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Results for “regulatory evolution”

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At least 1,135 records · Page 63Linked to original sources
PubMed2005

Discovery of regulatory elements in vertebrates through comparative genomics.

We have analyzed issues of reliability in studies in which comparative genomic approaches have been applied to the discovery of regulatory elements at a genome-wide level in vertebrates. We point out some potential problems with such studies, including difficulties in accurately identifying orthologous promoter regions. Many of these subtle analytical problems have become apparent only when studying the more complex vertebrate genomes. By determining motif reliability, we compared existing tools when applied to the discovery of vertebrate regulatory elements. We then used a statistical clustering method to produce a computational catalog of high quality putative regulatory elements from vertebrates, some of which are widely conserved among vertebrates and many of which are novel regulatory elements. The results provide a glimpse into the wealth of information that comparative genomics can yield and suggest the need for further improvement of genome-wide comparative computational techniques.

Algorithms↗
PubMed2005

Simulation of evolution-selected propeptide by high-throughput selection of a peptidomimetic inhibitor on a capillary DNA sequencer platform.

Many proteinases, including gelatinase B/MMP-9, fulfill crucial regulatory or effector functions in disease states and may be pharmacologically targeted by specific inhibitors. Denatured collagen type II provides one of the best gelatinase B substrates, and the characteristics of its cleavage were employed to define the requirements of a novel optimal substrate probe. A synthetic fluorescent derivative was used for the development of a new high-throughput technology for the selection of inhibitors on the principles of sensitivity of confocal fluorescence detection, resolution capacity of capillary electrophoresis, and multichannel power of DNA sequencers. Combinatorial chemical synthesis of a library of peptide-based inhibitors, library deconvolution, high-throughput screening, isolation, and mass spectrometric techniques enabled us to identify a novel single-peptide gelatinase B inhibitor. A notable finding is that the in vitro-selected inhibitor mimics many of the characteristics of the evolution-selected MMP propeptide sequence.

Binding Sites↗
PubMed1988

Multiple sclerosis and the evolution of growth hormone mechanisms in man.

This paper develops the hypothesis that a growth hormone-like substance and/or its receptor is the initial target of auto-antibodies in multiple sclerosis (MS). Regulatory mechanisms for hormone secretion may also be involved in the pathogenesis of MS. Demyelination may be subsequent (1) to an initial lesion to the anterior pituitary.

Biological Evolution↗
PubMed2006

Identification of evolutionarily conserved regulatory elements in the mouse Fgf8 locus.

The secreted signaling molecule fibroblast growth factor 8 (Fgf8) is an essential component of certain embryonic signaling centers including the mid-hindbrain (isthmic) organizer, the first branchial arch (BA1), and the apical ectodermal ridge (AER). In these signaling centers Fgf8 transcripts are expressed in a dynamic and transient fashion, but the mechanism by which this highly specific expression pattern is established remains largely unknown. We used DNA sequence comparisons coupled to transgenic approaches to obtain insight into the structure and function of regulatory elements in the Fgf8 locus. First, a bacterial artificial chromosome (BAC) containing the mouse Fgf8 gene partially rescues the embryonic lethality of Fgf8-deficient mice and controls Fgf8-specific gene expression of a coinjected lacZ reporter transgene. Second, sequence comparison of vertebrate Fgf8 loci revealed evolutionarily highly conserved noncoding sequences that were unexpectedly located mainly 3' of the Fgf8 coding region. Third, in transgenic mice some of these elements were sufficient to target expression to the AER, tail bud, and brain, including the isthmic organizer, indicating that they may represent Fgf8 cis-acting elements. Collectively, these data identify novel regulatory elements of the Fgf8 gene sufficient to drive expression to regions of known Fgf8 activity.

Animals↗
PubMed1989

Selection of new biological activities from random nucleotide sequences: evolutionary and practical considerations.

Recent advances in the selection of biologically active DNA sequences from random populations are reviewed. Within the framework of evolution, forces are considered that have precluded the testing of all possible DNA sequences, purely with regard to their functionality as genetic regulatory elements or protein coding sequences. Examples are drawn from cassette mutagenesis of enzyme active sites, protein domain replacement by fusion with random genomic digests, and the selection of bacterial promoters from random DNA. Efforts to derive new activities are examined, and the likelihood of future success is evaluated.

