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—Volcano plots of significance against fold change in expression for each murine species comparison in brain and liver. Layout is essentially the same as in Figure 2. Species comparisons are Mus spretus minus M. musculus (s m ), M. caroli minus M. musculus (c m), and M. caroli minus M. spretus (c s).
Source publication
An emerging issue in evolutionary genetics is whether it is possible to use gene expression profiling to identify genes that are associated with morphological, physiological, or behavioral divergence between species and whether these genes have undergone positive selection. Some of these questions were addressed in a recent study (Enard et al. 2002...
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Citations
... Transcriptomes are most commonly used in fish to characterize molecular physiology and identify genes that respond to or ameliorate environmental stresses (Basu et al., 2002;Cossins and Crawford, 2005). Gene expression regulation shows considerable variation among different organs, individuals, and species (Hsieh et al., 2003). All tissue-specific transcriptomes used in this study were from peripheral tissues, including the heart, intestine, liver, mucus, and muscle. ...
Channel catfish (Ictalurus punctatus) and blue catfish (Ictalurus furcatus) are two economically important freshwater aquaculture species in the United States, with channel catfish contributing to nearly half of the country’s aquaculture production. While differences in economic traits such as growth rate and disease resistance have been noted, the extent of transcriptomic variance across various tissues between these species remains largely unexplored. The hybridization of female channel catfish with male blue catfish has led to the development of superior hybrid catfish breeds that exhibit enhanced growth rates and improved disease resistance, which dominate more than half of the total US catfish production. While hybrid catfish have significant growth advantages in earthen ponds, channel catfish were reported to grow faster in tank culture environments. In this study, we confirmed channel fish’s superiority in growth over blue catfish in 60-L tanks at 10.8 months of age (30.3 g and 11.6 g in this study, respectively; p < 0.001). In addition, we conducted RNA sequencing experiments and established transcriptomic resources for the heart, liver, intestine, mucus, and muscle of both species. The number of expressed genes varied across tissues, ranging from 5,036 in the muscle to over 20,000 in the mucus. Gene Ontology analysis has revealed the functional specificity of differentially expressed genes within their respective tissues, with significant pathway enrichment in metabolic pathways, immune activity, and stress responses. Noteworthy tissue-specific marker genes, including lrrc10, fabp2, myog, pth1a, hspa9, cyp21a2, agt, and ngtb, have been identified. This transcriptome resource is poised to support future investigations into the molecular mechanisms underlying environment-dependent heterosis and advance genetic breeding efforts of hybrid catfish.
... The raw fluorescence intensity values were normalized applying quantile normalization. Differential gene expression was analysed on the basis of log-linear mixed model analysis of variance, 16 using a commercial software package SAS JMP8 Genomics, version 4.0, from SAS Institute (Cary, NC, USA). Hierarchical cluster analysis of differentially regulated genes in sham vs. MCAO mice was performed, and a false positive rate of a = 0.01 with false discovery rate correction was taken as the level of significance. ...
Background
Stroke can lead to cardiac dysfunction in patients, but the mechanisms underlying the interaction between the injured brain and the heart are poorly understood. The objective of the study is to investigate the effects of experimental murine stroke on cardiac function and molecular signalling in the heart.
