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PubMed1998

The evolutionary dynamics of sex determination.

REVIEW There is substantial cytogenetic data indicating that the process of sex determination can evolve relatively rapidly. However, recent molecular studies on the evolution of the regulatory genes that control sex determination in the insect Drosophila melanogaster, the nematode Caenorhabditis elegans, and mammals suggest that, although certain sex determination regulatory genes have evolved relatively rapidly, other sex determination regulatory genes are quite conserved. Thus, studies of the evolution of sex determination, a process that appears to have elements that undergo substantial evolutionary change and others that may be conserved, could provide substantial insights into the kinds of forces that both drive and constrain the evolution of developmental hierarchies.

Animals↗
PubMedDate not supplied

[The role of conserved sequences in the regulatory elements of the Antp-like homeobox-containing genes of vertebrates].

By the present time the homeobox genes have been found in the representatives of the main invertebrate and vertebrate taxa. It has been demonstrated that these genes play the key role in the space and time genome expression orchestration in ontogenesis. The autoregulatory and cross-regulatory functional interactions integrate the homeobox genes into the gene networks. We found a correlation in variability of the coding and regulatory regions for vertebrate homeobox genes. The phylogenetic relations of structure and regulatory elements involved into the cross- and autoregulatory connections have been investigated in detail. The comprehensive phylogenetic analysis of the promoter region for these genes compared to results of such analysis of their homeoboxes has revealed two opposed tendencies in evolution of the regulatory elements of genes. The first trend is conservation of many regulatory elements in evolution of vertebrate homeobox genes and the second one is high variability of other non-coding gene regions.

Amino Acid Sequence↗
PubMed2002

Evolution of transcription factor binding sites in Mammalian gene regulatory regions: conservation and turnover.

Comparisons between human and rodent DNA sequences are widely used for the identification of regulatory regions (phylogenetic footprinting), and the importance of such intergenomic comparisons for promoter annotation is expanding. The efficacy of such comparisons for the identification of functional regulatory elements hinges on the evolutionary dynamics of promoter sequences. Although it is widely appreciated that conservation of sequence motifs may provide a suggestion of function, it is not known as to what proportion of the functional binding sites in humans is conserved in distant species. In this report, we present an analysis of the evolutionary dynamics of transcription factor binding sites whose function had been experimentally verified in promoters of 51 human genes and compare their sequence to homologous sequences in other primate species and rodents. Our results show that there is extensive divergence within the nucleotide sequence of transcription factor binding sites. Using direct experimental data from functional studies in both human and rodents for 20 of the regulatory regions, we estimate that 32%-40% of the human functional sites are not functional in rodents. This is evidence that there is widespread turnover of transcription factor binding sites. These results have important implications for the efficacy of phylogenetic footprinting and the interpretation of the pattern of evolution in regulatory sequences.

Animals↗
PubMed2004

Evolution of developmental canalization in networks of competing boolean nodes.

Developmental canalization, which leads to a reduction in the variation of phenotype expression relative to the complexity of the genome, has long been thought to be an important property of evolving biological systems. We demonstrate that a highly canalized state develops in the process of self-organization recently discovered in N-K Boolean networks that evolve based on a competition between the nodes. The model provides a simplified description of the evolution of genetic regulatory networks in developmental systems. The mechanism responsible for the evolution is shown to be a balance of two dynamical effects which compete to bring the network to a nonrandom critical steady state. Unlike other proposed evolutionary mechanisms that select for canalization, this mechanism does so while maintaining the system's capacity for further evolution in the steady state.

Computer Simulation↗
PubMed2000

The Src/Csk regulatory circuit arose early in metazoan evolution.

We have identified a gene encoding a member of the Csk family of non-receptor protein-tyrosine kinases (PTKs) in the early-diverging metazoan Hydra. In situ hybridization analysis of the distribution of RNA from the Hydra Csk gene indicates that it is expressed in most of the epithelial cells of the adult polyp and in gametogenic cells. Comparison of the expression pattern of Hydra Csk with that of STK, the Hydra Src gene orthologue, reveals that the two genes are largely co-expressed. Such co-expression is consistent with a role for Hydra Csk in regulation of STK activity. This possibility was tested directly by coexpressing Hydra Csk with STK in yeast. Co-expression suppressed the growth inhibition seen when STK alone is expressed in yeast. Suppression was dependent on the presence of the putative regulatory tyrosine in the carboxyl-terminal tail of STK. Phosphotyrosine immunoblot analysis confirmed that expression of Csk resulted in suppression of STK kinase activity. Taken together these data indicate that the regulatory circuit involving Src and Csk PTKs was established prior to the divergence of the phylum Cnidaria from the rest of the metazoans.