Base Sequence↗
PubMed2006

Molecular evolution of 5' flanking regions of 87 candidate genes for atherosclerotic cardiovascular disease.

Inter-individual variation in quantitative traits as well as in disease susceptibility may be due to differences in the level and spatio-temporal pattern of gene expression. An evolutionary model of genetic variation in cis-regulatory regions may help identify loci of interest for the study of the genetic basis of complex diseases such as atherosclerotic cardiovascular disease (ASCVD). We studied the molecular evolution of 87 candidate genes for ASCVD to detect signatures of selection in 5' flanking regions. Resequenced data for these genes were available in 24 African-Americans, 23 European-Americans, and 1 chimpanzee (Pan troglodytes). Statistical tests of evolutionary neutrality (Tajima's D and Fay and Wu's H) were performed using coalescent simulations under a standard neutral model and a population structure model to differentiate selection from human demographic history. Evidence suggestive of selection was present in 5' flanking regions of 15 genes. A modified McDonald-Kreitman test was used to compare the ratio of putative functional and non-functional sites between and within species in 5' flanking regions. A significant excess or deficit of fixed changes over polymorphisms was noted in 16 genes. Of the 26 genes showing deviation from evolutionary neutrality based on the above two tests, 13 genes showed an unusual haplotype pattern in 5' flanking regions, providing supportive evidence of selection. These results indicate that selection may play a role in establishing variation in 5' flanking regions of a subset of candidate genes for ASCVD and motivate further studies of these loci in determining inter-individual susceptibility to ASCVD.

5' Flanking Region↗
PubMed1999

Molecular evolution: aminoacyl-tRNA synthetases on the loose.

Modified versions - paralogs - of the catalytic domain of at least three different aminoacyl-tRNA synthetases have been found to serve catalytic or regulatory roles in other reactions. These findings suggest that the first modern tRNA-synthetases could have been derived from amino-acid biosynthetic enzymes.

Amino Acids↗
PubMed2006

The UBX-regulated network in the haltere imaginal disc of D. melanogaster.

Hox proteins have been proposed to act at multiple levels within regulatory hierarchies and to directly control the expression of a plethora of target genes. However, for any specific Hox protein or tissue, very few direct in vivo-regulated target genes have been identified. Here, we have identified target genes of the Hox protein Ultrabithorax (UBX), which modifies the genetic regulatory network of the wing to generate the haltere, a modified hindwing. We used whole-genome microarrays and custom arrays including all predicted transcription factors and signaling molecules in the Drosophila melanogaster genome to identify differentially expressed genes in wing and haltere imaginal discs. To elucidate the regulation of selected genes in more detail, we isolated cis-regulatory elements (CREs) for genes that were specifically expressed in either the wing disc or haltere disc. We demonstrate that UBX binds directly to sites in one element, and these sites are critical for activation in the haltere disc. These results indicate that haltere and metathoracic segment morphology is not achieved merely by turning off the wing and mesothoracic development programs, but rather specific genes must also be activated to form these structures. The evolution of haltere morphology involved changes in UBX-regulated target genes, both positive and negative, throughout the wing genetic regulatory network.

Animals↗
PubMed2006

Johannes Reinke (1839-1931) and his "Dominanten" theory--an early concept of gene regulation and morphogenesis.

Johannes Reinke (1839-1931) was one of the most eminent and influential botanists, politician, philosopher and "anti-Haeckelist" of the 19th century. Educated in the mid 19th century he had faced revolutionary changes in the scientific understanding of the origin and evolution of life. Working mainly at the phenotypic level, Reinke was interested in the basic mechanisms and the guiding idea behind all processes which coordinated gene regulation and morphogenesis. What drove Reinke in his search of regulatory mechanisms for evolutionary patterns and processes was his religious belief. For the origin of the very first life, Reinke believed in creation but once life was established, evolution followed natural laws. This led to his early concept of "Dominanten" entities, which regulate gene transcription and morphogenesis, anticipating the ideas of Goldschmidt and v. Uexküll.

