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PubMed1984

Striking similarities in amino acid sequence among nonstructural proteins encoded by RNA viruses that have dissimilar genomic organization.

The plant viruses alfalfa mosaic virus (AMV) and brome mosaic virus (BMV) each divide their genetic information among three RNAs while tobacco mosaic virus (TMV) contains a single genomic RNA. Amino acid sequence comparisons suggest that the single proteins encoded by AMV RNA 1 and BMV RNA 1 and by AMV RNA 2 and BMV RNA 2 are related to the NH2-terminal two-thirds and the COOH-terminal one-third, respectively, of the largest protein encoded by TMV. Separating these two domains in the TMV RNA sequence is an amber termination codon, whose partial suppression allows translation of the downstream domain. Many of the residues that the TMV read-through domain and the segmented plant viruses have in common are also conserved in a read-through domain found in the nonstructural polyprotein of the animal alphaviruses Sindbis and Middelburg. We suggest that, despite substantial differences in gene organization and expression, all of these viruses use related proteins for common functions in RNA replication. Reassortment of functional modules of coding and regulatory sequence from preexisting viral or cellular sources, perhaps via RNA recombination, may be an important mechanism in RNA virus evolution.

Amino Acid Sequence↗
PubMed2000

A genetic screen for zygotic embryonic lethal mutations affecting cuticular morphology in the wasp Nasonia vitripennis.

We have screened for zygotic embryonic lethal mutations affecting cuticular morphology in Nasonia vitripennis (Hymenoptera; Chalcidoidea). Our broad goal was to investigate the use of Nasonia for genetically surveying conservation and change in regulatory gene systems, as a means to understand the diversity of developmental strategies that have arisen during the course of evolution. Specifically, we aim to compare anteroposterior patterning gene functions in two long germ band insects, Nasonia and Drosophila. In Nasonia, unfertilized eggs develop as haploid males while fertilized eggs develop as diploid females, so the entire genome can be screened for recessive zygotic mutations by examining the progeny of F1 females. We describe 74 of >100 lines with embryonic cuticular mutant phenotypes, including representatives of coordinate, gap, pair-rule, segment polarity, homeotic, and Polycomb group functions, as well as mutants with novel phenotypes not directly comparable to those of known Drosophila genes. We conclude that Nasonia is a tractable experimental organism for comparative developmental genetic study. The mutants isolated here have begun to outline the extent of conservation and change in the genetic programs controlling embryonic patterning in Nasonia and Drosophila.

Animals↗
PubMed1994

Steroidogenic and morphogenic characteristics of human peritubular cells in culture.

We have explored the morphogenic and functional characteristics of human peritubular cells originating from seminiferous tubule (ST) fragments isolated from the testes of two prepubertal patients with the androgen insensitivity syndrome. These ST were cultured in Dulbecco's Modified Eagle's Medium-Ham's F-12 supplemented with antibiotics, transferrin, hydrocortisone, vitamin E, and 3% fetal bovine serum. A centrifugal growth of elongated fibroblast-like cells peripheral to the ST explants was observed. Muscle-specific actin and 3 beta-hydroxysteroid dehydrogenase were evident in the peritubular area and in the elongated cells growing from the tubules. Histochemistry was negative in the tubules themselves, revealing the mixed nature of these cultures. The ST fragments were lost after subculturing, leaving a homogeneous monolayer of fibroblast-like cells. The steroidogenic potential of these cells was demonstrated by the secretion of testosterone (T) to the culture medium. T secretion was stimulated by hCG in a time-dependent fashion (patient 1: Day 11, 84% and Day 15, 200%; patient 2: Day 8, 73% and Day 11, 32% over basal). FSH also stimulated T secretion (patient 1: Day 5, 136% and Day 8, 89%; patient 2: Day 8, 117% and Day 11, 129% over basal). Furthermore, T secretion by these cultures was 100% higher than that observed in mesenchymal cells obtained from the testicular intertubular space in the same patient. Spontaneous T secretion and hormone responses declined progressively to cease by 25 days in culture. These results suggested the involvement of Sertoli cell (SC)-secreted factor(s) in the regulation of T secretion by peritubular cells. In order to further explore possible paracrine interactions between peritubular and Sertoli cells, we carried out heterologous cocultures with rat SC. After 72 h a striking redistribution of both cell types was observed with the formation of cord-like structures. Ultrastructural examination of these cords showed the formation of a basement membrane between epithelial (Sertoli) and mesenchymal cells of peritubular origin. No resumption of T secretion was observed, but an increase in androgen-binding protein (ABP) production by rat SC under basal (37%) and FSH-stimulated (52%) conditions was evident. Our results show that in the human peritubular compartment, cells exist that can alternatively express steroidogenic functions, associate with SC in a specific mesenchymal-epithelial interaction, and exert regulatory influences on ABP secretion by SC. In addition they indicate that communicating events in the testis are preserved throughout evolution.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

