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Gene loss, protein sequence divergence, gene dispensability, expression level, and interactivity are correlated in eukaryotic evolution.

Lineage-specific gene loss, to a large extent, accounts for the differences in gene repertoires between genomes, particularly among eukaryotes. We derived a parsimonious scenario of gene losses for eukaryotic orthologous groups (KOGs) from seven complete eukaryotic genomes. The scenario involves substantial gene loss in fungi, nematodes, and insects. Based on this evolutionary scenario and estimates of the divergence times between major eukaryotic phyla, we introduce a numerical measure, the propensity for gene loss (PGL). We explore the connection among the propensity of a gene to be lost in evolution (PGL value), protein sequence divergence, the effect of gene knockout on fitness, the number of protein-protein interactions, and expression level for the genes in KOGs. Significant correlations between PGL and each of these variables were detected. Genes that have a lower propensity to be lost in eukaryotic evolution accumulate fewer substitutions in their protein sequences and tend to be essential for the organism viability, tend to be highly expressed, and have many interaction partners. The dependence between PGL and gene dispensability and interactivity is much stronger than that for sequence evolution rate. Thus, propensity of a gene to be lost during evolution seems to be a direct reflection of its biological importance.

Amino Acid Substitution↗

A neutral model of transcriptome evolution.

Microarray technologies allow the identification of large numbers of expression differences within and between species. Although environmental and physiological stimuli are clearly responsible for changes in the expression levels of many genes, it is not known whether the majority of changes of gene expression fixed during evolution between species and between various tissues within a species are caused by Darwinian selection or by stochastic processes. We find the following: (1) expression differences between species accumulate approximately linearly with time; (2) gene expression variation among individuals within a species correlates positively with expression divergence between species; (3) rates of expression divergence between species do not differ significantly between intact genes and expressed pseudogenes; (4) expression differences between brain regions within a species have accumulated approximately linearly with time since these regions emerged during evolution. These results suggest that the majority of expression differences observed between species are selectively neutral or nearly neutral and likely to be of little or no functional significance. Therefore, the identification of gene expression differences between species fixed by selection should be based on null hypotheses assuming functional neutrality. Furthermore, it may be possible to apply a molecular clock based on expression differences to infer the evolutionary history of tissues.

Animals↗

Evolution and developmental expression of nuclear receptor genes in the ascidian Herdmania.

Nuclear receptors are a superfamily of metazoan transcription factors that have been shown to be involved in a wide range of developmental and physiological processes. A PCR-based survey of genomic DNA and developmental cDNAs from the ascidian Herdmania identifies eight members of this multigene family. Sequence comparisons and phylogenetic analyses reveal that these ascidian nuclear receptors are representative of five of the six previously defined nuclear receptor subfamilies and are apparent homologues of retinoic acid [NR1B], retinoid X [NR2B], peroxisome proliferator-activated [NR1C], estrogen related [NR3B], neuron-derived orphan (NOR) [NR4A3], nuclear orphan [NR4A], TR2 orphan [NR2C1] and COUP orphan [NR2F3] receptors. Phylogenetic analyses that include the ascidian genes produce topologically distinct trees that suggest a redefinition of some nuclear receptor subfamilies. These trees also suggest that extensive gene duplication occurred after the vertebrates split from invertebrate chordates. These ascidian nuclear receptor genes are expressed differentially during embryogenesis and metamorphosis.

Amino Acid Sequence↗

Expression patterns of developmental regulatory genes show comparable divisions in the telencephalon of Xenopus and mouse: insights into the evolution of the forebrain.

