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PubMed2006

Variation within and among species in gene expression: raw material for evolution.

Heritable variation in regulatory or coding regions is the raw material for evolutionary processes. The advent of microarrays has recently promoted examination of the extent of variation in gene expression within and among taxa and examination of the evolutionary processes affecting variation. This review examines these issues. We find: (i) microarray-based measures of gene expression are precise given appropriate experimental design; (ii) there is large inter-individual variation, which is composed of a minor nongenetic component and a large heritable component; (iii) variation among populations and species appears to be affected primarily by neutral drift and stabilizing selection, and to a lesser degree by directional selection; and (iv) neutral evolutionary divergence in gene expression becomes nonlinear with greater divergence times due to functional constraint. Evolutionary analyses of gene expression reviewed here provide unique insights into partitioning of regulatory variation in nature. However, common limitations of these studies include the tendency to assume a linear relationship between expression divergence and species divergence, and failure to test explicit hypotheses that involve the ecological context of evolutionary divergence.

Animals↗
PubMed2001

Language development and symbolic play in children with and without familial risk for dyslexia.

The purposes of this study were to investigate (a) whether children in families with a positive history of dyslexia were more likely to show delays in language development than children without family risk and (b) whether a delayed onset of expressive language (late talking) predicted later language development. We analyzed the language development of 200 children longitudinally at 14, 24, 30, and 42 months and assessed their symbolic play at 14 months. Half of the children (N = 106) were from families with a history of dyslexia (the Dyslexia Risk [DR] group), and other children served as age-matched controls. Parental reports and structured tests were used to assess children's receptive and expressive language and symbolic play. No differences emerged between the two groups in receptive language, symbolic play, or on the Bayley MDI. The groups, however, diverged in expressive language measures. The maximum sentence length at 2 years and object naming and inflectional morphology skills at 3.5 years were higher for the control group than for the DR group. Reynell receptive score at 2.5 years provided the greatest unique contribution to the prediction of the children's receptive and expressive language. Children's risk status did not contribute to receptive language, but provided a significant contribution to their expressive language at 3.5 years, even after the variance associated with parental education and children's previous language skills was controlled. Late talkers in the DR group differed from the other members of the DR group in both receptive and expressive language at 3.5 years, although in the control group children with a late-talking history performed at age-level expectations. The findings suggest that children with a familial risk for dyslexia and with a history of late talking are at higher risk for delays in language acquisition than children without the familial risk for dyslexia.

Dyslexia↗
PubMed1990

Affective expression in children's fantasy play, primary process thinking on the Rorschach, and divergent thinking.

The relationships among expression of primary process thinking on the Rorschach, affective expression in fantasy play, and divergent thinking were investigated in first and second grade children. Sixty children received the rorschach (Holt's scoring system), a play task (Affect in Play Scale), and the Alternate Uses Test. Major hypotheses were supported because the amount of primary process thinking on the Rorschach (frequency and percent) was significantly, positively related to amount of affective expression and primary process expression in play. Also, expression of affect in play (frequency, variety, integration, and comfort) was significantly, positively related to divergent thinking, independent of IQ for both boys and girls. On the Rorschach, percent of primary process was significantly related to divergent thinking for boys. The results suggest that the ability to think imaginatively in a free-association style and the ability to have access to affect-laden material are related processes.

Affect↗
PubMed1993

Brn-5 is a divergent POU domain factor highly expressed in layer IV of the neocortex.

We have identified rat cDNA clones that encode a POU domain protein, referred to as brain-5 (Brn-5). During embryogenesis in the rat, Brn-5 is widely expressed with highest levels in the developing brain and spinal cord from embryonic day 12.5. In the adult, Brn-5 mRNA is most abundant in the brain, where it is diffusely expressed with the exception of an enrichment in layer IV of the neocortex. However, Brn-5 is also found in multiple adult tissues outside the central nervous system, including kidney, lung, heart, adrenal, skin, testis, and anterior pituitary. This expression pattern contrasts with that of most other POU domain genes that are expressed predominantly in the developing nervous system and are progressively restricted to discrete regions of the brain. The predicted amino acid sequence of Brn-5 is considerably divergent from previously described POU domains and thus defines a new POU domain subclass (class VI). Consistent with its divergent sequence, the DNA-binding characteristics of Brn-5 overlap with, but are clearly distinct from, that of Oct-2. Although Brn-5 can bind to non-octamer sites, a random site selection indicates that its preferred binding site contains a variant octamer core motif. Finally, we show that the amino terminus of Brn-5 contains a transactivation domain.

