling across tissues, highlighting training effects on Gcgr, Gipr, and Sctr regulation in the adrenals, WAT, and brain. These findings help establish an exercise-responsive incretin signaling axis that may identify interactions from incretin-based therapies and exercise-based lifestyle interventions.

Animals↗
PubMed2026

Unraveling the genomic blueprint of the Indian black soldier fly: From genome assembly to evolutionary insights.

The black soldier fly (BSF) (Hermetia illucens) has been renowned for its sustainable bioconversion capabilities, resulting in smart protein production with wide applications in animal feed, bioenergy, and biofertilizer. However, the genetic mechanisms underlying efficient bioconversion and productivity remain poorly understood. To advance strain-specific applications and strengthen genetic resource availability, we present the whole genome sequencing (WGS) data for an Indian isolate of black soldier fly. The assembled genome was 1.46 Gb with a scaffold N50 of 172.7 Mb, and a GC content of 42.6%. Furthermore, 64.17% of genomic sequences were masked as repeated, and 14,317 protein-coding sequences were identified. Variant analysis against the reference genome identified 34.44 million variants (∼33.25 million SNPs and ∼ 1.18 million INDELs), with the majority (99.3%) classified as MODIFIER, 0.54% as LOW impact, 0.14% as MODERATE, and only 0.003% as HIGH impact. Comparative genomic analysis with other related species revealed expansions of gene families in BSF associated with Immune effector (Antimicrobial peptides (AMPs), Lysozymes, and Peptidoglycan Recognition Protein (PGRP) and Detoxification (cytochrome P450 enzymes). Notably, AMPs in the Indian isolate showed enhanced copy number variation in defensin (27) and PGRP (40) compared to reference BSF, suggesting potential regional adaptations to pathogen exposure. Collectively, this genomic data provides an improved resource for evolutionary studies, functional genomics, and targeted genetic improvement of BSF for sustainable bioconversion applications.

Comparative genomics↗
PubMed2003

Use of SAGE technology to reveal changes in gene expression in Arabidopsis leaves undergoing cold stress.

The genes expressed within an organism determine its biological characteristics. Various internal or external factors can modulate these gene expression patterns, which then elicit physiological or pathological changes. We have characterized the global gene expression patterns of Arabidopsis leaves by serial analysis of gene expression (SAGE). A total of 21,280 SAGE tags were sequenced and 12,049 unique tags were identified. Among these, only 3367 tags (27.9%) were matched to the Arabidopsis cDNA or EST database. Functional analysis of annotated tags indicated that a significant proportion of the genes expressed in normal leaves were involved in energy and metabolism, especially in photosynthesis. To systematically analyze differential gene expression profiles under cold stress, a similar SAGE tag library from cold-treated leaves was constructed and analyzed. A comparison of the tags derived from the cold-treated leaves with those identified in the normal leaves revealed 272 differentially expressed genes (P<0.01): 82 genes were highly expressed in the normal leaves and 190 genes were highly expressed in the cold-treated leaves. After cold stress, in general, many of the genes involved in cell rescue/defense/cell death/aging, protein synthesis, metabolism, transport facilitation, and protein destination were induced. They included various COR genes, lipid transfer protein genes, alcohol dehydrogenase, beta-amylase and many novel genes. By comparison, down-regulated genes were mostly photosynthesis related genes involved in energy metabolism. The expression patterns of several cold responsive transcripts identified by SAGE were confirmed by northern analysis. The results presented here will provide valuable information for understanding the mechanisms of the freezing tolerance of plants.

Arabidopsis↗
PubMed2002

Medium-chain dehydrogenases/reductases (MDR). Family characterizations including genome comparisons and active site modeling.

Completed eukaryotic genomes were screened for medium-chain dehydrogenases/reductases (MDR). In the human genome, 23 MDR forms were found, a number that probably will increase, because the genome is not yet fully interpreted. Partial sequences already indicate that at least three further members exist. Within the MDR superfamily, at least eight families were distinguished. Three families are formed by dimeric alcohol dehydrogenases (ADH; originally detected in animals/plants), cinnamyl alcohol dehydrogenases (originally detected in plants) and tetrameric alcohol dehydrogenases (originally detected in yeast). Three further families are centred around forms initially detected as mitochondrial respiratory function proteins, acetyl-CoA reductases of fatty acid synthases, and leukotriene B4 dehydrogenases. The two remaining families with polyol dehydrogenases (originally detected as sorbitol dehydrogenase) and quinone reductases (originally detected as zeta-crystallin) are also distinct but with variable sequences. The most abundant families in the human genome are the dimeric ADH forms and the quinone oxidoreductases. The eukaryotic patterns are different from those of Escherichia coli. The different families were further evaluated by molecular modelling of their active sites as to geometry, hydrophobicity and volume of substrate-binding pockets. Finally, sequence patterns were derived that are diagnostic for the different families and can be used in genome annotations.