Methods and results
Mice were subjected to filament‐induced left middle cerebral artery occlusion for 30 or 60 min or sham surgery and underwent repetitive micro‐echocardiography. Left ventricular contractility was reduced early (24–72 h) but not late (2 months) after brain ischaemia. Cardiac dysfunction was accompanied by a release of high‐sensitive cardiac troponin (hsTNT (ng/ml): d1: 7.0 ± 1.0 vs. 25.0 ± 3.2*; d3: 7.3 ± 1.1 vs. 52.2 ± 16.7*; d14: 5.7 ± 0.8 vs. 5.2 ± 0.3; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); reduced heart weight (heart weight/tibia length ratio: d1: 6.9 ± 0.2 vs. 6.4 ± 0.1*; d3: 6.7 ± 0.2 vs. 5.8 ± 0.1*; d14: 6.7 ± 0.2 vs. 6.4 ± 03; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); resulting from cardiomyocyte atrophy (cardiomyocyte size: d1: 12.8% ± 0.002**; d3: 13.5% ± 0.002**; 14d: 6.3% ± 0.003*; 60 min. MCAO vs. sham; mean ± SEM; **p < 0.01; *p < 0.05), accompanied by increased atrogin‐1 and the E3 ubiquitin ligase murf‐1. Net norepinephrine but not synthesis was increased, suggesting a reduced norepinephrine release or an increase of norepinephrine re‐uptake, resulting in a functional denervation. Transcriptome analysis in cardiac tissue identified the transcription factor peroxisome proliferator‐activated receptor gamma as a potential mediator of stroke‐induced transcriptional dysregulation involved in cardiac atrophy.
Conclusions
Stroke induces a complex molecular response in the heart muscle with immediate but transient cardiac atrophy and dysfunction.
... Previous transcriptome analyses have reported that there are more genes higher expressed in the adult human brain than in the non-human primate brain, and not in other examined tissues (Caceres et al., 2003;Gu and Gu, 2003;Khaitovich et al., 2004). Also it was found that there is little evidence for accelerated divergence in gene expression in the human brain (Hsieh et al., 2003). Other studies have reported several interesting findings on human-specific differences in the expression of genes involved in metabolism (Uddin et al., 2008;Babbitt et al., 2010) and on genes that are organized into human-specific co-expressed modules (Oldham et al., 2006;Konopka et al., 2012). ...
Key to the human brain's unique capacities are a myriad of neural cell types, specialized molecular expression signatures, and complex patterns of neuronal connectivity. Neurons in the human brain communicate via well over a quadrillion synapses. Their specific contribution might be key to the dynamic activity patterns that underlie primate-specific cognitive function. Recently, functional differences were described in transmission capabilities of human and rat synapses. To test whether unique expression signatures of synaptic proteins are at the basis of this, we performed a quantitative analysis of the hippocampal synaptic proteome of four mammalian species, two primates, human and marmoset, and two rodents, rat and mouse. Abundance differences down to 1.15-fold at an FDR-corrected p-value of 0.005 were reliably detected using SWATH mass spectrometry. The high measurement accuracy of SWATH allowed the detection of a large group of differentially expressed proteins between individual species and rodent vs. primate. Differentially expressed proteins between rodent and primate were found highly enriched for plasticity-related proteins.
... Hence, if transcript profiling experiments aim at a comparison of data from varied accessions the results are confounded because differential hybridisation may reflect differences in transcript abundance and/or it may be caused by sequence polymorphisms in the gene sequences of these accessions (Alberts et al. 2007). The same holds true if transcript profiles of related species are compared among each other using the GeneChip Ò technology (Hsieh et al. 2003). This shortcoming has been noted previously and to achieve reliable comparisons of different accessions or species with respect to transcript levels the expression values were for example adjusted based on the results of hybridisations with genomic DNA (Chen et al. 2005;Hammond et al. 2005;DeCook et al. 2006). ...
... This shortcoming has been noted previously and to achieve reliable comparisons of different accessions or species with respect to transcript levels the expression values were for example adjusted based on the results of hybridisations with genomic DNA (Chen et al. 2005;Hammond et al. 2005;DeCook et al. 2006). Alternatively, statistical tests were used for the detection of probes within probe sets that showed deviating hybridisation behaviour (Hsieh et al. 2003;Alberts et al. 2007;Dannemann et al. 2012). The removal of such problematic probes reduced the error rate in studies aimed at the discovery of interspecific gene expression differences. ...