Amino Acid Sequence↗
PubMed1986

Mechanism for the autogenous control of the crp operon: transcriptional inhibition by a divergent RNA transcript.

Expression of the crp gene is negatively autoregulated by the complex of cyclic AMP and its receptor protein (cAMP-CRP). We find a second promoter in this region that is strongly activated in vitro and in vivo by cAMP-CRP. Transcription from this promoter is initiated 3 nucleotides upstream and on the opposite strand from the start of crp mRNA. The addition of the purified 5' segment of the divergent RNA specifically inhibits crp transcription in vitro. cAMP-CRP does not block crp expression if the new promoter is altered so that divergent RNA cannot be made. The initial nucleotides of the divergent RNA are complementary to 10 of the first 11 nucleotides of the crp mRNA. Since the next 11 nucleotides of crp mRNA are A + U-rich, and RNA hybrid between the divergent RNA and the 5' end of crp mRNA could produce a structure similar to a rho-independent terminator, leading to inhibition of crp transcription.

Bacterial Proteins↗
PubMed2001

The sheep genome contributes to localization of control elements in a human gene with complex regulatory mechanisms.

Genes that show complex tissue-specific and temporal control by regulatory elements located outside their promoters present a considerable challenge to identify the sequences involved. The rapid accumulation of genomic sequence information for a number of species has enabled a comparative phylogenetic approach to find important regulatory elements. For some genes, which show a similar pattern of expression in humans and rodents, genomic sequence information for these two species may be sufficient. Others, such as the cystic fibrosis transmembrane conductance regulator (CFTR) gene, show significant divergence in expression patterns between mouse and human, necessitating phylogenetic approaches involving additional species. The ovine CFTR gene has a temporal and spatial expression pattern that is very similar to that of human CFTR. Comparative genomic sequence analysis of ovine and human CFTR identified high levels of homology between the core elements in several potential regulatory elements defined as DNase I hypersensitive sites in human CFTR. These data provide a case for the power of an artiodactyl genome to contribute to the understanding of human genetic disease.

Animals↗
PubMed1997

Structure, chromosomal localization and expression of mouse genes encoding type III Reg, RegIII alpha, RegIII beta, RegIII gamma.

Reg (regenerating gene), first isolated from a rat regenerating islet cDNA library, is expressed in regenerating islet beta-cells. Recently, it has been revealed that Reg and Reg-related genes constitute a multigene family, Reg family, which consists of three subtypes (type I, II, III) based on the primary structures of the encoded proteins of the genes. In mouse, type I and type II Reg genes (i.e. RegI and RegII gene) have so far been isolated. In the present study, the complete nucleotide (nt) sequences of the cDNAs and genes encoding murine type III Reg (regenerating gene product), RegIII alpha, RegIII beta and RegIII gamma were determined. RegIII alpha, RegIII beta and RegIII gamma encode 175-, 175- and 174-amino acid (aa) proteins, respectively, with 60-70% homology. All three genes are composed of six exons and five introns spanning approx. 3 kb, and exhibit distinctive structural features unique for members of the Reg gene family. All the mouse Reg genes, RegIII alpha, RegIII beta, RegIII gamma, RegI and RegII, are assigned to the adjacent site of chromosome 6C by fluorescence in situ hybridization (FISH). RegIII alpha, RegIII beta and RegIII gamma were expressed weakly in pancreas, strongly in intestinal tract, but not in hyperplastic islets, whereas both RegI and RegII were expressed in hyperplastic islets. These results suggest that genes of the mouse Reg family are derived from a common ancestor gene by several gene duplications, and have obtained divergency in expression and function in the process of genetic evolution.

