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PubMed2002

Near-neutrality in evolution of genes and gene regulation.

The nearly neutral theory contends that the interaction of drift and selection is important and occurs at various levels, including synonymous and nonsynonymous substitutions in protein coding regions and sequence turnover of regulatory elements. Recent progress of the theory is reviewed, and the interaction between drift and selection is suggested to differ at these different levels. Weak selective force on synonymous changes is stable, whereas its consequence on nonsynonymous changes depends on environmental factors. Selection on differentiation of regulatory elements is even more dependent on environmental factors than on amino acid changes. Of particular significance is the role of drift in the evolution of gene regulation that directly participates in morphological evolution. The range of near neutrality depends on the effective size of the population that is influenced by selected linked loci. In addition to the effective population size, molecular chaperones such as heat shock protein 90 have significant effects on the range of near neutrality.

Amino Acid Substitution↗

PubMed1990

Evolution of insulin-like growth factor I (IGF-I): structure and expression of an IGF-I precursor from Xenopus laevis.

By means of a cloning strategy employing the polymerase chain reaction, we have isolated and characterized cDNAs for Xenopus laevis insulin-like growth factor I (IGF-I). These cDNAs encode a primary IGF-I translation product of 153 residues that demonstrates considerable amino acid sequence similarity with IGF-IA peptides from other species. Fifty-seven of 70 residues of the mature protein are identical among human, rat, chicken, and Xenopus IGF-I, while less amino acid conservation is found at the COOH-terminus (25/35 identities) or at the NH2-terminus (24/48 identities) of the precursor protein. Despite the lower degree of structural similarity at the NH2-terminus, in vitro studies of IGF-I biosynthesis and proteolytic processing support a conserved function for the atypically long 48 residue NH2-terminal signal sequence in directing the nascent IGF-I peptide through the secretory pathway. The 5'-untranslated region of Xenopus IGF-I mRNA matches the human, rat, and chicken sequences in greater than 90% of 279 nucleotides. IGF-I mRNAs from all four species encode a conserved upstream open reading frame of 14 amino acids starting 240-250 nucleotides 5' to the translation start site, suggesting a possible role for this region in modulating IGF-I gene expression. The X. laevis IGF-I gene is transcribed and processed into three mRNAs of 1.6, 2.1, and 3.0 kilobases in liver, and IGF-I mRNAs can be detected in liver, lung, heart, kidney, and peritoneal fat of adult animals. These studies demonstrate that both the IGF-I protein precursor and potential regulatory regions of IGF-I mRNA have been conserved during vertebrate evolution, and indicate that like several other polypeptide growth factors, IGF-I may be of fundamental importance in regulating specific aspects of growth and development in all vertebrates.

Amino Acid Sequence↗

PubMed1997

Ether lipids and platelet-activating factor: evolution and cellular function.

This review considers the relation between the evolution of ether lipids and platelet-activating factor (PAF) in living organisms for the first time. Ether lipids are shown to be the main structural lipid components in the cells of the most primitive organisms on the Earth; during evolution they were gradually substituted for lipids with ester and vinyl bonds. Synthesis of PAF has been found in some bacteria, protozoans, yeasts, plants, marine invertebrates, lower vertebrates, and mammals. The regulatory role of PAF is suggested to already appear in protozoans and later be maintained during the subsequent evolution of living organisms. During evolution, functions of PAF in the cell have been changing and enlarging, while ether lipids have been gradually losing their role as the main structural lipid component of the cells of living organisms.

Animals↗

PubMed1980

Some thoughts on evolution.

The sparsity of transitional forms and the abrupt appearance of higher taxa in the fossil record are enigmas for the neo-Darwinian theory of evolution. If the cell is considered to be a steady state system then mutations affecting non-regulatory proteins will have far less effect on the steady state than mutations affecting regulatory proteins. This latter type of mutation, when expressed in multicellular biological systems, is a sufficient explanation for the discontinuities observed between species. Such a mechanism, however, has its own implications for any theory of evolution.