A cross-kingdom internal ribosome entry site reveals a simplified mode of internal ribosome entry.

Rhopalosiphum padi virus (RhPV) is an insect virus of the Dicistroviridae family. Recently, the 579-nucleotide-long 5' untranslated region (UTR) of RhPV has been shown to contain an internal ribosome entry site (IRES) that functions efficiently in mammalian, plant, and insect in vitro translation systems. Here, the mechanism of action of the RhPV IRES has been characterized by reconstitution of mammalian 48S initiation complexes on the IRES from purified components combined with the toeprint assay. There is an absolute requirement for the initiation factors eIF2 and eIF3 and the scanning factor eIF1 to form 48S complexes on the IRES. In addition, eIF1A, eIF4F (or the C-terminal fragment of eIF4G), and eIF4A strongly stimulated the assembly of this complex, whereas eIF4B had no effect. Although the eIF4-dependent pathway is dominant in the RhPV IRES-directed cell-free translation, omission of either eIF4G or eIF4A or both still allowed the assembly of 48S complexes from purified components with approximately 23% of maximum efficiency. Deletions of up to 100 nucleotides throughout the 5'-UTR sequence produced at most a marginal effect on the IRES activity, suggesting the absence of specific binding sites for initiation factors. Only deletion of the U-rich unstructured 380-nucleotide region proximal to the initiation codon resulted in a complete loss of the IRES activity. We suggest that the single-stranded nature of the RhPV IRES accounts for its strong but less selective potential to bind key mRNA recruiting components of the translation initiation apparatus from diverse origins.

5' Untranslated Regions↗
PubMed2004

Selection for gene clustering by tandem duplication.

In prokaryotic genomes, related genes are frequently clustered in operons and higher-order arrangements that reflect functional context. Organization emerges despite rearrangements that constantly shuffle gene and operon order. Evidence is presented that the tandem duplication of related genes acts as a driving evolutionary force in the origin and maintenance of clusters. Gene amplification can be viewed as a dynamic and reversible regulatory mechanism that facilitates adaptation to variable environments. Clustered genes confer selective benefits via their ability to be coamplified. During evolution, rearrangements that bring together related genes can be selected if they increase the fitness of the organism in which they reside. Similarly, the benefits of gene amplification can prevent the dispersal of existing clusters. Examples of frequent and spontaneous amplification of large genomic fragments are provided. The possibility is raised that tandem gene duplication works in concert with horizontal gene transfer as interrelated evolutionary forces for gene clustering.

Benzoates↗
PubMed2006

Sigma: multiple alignment of weakly-conserved non-coding DNA sequence.

BACKGROUND: Existing tools for multiple-sequence alignment focus on aligning protein sequence or protein-coding DNA sequence, and are often based on extensions to Needleman-Wunsch-like pairwise alignment methods. We introduce a new tool, Sigma, with a new algorithm and scoring scheme designed specifically for non-coding DNA sequence. This problem acquires importance with the increasing number of published sequences of closely-related species. In particular, studies of gene regulation seek to take advantage of comparative genomics, and recent algorithms for finding regulatory sites in phylogenetically-related intergenic sequence require alignment as a preprocessing step. Much can also be learned about evolution from intergenic DNA, which tends to evolve faster than coding DNA. Sigma uses a strategy of seeking the best possible gapless local alignments (a strategy earlier used by DiAlign), at each step making the best possible alignment consistent with existing alignments, and scores the significance of the alignment based on the lengths of the aligned fragments and a background model which may be supplied or estimated from an auxiliary file of intergenic DNA. RESULTS: Comparative tests of sigma with five earlier algorithms on synthetic data generated to mimic real data show excellent performance, with Sigma balancing high "sensitivity" (more bases aligned) with effective filtering of "incorrect" alignments. With real data, while "correctness" can't be directly quantified for the alignment, running the PhyloGibbs motif finder on pre-aligned sequence suggests that Sigma's alignments are superior. CONCLUSION: By taking into account the peculiarities of non-coding DNA, Sigma fills a gap in the toolbox of bioinformatics.