Amino Acid Motifs↗
PubMed2004

Validation of alternative methods of data normalization in gene co-expression studies.

MOTIVATION: Clusters of genes encoding proteins with related functions, or in the same regulatory network, often exhibit expression patterns that are correlated over a large number of conditions. Protein associations and gene regulatory networks can be modelled from expression data. We address the question of which of several normalization methods is optimal prior to computing the correlation of the expression profiles between every pair of genes. RESULTS: We use gene expression data from five experiments with a total of 78 hybridizations and 23 diverse conditions. Nine methods of data normalization are explored based on all possible combinations of normalization techniques according to between and within gene and experiment variation. We compare the resulting empirical distribution of gene x gene correlations with the expectations and apply cross-validation to test the performance of each method in predicting accurate functional annotation. We conclude that normalization methods based on mixed-model equations are optimal.

Algorithms↗
PubMed2001

GeneMarkS: a self-training method for prediction of gene starts in microbial genomes. Implications for finding sequence motifs in regulatory regions.

Improving the accuracy of prediction of gene starts is one of a few remaining open problems in computer prediction of prokaryotic genes. Its difficulty is caused by the absence of relatively strong sequence patterns identifying true translation initiation sites. In the current paper we show that the accuracy of gene start prediction can be improved by combining models of protein-coding and non-coding regions and models of regulatory sites near gene start within an iterative Hidden Markov model based algorithm. The new gene prediction method, called GeneMarkS, utilizes a non-supervised training procedure and can be used for a newly sequenced prokaryotic genome with no prior knowledge of any protein or rRNA genes. The GeneMarkS implementation uses an improved version of the gene finding program GeneMark.hmm, heuristic Markov models of coding and non-coding regions and the Gibbs sampling multiple alignment program. GeneMarkS predicted precisely 83.2% of the translation starts of GenBank annotated Bacillus subtilis genes and 94.4% of translation starts in an experimentally validated set of Escherichia coli genes. We have also observed that GeneMarkS detects prokaryotic genes, in terms of identifying open reading frames containing real genes, with an accuracy matching the level of the best currently used gene detection methods. Accurate translation start prediction, in addition to the refinement of protein sequence N-terminal data, provides the benefit of precise positioning of the sequence region situated upstream to a gene start. Therefore, sequence motifs related to transcription and translation regulatory sites can be revealed and analyzed with higher precision. These motifs were shown to possess a significant variability, the functional and evolutionary connections of which are discussed.

Algorithms↗
PubMed2006

Human-specific insertions and deletions inferred from mammalian genome sequences.

It has been suggested that insertions and deletions (indels) have contributed to the sequence divergence between the human and chimpanzee genomes more than do nucleotide changes (3% vs. 1.2%). However, although there have been studies of large indels between the two genomes, no systematic analysis of small indels (i.e., indels </= 100 bp) has been published. In this study, we first estimated that the false-positive rate of small indels inferred from human-chimpanzee pairwise sequence alignments is quite high, suggesting that the chimpanzee genome draft is not sufficiently accurate for our purpose. We have therefore inferred only human-specific indels using multiple sequence alignments of mammalian genomes. We identified >840,000 "small" indels, which affect >7000 UCSC-annotated human genes (>11,000 transcripts). These indels, however, amount to only approximately 0.21% sequence change in the human lineage for the regions compared, whereas in pseudogenes indels contribute to a sequence divergence of 1.40%, suggesting that most of the indels that occurred in genic regions have been eliminated. Functional analysis reveals that the genes whose coding exons have been affected by human-specific indels are enriched in transcription and translation regulatory activities but are underrepresented in catalytic and transporter activities, cellular and physiological processes, and extracellular region/matrix. This functional bias suggests that human-specific indels might have contributed to human unique traits by causing changes at the RNA and protein level.