Animals↗

PubMed2006

Genomic organization, alternative splicing, and multiple regulatory regions of the zebrafish fgf8 gene.

Fgf8 is among the members of the fibroblast growth factor (FGF) family that play pivotal roles in vertebrate development. In the present study, the genomic DNA of the zebrafish fgf8 gene was cloned to elucidate the regulatory mechanism behind the temporally and spatially restricted expression of the gene in vertebrate embryos. Structural analysis revealed that the exon-intron organization of fgf8 is highly conserved during vertebrate evolution, from teleosts to mammals. Close inspection of the genomic sequence and reverse transcription-polymerase chain reaction analysis revealed that zebrafish fgf8 encodes two splicing variants, corresponding to Fgf8a and Fgf8b, among the four to seven splicing variants known in mammals. Misexpression of the two variants in zebrafish embryos following mRNA injection showed that both variants have dorsalizing activities on zebrafish embryos, with Fgf8b being more potent. Reporter gene analysis of the transcriptional regulation of zebrafish fgf8 suggested that its complicated expression pattern, which is considered essential for its multiple roles in development, is mediated by combinations of different regulatory regions in the upstream and downstream regions of the gene. Furthermore, comparison of the genomic sequence of fgf8 among different vertebrate species suggests that this regulatory mechanism is conserved during vertebrate evolution.

Alternative Splicing↗

PubMedDate not supplied

Evolution of a regulated operon in the laboratory.

The evolution of new metabolic functions is being studied in the laboratory using the EBG system of E. coli as a model system. It is demonstrated that the evolution of lactose utilization by lacZ deletion strains requires a series of structural and regulatory gene mutations. Two structural gene mutations act to increase the activity of ebg enzyme toward lactose, and to permit ebg enzyme to convert lactose into allolactose, and inducer of the lac operon. A regulatory mutation increases the sensitivity of the ebg repressor of lactose, and permits sufficient ebg enzyme activity for growth. The resulting fully evolved ebg operon regulates its own expression, and also regulates the synthesis of the lactose permease.

Biological Evolution↗

PubMed1994

Reconstitution of the water-oxidizing complex in manganese-depleted photosystem II complexes by using synthetic binuclear manganese complexes.

The efficiency of synthetic binuclear manganese complexes in reconstituting PS II electron flow and oxygen-evolution capacity was analyzed in PS II enriched preparations deprived of their manganese and of the extrinsic regulatory subunits. Measurements of the variable fluorescence induced by actinic illumination with continuous light led to the following results: (a) the synthetic binuclear complexes are more efficient than MnCl2 in establishing a PS II electron flow; (b) an almost complete restoration is achieved at concentrations of these complexes that correspond with an overall stoichiometry of two manganese per PS II; and (c) the electron flow restored by the binuclear manganese complexes closely resembles that of normal O2-evolving PS II preparations in its resistance to addition of 50 microM EDTA, while that supported by MnCl2 is practically completely suppressed at the same chelator concentration. The rate of O2 evolution was used as a measure of the capability to function as manganese source in reconstitution of the oxygen evolution capacity. It was found that (i) as in the case of PS II electron transport, the synthetic binuclear manganese complexes are significantly more efficient than MnCl2; (ii) with respect to the manganese concentration, the maximum effect is achieved with a mu-oxo bridged binuclear Mn(III) complex (symbolized by M-3) at concentrations corresponding to four manganese per PS II; and (iii) at all concentrations of binuclear manganese complex M-3 a significantly higher restoration of the O2 evolution rate is achieved if the reconstitution assay contains in addition the extrinsic regulatory 33 kDa protein (PS II-O protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorides↗

PubMed2005

Human-zebrafish non-coding conserved elements act in vivo to regulate transcription.

