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PubMed2006

Evolution of an intronic microsatellite polymorphism in Toll-like receptor 2 among primates.

Nonhuman primates express varying responses to Mycobacterium tuberculosis: New World monkeys appear to be resistant to tuberculosis (TB) while Old World monkeys seem to be particularly susceptible. The aim of this study was to elucidate the presence of the regulatory guanine-thymine (GT) repeat polymorphisms in intron 2 of Toll-like receptor 2 (TLR2) associated with the development of TB in humans and to determine any variations in these microsatellite polymorphisms in primates. We sequenced the region encompassing the regulatory GT repeat microsatellites in intron 2 of TLR2 in 12 different nonhuman primates using polymerase chain reaction amplification, TA cloning, and automatic sequencing. The nonhuman primates included for this study were as follows: chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla), orangutan (Pongo pygmaeus), Celebes ape (Macaca nigra), rhesus monkey (Macaca mulatta), pigtail macaque (Macaca nemestrina), patas monkey (Erythrocebus patas), spider monkey (Ateles geoffroyi), Woolly monkey (Lagothrix lagotricha), tamarin (Saguinus labiatus), and ring-tailed lemur (Lemur catta). Nucleotide sequences encompassing the regulatory GT repeat region are similar across species and are completely conserved in great apes. However, Old World monkeys lack GT repeats altogether, while New World monkeys and ring-tailed lemurs have much more complex structures around the position of the repeats. In conclusion, the genetic structures encompassing the regulatory GT repeats in intron 2 of human TLR2 are similar among nonhuman primates. The sequence is most conserved in New World monkeys and less in Old World monkeys.

Animals↗

PubMed2003

Molecular evolution of the modulator of chloroplast ATP synthase: origin of the conformational change dependent regulation.

Chloroplast ATP synthase synthesizes ATP by utilizing a proton gradient as an energy supply, which is generated by photosynthetic electron transport. The activity of the chloroplast ATP synthase is regulated in several specific ways to avoid futile hydrolysis of ATP under various physiological conditions. Several regulatory signals such as Delta mu H(+), tight binding of ADP and its release, thiol modulation, and inhibition by the intrinsic inhibitory subunit epsilon are sensed by this complex. In this review, we describe the function of two regulatory subunits, gamma and epsilon, of ATP synthase based on their possible conformational changes and discuss the evolutionary origin of these regulation systems.

Chloroplast Proton-Translocating ATPases↗

PubMed2000

Variation and selection at the CAULIFLOWER floral homeotic gene accompanying the evolution of domesticated Brassica oleracea.

The evolution of plant morphologies during domestication events provides clues to the origin of crop species and the evolutionary genetics of structural diversification. The CAULIFLOWER gene, a floral regulatory locus, has been implicated in the cauliflower phenotype in both Arabidopsis thaliana and Brassica oleracea. Molecular population genetic analysis indicates that alleles carrying a nonsense mutation in exon 5 of the B. oleracea CAULIFLOWER (BoCAL) gene are segregating in both wild and domesticated B. oleracea subspecies. Alleles carrying this nonsense mutation are nearly fixed in B. oleracea ssp. botrytis (domestic cauliflower) and B. oleracea ssp. italica (broccoli), both of which show evolutionary modifications of inflorescence structures. Tests for selection indicate that the pattern of variation at this locus is consistent with positive selection at BoCAL in these two subspecies. This nonsense polymorphism, however, is also present in both B. oleracea ssp. acephala (kale) and B. oleracea ssp. oleracea (wild cabbage). These results indicate that specific alleles of BoCAL were selected by early farmers during the domestication of modified inflorescence structures in B. oleracea.

Base Sequence↗

PubMed2004

Benchmarking tools for the alignment of functional noncoding DNA.