Amino Acid Sequence↗
PubMed2000

Lipopolysaccharide induces scavenger receptor A expression in mouse macrophages: a divergent response relative to human THP-1 monocyte/macrophages.

Gene deletion studies indicate that the macrophage scavenger receptor A (SR-A) protects mice from LPS-induced endotoxemia. Paradoxically, cultured human monocyte-derived macrophages down-regulate SR-A expression when exposed to LPS. We found that human THP-1 monocyte/macrophages decrease SR-A expression in response to LPS independent of their differentiation status. In contrast, primary and elicited mouse peritoneal macrophages as well as the J774A.1 and RAW264.7 mouse macrophage lines increase SR-A expression in response to LPS. Exposure to LPS caused J774A.1 and RAW264.7 cells to increase SR-A transcripts by 3- and 5-fold, respectively. LPS caused a concomitant 3-fold increase in SR-A protein levels and increased cell membrane expression of the receptor. RAW264.7 cells increased SR-A transcript levels in response to LPS at concentrations as low as 1 ng/ml, and the response was saturated at 10 ng/ml. The LPS induction of SR-A transcripts required continual protein synthesis and began at 8 h, peaked by 16 h, and persisted for at least 48 h. LPS induction did not increase SR-A gene transcription or affect alternative transcript splicing, but mildly increased mature transcript stability and proceeded in the presence of actinomycin D. Finally, treatment of RAW264.7 cells with TNF-alpha did not induce SR-A transcript levels, indicating that a TNF-alpha autocrine/paracrine signaling mechanism alone is not sufficient to recapitulate the LPS induction of SR-A transcripts. The induction of SR-A expression by LPS-stimulated mouse macrophages is the opposite of the down-regulation of SR-A reported in human monocyte-derived macrophages and may have implications for the observed resistance mice show toward endotoxemia.

Alternative Splicing↗
PubMed1996

Cyclic AMP inhibition of thrombin-induced growth in vascular smooth muscle cells correlates with decreased JNK1 activity and c-Jun expression.

Thrombin is a potent modulator of vascular tone and vascular smooth muscle cell (VSMC) mitogenesis. Early studies from other laboratories demonstrated that cyclic AMP (cAMP) antagonizes the mitogenic effects of platelet-derived growth factor and epidermal growth factor by inhibiting the extracellular signal-regulated protein kinases (ERKs; p42, p44) group of mitogen-activated protein kinases (MAPKs) in several cell types. This report examines the role of ERKs and Jun N-terminal kinase 1 (JNK1) groups of mitogen-activated protein kinases in thrombin-induced DNA synthesis in VSMCs using agents such as forskolin and dibutyrylcyclic AMP that increase intracellular cAMP levels. Both agents significantly inhibited thrombin-stimulated DNA synthesis in VSMCs. These agents, however, had no effect on thrombin induction of ERKs activation and c-Fos expression, suggesting divergence of the latter two events from the growth-signaling events of thrombin that are sensitive to inhibition by cAMP. Thrombin activated JNK1 and induced c-Jun expression in VSMCs in a time-dependent manner. In contrast to ERKs and c-Fos, thrombin-induced JNK1 activation and c-Jun expression were sensitive to inhibition by forskolin, suggesting an association of these events with thrombin-stimulated growth in these cells. Thrombin also increased AP-1 activity, and this response was significantly blunted by forskolin. Together, these results demonstrate a correlation between JNK1 activation and c-Jun expression by thrombin and their association with the mitogenic signaling events of thrombin in VSMCs.

Animals↗
PubMed2001

Amphioxus Evx genes: implications for the evolution of the Midbrain-Hindbrain Boundary and the chordate tailbud.