Animals↗
PubMed1996

Evolution of anthocyanin biosynthesis in maize kernels: the role of regulatory and enzymatic loci.

Understanding which genes contribute to evolutionary change and the nature of the alterations in them are fundamental challenges in evolution. We analyzed regulatory and enzymatic genes in the maize anthocyanin pathway as related to the evolution of anthocyanin-pigmented kernels in maize from colorless kernels of its progenitor, teosinte. Genetic tests indicate that teosinte possesses functional alleles at all enzymatic loci. At two regulatory loci, most teosintes possess alleles that encode functional proteins, but ones that are not expressed during kernel development and not capable of activating anthocyanin biosynthesis there. We investigated nucleotide polymorphism at one of the regulatory loci, cl. Several observations suggest that cl has not evolved in a strictly neutral manner, including an exceptionally low level of polymorphism and a biased representation of haplotypes in maize. Curiously, sequence data show that most of our teosinte samples possess a promoter element necessary for the activation of the anthocyanin pathway during kernel development, although genetic tests indicate that teosinte cl alleles are not active during kernel development. Our analyses suggest that the evolution of the purple kernels resulted from changes in cis regulatory elements at regulatory loci and not changes in either regulatory protein function nor the enzymatic loci.

Alleles↗
PubMed2000

The molecular population genetics of regulatory genes.

Regulatory loci, which may encode both trans acting proteins as well as cis acting promoter regions, are crucial components of an organism's genetic architecture. Although evolution of these regulatory loci is believed to underlie the evolution of numerous adaptive traits, there is little information on natural variation of these genes. Recent molecular population genetic studies, however, have provided insights into the extent of natural variation at regulatory genes, the evolutionary forces that shape them and the phenotypic effects of molecular regulatory variants. These recent analyses suggest that it may be possible to study the molecular evolutionary ecology of regulatory diversification by examining both the extent and patterning of regulatory gene diversity, the phenotypic effects of molecular variation at these loci and their ecological consequences.

Adaptation, Physiological↗
PubMed2003

Conserved noncoding sequences among cultivated cereal genomes identify candidate regulatory sequence elements and patterns of promoter evolution.

Surveys for conserved noncoding sequences (CNS) among genes from monocot cereal species were conducted to assess the general properties of CNS in grass genomes and their correlation with known promoter regulatory elements. Initial comparisons of 11 orthologous maize-rice gene pairs found that previously defined regulatory motifs could be identified within short CNS but could not be distinguished reliably from random sequence matches. Among the different phylogenetic footprinting algorithms tested, the VISTA tool yielded the most informative alignments of noncoding sequence. VISTA was used to survey for CNS among all publicly available genomic sequences from maize, rice, wheat, barley, and sorghum, representing >300 gene comparisons. Comparisons of orthologous maize-rice and maize-sorghum gene pairs identified 20 bp as a minimal length criterion for a significant CNS among grass genes, with few such CNS found to be conserved across rice, maize, sorghum, and barley. The frequency and length of cereal CNS as well as nucleotide substitution rates within CNS were consistent with the known phylogenetic distances among the species compared. The implications of these findings for the evolution of cereal gene promoter sequences and the utility of using the nearly completed rice genome sequence to predict candidate regulatory elements in other cereal genes by phylogenetic footprinting are discussed.

Algorithms↗
PubMed2002

Of mice and men: species variations of Toll-like receptor expression.

Toll-like receptors (TLRs) comprise a family of evolutionary conserved pattern recognition molecules that have an essential role in mammalian innate immune defense. Recent observations suggest that several TLR orthologues are expressed differently in mice and humans - variations among both species include the expression of TLR transcripts in different cell types and different transcription regulation on cellular activation. Apparently some TLR genes have been placed into a completely different regulatory context during evolution. It will be interesting and important to clarify whether the observed regulatory differences influence innate immune responses in a species-specific manner.