Animals↗
PubMed2006

A new measure for functional similarity of gene products based on Gene Ontology.

BACKGROUND: Gene Ontology (GO) is a standard vocabulary of functional terms and allows for coherent annotation of gene products. These annotations provide a basis for new methods that compare gene products regarding their molecular function and biological role. RESULTS: We present a new method for comparing sets of GO terms and for assessing the functional similarity of gene products. The method relies on two semantic similarity measures; simRel and funSim. One measure (simRel) is applied in the comparison of the biological processes found in different groups of organisms. The other measure (funSim) is used to find functionally related gene products within the same or between different genomes. Results indicate that the method, in addition to being in good agreement with established sequence similarity approaches, also provides a means for the identification of functionally related proteins independent of evolutionary relationships. The method is also applied to estimating functional similarity between all proteins in Saccharomyces cerevisiae and to visualizing the molecular function space of yeast in a map of the functional space. A similar approach is used to visualize the functional relationships between protein families. CONCLUSION: The approach enables the comparison of the underlying molecular biology of different taxonomic groups and provides a new comparative genomics tool identifying functionally related gene products independent of homology. The proposed map of the functional space provides a new global view on the functional relationships between gene products or protein families.

Algorithms↗
PubMed2006

Identification and characterization of genes associated with the induction of embryogenic competence in leaf-protoplast-derived alfalfa cells.

Alfalfa leaf protoplast-derived cells can develop into somatic embryos depending on the concentration of 2,4-dichlorophenoxyacetic acid (2,4-D) in the initial culture medium. In order to reveal gene expression changes during the establishment of embryogenic competence, we compared the cell types developed in the presence of 1 and 10 microM 2,4-D, respectively, at the time of their first cell divisions (fourth day of culture) using a PCR-based cDNA subtraction approach. Although the subtraction efficiency was relatively low, applying an additional differential screening step allowed the identification of 38 10 microM 2,4-D up-regulated transcripts. The corresponding genes/proteins were annotated and representatives of various functional groups were selected for more detailed gene expression analysis. Real-time quantitative PCR (RT-QPCR) analysis was used to determine relative expression of the selected genes in 2,4-D-treated leaves as well as during the whole process of somatic embryogenesis. Gene expression patterns confirmed 2,4-D inducibility for all but one of the 11 investigated genes as well as for the positive control leafy cotyledon1 (MsLEC1) gene. The characterized genes exhibited differential expression patterns during the early induction phase and the late embryo differentiation phase of somatic embryogenesis. Genes coding for a GST-transferase, a PR10 pathogenesis-related protein, a cell division-related ribosomal (S3a) protein, an ARF-type small GTPase and the nucleosome assembly factor family SET protein exhibited higher relative expression not only during the induction of somatic embryogenesis but at the time of somatic embryo differentiation as well. This may indicate that the expression of these genes is associated with developmental transitions (differentiation as well as de-differentiation) during the process of somatic embryogenesis.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2004

Compact intergenic regions of the pufferfish genome facilitate isolation of gene promoters: characterization of Fugu 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (fPapss2) gene promoter function in transgenic Xenopus.

The highly compact nature of the pufferfish (Fugu rubripes) genome renders it a useful tool not only for annotating coding regions within vertebrate genomes, but also for the identification of sequences important to gene regulation. Indeed, owing to this compaction it will be feasible in many instances to initiate analyses using entire intergenic regions when mapping gene promoters; a strategy that is very rarely feasible with the expanded genomes of other species. Stemming from our interest in studying promoters expressed in chondrocytes, we selected for study the intergenic region upstream of Fugu 3'-phosphoadenosine 5'-phosphosulfate synthase 2, fPapss2, a gene required for the normal development of cartilage extracellular matrix. Functional characterization of the entire fPapss2 5' intergenic region was carried out by monitoring expression of the enhanced green fluorescent protein (EGFP) gene reporter in the developing cartilage of transgenic Xenopus laevis. By evaluating a series of 5' intergenic region deletions we defined a minimal fPapss2 sequence of approximately 300 bp that was essential for EGFP expression in tadpole cartilage. This functional analysis of an entire Fugu intergenic region, combined with the efficiency of Xenopus transgenesis, serves as a model for the rapid characterization of evolutionarily-conserved regulatory regions of other pufferfish genes.

Animals↗