Evx genes are widely used in animal development. In vertebrates they are crucial in gastrulation, neurogenesis, appendage development and tailbud formation, whilst in protostomes they are involved in gastrulation and neurogenesis, as well as segmentation at least in Drosophila. We have cloned the Evx genes of amphioxus (Branchiostoma floridae), and analysed their expression to understand how the functions of Evx have evolved between invertebrates and vertebrates, and in particular at the origin of chordates and during their subsequent evolution. Amphioxus has two Evx genes (AmphiEvxA and AmphiEvxB) which are genomically linked. AmphiEvxA is prototypical to the vertebrate Evx1 and Evx2 genes with respect to its sequence and expression, whilst AmphiEvxB is very divergent. Mapping the expression of AmphiEvxA onto a phylogeny shows that a role in gastrulation, dorsal-ventral patterning and neurogenesis is probably retained throughout bilaterian animals. AmphiEvxA expression during tailbud development implies a role for Evx throughout the chordates in this process, whilst lack of expression at the homologous region to the vertebrate Midbrain-Hindbrain Boundary (MHB) is consistent with the elaboration of the full organiser properties of this region being a vertebrate innovation.

Amino Acid Sequence↗
PubMed2005

Evolution of proteins and gene expression levels are coupled in Drosophila and are independently associated with mRNA abundance, protein length, and number of protein-protein interactions.

Organismic evolution requires that variation at distinct hierarchical levels and attributes be coherently integrated, often in the face of disparate environmental and genetic pressures. A central part of the evolutionary analysis of biological systems remains to decipher the causal connections between organism-wide (or genome-wide) attributes (e.g., mRNA abundance, protein length, codon bias, recombination rate, genomic position, mutation rate, etc) as well as their role-together with mutation, selection, and genetic drift-in shaping patterns of evolutionary variation in any of the attributes themselves. Here we combine genome-wide evolutionary analysis of protein and gene expression data to highlight fundamental relationships among genomic attributes and their associations with the evolution of both protein sequences and gene expression levels. Our results show that protein divergence is positively coupled with both gene expression polymorphism and divergence. We show moreover that although the number of protein-protein interactions in Drosophila is negatively associated with protein divergence as well as gene expression polymorphism and divergence, protein-protein interactions cannot account for the observed coupling between regulatory and structural evolution. Furthermore, we show that proteins with higher rates of amino acid substitutions tend to have larger sizes and tend to be expressed at lower mRNA abundances, whereas genes with higher levels of gene expression divergence and polymorphism tend to have shorter sizes and tend to be expressed at higher mRNA abundances. Finally, we show that protein length is negatively associated with both number of protein-protein interactions and mRNA abundance and that interacting proteins in Drosophila show similar amounts of divergence. We suggest that protein sequences and gene expression are subjected to similar evolutionary dynamics, possibly because of similarity in the fitness effect (i.e., strength of stabilizing selection) of disruptions in a gene's protein sequence or its mRNA expression. We conclude that, as more and better data accumulate, understanding the causal connections among biological traits and how they are integrated over time to constrain or promote structural and regulatory evolution may finally become possible.

Animals↗
PubMed1985

Two divergent cellular src genes are expressed in Xenopus laevis.

Genomic and cDNA clones of the X. laevis src gene have been isolated and characterized by hybridization and DNA sequence analyses. The haploid genome of X. laevis contains two src genes, which can be distinguished from one another by virtue of sequence divergence in the 3' untranslated regions. Both of the genes are functional as indicated by the fact that oocytes contain RNAs transcribed from each of the genes. The two genes each encode an RNA which is 3.3 kb in length, or twice the length required to encode the 60,000 dalton src protein (pp60). Sequence analysis of the cDNA clones revealed that nearly all of the non-coding sequence is located at the 3' end. The availability of sequence data from cDNA clones has also made it possible for the first time to identify with certainty the carboxyl terminal sequence of a cellular pp60 molecule.

Amino Acid Sequence↗
PubMed2005

Expression patterns of duplicate genes in the developing root in Arabidopsis thaliana.