Animals↗
PubMed2003

Distinguishing regulatory DNA from neutral sites.

We explore several computational approaches to analyzing interspecies genomic sequence alignments, aiming to distinguish regulatory regions from neutrally evolving DNA. Human-mouse genomic alignments were collected for three sets of human regions: (1) experimentally defined gene regulatory regions, (2) well-characterized exons (coding sequences, as a positive control), and (3) interspersed repeats thought to have inserted before the human-mouse split (a good model for neutrally evolving DNA). Models that potentially could distinguish functional noncoding sequences from neutral DNA were evaluated on these three data sets, as well as bulk genome alignments. Our analyses show that discrimination based on frequencies of individual nucleotide pairs or gaps (i.e., of possible alignment columns) is only partially successful. In contrast, scoring procedures that include the alignment context, based on frequencies of short runs of alignment columns, dramatically improve separation between regulatory and neutral features. Such scoring functions should aid in the identification of putative regulatory regions throughout the human genome.

Animals↗
PubMed1989

Nonuniform evolution of duplicated, developmentally controlled chorion genes in a silkmoth.

We report the sequence of A/B.L1, a tightly linked pair of genes from the A and B chorion families in Bombyx mori. Comparison with the previously characterized A/B.L11 and A/B.L12 pairs from the same species reveals moderate sequence divergence, which is clearly nonuniform. Although the average divergence of A/B.L12 from the other two pairs is more than double that between A/B.L11 and A/B.L1, the ratio differs by more than 30-fold in different DNA regions. One domain of the A gene is highly divergent between A/B.L12 and A/B.L1 or A/B.L11, but essentially invariable in the latter two. In well-aligned DNA segments, nearly all mutated sites (111/112) show variants shared by two of the three sequences, in 42% of the cases between the more distantly related pairs (A/B.L12 and either A/B.L1 or A/B.L11). Eight of the variants shared by distantly related pairs are clustered within 51 bp, suggesting the possibility that they arose through sequence transfers between gene pairs, rather than being primitive or resulting from independent mutations. The short intergenic, putatively regulatory DNA of the developmentally middle A/B.L1 and A/B.L11 pairs resembles that of the late HcA/HcB pairs, particularly in patches that may correspond to cis-regulatory elements.

Animals↗
PubMed1998

Neuroimmunomodulation of aging. A program in the pineal gland.

We have investigated for 35 years the relationship between the neuroendocrine and the thymo-lymphatic, immune system. In the last decade we have shown that the pineal gland is a main adapter and fine synchronizer of environmental variables and endogenous messages into physiological modifications of basic functions. In particular the pineal gland itself seems to regulate, via circadian, night secretion of melatonin, all basic hormonal functions and also immunity. We have shown with several in vivo models that this fundamental role of the pineal gland decays during aging. Aging itself seems to be a strictly pineal-programmed event similar to growth and puberty. The continuation of our interventions with melatonin against the typical degenerative diseases of aging must be based on an accurate evaluation of its mechanisms of action. Melatonin being a ubiquitous molecule in nature, we suggest that it has acquired during evolution of the species numerous levels of activities. In fact, melatonin can be found in a large variety of cells and tissues, and bindings sites and "receptors" have been identified in many tissues and cells of the neuroendocrine and immune system. Therefore, the progressive understanding of the aging-programming role of the pineal gland also depends on studies of melatonin and its basic regulatory function. Our present studies will be described.

Aging↗
PubMed2004

Nonneutral evolution of the transcribed pseudogene Makorin1-p1 in mice.