In this study, we review data on the existence of comparable divisions and subdivisions in the telencephalon of different groups of tetrapods based on expression of some developmental regulatory genes, having a particular focus in the comparison of the anuran amphibian Xenopus and the mouse. The available data on Xenopus, mouse, chick and turtle indicate that apparently all tetrapod groups possess the same molecularly distinct divisions and subdivisions in the telencephalon. This basic organization was likely present in the telencephalon of stem tetrapods. Each division/subdivision is characterized by expression of a unique combination of developmental regulatory genes, and appears to represent a self-regulated and topologically constant histogenetic brain compartment that gives rise to specific groups of cells. This interpretation has an important consequence for searching homologies, since a basic condition for cell groups in different vertebrates to be considered homologous is that they originate in the same compartment. However, evolution may allow individual cell groups derived from comparable (field homologous) subdivisions to be either similar or dissimilar across the vertebrate groups, giving rise to several possible scenarios of evolution, which include both the evolutionary conservation of similar (homologous) cells or the production of novel cell groups. Finally, available data in the lamprey, a jawless fish, suggest that not all telencephalic subdivisions were present at the origin of vertebrates, raising important questions about their evolution.

Animals↗

Stochastic modeling of single-cell gene expression adaptation reveals non-genomic contribution to evolution of tumor subclones.

Cancer progression is an evolutionary process driven by the selection of cells adapted to gain growth advantage. We present a formal study on the adaptation of gene expression in subclonal evolution. We model evolutionary changes in gene expression as stochastic Ornstein-Uhlenbeck processes, jointly leveraging the evolutionary history of subclones and single-cell expression data. Applying our model to sublines derived from single cells of a mouse melanoma revealed that sublines with distinct phenotypes are underlined by different patterns of gene expression adaptation, indicating non-genetic mechanisms of cancer evolution. Sublines previously observed to be resistant to anti-CTLA4 treatment showed adaptive expression of genes related to invasion and non-canonical Wnt signaling, whereas sublines that responded to treatment showed adaptive expression of genes related to proliferation and canonical Wnt signaling. Our results suggest that clonal phenotypes emerge as the result of specific adaptivity patterns of gene expression. A record of this paper's transparent peer review process is included in the supplemental information.

Animals↗

Rapid evolution of expression and regulatory divergences after yeast gene duplication.

Although gene duplication is widely believed to be the major source of genetic novelty, how the expression or regulatory network of duplicate genes evolves remains poorly understood. In this article, we propose an additive expression distance between duplicate genes, so that the evolutionary rate of expression divergence after gene duplication can be estimated through phylogenomic analysis. We have analyzed yeast genome sequences, microarrays, and transcriptional regulatory networks, showing a >10-fold increase in the initial rate for both expression and regulatory network evolution after gene duplication but only an approximately 20% rate increase in the early stage for protein sequences. Based on the estimated age distribution of yeast duplicate genes, we roughly estimate that the initial rate of expression divergence shortly after gene duplication is 2.9 x 10(-9) per year, whereas the baseline rate for very ancient gene duplication is 0.14 x 10(-9) per year. Relative expression rate tests suggest that the expression of duplicate genes tends to evolve asymmetrically, that is, the expression of one copy evolves rapidly, whereas the other one largely maintains the ancestral expression profile. Our study highlights the crucial role of early rapid evolution after gene/genome duplication for continuously increasing the complexity of the yeast regulatory network.

Evolution, Molecular↗

Evolution by gene duplication revisited: differentiation of regulatory elements versus proteins.

For evolution by gene duplication, differentiation of both regulatory elements and proteins is important. Particularly the former is thought to have large effects on morphological evolution, since differential expression of genes is essential for development. In this report, recent knowledge on regulatory elements is reviewed that is relevant to the population genetics aspects of gene duplication. Regulatory elements usually consist of multiple binding sites of two or more transcription factors. The amount of gene product is quantitatively regulated, and is thought to be subject to stabilizing selection. The intensity of stabilizing selection depends upon the level of constraint imposed by regulatory networks. Gene duplication has significant effects on stabilizing selection via perturbation of gene expression. It is pointed out that constraints coming from regulatory networks are most important for survival of duplicate genes, and that both drift and selection are at work in the process of acquisition of new gene expression and function.