Data on gene expression in the development of the root in Arabidopsis thaliana were used to test for expression profile differences among multi-gene families and to examine the extent to which expression differences accompanied coding sequences divergence within families. Significant differences among families were observed on two principal axes, accounting for over 80% of the variance in the expression data. The number of synonymous nucleotide substitutions per synonymous site (d(S)) and the number of nonsynonymous nucleotide substitutions per nonsynonymous site (d(N)) were estimated between the members of two-member families (N = 428) and between phylogenetically independent sister pairs (N = 190) of sequences within larger families. Ribosomal proteins and a few other proteins were exceptional in showing highly divergent expression patterns in spite of very low levels of amino acid sequence divergence, as indicated by the low d(N) relative to d(S). However, the majority of gene duplicates showed relatively high levels of amino acid sequence divergence without appreciable change in expression pattern in the cell types analyzed.

Arabidopsis↗
PubMed2000

Discoordinate expression of pancreatic lipase and two related proteins in the human fetal pancreas.

The lipase gene family contains a large number of members. Among the most closely related are pancreatic triglyceride lipase (PTL) and two pancreatic lipase-related proteins (PLRP1 and PLRP2). Previous studies in rodents demonstrated divergent temporal expression of the genes encoding these proteins. PLRP1 and PLRP2 were expressed in fetal pancreas, whereas PTL was not expressed until pups were several weeks old. To determine whether the human pancreas has a similar expression pattern for these genes, we determined the levels of each mRNA in fetal pancreas at various ages. A reverse transcriptase-PCR method was developed and used to quantify the mRNA levels for the three species normalized to the mRNA encoding cyclophillin. The mRNA encoding PLRP1 and PLRP2 was present by 16 wk in the fetal pancreas. In contrast, the mRNA encoding PTL was not present in the fetal pancreas. This pattern of expression suggests that the genes encoding theses proteins have different regulatory elements controlling temporal expression and provides another example of nonparallel expression of genes encoding pancreatic exocrine proteins.

Electrophoresis, Polyacrylamide Gel↗
PubMed2005

Evolutionarily conserved and diverged alternative splicing events show different expression and functional profiles.

To better decipher the functional impact of alternative splicing, we classified alternative splicing events in 10,818 pairs of human and mouse genes based on conservation at genome and transcript levels. Expression levels of conserved alternative splices in human and mouse expressed sequence tag databases show strong correlation, indicating that alternative splicing is similarly regulated in both species. A total of 43% (8921) of mouse alternative splices could be found in the human genome but not in human transcripts. Five of eleven tested mouse predictions were observed in human tissues, demonstrating that mouse transcripts provide a valuable resource for identifying alternative splicing events in human genes. Combining gene-specific measures of conserved and diverged alternative splicing with both gene classification based on Gene Ontology (GO) and microarray-determined gene expression in 52 diverse human tissues and cell lines, we found conserved alternative splicing most enriched in brain-expressed signaling pathways. Diverged alternative splicing is more prevalent in testis and cancerous cell line up-regulated processes, including protein biosynthesis, responses to stress and responses to endogenous stimuli. Using conservation as a surrogate for functional significance, these results suggest that alternative splicing plays an important role in enhancing the functional capacity of central nervous systems, while non-functional splicing more frequently occurs in testis and cell lines, possibly as a result of cellular stress and rapid proliferation.

Alternative Splicing↗
PubMed1993

Modulation of cytokeratin expression in the hamster thymus: evidence for a plasticity of the thymic epithelium.