BACKGROUND: Numerous tools have been developed to align genomic sequences. However, their relative performance in specific applications remains poorly characterized. Alignments of protein-coding sequences typically have been benchmarked against "correct" alignments inferred from structural data. For noncoding sequences, where such independent validation is lacking, simulation provides an effective means to generate "correct" alignments with which to benchmark alignment tools. RESULTS: Using rates of noncoding sequence evolution estimated from the genus Drosophila, we simulated alignments over a range of divergence times under varying models incorporating point substitution, insertion/deletion events, and short blocks of constrained sequences such as those found in cis-regulatory regions. We then compared "correct" alignments generated by a modified version of the ROSE simulation platform to alignments of the simulated derived sequences produced by eight pairwise alignment tools (Avid, BlastZ, Chaos, ClustalW, DiAlign, Lagan, Needle, and WABA) to determine the off-the-shelf performance of each tool. As expected, the ability to align noncoding sequences accurately decreases with increasing divergence for all tools, and declines faster in the presence of insertion/deletion evolution. Global alignment tools (Avid, ClustalW, Lagan, and Needle) typically have higher sensitivity over entire noncoding sequences as well as in constrained sequences. Local tools (BlastZ, Chaos, and WABA) have lower overall sensitivity as a consequence of incomplete coverage, but have high specificity to detect constrained sequences as well as high sensitivity within the subset of sequences they align. Tools such as DiAlign, which generate both local and global outputs, produce alignments of constrained sequences with both high sensitivity and specificity for divergence distances in the range of 1.25-3.0 substitutions per site. CONCLUSION: For species with genomic properties similar to Drosophila, we conclude that a single pair of optimally diverged species analyzed with a high performance alignment tool can yield accurate and specific alignments of functionally constrained noncoding sequences. Further algorithm development, optimization of alignment parameters, and benchmarking studies will be necessary to extract the maximal biological information from alignments of functional noncoding DNA.

Animals↗

PubMed1985

Proteolytic enzymes, past and present.

William Beaumont's pioneering research on gastric secretion has been germinal in the discovery of proteolytic enzymes and the elucidation of their chemical structure, physiological roles, and biochemical evolution. Although the mammalian digestive enzymes, notably those of gastric and pancreatic origin, have been among the best characterized, of even greater interest and complexity are those that fulfill regulatory functions by limiting their action on specific peptide bonds in target protein substrates. The difference between digestive and regulatory proteases can best be understood by considering their evolutionary relationships on the basis of the organization of both their genes and the proteins themselves. An analysis of representative members of protease families, notably the mammalian serine proteases, suggests that they are the products of processes of recombination of gene segments that give rise to functionally and structurally distinct domains. The evolutionary variability introduced by combinations of domains appears to be far more restricted than if each protein molecule were the product of a single and unique evolutionary event.

Amino Acid Sequence↗

PubMed2004

Interpreting mammalian evolution using Fugu genome comparisons.

Recently, it has been shown that a significant number of evolutionarily conserved human-Fugu noncoding elements function as tissue-specific transcriptional enhancers in vivo, suggesting that distant comparisons are capable of identifying a particular class of regulatory elements. We therefore hypothesized that by juxtaposing human/Fugu and human/mouse conservation patterns we can define conservation criteria for discovering transcriptional regulatory elements specific to mammals. Genome-scale comparisons of noncoding human/Fugu evolutionary conserved elements (ECRs) and their humans/mouse counterparts revealed a particular signature common to human/mouse ECRs (>or=350 bp long, >or=77% identity) that are also conserved in fishes. This newly defined threshold identifies 90% of all human/Fugu noncoding ECRs without the assistance of human-Fugu genome alignments and provides a very efficient filter for identifying functional human/mouse ECRs.

Animals↗

PubMed1999

High sequence turnover in the regulatory regions of the developmental gene hunchback in insects.

Extensive sequence analysis of the developmental gene hunchback and its 5' and 3' regulatory regions in Drosophila melanogaster, Drosophila virilis, Musca domestica, and Tribolium castaneum, using a variety of computer algorithms, reveals regions of high sequence simplicity probably generated by slippage-like mechanisms of turnover. No regions are entirely refractory to the action of slippage, although the density and composition of simple sequence motifs varies from region to region. Interestingly, the 5' and 3' flanking regions share short repetitive motifs despite their separation by the gene itself, and the motifs are different in composition from those in the exons and introns. Furthermore, there are high levels of conservation of motifs in equivalent orthologous regions. Detailed sequence analysis of the P2 promoter and DNA footprinting assays reveal that the number, orientation, sequence, spacing, and protein-binding affinities of the BICOID-binding sites varies between species and that the 'P2' promoter, the nanos response element in the 3' untranslated region, and several conserved boxes of sequence in the gene (e.g., the two zinc-finger regions) are surrounded by cryptically-simple-sequence DNA. We argue that high sequence turnover and genetic redundancy permit both the general maintenance of promoter functions through the establishment of coevolutionary (compensatory) changes in cis- and trans-acting genetic elements and, at the same time, the possibility of subtle changes in the regulation of hunchback in the different species.