Evolution, Molecular↗

The phenylalanine ammonia-lyase gene family in raspberry. Structure, expression, and evolution.

In raspberry (Rubus idaeus), development of fruit color and flavor are critically dependent on products of the phenylpropanoid pathway. To determine how these metabolic functions are integrated with the fruit ripening program, we are examining the properties and expression of key genes in the pathway. Here, we report that L- phenylalanine ammonia-lyase (PAL) is encoded in raspberry by a family of two genes (RiPAL1 and RiPAL2). RiPAL1 shares 88% amino acid sequence similarity to RiPAL2, but phylogenetic analysis places RiPAL1 and RiPAL2 in different clusters within the plant PAL gene family. The spatial and temporal expression patterns of the two genes were investigated in various vegetative and floral tissues using the reverse transcriptase competitor polymerase chain reaction assay. Although expression of both genes was detected in all tissues examined, RiPAL1 was associated with early fruit ripening events, whereas expression of RiPAL2 correlated more with later stages of flower and fruit development. Determination of the absolute levels of the two transcripts in various tissues showed that RiPAL1 transcripts were 3- to 10-fold more abundant than those of RiPAL2 in leaves, shoots, roots, young fruits, and ripe fruits. The two RiPAL genes therefore appear to be controlled by different regulatory mechanisms.

Acyltransferases↗

Rapidly evolving genes of Drosophila: differing levels of selective pressure in testis, ovary, and head tissues between sibling species.

Investigations of rapidly evolving sex- and reproduction-related genes are expected to reveal important information about the process of speciation and species divergence. We screened testis, ovary, and head tissues to identify and characterize rapidly evolving genes (REGs) between closely related species. The results show differential patterns of evolution of genes expressed in reproductive and nonreproductive tissues. (1) There is a differential distribution of REGs in the Drosophila genome, with most REGs localized in the testis, followed by ovary, and then head. (2) Sequence analysis indicates that differential selective pressures are driving the rapid evolution of genes expressed in sex and nonsex tissues. Testis REGs from our data, on average, yielded higher rates of nonsynonymous substitutions relative to transcripts in ovary and head, indicating stronger selective pressures on the male reproductive system. (3) We identified REGs in the testis, ovary, as well as in head tissue that show evidence of evolving under positive selection. Identification of rapidly evolving sex genes is important for detailed investigations of cryptic female choice, sexual conflict, and faster male evolution and is pertinent to our understanding of the process of species divergence and speciation.

Animals↗

Gene expression evolves faster in narrowly than in broadly expressed mammalian genes.

Despite much recent interest, it remains unclear what determines the rate of evolution of gene expression. To study this issue we develop a new measure, called "Expression Conservation Index" (ECI), to quantify the degree of tissue-expression conservation between two homologous genes. Applying this measure to a large set of gene expression data from human and mouse, we show that tissue expression tends to evolve rapidly for genes that are expressed in only a limited number of tissues, whereas tissue expression can be conserved for a long time for genes expressed in a large number of tissues. Therefore, expression breadth is an important determinant for evolutionary conservation of tissue expression. In addition, we find a rapid decrease in ECI with the synonymous divergence between duplicate genes, suggesting fast divergence in tissue expression between duplicate genes.

Animals↗

Detecting lineage-specific adaptive evolution of brain-expressed genes in human using rhesus macaque as outgroup.

Comparative genetic analysis between human and chimpanzee may detect genetic divergences responsible for human-specific characteristics. Previous studies have identified a series of genes that potentially underwent Darwinian positive selection during human evolution. However, without a closely related species as outgroup, it is difficult to identify human-lineage-specific changes, which is critical in delineating the biological uniqueness of humans. In this study, we conducted phylogeny-based analyses of 2633 human brain-expressed genes using rhesus macaque as the outgroup. We identified 47 candidate genes showing strong evidence of positive selection in the human lineage. Genes with maximal expression in the brain showed a higher evolutionary rate in human than in chimpanzee. We observed that many immune-defense-related genes were under strong positive selection, and this trend was more prominent in chimpanzee than in human. We also demonstrated that rhesus macaque performed much better than mouse as an outgroup in identifying lineage-specific selection in humans.