Pseudogenes are nonfunctional relics of formerly functional genes and are thought to evolve neutrally. In some pseudogenes, however, the molecular evolutionary patterns are atypical of neutrally evolving sequences, exhibiting sequence conservation, codon-usage bias, and other features associated with functional genes. Makorin1-p1 is a transcribed pseudogene first identified in the mouse Mus musculus. The transcript of Makorin1-p1 can regulate the stability of the transcript of its paralogous functional gene Makorin1. Specifically, the half-life of Makorin1 mRNA increases significantly in the presence of Makorin1-p1 transcript, and targeted deletion of Makorin1-p1 is lethal in mice. Here, we show that Makorin1-p1 originated after the separation of Mus and Rattus but before the divergence of M. musculus and M. pahari. The transcribed region of Makorin1-p1 exhibits rates of point and indel substitutions that are two to four times lower than those in the untranscribed region, suggesting that the transcribed region is under functional constraint and is not evolving neutrally. Although the transcript of Makorin1-p1 likely functions by its sequence similarity to Makorin1, we find no evidence of gene conversion between them, indicating that functional conservation alone is sufficient to maintain their coordinated evolution. A duplication-degeneration model is proposed to explain how Makorin1-p1 was co-opted into the regulatory system of Makorin1. There are over 10,000 pseudogenes in a typical mammalian genome, and it is plausible that many functional but untranslatable pseudogenes exist. Our results illustrate the potential of using evolutionary analysis to identify such pseudogenes from genome sequences.

Animals↗
PubMed2025

Integrative Genomic, Transcriptomic and Epigenomic Analysis Reveals cis-regulatory Contributions to High-altitude Adaptation in Tibetan Pigs.

The Qinghai-Tibet Plateau, characterized by its extreme environmental conditions, presents significant challenges to life, making it an ideal region for studying adaptation and evolution. Tibetan pigs, known for their high genetic diversity and exceptional adaptability to high altitudes, serve as excellent models for investigating high-altitude adaptation. While previous studies have extensively identified genetic determinants associated with high-altitude adaptation, the molecular mechanisms, particularly cis-regulatory patterns, remain poorly understood. Here, we conducted a selective sweep analysis using 484 genomes from Chinese and Western pig breeds across various altitudes, revealing 38.56 Mb of genomic regions under selection in Tibetan pigs. Enrichment analysis identified the lung as the primary functional tissue involved in high-altitude adaptation, supported by tissue-specific transcriptional and regulatory patterns observed between Tibetan and Meishan pigs (low altitude). By integrating genomic, RNA-seq, ATAC-seq, and H3K27ac HiChIP data, we constructed comprehensive enhancer-promoter regulatory maps of candidate genes and pinpointed promising genetic determinants associated with high-altitude adaptation, including SNPs in EPAS1, KLF13, SPRED1, and CFD. These loci were predicted to influence chromatin accessibility and the interactions of regulatory elements, with altered binding strength of relevant transcription factors. Further in vitro experiments confirmed that these loci function as allele-specific enhancers, modulating the expression of target genes. Our findings elucidate the regulatory basis of high-altitude adaptation in Tibetan pigs and provide valuable insights for exploring hypoxia-related diseases in livestock and humans.

Animals↗
PubMed1995

Negative and positive regulation of Tn10/IS10-promoted recombination by IHF: two distinguishable processes inhibit transposition off of multicopy plasmid replicons and activate chromosomal events that favor evolution of new transposons.

Tn10 is a composite transposon; inverted repeats of insertion sequence IS10 flank a tetracycline-resistance determinant. Previous work has identified several regulatory processes that modulate the interaction between Tn10 and its host. Among these, host-specified DNA adenine methylation, an IS10-encoded antisense RNA and preferential cis action of transposase are particularly important. We now find that the accessory host protein IHF and the sequences that encode the IHF-binding site in IS10 are also important regulators of the Tn10 transposition reaction in vivo and that these determinants are involved in two distinguishable regulatory processes. First, IHF and the IHF-binding site of IS10, together with other host components (e.g., HU), negatively regulate the normal intermolecular transposition process. Such negative regulation is prominent only for elements present on multicopy plasmid replicons. This multicopy plasmid-specific regulation involves effects both on the transposition reaction per se and on transposase gene expression. Second, specific interaction of IHF with its binding site stimulates transposon-promoted chromosome rearrangements but not transposition of a short Tn10-length chromosomal element. However, additional considerations predict that IHF action should favor chromosomal transposition for very long composite elements. On the basis of these and other observations we propose that, for chromosomal events, the major role of IHF is to promote the evolution of new IS10-based composite transposons.

Bacterial Proteins↗