... Comparative gene expression studies of accessions and/or species with GeneChip Ò arrays are biased because sequence polymorphisms affect the binding efficiency of a certain subset of probes (Hsieh et al. 2003;Chen et al. 2005;Hammond et al. 2005;Alberts et al. 2007;Dannemann et al. 2012). It was the aim of this study to focus differential expression studies of A. thaliana accessions on those probes of a GeneChip Ò array that are identical in sequence in the analysed accessions. ...
Key message:
Excluding polymorphic probes from GeneChip (®) transcript profiling experiments via a sequence-based approach results in improved detection of differentially expressed genes in developing seeds of Arabidopsis thaliana accessions Col-0 and C24. GeneChip(®) arrays represent a powerful tool for transcript profiling experiments. The ATH1 GeneChip(®) has been designed based on the sequence of the Arabidopsis thaliana reference genome Col-0, hence the features on the array exactly match the sequences of Col-0 transcripts. In contrast, transcripts of other A. thaliana accessions or related species may show nucleotide differences and/or insertions/deletions when compared to the corresponding Col-0 transcripts, therefore, comparisons of transcript abundance involving different A. thaliana accessions or related species may be compromised for a certain number of transcripts. To tackle this limitation, a sequence-based strategy was developed. Only features on the array that were identical in sequence for the specimen to be compared were considered for transcript profiling. The impact of the proposed strategy was evaluated for transcript profiles that were established for developing seeds of A. thaliana accessions Col-0 and C24.
... Some of these comparative analyses have reported that there are more genes upregulated in the human brain compared to NHP brain, but not in other examined tissues (Cá ceres et al., 2003;Gu and Gu, 2003;Khaitovich et al., 2004). However, these findings were not corroborated by other studies, which have reported that gene expression in the human brain is not more divergent (Hsieh et al., 2003) and that there is no bias for upregulated expression in the human brain (Uddin et al., 2004). Other works reported several interesting findings on human-specific differences in the expression of genes involved in aerobic metabolism (Babbitt et al., 2011;Uddin et al., 2008) and on genes that are organized into modules of co-expression that are specific to humans Oldham et al., 2006), as well as a surprising conservation of noncoding RNAs among the analyzed species . ...
The nervous system—in particular, the brain and its cognitive abilities—is among humans’ most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations.
... Phylogenetic comparisons may also concern expression disparities among species. For example, contradictory works have been published about accelerated KHAITOVICH et al. 2005) or decelerated (HSIEH et al. 2003;) rates of expression changes within the human lineage. In comparative studies, phylogenetic relationships need to be taken into account to decipher between historical and adaptive correlations. ...
Les séquences non-codantes régulatrices de l’expression des gènes sont tout aussi importantes pour le phénotype d’un individu que les séquences codantes. De nombreux travaux se sont attachés à identifier les forces influençant l’évolution de ces séquences non-codantes. Ici, nous théorisons une nouvelle force sélective influençant potentiellement l’évolution de certaines séquences régulatrices. En utilisant des modèles multi-locus, nous montrons que les promoteurs génétiques les plus forts (activateurs de la transcription) gagnent un avantage à voir la copie du gène qui leur est associée (située sur le même chromosome) davantage exprimée que la copie homologue, contrôlée par un promoteur homologue moins fort. La surexpression des copies associées aboutit à une meilleure purge des mutations délétères chez ces copies, et ainsi à une association génétique entre promoteurs forts et contexte génétique favorable. Si la recombinaison entre le gène et le promoteur est suffisamment faible pour que cette association persiste, la force des promoteurs est sélectionnée pour augmenter. L’escalade des forces des promoteurs ne conduit pas forcément à une surproduction de protéines : d’autres régulateurs peuvent co-évoluer pour maintenir un niveau d’expression optimal, à condition que la sélection stabilisante tolère des niveaux d’expression transitoirement sub-optimaux. En variant les modes de reproduction, nous avons montré que ce nouveau processus sélectif ne menait pas nécessairement à une escalade de la force des promoteurs. Lorsque les chromosomes sont suffisamment isolés génétiquement (peu de recombinaison, peu de fécondation croisée), la sélection pour des associations génétiques favorables mène à une divergence des chromosomes : un chromosome accumule des promoteurs forts et possède des copies viables du gène, tandis que le chromosome homologue