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PubMed2002

Directed molecular evolution of ADP-glucose pyrophosphorylase.

ADP-glucose pyrophosphorylase catalyzes a rate-limiting reaction in prokaryotic glycogen and plant starch biosynthesis. Despite sharing similar molecular size and catalytic and allosteric regulatory properties, the prokaryotic and higher plant enzymes differ in higher-order protein structure. The bacterial enzyme is encoded by a single gene whose product of ca. 50,000 Da assembles into a homotetrameric structure. Although the higher plant enzyme has a similar molecular size, it is made up of a pair of large subunits and a pair of small subunits, encoded by different genes. To identify the basis for the evolution of AGPase function and quaternary structure, a potato small subunit homotetrameric mutant, TG-15, was subjected to iterations of DNA shuffling and screened for enzyme variants with up-regulated catalytic and/or regulatory properties. A glycogen selection/screening regimen of buoyant density gradient centrifugation and iodine vapor colony staining on glucose-containing media was used to increase the stringency of selection. This approach led to the isolation of a population of AGPase small subunit homotetramer enzymes with enhanced affinity toward ATP and increased sensitivity to activator and/or greater resistance to inhibition than TG-15. Several enzymes displayed a shift in effector preference from 3-phosphoglycerate to fructose-6 phosphate or fructose-1,6-bis-phosphate, effectors used by specific bacterial AGPases. Our results suggest that evolution of AGPase, with regard to quaternary structure, allosteric effector selectivity, and effector sensitivity, can occur through the introduction of a few point mutations alone with low-level recombination hastening the process.

Directed Molecular Evolution↗

PubMed2005

The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.

Originally identified in Drosophila melanogaster, the Warts(Wts)/Lats protein kinase has been proposed to function with two other Drosophila proteins, Hippo (Hpo) and Salvador (Sav), in the regulation of cell cycle exit and apoptosis. In mammals, two candidate Warts/Lats homologs, termed Lats1 and Lats2, have been described, and the targeted disruption of LATS1 in mice increases tumor formation. Little, however, is known about the function and regulation of human Lats kinases. Here we report that human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2. Deletion analysis revealed that regulation of Lats1 occurs through the C-terminal, catalytic domain. Within this domain, two regulatory phosphorylation sites were identified by mass spectrometry. These sites, S909 in the activation loop and T1079 within a hydrophobic motif, have been highly conserved during evolution. Moreover, a direct interaction was observed between Mst2 and hWW45, a putative ortholog of Drosophila Sav. These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. Although the function of this pathway remains poorly understood in mammals, it is intriguing that, in Drosophila, it has been linked to development and tissue homeostasis.

Amino Acid Sequence↗

PubMed2005

Comparative genomics using fugu: a tool for the identification of conserved vertebrate cis-regulatory elements.

With the imminent completion of the whole genome sequence of humans, increasing attention is being focused on the annotation of cis-regulatory elements in the human genome. Comparative genomics approaches based on evolutionary conservation have proved useful in the detection of conserved cis-regulatory elements. The pufferfish, Fugu rubripes, is an attractive vertebrate model for comparative genomics, by virtue of its compact genome and maximal phylogenetic distance from mammals. Fugu has lost a large proportion of nonessential DNA, and retained single orthologs for many duplicate genes that arose in the fish lineage. Non-coding sequences conserved between fugu and mammals have been shown to be functional cis-regulatory elements. Thus, fugu is a model fish genome of choice for discovering evolutionarily conserved regulatory elements in the human genome. Such evolutionarily conserved elements are likely to be shared by all vertebrates, and related to regulatory interactions fundamental to all vertebrates. The functions of these conserved vertebrate elements can be rapidly assayed in mammalian cell lines or in transgenic systems such as zebrafish/medaka and Xenopus, followed by validation of crucial elements in transgenic rodents.

Animals↗

PubMed1988

[Evolutionary significance of the presence in mobile genetic elements of regulatory sites reacting to the environment. Regulatory site as a trigger].