Algorithms↗
PubMed2003

Identification of conserved regulatory elements by comparative genome analysis.

BACKGROUND: For genes that have been successfully delineated within the human genome sequence, most regulatory sequences remain to be elucidated. The annotation and interpretation process requires additional data resources and significant improvements in computational methods for the detection of regulatory regions. One approach of growing popularity is based on the preferential conservation of functional sequences over the course of evolution by selective pressure, termed 'phylogenetic footprinting'. Mutations are more likely to be disruptive if they appear in functional sites, resulting in a measurable difference in evolution rates between functional and non-functional genomic segments. RESULTS: We have devised a flexible suite of methods for the identification and visualization of conserved transcription-factor-binding sites. The system reports those putative transcription-factor-binding sites that are both situated in conserved regions and located as pairs of sites in equivalent positions in alignments between two orthologous sequences. An underlying collection of metazoan transcription-factor-binding profiles was assembled to facilitate the study. This approach results in a significant improvement in the detection of transcription-factor-binding sites because of an increased signal-to-noise ratio, as demonstrated with two sets of promoter sequences. The method is implemented as a graphical web application, ConSite, which is at the disposal of the scientific community at http://www.phylofoot.org/. CONCLUSIONS: Phylogenetic footprinting dramatically improves the predictive selectivity of bioinformatic approaches to the analysis of promoter sequences. ConSite delivers unparalleled performance using a novel database of high-quality binding models for metazoan transcription factors. With a dynamic interface, this bioinformatics tool provides broad access to promoter analysis with phylogenetic footprinting.

Algorithms↗
PubMed2006

Forces shaping the fastest evolving regions in the human genome.

Comparative genomics allow us to search the human genome for segments that were extensively changed in the last approximately 5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements are dramatically changed in human but not in other primates, with seven times more substitutions in human than in chimp. The accelerated elements, and in particular the top five, show a strong bias for adenine and thymine to guanine and cytosine nucleotide changes and are disproportionately located in high recombination and high guanine and cytosine content environments near telomeres, suggesting either biased gene conversion or isochore selection. In addition, there is some evidence of directional selection in the regions containing the two most accelerated regions. A combination of evolutionary forces has contributed to accelerated evolution of the fastest evolving elements in the human genome.

Animals↗
PubMed2001

Biopharmaceutical statistics in a pharmaceutical regulated environment: past, present, and future.

The practice of statistics in the pharmaceutical industry has changed markedly over the last 25 years. This paper examines the evolution of clinical trial statistics in relationship to advances in statistical methodology and computational power as well as the changing regulatory environment. The current role of the biopharmaceutical statistician is assessed along with the drivers for future change.

Biopharmaceutics↗
PubMed2006

Sequence analysis shows that Lifeguard belongs to a new evolutionarily conserved cytoprotective family.

Cellular sensitivity to apoptotic stimuli is determined by several regulatory proteins. The biological and biomedical impact of these regulatory proteins is of fundamental importance for understanding and controlling apoptotic processes. We used a bioinformatic approach to characterise the antiapoptotic protein Lifeguard (LFG). LFG is an evolutionarily well-conserved protein with homologues in many species. Due to its hydrophobic nature it is predicted to reside in cellular membranes, namely the endoplasmatic reticulum and the plasma membrane, with seven transmembrane spanners and a small cytoplasmic domain. The consensus motif of a protein family with unknown function UPF0005 was found in the C-terminus. The structure of Lifeguard resembles the antiapoptotic protein Bax Inhibitor-1 (BI-1). Concordantly, it was shown that Bax co-immunoprecipitates with LFG. Our results indicate that LFG belongs to a new cytoprotective family with evolutionarily conserved functions in the prevention of programmed cell death.