Whole genome comparisons of distantly related species effectively predict biologically important sequences--core genes and cis-acting regulatory elements (REs)--but require experimentation to verify biological activity. To examine the efficacy of comparative genomics in identification of active REs from anonymous, non-coding (NC) sequences, we generated a novel alignment of the human and draft zebrafish genomes, and contrasted this set to existing human and fugu datasets. We tested the transcriptional regulatory potential of candidate sequences using two in vivo assays. Strict selection of non-genic elements which are deeply conserved in vertebrate evolution identifies 1744 core vertebrate REs in human and two fish genomes. We tested 16 elements in vivo for cis-acting gene regulatory properties using zebrafish transient transgenesis and found that 10 (63%) strongly modulate tissue-specific expression of a green fluorescent protein reporter vector. We also report a novel quantitative enhancer assay with potential for increased throughput based on normalized luciferase activity in vivo. This complementary system identified 11 (69%; including 9 of 10 GFP-confirmed elements) with cis-acting function. Together, these data support the utility of comparative genomics of distantly related vertebrate species to identify REs and provide a scaleable, in vivo quantitative assay to define functional activity of candidate REs.

Animals↗

PubMed2003

Genome-wide targeted search for human specific and polymorphic L1 integrations.

Retroelements (REs) occupy up to 40% of the human genome. Newly integrated REs can change the pattern of expression of pre-existing host genes and therefore might play a significant role in evolution. In particular, human- and primate-specific REs could affect the divergence of the Hominoidea superfamily. A comparative genome-wide analysis of RE sites of integration, neighboring genes, and their regulatory interplay in human and ape genomes would be of help in understanding the impact of REs on evolution and genome regulation. We have developed a technique for the genome-wide comparison of the integrations of transposable elements in genomic DNAs of closely related species. The technique called targeted genome differences analysis (TGDA) is also useful for the detection of deletion/insertion polymorphisms of REs. The technique is based on an enhanced version of subtractive hybridization and does not require preliminary knowledge of the genome sequences under comparison. In this report, we describe its application to the detection and analysis of human specific L1 integrations and their polymorphisms. We obtained a library highly enriched in human-specific L1 insertions and identified 24 such new insertions. Many of these insertions are polymorphic in human populations. The total number of human-specific L1 inserts was estimated to be approximately 4000. The results suggest that TGDA is a universal method that can be successfully used for the detection of evolutionary and polymorphic markers in any closely related genomes.

Gene Library↗

PubMed2003

Sequencing and comparison of yeast species to identify genes and regulatory elements.

Identifying the functional elements encoded in a genome is one of the principal challenges in modern biology. Comparative genomics should offer a powerful, general approach. Here, we present a comparative analysis of the yeast Saccharomyces cerevisiae based on high-quality draft sequences of three related species (S. paradoxus, S. mikatae and S. bayanus). We first aligned the genomes and characterized their evolution, defining the regions and mechanisms of change. We then developed methods for direct identification of genes and regulatory motifs. The gene analysis yielded a major revision to the yeast gene catalogue, affecting approximately 15% of all genes and reducing the total count by about 500 genes. The motif analysis automatically identified 72 genome-wide elements, including most known regulatory motifs and numerous new motifs. We inferred a putative function for most of these motifs, and provided insights into their combinatorial interactions. The results have implications for genome analysis of diverse organisms, including the human.

Base Sequence↗

PubMed2005

Diversification and independent evolution of troponin C genes in insects.

Troponin C (TpnC), the calcium-binding subunit of the troponin regulatory complex in the muscle thin filament, is encoded by multiple genes in insects. To understand how TpnC genes have evolved, we characterized the gene number and structure in a number of insect species. The TpnC gene complement is five genes in Drosophilidae as previously reported for D. melanogaster. Gene structures are almost identical in D. pseudoobscura, D. suboboscura, and D. virilis. Developmental patterns of expression are also conserved in Drosophila subobscura and D. virilis. Similar, but not completely equivalent, TpnC gene repertoires have been identified in the Anopheles gambiae and Apis mellifera genomes. Insect TpnC sequences can be divided into three groups, allowing a systematic classification of newly identified genes. The pattern of expression of the Apis mellifera genes essentially agrees with the pattern in Drosophilidae, providing further functional support to the classification. A model for the evolution of the TpnC genes is proposed including the most likely pathway of insect TpnC diversification. Our results suggest that the rapid increase in number and sequence specialization of the adult Type III isoforms can be correlated with the evolution of the holometabolous mode of development and the acquisition of asynchronous indirect flight muscle function in insects. This evolutionarily specialization has probably been achieved independently in different insect orders.