accumule des promoteurs faibles et des mutations délétères sur le gène. Dans le cas de lignées clonales peu ou pas recombinantes, on s’attend ainsi à observer une haploïdisation de l’expression des gènes : une copie de chaque gène concerné est éteinte et dégénère. Cette divergence s’applique aussi à des chromosomes sexuels ayant cessé de recombiner : on a pu montrer que la divergence des chromosomes menait à une extinction et une dégénérescence des gènes situés sur les chromosomes Y, et à une surexpression des gènes situés sur le chromosome X. En utilisant notre modèle, on propose ainsi une nouvelle théorie pour expliquer l’évolution des chromosomes sexuels non-recombinants. Enfin, on a utilisé des données de divergence entre Mus musculus et Rattus norvegicus pour isoler un signal ne pouvant être expliqué que par une sélection positive pour des promoteurs proximaux plus forts. Ce signal est faible, mais détectable, nous permettant d’apporter une première confirmation empirique du processus d’escalade des forces des promoteurs.
... This association existed for most of all organ-specific expression data, except in some cases for testis and liver. Distinct expression patterns in these organs have also been observed by others (Hsieh et al. 2003;Somel et al. 2008;Brawand et al. 2011) in different contexts. ...
Tandem repeats (TR) are stretches of DNA that are highly variable in length and mutate rapidly, and thus an important source of genetic variation. This variation is highly informative for population and conservation genetics, and has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation in humans and close species have been scarce due to the technical difficulties derived from short-read technology. Here, we explored the genome-wide diversity of TRs in a panel of 83 human and nonhuman great ape genomes, in a total of 6 different species, and their impact on gene expression evolution. We found that population diversity patterns can be efficiently captured with short TRs (repeat unit length 1-5 base pairs). We examined the potential evolutionary role of TRs in gene expression differences between humans and primates by using 30,275 larger TRs (repeat unit length 2-50 base pairs). Genes that contained TRs in the promoters, in their 3' untranslated region, in introns, and in exons had higher expression divergence than genes without repeats in the regions. Polymorphic small repeats (1-5 base pairs) had also higher expression divergence compared to genes with fixed or no TRs in the gene promoters. Our findings highlight the potential contribution of TRs to human evolution through gene regulation.
Published by Cold Spring Harbor Laboratory Press.
... The raw fluorescence intensity values were normalized applying quantile normalization. Differential gene expression was analyzed based on log-linear mixed model ANOVA (Hsieh et al, 2003;Roy, 2007), using a commercial software package SAS JMP7 Genomics, version 5, from SAS (SAS Institute, Cary, NC, USA). A false-positive rate of a =0.05 with FDR correction was taken as the level of significance. ...
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency-dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
... This association existed for most of all organ-specific expression data, except in some cases for testis and liver. Distinct expression patterns in these organs have also been observed by others (Hsieh et al. 2003;Somel et al. 2008;Brawand et al. 2011) in different contexts. ...
Tandem repeats (TR) are stretches of DNA that are highly variable in length and mutate rapidly, and thus an important source of genetic variation. This variation is highly informative for population and conservation genetics, and has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation have been scarce due to the technical difficulties derived from short-read technology. Here, we explored the genome-wide diversity of TRs in a panel of 83 human and nonhuman great ape genomes, and their impact on gene expression evolution. We found that populations and species diversity patterns can be efficiently captured with short TRs (repeat unit length 1-5 base pairs) with potential applications in conservation genetics. We also examined the potential evolutionary role of TRs in gene expression differences between humans and primates by using 30,275 larger TRs (repeat unit length 2-50 base pairs). About one third of the 13,035 one-to-one orthologous genes contained TRs within 5 kilobase pairs of their transcription start site, and had higher expression divergence than genes without such TRs. The same observation held for genes with repeats in their 3′ untranslated region, in introns, and in exons. Using our polymorphism data for the shortest TRs, we found that genes with polymorphic repeats in their promoters showed higher expression divergence in humans and chimpanzees compared to genes with fixed or no TRs in the promoters. Our findings highlight the potential contribution of TRs to recent human evolution through gene regulation.