Amino Acid Sequence↗
PubMed1989

IL-4-responsive human helper T cell clones are resistant to growth inhibition by tumor necrosis factor-alpha.

Positive and negative signals for clonal expansion of preactivated human CD4+ alloreactive Th cells have been examined. Fifteen T cell clones tested 3 days after Ag-specific stimulation proliferated with IL-2 but only five of these responded to IL-4. The remaining 10 also failed to respond to IL-4 in the presence of IL-1 and/or autologous B-LCL. The response of the latter five to IL-4 was independent of IL-2 as shown by the inability of IL-2R mAb to prevent proliferation. In contrast, transferrin R mAb blocked responses to both IL-2 and IL-4. IL-4 responder but not nonresponder clones demonstrated IL-4-enhanced responses to suboptimal concentrations of IL-2 (1 U/ml), but none of the clones showed enhanced responses with 1 U/ml IL-2 plus IL-1, IL-3, IL-5, or granulocyte-macrophage-CSF. IFN-gamma did not enhance or inhibit responses to either IL-2 or IL-4. TNF-alpha did not block proliferation supported by IL-4. In contrast, TNF-alpha did block proliferative responses to IL-2, but only by those clones which were incapable of responding to IL-4. Thus, proliferation of the IL-4-responder clones was not blocked by TNF-alpha when optimal or even supraoptimal concentrations of IL-2 were used as growth factor. Because all T cell clones themselves secreted TNF-alpha after specific stimulation, these results suggest a novel autocrine negative regulatory pathway, whereby IL-4-reactive helper cells would have a selective advantage over IL-4-nonreactive cells during the evolution of an immune response.

Cell Differentiation↗
PubMedDate not supplied

[Regulatory properties of digestive enzymes and the biology of multiple substrate digestive processes].

Characteristics of functional organization and autoregulation of natural polysubstrate digestion in various animals are largely defined by regulatory properties of the enzymes ensuring membrane digestion. This has been demonstrated for both the animals which are at different evolutional levels and those specialized for different types of food. The effective organization of the digestive and transport processes in time and space is provided by an interaction of food substances at the stage of membrane digestion.

Alkaline Phosphatase↗
PubMed1993

Tumorigenic activity of rho genes from Aplysia californica.

rho genes have been found in both lower and higher eucaryotes. They code for proteins of 21 kDa, highly conserved in evolution, which belong to the superfamily of ras GTPases. Among the members of this superfamily there are proteins with a regulatory function, such as ras, and proteins involved in vesicular trafficking, such as the family of rab proteins. We have investigated the putative role of rho proteins from Aplysia californica as transforming GTPases utilizing the wild-type and a Val-14 mutant, equivalent to the oncogenic Val-12 mutation of ras genes found in animal and human tumors. Over-expression of either rho gene was sufficient to confer anchorage- and serum-independent growth. Moreover, when introduced into nude mice, selected clones generated from either gene were able to induce tumors, although those carrying the mutated version were more efficient. Pathological analysis indicated that generated tumors corresponded to well-differentiated fibrosarcomas with distinct and intersecting bundles and spindle cells. By contrast, ras-induced tumors were poorly differentiated fibrosarcomas. Thus, our results indicate that under appropriate conditions rho genes function as oncogenes and may have a role in the regulation of proliferation in fibroblast cells.

3T3 Cells↗
PubMed2003

Evolution of c4 phosphoenolpyruvate carboxylase. Genes and proteins: a case study with the genus Flaveria.