Amino Acid Sequence↗

PubMed2003

Inference of positive and negative selection on the 5' regulatory regions of Drosophila genes.

Both positive selection and negative selection have been shown to drive the evolution of coding regions. It is of interest to know if the corresponding 5' regions of genes may be subjected to selection of comparable intensities. For such a comparison, we chose the Accessory gland protein (Acp) genes as our test case. About 700 bp and 600 bp for the 5' and coding regions, respectively, of eight previously unstudied genes were sequenced from 21 isogenic lines of D. melanogaster and one line from D. simulans. The ratio of divergence at the amino-acid replacement sites (A) over that at the synonymous sites (S) was twice the ratio for common polymorphism. Interestingly, the 5' region shows the same trend, with the 5'/S divergence ratio being 1.8 times higher than the 5'/S ratio for common polymorphism. There are several possible explanations for the 5'/S ratios, including demography, negative selection, and positive selection. Under normal conditions, positive selection is the most likely explanation. If that is true, about 45 to 50 percent of all fixed differences at both the replacement and 5' sites were adaptive, even though the substitution rate in the former is only half that of the latter (K(A)/K(S) approximately 0.3 vs. K(5')/K(S) approximately 0.6). As previous analyses have indicated, the inclusion of slightly deleterious polymorphism confounds the inference of positive selection. The analysis of published polymorphism data covering 97 verified 5' regions of Drosophila suggests more pronounced selective constraint on the 5' untranslated region and the core promoter (together corresponding to approximately 200 bp in this data set) when compared to the more distal portion of the 5' region of genes.

5' Flanking Region↗

PubMed2003

Imprinting evolution and the price of silence.

In contrast to the biallelic expression of most genes, expression of genes subject to genomic imprinting is monoallelic and based on the sex of the transmitting parent. Possession of only a single active allele can lead to deleterious health consequences in humans. Aberrant expression of imprinted genes, through either genetic or epigenetic alterations, can result in developmental failures, neurodevelopmental and neurobehavioral disorders and cancer. The evolutionary emergence of imprinting occurred in a common ancestor to viviparous mammals after divergence from the egg-laying monotremes. Current evidence indicates that imprinting regulation in metatherian mammals differs from that in eutherian mammals. This suggests that imprinting mechanisms are evolving from those that were established 150 million years ago. Therefore, comparing genomic sequence of imprinted domains from marsupials and eutherians with those of orthologous regions in monotremes offers a potentially powerful bioinformatics approach for identifying novel imprinted genes and their regulatory elements. Such comparative studies will also further our understanding of the molecular evolution and phylogenetic distribution of imprinted genes.

Alleles↗

PubMed2005

Origination and innovation in the vertebrate limb skeleton: an epigenetic perspective.

The vertebrate limb has provided evolutionary and developmental biologists with grist for theory and experiment for at least a century. Its most salient features are its pattern of discrete skeletal elements, the general proximodistal increase in element number as development proceeds, and the individualization of size and shape of the elements in line with functional requirements. Despite increased knowledge of molecular changes during limb development, however, the mechanisms for origination and innovation of the vertebrate limb pattern are still uncertain. We suggest that the bauplan of the limb is based on an interplay of genetic and epigenetic processes; in particular, the self-organizing properties of precartilage mesenchymal tissue are proposed to provide the basis for its ability to generate regularly spaced nodules and rods of cartilage. We provide an experimentally based "core" set of cellular and molecular processes in limb mesenchyme that, under realistic conditions, exhibit the requisite self-organizing behavior for pattern origination. We describe simulations that show that under limb bud-like geometries the core mechanism gives rise to skeletons with authentic proximodistal spatiotemporal organization. Finally, we propose that evolution refines skeletal templates generated by this process by mobilizing accessory molecular and biomechanical regulatory processes to shape the developing limb and its individual elements. Morphological innovation may take place when such modulatory processes exceed a threshold defined by the dynamics of the skeletogenic system and elements are added or lost.