A mathematical model of the Markov's process type describing the duplicative transposition of mobile genetic elements (MGE) has been developed. The possible role of MGE containing regulatory sites activated under unfavourable conditions has been considered. An analysis of the model has shown that there may be such regimes of environmental changes (sharp but random changes of the environment parameters) when sufficiently reliable survival of population is dependent on such MGE.

Animals↗

PubMed2003

Developmental basis for vein pattern variations in insect wings.

The venation patterns characteristics of different insect orders and of families belonging to the same order possess enormous variation in vein number, position and differentiation. Although the developmental basis of changes in vein patterns during evolution is entirely unknown, the identification of the genes and developmental processes involved in Drosophila vein pattern formation facilitates the elaboration of construction rules. It is thus possible to identify the likely changes which may constitute a source of pattern variation during evolution. In this review, we discuss how actual patterns of venation could be accounted for by modifications in different Pterygota of a common set of developmental operations. We argue that the individual specification of each vein and the modular structure of the regulatory regions of the key genes identified in Drosophila offer candidate entry points for pattern modifications affecting individual veins or interveins independently. Assuming a general conservation of the processes involved in different species, the transitions between different patterns may require few changes in the regulatory gene networks involved.

Animals↗

PubMed2004

A small family of LLS1-related non-heme oxygenases in plants with an origin amongst oxygenic photosynthesizers.

Conservation of Lethal-leaf spot 1 (Lls1) lesion mimic gene in land plants including moss is consistent with its recently reported function as pheophorbide a oxygenase (Pao) which catalyzes a key step in chlorophyll degradation (Pruzinska et al., 2003). A bioinformatics survey of complete plant genomes reveals that LLS1(PAO) belongs to a small 5-member family of non-heme oxygenases defined by the presence of Rieske and mononuclear iron-binding domains. This gene family includes chlorophyll a oxygenase (Cao), choline monooxygenase (Cmo), the gene for a 55 kDa protein associated with protein transport through the inner chloroplast membrane (Tic 55) and a novel 52 kDa protein isolated from chloroplasts (Ptc 52). Analysis of gene structure reveals that these genes diverged prior to monocot/dicot divergence. Homologues of LLS1(PAO), CAO, TIC55 and PTC52 but not CMO are found in the genomes of several cyanobacteria. LLS1(PAO), PTC52, TIC55 and a set of related cyanobacterial homologues share an extended carboxyl terminus containing a novel F/Y/W-x(2)-H-x(3)-C-x(2)-C motif not present in CAO. These proteins appear to have evolved during the transition to oxygenic photosynthesis to play various roles in chlorophyll metabolism. In contrast, CMO homologues are found only in plants and are most closely related to aromatic ring-hydroxylating enzymes from soil-dwelling bacteria, suggesting a more recent evolution of this enzyme, possibly by horizontal gene transfer. Our phylogenetic analysis of 95 extant non-heme dioxygenases provides a useful framework for the classification of LLS1(PAO)-related non-heme oxygenases.

Amino Acid Motifs↗

PubMed1992

Evolution and current status of the Orphan Drug Act.

The 1983 Orphan Drug Act was designed in response to market and regulatory disincentives that limited industrial interest in developing drugs needed by people in the United States with rare diseases and conditions. These disincentives evolved from changes in the pharmaceutical industry and in regulatory testing requirements. In the eight years since the Act and subsequent amendments have been in effect, the law has been associated with the new development and approval of 40 marketed drugs and 12 biologicals to treat rare (orphan) diseases. An additional 281 drugs and 141 biologicals have been entered into development and designated as orphans. Finally, the law has mandated exploration of whether the incentives of the Act are necessary and appropriate for stimulating industrial development of orphan medical drugs and devices. Despite this progress, controversies have arisen over three profitable orphan products that have benefited from the law's provisions. This has created the need for continued assessment of the Act's benefits and costs.

Drug Approval↗

PubMed2000

Conservation and Evolution of the "Core Apoptotic Engine" Lesson from the Genome Comparison of Drosophila.