Adaptation, Biological↗

Wnt gene expression in sea urchin development: heterochronies associated with the evolution of developmental mode.

The Wnt genes encode a large family of conserved secreted proteins that are widely involved in animal development. The variety and ubiquity of this ancient family suggest that Wnt genes may have been important in the evolution of animal development, including early development. To test this hypothesis, we have characterized the expression of several Wnt genes in closely related sea urchins that exhibit radically different modes of early development. Wnt-1, -4, and -5 genes exhibit several conserved molecular and developmental characteristics, both within sea urchins and with Wnt genes examined in other animals (Ferkowicz et al. 1998). Here, we demonstrate that sea urchin Wnt-5 transcripts are specifically detected by in situ hybridization in discrete embryonic, larval, and developing adult tissues and processes: (1) in a band of vegetal ectoderm in mesenchyme blastula stage embryos, (2) in the larval ciliary bands, (3) in tissues that form the early adult rudiment (left coelomic pouch and overlying vestibular ectoderm), and (4) in the developing adult radial nervous system. We find that the sites of Wnt-5 transcript accumulation are conserved in species exhibiting either indirect- or direct-developmental modes, suggesting that Wnt-5 function(s) have been conserved in sea urchin development. However, dramatic heterochronic changes in Wnt-5 gene expression have occurred in the direct-developing species that parallel the accelerated morphological changes that occur during direct development. These results suggest that heterochronic changes in the expression of conserved developmental regulatory genes, such as the Wnt family members, are agents of evolutionary change in animal development.

Animals↗

Expression and evolution of the mammalian brain gene Ttyh1.

Homologues of the Drosophila melanogaster tweety (tty) gene are present in mammals and Caenorhabditis elegans. The encoded proteins have five predicted membrane-spanning regions and recent findings suggest that some family members may be chloride channels. Phylogenetic analysis of the tty family including novel members from slime mould Entamoeba and plants has revealed the occurrence of independent gene duplication events in different lineages. expressed sequence tag data indicate that expression of the mammalian Ttyh1 gene is restricted mainly to neural tissue and is up-regulated in astrocytoma, glioma and several other cancers. In this study, mammalian expression vectors were used to investigate the subcellular localization and the effect of over-expression of Ttyh1 in human epithelial kidney cells. The results confirm that Ttyh1 is a membrane protein and show that it is deposited on the substratum along the migration paths of motile cells above the alpha5beta1-integrin complex. The ectopic expression of Ttyh1 also induced long filopodia, which were branched and dynamic in both stationary and migratory cells. The filopodia contained F-actin and occurred at the ends of microtubules which were polarized towards the membrane. Upon contact with nearby cells some filopodia stabilized and filled with F-actin, whereas Ttyh1 was highly concentrated at the cell-cell interface. Ttyh1 N- and C-terminal antipeptide antibodies detected Ttyh1 along the axons of neurones in primary rat hippocampal cell cultures, and in situ in whole rat brain slices around the hippocampus and occasionally between cells. These data suggest a role for Ttyh1 in process formation, cell adhesion and possibly as a transmembrane receptor.

Actins↗

A genetic signature of interspecies variations in gene expression.

Phenotypic diversity is generated through changes in gene structure or gene regulation. The availability of full genomic sequences allows for the analysis of gene sequence evolution. In contrast, little is known about the principles driving the evolution of gene expression. Here we describe the differential transcriptional response of four closely related yeast species to a variety of environmental stresses. Genes containing a TATA box in their promoters show an increased interspecies variability in expression, independent of their functional association. Examining additional data sets, we find that this enhanced expression divergence of TATA-containing genes is consistent across all eukaryotes studied to date, including nematodes, fruit flies, plants and mammals. TATA-dependent regulation may enhance the sensitivity of gene expression to genetic perturbations, thus facilitating expression divergence at particular genetic loci.