Animals↗

PubMed1997

JC virus regulatory region rearrangements and genotypes in progressive multifocal leukoencephalopathy: two independent aspects of virus variation.

JC virus (JCV) causes the central demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV strains excreted in the urine are distinguishable from those in PML tissue by the configuration of their regulatory region to the right of ori: the archetypal regulatory region, 267 nucleotides long, is rearranged in PML tissue by deletion and duplication. Within the coding region JCV shows variations as a result of virus evolution. Four major genotypes are distinguishable of which Type 1 is based in Europe and Type 2 in Asia. Here, the regulatory region rearrangements and the viral genotypes of 29 JCV strains from PML brain were determined. Rearrangement patterns and genotypes were not associated. In general, deletions occurred before duplications, but exceptions to this rule exist. Each configuration of the 29 rearranged regulatory regions was unique and could be derived directly from the non-rearranged, archetypal form.

Gene Rearrangement↗

PubMed1993

Localization of human cell cycle regulatory genes CDC25C to 5q31 and WEE1 to 11p15.3-11p15.1 by fluorescence in situ hybridization.

The cell cycle control genes are highly conserved during evolution since they play a key role in the regulation of cell division. We have localized CDC25C and WEE1 respectively at 5q31 and 11p15.3-11p15.1 using fluorescent in situ hybridization of cDNA probes on human chromosomes. This shows that genes acting through a regulatory phosphorylation cascade are not clustered on the same chromosome. Furthermore, they appear to map on chromosomal regions involved in tumorigenesis. The 5q23-q31 region of chromosome 5 is deleted in some hematologic disorders, and the p15 region of chromosome 11 is involved in development of embryonic tumors.

Cell Cycle↗

PubMed1996

Skeletal muscle determination and differentiation: story of a core regulatory network and its context.

Regulation of skeletal muscle determination and differentiation in vertebrates centers on a core regulatory network which is composed of two families of transcription factors, the MyoD group basic helix-loop-helix (bHLH) muscle regulatory factors (MRFs) and the myocyte enhancer factor 2 (MEF2) group of MADS-box regulators. Members of this network interact with each other genetically and physically, and together they cooperate to positively regulate transcription of downstream muscle-specific differentiation genes. During development, the myogenic network can be activated or repressed in response to patterning signals, some of which have recently been identified. Once activated, the powerful myogenic activity of the core network can be modulated and held in check by a remarkably large group of negative regulators that operate on network components by diverse mechanisms. Recent discoveries highlight extensive parallels between myogenesis and peripheral neurogenesis in the structures of their respective regulatory networks and in the interaction of their bHLH networks with other regulatory circuits. Comparisons with Drosophila indicate that these ensembles of interacting molecular circuits have been highly conserved during evolution.

Animals↗

PubMed2006

Cell cycle control in bacteria and yeast: a case of convergent evolution?

Superficially similar traits in phylogenetically unrelated species often result from adaptation to common selection pressures. Examples of convergent evolution are known at the levels of whole organisms, organ systems, gene networks and specific proteins. The phenotypic properties of living things, on the other hand, are determined in large part by complex networks of interacting proteins. Here we present a mathematical model of the network of proteins that controls DNA synthesis and cell division in the alpha-proteobacterium, Caulobacter crescentus. By comparing the protein regulatory circuits for cell reproduction in Caulobacter with that in budding yeast (Saccharomyces cerevisiae), we suggest that convergent evolution may have created similar molecular reaction networks in order to accomplish the same purpose of coordinating DNA synthesis to cell division. Although the genes and proteins involved in cell cycle regulation in prokaryotes and eukaryotes are very different and (apparently) phylogenetically unrelated, they seem to be wired together in similar regulatory networks, which coordinate cell cycle events by identical dynamical principles.

Biological Evolution↗