Genome comparison is the main approach to deduce regulatory network from genome sequence. Apoptotic network is one kind of typical regulatory networks. EGL1, CED3, CED4, CED9 and their homologous proteins play essential roles in apoptosis of C.elegans and mammals, and were regarded as the components of the"core apoptotic engine". But in fruit fly, Drosophila melanogaster, this network is incomplete. A series of bioinformatic analyses found the lost chains of "core apoptotic engine" by discovering two homologues of BCL2/CED9 and one of EGL1 in fruit fly genome sequences. These findings proved that the "core apoptotic engine" is indeed widely conserved among multicellular organisms and the evolutionary complexity of this network of Drosophila is between that of C.elegans and mammals.

Journal Article↗

PubMed2002

The evolution of informed consent: failures of the current system of human protection.

The reliance of subjects and researchers on the current regulatory scheme for human subject protection is misplaced. Investigators often assume that compliance with the requirements of the Common Rule, including Institutional Review Board approval of their research project, adequately fulfills the spirit of the federal regulation and protects them from liability for lack of adequate informed consent. Subjects and physicians referring subjects, believe that institutional approval of studies assures that they are scientifically valid and ethical. Unfortunately the current scheme of human research protection has failed to fulfill the spirit of the Nuremberg Code and The Belmont Report. Not only are large numbers of studies left out of the current protection scheme but the scheme is also flawed on several levels. This leaves researchers at risk for liability and subjects may have their right to autonomy violated even while the requirements of the current regulatory scheme are satisfied. It is time for a wholesale restructuring of human subject protection. If physician researchers ignore the deficits of the current system we will lose control and input into the formulation of the new scheme.

Journal Article↗

PubMed1994

The evolution of kinetoplastid glycosomes.

The available data on carbohydrate metabolism in Kinetoplastida have been reviewed. Based on the metabolic pattern of different kinetoplastid organisms, on the subcellular distribution of their glycolytic enzymes, and on the structural and regulatory properties of these proteins, we propose that the glycosome developed from an endosymbiont, as a specific manner to control carbohydrate and energy metabolism. It is discussed how the enzymes were subcellularly recompartmentalized during evolution as adaptation to the environment encountered by the organisms.

Amino Acid Sequence↗

PubMedDate not supplied

Molecular studies of hemichordate development: a key to understanding the evolution of bilateral animals and chordates.

Using the Hawaiian acorn worm, Ptychodera flava, we began molecular studies on the development of hemichordates, a phylum previously unstudied at this level. Here we review results garnered from the examination of a few specific genes selected to help understand the evolution of vertebrate structures. These studies suggest new ideas about the evolution of developmental mechanisms in the deuterostomes. In a seminal observation, we noted an unexpected zone of expression of the Brachyurygene in the early anterior embryonic ectoderm where the mouth will form. Typically, the Brachyury gene is closely linked to development of the notochord and is expressed around the blastopore and in the posterior mesoderm in most animals. This first expression of Brachyury at the blastopore may represent a regulatory program associated with organizing the original animal head and gut opening, as suggested by the expression of Brachyury during hypostome formation in hydra. We believe that the anterior expression of Brachyury in deuterostomes represents the cooption of the program for organizing the original animal gut opening to form the deuterostome mouth. Recent data from the trochophore larva of a polychaete show that an anterior zone of expression of Brachyury is produced in this protostome by splitting of the Brachyury field during the formation of a gut with a mouth and anus by the lateral fusion of the sides of the blastopore. The ability to initiate independently a secondary regulatory program to organize the new mouth leading to an anterior field of Brachyury expression may be a signal event in the evolution of the deuterostomes. We also noted that the P. flava homolog of T-brain/Eomes, a gene closely related by sequence and expression around the blastopore to Brachyury and associated with development of the vertebrate brain, also exhibits early posterior expression around the blastopore and a field of de novo anterior ectoderm expression during later embryogenesis. The tissue in the zone of de novo anterior ectoderm expression of Pf-Tbrain produces the apical organ, a larval neural structure that has been touted as an evolutionary precursor of the chordate dorsal brain. The gene regulatory mechanisms responsible for initiating the anterior zone of de novo expression of T-brain may represent a cooption to specify early neuroectoderm of the regulatory program evolved first to drive anterior Brachyury expression for deuterostome mouth formation. It will be interesting to examine the possibilities that an ability to initiate the de novo anterior expression of the program that includes T-brain may be a key event in the evolution of the developmental mechanisms leading to the chordate dorsal nervous system.