DNA↗

Genes "waiting" for recruitment by the adaptive immune system: the insights from amphioxus.

In seeking evidence of the existence of adaptive immune system (AIS) in ancient chordate, cDNA clones of six libraries from a protochordate, the Chinese amphioxus, were sequenced. Although the key molecules such as TCR, MHC, Ig, and RAG in AIS have not been identified from our database, we demonstrated in this study the extensive molecular evidence for the presence of genes homologous to many genes that are involved in AIS directly or indirectly, including some of which may represent the putative precursors of vertebrate AIS-related genes. The comparative analyses of these genes in different model organisms revealed the different fates of these genes during evolution. Their gene expression pattern suggested that the primitive digestive system is the pivotal place of the origin and evolution of the AIS. Our studies support the general statement that AIS appears after the jawless/jawed vertebrate split. However our study further reveals the fact that AIS is in its twilight in amphioxus and the evolution of the molecules in amphioxus are waiting for recruitment by the emergence of AIS.

Amino Acid Sequence↗

Odorant receptor gene regulation: implications from genomic organization.

Odorant receptor genes comprise the largest known family of G-protein-coupled receptors in vertebrates. These receptor genes are tightly clustered in the genomes of every vertebrate organism investigated, including zebrafish, mice and humans, and they appear to have expanded and duplicated throughout evolution. In a mechanism that has yet to be elucidated, each olfactory neuron expresses a single receptor gene. This highly restricted expression pattern underlies the ability to distinguish between a wide variety of odorants. Here, we address the evolutionary expansion of odorant receptor genes and the role genomic organization of these genes might have in their tightly regulated expression.

Alleles↗

The carcinoembryonic antigen gene family: structure, expression and evolution.

The molecular cloning of carcinoembryonic antigen (CEA) and several cross-reacting antigens reveals a basic domain structure for the whole family, which shows structural similarities to the immunoglobulin superfamily. The CEA family consists of approximately 10 genes which are localized in two clusters on chromosome 19. So far, mRNA species for five of these genes have been identified which show tissue variability in their transcriptional activity. Expression of some of these genes in heterologous systems has been achieved, allowing the localization of some epitopes. The characterization of a CEA gene family in the rat and a comparison with its human counterpart has been utilized in the development of an evolutionary model.

Amino Acid Sequence↗

Neofunctionalization in vertebrates: the example of retinoic acid receptors.

Understanding the role of gene duplications in establishing vertebrate innovations is one of the main challenges of Evo-Devo (evolution of development) studies. Data on evolutionary changes in gene expression (i.e., evolution of transcription factor-cis-regulatory elements relationships) tell only part of the story; protein function, best studied by biochemical and functional assays, can also change. In this study, we have investigated how gene duplication has affected both the expression and the ligand-binding specificity of retinoic acid receptors (RARs), which play a major role in chordate embryonic development. Mammals have three paralogous RAR genes--RAR alpha, beta, and gamma--which resulted from genome duplications at the origin of vertebrates. By using pharmacological ligands selective for specific paralogues, we have studied the ligand-binding capacities of RARs from diverse chordates species. We have found that RAR beta-like binding selectivity is a synapomorphy of all chordate RARs, including a reconstructed synthetic RAR representing the receptor present in the ancestor of chordates. Moreover, comparison of expression patterns of the cephalochordate amphioxus and the vertebrates suggests that, of all the RARs, RAR beta expression has remained most similar to that of the ancestral RAR. On the basis of these results together, we suggest that while RAR beta kept the ancestral RAR role, RAR alpha and RAR gamma diverged both in ligand-binding capacity and in expression patterns. We thus suggest that neofunctionalization occurred at both the expression and the functional levels to shape RAR roles during development in vertebrates.

Amino Acid Sequence↗