Cytokeratin (CK) expression was investigated, by means of immunocytochemistry, in the hamster thymic epithelium during ontogeny, as well as in primary cultures and upon glucocorticoid hormone treatment in vivo. As compared to the distribution pattern of distinct monoclonal antibody-defined cytokeratins in the normal adult thymus, CK modulation was evidenced in the three situations studied. During thymus ontogeny, both cytokeratins of simple lining epithelia, as CK8 and CK18, as well as the CK1/CK10 pair (typical marker of terminal stage of keratinization), were expressed since early stages of thymus development. They were located in the central region of thymic lobules preceding the cortical-medullary distinctions. This differed from what had been previously shown for mouse thymus ontogeny, revealing that the interspecific diversity in the distribution pattern of thymic cytokeratins occurred early in fetal life. A modulation of CK expression was also detected when hamster thymic epithelial cells (TEC) were led to grow in culture, with a down-regulation of CK19 contrasting with an enhancement of CK18 expression. This diverged from the maintenance of the in situ pattern when human TEC were cultured. Last, in vivo hydrocortisone treatment, known to increase the numbers of KL1+ cells in the mouse thymus medulla, promoted a cortical expression of the CK1/CK10 pair in the hamster thymus. Taken together, our findings demonstrate a continuous plasticity of the thymic epithelium, at least regarding cytokeratin expression, and enlarge the concept of interspecific diversity of intrathymic CK distribution in conditions as morphogenesis, in vitro system, and responsiveness to glucocorticoid hormone treatment.

Animals↗
PubMed2001

Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways.

In this study, we defined the signaling cascade responsible for increased eNOS mRNA expression in response to laminar shear stress. This pathway depends on the tyrosine kinase c-Src because shear induction of eNOS mRNA is blocked by the c-Src inhibitors PP1 and PP2, as well as an adenovirus encoding kinase inactive c-Src. After activation of c-Src, this pathway diverges. One arm is responsible for the short-term (6 hour) increase in eNOS mRNA. This involves a transient, 1-hour increase in eNOS transcription, as detected by nuclear run-on, that is dependent on activation of Ras and is blocked by adenoviral infection with dominant negative Ras. Downstream of Ras, MEK1/2 and ERK1/2 are important in this pathway, as 2 inhibitors of MEK1/2, PD98059 and UO126, completely prevented this early increase in eNOS mRNA. ERK1/2 was rapidly phosphorylated in response to shear, and this was prevented by c-Src and Ras inhibition. Further, Raf is phosphorylated in response to shear stress, and this is prevented by c-Src inhibition, suggesting that Raf may transduce the signal between Ras and ERK1/2. The second arm of the pathway linking activation of c-Src to eNOS expression involves stabilization of eNOS mRNA by shear stress. This response to shear is completely abrogated by the c-Src inhibitor PP1 but not altered by Ras or MEK1/2 inhibition. Thus, c-Src plays a central role in modulation of eNOS expression in response to shear stress via divergent pathways involving a short-term increase in eNOS transcription and a longer-term stabilization of eNOS mRNA.

Animals↗
PubMed2004

The PIN and LAX families of auxin transport genes in Medicago truncatula.

Auxin transport proteins may be involved in nodule development. As a prelude to investigating the roles of these proteins in nodule development, we took advantage of the genetic and molecular resources available in the legume Medicago truncatula to characterize the gene families encoding auxin efflux and influx carriers. We identified ten auxin efflux carrier sequences (MtPINs) and five auxin influx/permease sequences (MtLAXs). The genomic sequence of each of these fifteen genes was determined, the genes were mapped on the publicly available map of M. truncatula, and their expression was examined in shoot and root tissue of nodulating plants. With one exception, transcripts of all MtPIN genes were detected. The expression of MtPIN2 was limited to nodulating roots, while transcripts of all other expressed genes were detected in both shoots and roots. Both the PIN and LAX gene families contain more members in M. truncatula than in Arabidopsis, but the gene families are not significantly expanded. Sequence comparison of the M. truncatula PIN and LAX genes with PIN and LAX genes from other dicots and monocots indicates that both gene families share a common overall structure, with areas of high homology both within M. truncatula and across species boundaries. Molecular phylogenies of both the PIN and LAX gene families were constructed. Combined with intron position and expression data, the phylogenies were used to assign relationships between MtPIN and MtLAX genes and the orthologous Arabidopsis PIN and LAX genes. MtPIN2 and MtPIN7 appear to be the result of a recent gene duplication with subsequent divergence of expression patterns. These results set the stage for the use of these genes in research on the role of auxin in nodulation.

Base Sequence↗