... The Raw fluorescence intensity values were normalized applying quantile normalization. Differential gene expression was analyzed based on loglinear mixed model ANOVA (Hsieh W.P., 2003;Roy J., 2007), using a commercial software package SAS® JMP7 Genomics (version 4) from SAS® (SAS® Institute, Cary, NC, USA). A false positive rate of a=0.05 with false discovery rate (FDR) correction was taken as the level of significance. ...
Cancer cachexia affects the majority of patients suffering from advanced cancers, thereby reducing response to cancer treatment, quality of life and survival. Despite the tremendous research in the cancer cachexia field, the etiology remains elusive and cachexia still represents an unmet medical need as preventive or therapeutic approaches are lacking. While skeletal muscle and adipose tissue have been studied extensively in this context, the impact of cancer cachexia on other peripheral organs remains mostly unknown.
Therefore, the present study investigated the impact of cancer-related cachexia on the cardiac muscle and the role of tumor-secreted factors in this context.
By using the cachectic Colon-26 (C26) allograft and the adenomatous polyposis coli (APC) mouse model for colorectal cancer it was shown that cardiac performance was impaired in the course of cachexia. This was associated with reduced expression of genes encoding for contractile proteins, but not an increase in fibrosis. In addition, cachectic mice developed atrophy resulting from a reduction in cardiomyocyte size which was primarily mediated through autophagy. In contrast to previous studies in skeletal muscle, activation of the ubiquitin-proteasome system was not detected. Additionally, the non-cachectic mouse colon 38 (MC38) allograft model did not show any alterations in heart function, size or gene expression.
To identify cell-specific molecular changes in cardiomyocytes, an in vitro model was established where primary cardiomyocytes were exposed to conditioned medium from cachexia- or non-cachexia-inducing cells. Similar to the observations in cachectic animals, primary cardiomyocytes treated with conditioned medium from C26 cells developed atrophy.
Gene expression analysis of hearts from the C26-bearing mice and of primary mouse cardiomyocytes treated with C26-conditioned medium revealed that cardiac fatty acid (FA) metabolism was altered under cachectic conditions. Transcription levels of genes encoding for proteins involved in FA transport and mitochondrial -oxidation were elevated, whereas expression of genes encoding for glucose transporters were reduced. Further analysis showed that triglyceride storage in both hearts and primary cardiomyocytes was diminished, and functional analysis by metabolic flux analysis revealed that palmitate-driven -oxidation and uncoupling capacity were increased under cachectic conditions.
The results obtained from the established in vitro model suggested that the cachexia-induced effects on the heart were mediated by tumor-secreted factors in a cell autonomous manner. Therefore, an unbiased differential secretome analysis of C26 cells combined with high-throughput cardiomyocyte phenotyping was performed to define a set of tumor-secreted mediators with cachexia-inducing capacities. A signature of seven “cachexokines” was sufficient to mediate atrophy and aberrant FA metabolism in primary cardiomyocytes. The most promising candidate amongst these seven was Ataxin10 which showed elevated serum levels in cachectic mice.
Taken together, this study demonstrates that cardiac dysfunction is an understudied clinical feature of cancer cachexia and that alterations in FA metabolism represent a distinct feature of the cachectic heart. In addition, this study provides an unbiased and functional screening setup for the investigation of tumor-secreted factors with cachexia-inducing capacity and delivers a new therapeutic starting point.
