| 1. |
- Gloriam, David E, et al.
(author)
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The G protein-coupled receptor subset of the rat genome
- 2007
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8, s. 338-
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Journal article (peer-reviewed)abstract
- Background: The superfamily of G protein-coupled receptors (GPCRs) is one of the largest within most mammals. GPCRs are important targets for pharmaceuticals and the rat is one of the most widely used model organisms in biological research. Accurate comparisons of protein families in rat, mice and human are thus important for interpretation of many physiological and pharmacological studies. However, current automated protein predictions and annotations are limited and error prone. Results: We searched the rat genome for GPCRs and obtained 1867 full-length genes and 739 pseudogenes. We identified 1277 new full-length rat GPCRs, whereof 1235 belong to the large group of olfactory receptors. Moreover, we updated the datasets of GPCRs from the human and mouse genomes with 1 and 43 new genes, respectively. The total numbers of full-length genes ( and pseudogenes) identified were 799 ( 583) for human and 1783 ( 702) for mouse. The rat, human and mouse GPCRs were classified into 7 families named the Glutamate, Rhodopsin, Adhesion, Frizzled, Secretin, Taste2 and Vomeronasal1 families. We performed comprehensive phylogenetic analyses of these families and provide detailed information about orthologues and species-specific receptors. We found that 65 human Rhodopsin family GPCRs are orphans and 56 of these have an orthologue in rat. Conclusion: Interestingly, we found that the proportion of one-to-one GPCR orthologues was only 58% between rats and humans and only 70% between the rat and mouse, which is much lower than stated for the entire set of all genes. This is in mainly related to the sensory GPCRs. The average protein sequence identities of the GPCR orthologue pairs is also lower than for the whole genomes. We found these to be 80% for the rat and human pairs and 90% for the rat and mouse pairs. However, the proportions of orthologous and species-specific genes vary significantly between the different GPCR families. The largest diversification is seen for GPCRs that respond to exogenous stimuli indicating that the variation in their repertoires reflects to a large extent the adaptation of the species to their environment. This report provides the first overall roadmap of the GPCR repertoire in rat and detailed comparisons with the mouse and human repertoires.
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| 2. |
- Haitina, Tatjana, et al.
(author)
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The G protein-coupled receptor subset of the dog genome is more similar to that in humans than rodents
- 2009
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 10, s. 24-
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Journal article (peer-reviewed)abstract
- BACKGROUND The dog is an important model organism and it is considered to be closer to humans than rodents regarding metabolism and responses to drugs. The close relationship between humans and dogs over many centuries has lead to the diversity of the canine species, important genetic discoveries and an appreciation of the effects of old age in another species. The superfamily of G protein-coupled receptors (GPCRs) is one of the largest gene families in most mammals and the most exploited in terms of drug discovery. An accurate comparison of the GPCR repertoires in dog and human is valuable for the prediction of functional similarities and differences between the species. RESULTS We searched the dog genome for non-olfactory GPCRs and obtained 353 full-length GPCR gene sequences, 18 incomplete sequences and 13 pseudogenes. We established relationships between human, dog, rat and mouse GPCRs resolving orthologous pairs and species-specific duplicates. We found that 12 dog GPCR genes are missing in humans while 24 human GPCR genes are not part of the dog GPCR repertoire. There is a higher number of orthologous pairs between dog and human that are conserved as compared with either mouse or rat. In almost all cases the differences observed between the dog and human genomes coincide with other variations in the rodent species. Several GPCR gene expansions characteristic for rodents are not found in dog. CONCLUSION The repertoire of dog non-olfactory GPCRs is more similar to the repertoire in humans as compared with the one in rodents. The comparison of the dog, human and rodent repertoires revealed several examples of species-specific gene duplications and deletions. This information is useful in the selection of model organisms for pharmacological experiments.
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| 3. |
- Sreedharan, Smitha, et al.
(author)
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Glutamate, aspartate and nucleotide transporters in the SLC17 family form four main phylogenetic clusters : evolution and tissue expression
- 2010
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11:1, s. 17-
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Journal article (peer-reviewed)abstract
- BACKGROUND: The SLC17 family of transporters transports the amino acids: glutamate and aspartate, and, as shown recently, also nucleotides. Vesicular glutamate transporters are found in distinct species, such as C. elegans, but the evolutionary origin of most of the genes in this family has been obscure. RESULTS: Our phylogenetic analysis shows that the SLC17 family consists of four main phylogenetic clades which were all present before the divergence of the insect lineage. One of these clades has not been previously described and it is not found in vertebrates. The clade containing Slc17a9 had the most restricted evolutionary history with only one member in most species. We detected expression of Slc17a1-17a4 only in the peripheral tissues but not in the CNS, while Slc17a5- Slc17a9 are highly expressed in both the CNS and periphery. CONCLUSIONS: The in situ hybridization studies on vesicular nucleotide transporter revealed high expression throughout the cerebral cortex, certain areas in the hippocampus and in specific nuclei of the hypothalamus and thalamus. Some of the regions with high expression, such as the medial habenula and the dentate gyrus of the hippocampus, are important sites for purinergic neurotransmission. Noteworthy, other areas relying on purine-mediated signaling, such as the molecular layer of the dentate gyrus and the periaqueductal gray, lack or have a very low expression of Slc17a9, suggesting that there could be another nucleotide transporter in these regions.