C4 photosynthesis is characterized by a division of labour between two different photosynthetic cell types, mesophyll and bundle-sheath cells. Relying on phosphoenolpyruvate carboxylase (PEPC) as the primary carboxylase in the mesophyll cells a CO2 pump is established in C4 plants that concentrates CO2 at the site of ribulose 1,5-bisphosphate carboxylase/oxygenase in the bundle-sheath cells. The C4 photosynthetic pathway evolved polyphyletically implying that the genes encoding the C4 PEPC originated from non-photosynthetic PEPC progenitor genes that were already present in the C3 ancestral species. The dicot genus Flaveria (Asteraceae) is a unique system in which to investigate the molcular changes that had to occur in order to adapt a C3 ancestral PEPC gene to the special conditions of C4 photosynthesis. Flaveria contains not only C3 and C4 species but also a large number of C3-C4 intermediates which vary to the degree in which C4 photosynthetic traits are expressed. The C4 PEPC gene of Flaveria trinervia, which is encoded by the ppcA gene class, is highly expressed but only in mesophyll cells. The encoded PEPC protein possesses the typical kinetic and regulatory features of a C4-type PEPC. The orthologous ppcA gene of the C3 species Flaveria pringlei encodes a typical non-photosynthetic, C3-type PEPC and is weakly expressed with no apparent cell or organ specificity. PEPCs of the ppcA type have been detected also in C3-C4 intermediate Flaveria species. These orthologous PEPCs have been used to determine the molecular basis for C4 enzyme characteristics and to understand their evolution. Comparative and functional analyses of the ppcA promoters from F. trinervia and F. pringlei make it possible to identity the cis-regulatory sequences for mesophyll-specific gene expression and to search for the corresponding trans-regulatory factors.

Amino Acid Sequence↗
PubMed2002

Congruent evolution of different classes of non-coding DNA in prokaryotic genomes.

Prokaryotic genomes are considered to be 'wall-to-wall' genomes, which consist largely of genes for proteins and structural RNAs, with only a small fraction of the genomic DNA allotted to intergenic regions, which are thought to typically contain regulatory signals. The majority of bacterial and archaeal genomes contain 6-14% non-coding DNA. Significant positive correlations were detected between the fraction of non-coding DNA and inter- and intra-operonic distances, suggesting that different classes of non-coding DNA evolve congruently. In contrast, no correlation was found between any of these characteristics of non-coding sequences and the number of genes or genome size. Thus, the non-coding regions and the gene sets in prokaryotes seem to evolve in different regimes. The evolution of non-coding regions appears to be determined primarily by the selective pressure to minimize the amount of non-functional DNA, while maintaining essential regulatory signals, because of which the content of non-coding DNA in different genomes is relatively uniform and intra- and inter-operonic non-coding regions evolve congruently. In contrast, the gene set is optimized for the particular environmental niche of the given microbe, which results in the lack of correlation between the gene number and the characteristics of non-coding regions.

DNA, Intergenic↗
PubMed2003

Origin of new genes: evidence from experimental and computational analyses.

Exon shuffling is an essential molecular mechanism for the formation of new genes. Many cases of exon shuffling have been reported in vertebrate genes. These discoveries revealed the importance of exon shuffling in the origin of new genes. However, only a few cases of exon shuffling were reported from plants and invertebrates, which gave rise to the assertion that the intron-mediated recombination mechanism originated very recently. We focused on the origin of new genes by exon shuffling and retroposition. We will first summarize our experimental work, which revealed four new genes in Drosophila, plants, and humans. These genes are 10(6) to 10(8) million years old. The recency of these genes allows us to directly examine the origin and evolution of genes in detail. These observations show firstly the importance of exon shuffling and retroposition in the rapid creation of new gene structures. They also show that the resultant chimerical structures appearing as mosaic proteins or as retroposed coding structures with novel regulatory systems, often confer novel functions. Furthermore, these newly created genes appear to have been governed by positive Darwinian selection throughout their history, with rapid changes of amino acid sequence and gene structure in very short periods of evolution. We further analyzed the distribution of intron phases in three non-vertebrate species, Drosophila melanogaster, Caenorhabditis elegans, and Arabidosis thaliana, as inferred from their genome sequences. As in the case of vertebrate genes, we found that intron phases in these species are unevenly distributed with an excess of phase zero introns and a significant excess of symmetric exons. Both findings are consistent with the requirements for the molecular process of exon shuffling. Thus, these non-vertebrate genomes may have also been strongly impacted by exon shuffling in general.

Cytochromes c1↗
PubMed1997

Fossils, genes and the evolution of animal limbs.

The morphological and functional evolution of appendages has played a crucial role in the adaptive radiation of tetrapods, arthropods and winged insects. The origin and diversification of fins, wings and other structures, long a focus of palaeontology, can now be approached through developmental genetics. Modifications of appendage number and architecture in each phylum are correlated with regulatory changes in specific patterning genes. Although their respective evolutionary histories are unique, vertebrate, insect and other animal appendages are organized by a similar genetic regulatory system that may have been established in a common ancestor.

Adaptation, Physiological↗