Animals↗

PubMed1999

Evolution of the biopharmaceutics classification system (BCS) to oral modified release (MR) formulations; what do we need to consider?

The Biopharmaceutics Classification System (BCS) has provided a mechanistic framework for understanding the concept of drug absorption in terms of permeability and solubility. Regulatory guidance for Immediate Release (IR) products incorporating the BCS has appeared over recent months. Extrapolation of the approach to oral Modified Release (MR) formulations is therefore inevitable, however, further evolution of our thinking is first required. MR products can deliver drug throughout the gastrointestinal tract and it is important that we recognise there is significant heterogeneity in permeability, lumenal pH/contents and gut wall metabolism from stomach to colon.

Administration, Oral↗

PubMed2026

BnaPAP2.C2 plays a novel inhibitory role in anthocyanin accumulation compared to its paralogs in rapeseed (Brassica napus L.).

Tissue-specific anthocyanin pigmentation is observed in rapeseed (Brassica napus L. AACC, 2n = 38) as well as in its ancestral diploids Brassica rapa (AA, 2n = 20) and Brassica oleracea (CC, 2n = 18). We previously identified the MYB genes BnaPAP2.A7b and BnaPAP2.C6a as key regulators of anthocyanin biosynthesis. Here we uncover an antagonistic regulatory mechanism in leaves involving their paralog BnaPAP2.C2. Unlike the pigmentation-associated genes, BnaPAP2.C2 is constitutively expressed in both green and purple leaves, regardless of anthocyanin levels. Its promoter contains two enhancers (463 and 486 bp) that synergistically regulate transcription. Competitive binding studies reveal that BnaPAP2.C2, although lacking activation capacity, sequesters BnaTT8 and outcompetes BnaPAP2.A7b, thereby suppressing anthocyanin biosynthesis. Under environmental stress, elevated expression of BnaPAP2.A7b promotes anthocyanin biosynthesis, whereas BnaPAP2.C2 is downregulated. This paralog-specific molecular antagonism provides new insight into the evolution of MYB-bHLH interaction specificity. Together, these findings uncover a novel inhibitory mechanism within the anthocyanin regulatory hierarchy of polyploid rapeseed, highlighting competitive binding as an evolutionary innovation driving functional diversification of duplicated MYB regulators.

Anthocyanins↗

PubMed1999

Hox genes in digit development and evolution.

Homeobox genes located in the 5' part of the HoxA and HoxD complexes are required for proliferation of skeletal progenitor cells of the vertebrate limb. Specific combinations of gene products determine the length of the upper arm (genes belonging to groups 9 and 10), the lower arm (groups 10, 11 and 12) and the digits (groups 11, 12 and 13). In these different domains, individual gene products quantitatively contribute to an overall protein dose, with predominant roles for groups 11 and 13. Quantitative reduction in the gene dose in each set results in truncations of the corresponding anatomical regions. The physical order of the genes in the HoxA and HoxD complexes, as well as a unidirectional sequence in gene activation, allow for completion of the process in a precise order, which in turn makes possible the sequential outgrowth of the respective primordia. While the skeletal patterns of upper and lower limb are relatively stable throughout the tetrapods, more variation is seen in the digits. Molecular analysis of the underlying regulatory processes promises further exciting insights into the genetic control of development, pathology and the course of evolution.

Animals↗

PubMed1995

Different patterns of HIV-1-specific cytotoxic T-lymphocyte activity after primary infection.