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| 4. |
- Attwood, Misty M., et al.
(author)
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Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome
- 2016
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 17
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Journal article (peer-reviewed)abstract
- Background: Membrane proteins are key components in a large spectrum of diverse functions and thus account for the major proportion of the drug-targeted portion of the genome. From a structural perspective, the a-helical transmembrane proteins can be categorized into major groups based on the number of transmembrane helices and these groups are often associated with specific functions. When compared to the well-characterized seven-transmembrane containing proteins (7TM), other TM groups are less explored and in particular the 4TM group. In this study, we identify the complete 4TM complement from the latest release of the human genome and assess the 4TM structure group as a whole. We functionally characterize this dataset and evaluate the resulting groups and ubiquitous functions, and furthermore describe disease and drug target involvement.Results: We classified 373 proteins, which represents similar to 7 % of the human membrane proteome, and includes 69 more proteins than our previous estimate. We have characterized the 4TM dataset based on functional, structural, and/or evolutionary similarities. Proteins that are involved in transport activity constitute 37 % of the dataset, 23 % are receptor-related, and 13 % have enzymatic functions. Intriguingly, proteins involved in transport are more than double the 15 % of transporters in the entire human membrane proteome, which might suggest that the 4TM topological architecture is more favored for transporting molecules over other functions. Moreover, we found an interesting exception to the ubiquitous intracellular N- and C-termini localization that is found throughout the entire membrane proteome and 4TM dataset in the neurotransmitter gated ion channel families. Overall, we estimate that 58 % of the dataset has a known association to disease conditions with 19 % of the genes possibly involved in different types of cancer.Conclusions: We provide here the most robust and updated classification of the 4TM complement of the human genome as a platform to further understand the characteristics of 4TM functions and to explore pharmacological opportunities.
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| 5. |
- Babenko, Vladislav V., et al.
(author)
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Draft genome sequences of Hirudo medicinalis and salivary transcriptome of three closely related medicinal leeches
- 2020
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 21:1
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Journal article (peer-reviewed)abstract
- BackgroundSalivary cell secretion (SCS) plays a critical role in blood feeding by medicinal leeches, making them of use for certain medical purposes even today.ResultsWe annotated the Hirudo medicinalis genome and performed RNA-seq on salivary cells isolated from three closely related leech species, H. medicinalis, Hirudo orientalis, and Hirudo verbana. Differential expression analysis verified by proteomics identified salivary cell-specific gene expression, many of which encode previously unknown salivary components. However, the genes encoding known anticoagulants have been found to be expressed not only in salivary cells. The function-related analysis of the unique salivary cell genes enabled an update of the concept of interactions between salivary proteins and components of haemostasis.ConclusionsHere we report a genome draft of Hirudo medicinalis and describe identification of novel salivary proteins and new homologs of genes encoding known anticoagulants in transcriptomes of three medicinal leech species. Our data provide new insights in genetics of blood-feeding lifestyle in leeches.
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| 6. |
- Harty, Breanne L., et al.
(author)
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Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish
- 2015
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Journal article (peer-reviewed)abstract
- Background: Adhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species. Results: Here, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans; compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4. We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication. Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology. Conclusions: Our results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets.
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| 7. |
- Schiöth, Helgi B., et al.
(author)
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A targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease
- 2016
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 17
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Journal article (peer-reviewed)abstract
- Background: Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events. Methods: We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcriptional expression in a third cohort using robust multiple linear regression approaches. Results: We detected 64 genes involved in BA homeostasis and DM to be significantly differentially methylated. In 26 of these genes, methylation significantly correlated with RNA expression, detecting i.e. genes such as CYP27A1, OST alpha, and SLC27A5 (BA homeostasis), and SLCO2B1, SLC47A1, and several UGT and CYP genes (DM) to be NAFLD dependently modulated. Conclusions: NAFLD is associated with significant shifts in the methylation of key genes responsible for BA and DM that are associated with transcriptional modulations. These findings have implications for BA composition, BA regulated metabolic pathways and for drug safety and efficacy.
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