Animals↗
PubMed2004

Gene therapy progress and prospects: bringing gene therapy into medical practice: the evolution of international ethics and the regulatory environment.

The concept and application of ethical principles in the context of medical research is changing rapidly. This is especially true for fast moving fields such as gene therapy, a relatively new but rapidly maturing field offering opportunities to influence health at a fundamental level, which may become a cornerstone of medicine. By 2004, over 700 gene therapy clinical protocols had been initiated worldwide, and two highly publicized gene therapy-related side effects have helped to shape recent ethical debate. These events have influenced not only clinical trial design but also public opinion and systems of independent oversight. Both the science of gene therapy and the regulatory environment are continually evolving. How well the field is able to respond to these challenges will determine the extent to which gene therapy will ultimately be integrated into medical practice.

Animals↗
PubMed2006

Network growth models and genetic regulatory networks.

We study a class of growth algorithms for directed graphs that are candidate models for the evolution of genetic regulatory networks. The algorithms involve partial duplication of nodes and their links, together with the innovation of new links, allowing for the possibility that input and output links from a newly created node may have different probabilities of survival. We find some counterintuitive trends as the parameters are varied, including the broadening of the in-degree distribution when the probability for retaining input links is decreased. We also find that both the scaling of transcription factors with genome size and the measured degree distributions for genes in yeast can be reproduced by the growth algorithm if and only if a special seed is used to initiate the process.

Animals↗
PubMed1993

A model for the evolution of networks of genes.

An organism persists through the activity of structural genes, which is co-ordinated by clusters of coupled regulatory genes. During evolution, changes of coupling within a cluster can increase the reliability with which its structural genes perform a task. To study the evolution of coupling, we have simulated and analyzed a stochastic model for a simple problem. The assumptions of the model are these: A network of regulatory genes co-ordinates the synthesis of four structural proteins, which associate in distinct heterodimers that form a heterotetramer. Mutation in cis-regulatory regions produces transitions among 64 types of network. In a population, each network reproduces in proportion to its fitness, which depends on its probability (reliability) of synthesizing the tetramer. Fitness-dependent attrition keeps the size of the population constant. Regulatory genes occur in a sequence of levels; each level is associated with a different family of transcription factors. The following results emerge: Because different messengers within a family can give networks with the same connectivity, the 64 types of networks cluster into eight equivalence classes. During evolution with a low mutation rate, high-fitness classes can be approached through various paths on a fitness landscape. With a higher mutation rate, networks remain more uniformly distributed among the 64 types, and lower-fitness networks remain preponderant. An initially homogeneous population becomes more heterogeneous through mutation, but selection according to fitness later reduces its diversity. During this process the dispersion of the population over the possible networks increases, then decreases as the population approaches a unique steady state.

Animals↗
PubMed2005

Fostering rational regulation of patient safety.

After decades of inattention to the problem of medical injuries, patient safety is now occupying a prominent place on the health policy agenda and garnering renewed regulatory interest. Health care providers' behavior, with respect to patient safety and health care quality improvement, is now being shaped by top-down regulation through statutes and administrative agency oversight, as well as bottom-up drivers such as tort litigation and the forces of the consumer-driven health care market. Patient safety today exemplifies that eclectic mix of regulation that can occur when a new problem is exposed to the general public; it also demonstrates the difficulties of coordinating regulatory signals from multiple sources and regulating incomplete information. This article reviews the evolution of the regulatory environment for patient safety, examines some of the tensions and challenges that currently define patient safety oversight, and suggests strategies for more rational and responsive regulation.

Government Regulation↗
PubMed1998

Transcription and translation in Archaea: a mosaic of eukaryal and bacterial features.

The principal components involved in the processes of transcription and translation in Archaea have been identified by a combination of biochemistry and genome sequencing. In many cases, these factors are closely related to previously characterized proteins from Eukarya and Bacteria. Elucidating the function of these proteins will shed considerable light on the evolution of gene regulatory processes.

Archaea↗