OBJECTIVE: To analyse the HIV-1-specific cytotoxic T-lymphocyte (CTL) responses of nine HIV-seropositive subjects in relation with primary infection. METHODS: Anti-HIV CTL were generated by in vitro stimulation of peripheral mononuclear cells obtained from HIV-seropositive donors at various times after primary infection. They were tested against several structural or regulatory HIV-1 proteins, using autologous target cells infected with recombinant vaccinia viruses expressing one of the HIV-1LAI proteins. RESULTS: An important CTL activity was found during the first month following seroconversion only in those donors who showed clinical symptoms during primary infection. The temporal evolution of this response differed for each subject; one remained a non-responder even 30 months after seroconversion. The structural proteins were recognized particularly early, while the antigenicity of regulatory proteins appeared later. CONCLUSION: Different patterns of HIV-specific CTL response can be observed after primary infection. The evolution of infection in these different HIV-seropositive subjects will be particularly interesting to analyse.

Adult↗

PubMed1980

The cDNA for the beta-subunit of human chorionic gonadotropin suggests evolution of a gene by readthrough into the 3'-untranslated region.

A 579-base pair approximately full-length cDNA which codes for the 145-amino acid long beta-subunit of human chorionic gonadotropin (HCG) has been cloned in the plasmid vector pBR322 and its complete nucleotide sequence determined. A hydrophobic presequence of 20 amino acids can be identified from the nucleotide sequence. The amino acid sequence of the beta-subunit is known to be related to those of the beta-subunits of the other glycoprotein hormones LH, FSH and TSH, but the beta-subunit of HCG is unique in that it contains a C-terminal extension of about 30 amino acids which has no homologous counterpart in the other three hormones. Analysis of the beta HCG cDNA nucleotide sequence suggests that this extension may have arisen by the loss of the termination codon of an ancestral beta-like gene so that most of what was previously the 3'-untranslated region now codes for protein. The beta-subunit of HCG terminates with the codon UAA located 16 bases before the poly(A) in the sequence AAUAAA. This sequence is believed to be a recognition signal involved in either polyadenylation or processing and therefore has a dual role in this gene, serving both a coding and a regulatory function.

Base Sequence↗

PubMed2003

The evolution of transcriptional regulation in eukaryotes.

Gene expression is central to the genotype-phenotype relationship in all organisms, and it is an important component of the genetic basis for evolutionary change in diverse aspects of phenotype. However, the evolution of transcriptional regulation remains understudied and poorly understood. Here we review the evolutionary dynamics of promoter, or cis-regulatory, sequences and the evolutionary mechanisms that shape them. Existing evidence indicates that populations harbor extensive genetic variation in promoter sequences, that a substantial fraction of this variation has consequences for both biochemical and organismal phenotype, and that some of this functional variation is sorted by selection. As with protein-coding sequences, rates and patterns of promoter sequence evolution differ considerably among loci and among clades for reasons that are not well understood. Studying the evolution of transcriptional regulation poses empirical and conceptual challenges beyond those typically encountered in analyses of coding sequence evolution: promoter organization is much less regular than that of coding sequences, and sequences required for the transcription of each locus reside at multiple other loci in the genome. Because of the strong context-dependence of transcriptional regulation, sequence inspection alone provides limited information about promoter function. Understanding the functional consequences of sequence differences among promoters generally requires biochemical and in vivo functional assays. Despite these challenges, important insights have already been gained into the evolution of transcriptional regulation, and the pace of discovery is accelerating.

Animals↗

PubMed2003

Hox gene evolution in nematodes: novelty conserved.

The conserved homeobox (Hox) gene cluster is neither conserved nor clustered in the nematode Caenorhabditis elegans. Instead, C. elegans has a reduced and dispersed gene complement that is the result the loss of Hox genes in stages throughout its evolutionary history. The roles of Hox genes in patterning the nematode body axis are also divergent, although there are tantalising remnants of ancient regulatory systems. Hox patterning also differs greatly between C. elegans and a second 'model' nematode, Pristionchus pacificus. The pattern of Hox gene evolution may be indicative of the move to deterministic developmental modes in nematodes.

Animals↗