Amino Acid Sequence↗

PubMed1992

Examination of four HLA class I pseudogenes. Common events in the evolution of HLA genes and pseudogenes.

The HLA class I gene family in lymphoblastoid cell line 721 has been studied in detail and a number of sequences in addition to the classical genes have been identified. The cloning, characterization, and nucleotide sequences of four sequences, all full length HLA class I pseudogenes, are described in this report. These pseudogenes, contained within 5.4-, 5.9-, 7.0-, and 9.2-kb HindIII fragments, each have the class I exon-intron structure as well as class I homology in their 5' and 3' flanking regions. However, all four sequences have one or more substitutions that perturb the coding region, leaving little doubt that they are in fact pseudogenes. Comparisons among these sequences and the HLA class I genes revealed that their homology with the class I genes is patchwork. Thus, although some regions have diverged, other contiguous intron-exon sequences are highly conserved. Comparisons in the 5' regions indicate that the pseudogene promoters more closely resemble the classical HLA promoters than the nonclassical promoters as none of the unique structural features found in the HLA-E, -F, or -G regulatory regions are present in any of the pseudogene promoters. Further comparisons revealed that at least two putative gene conversion events, similar to those hypothesized to have occurred in the evolution of some HLA genes, may have occurred in the evolution of some of the pseudogenes. These and other hypothetical events in the evolution of the class I gene family are discussed.

Base Sequence↗

PubMed1992

Conservation of the organization of five tightly clustered genes over 600 million years of divergent evolution.

The organization of the mouse surfeit locus is unusual in that it contains six housekeeping genes (Surf-1-Surf-6), which are unrelated by sequence homology, in the tightest mammalian gene cluster thus far described. A maximum of only 73 base pairs separates any two of the four well-characterized genes, and two of the genes overlap at their 3' ends. The direction of transcription of each of the five surfeit genes, Surf-1-Surf-5, alternates with respect to that of its neighbor, suggesting cis-interaction or coregulation between the genes by mechanisms such as the sharing of regulatory elements and/or antisense regulation. The Surf-3 gene has been identified as encoding the ribosomal protein L7a (Rpl7a). We have used the high conservation of the Rpl7a gene to clone the chicken gene and surrounding genomic DNA. The tight clustering and juxtaposition of at least five of the surfeit genes (Surf-1-Surf-5) and their associated CpG-rich islands have been found to be conserved over the 600 million years of divergent evolution that separates birds and mammals. This strongly suggests that the surfeit locus represents a different form of gene cluster in which gene organization may play both a positive and negative regulatory role in gene expression possibly via cis-interactions between the closely spaced genes.

Amino Acid Sequence↗

PubMed2004

Inactive enzyme-homologues find new function in regulatory processes.

Although the catalytic center of an enzyme is usually highly conserved, there have been a few reports of proteins with substitutions at essential catalytic positions, which convert the enzyme into a catalytically inactive form. Here, we report a large-scale analysis of substitutions at enzymes' catalytic sites in order to gain insight into the function and evolution of inactive enzyme-homologues. Our analysis revealed that inactive enzyme-homologues are not an exception only found in single enzyme families, but that they are represented in a large variety of enzyme families and conserved among metazoan species. Even though they have lost their catalytic activity, they have adopted new functions and are now mainly involved in regulatory processes, as shown by several case studies. This modification of existing modules is an efficient mechanism to evolve new functions. The invention of inactive enzyme-homologues in metazoa has thereby led to an enhancement of complexity of regulatory networks.

Enzymes↗

PubMed1990

The molecular genetics of the bithorax complex of Drosophila: cis-regulation in the Abdominal-B domain.

In Drosophila the Abdominal-B (Abd-B) domain of the bithorax complex (BX-C) spans over 100 kb and is responsible for specifying the identities of adult abdominal segments five (A5) to nine (A9), inclusive, and correspondingly, neuromeres 10-14 of the embryonic central nervous system. The domain consists of a region coding for two proteins, ABD-BI (54 kd) and ABD-BII (36 kd) and cis-regulatory regions extending from infra-abdominal-5 (iab-5) to iab-9, inclusive. We have used a monoclonal anti-ABD-B antibody to infer that mutants in iab-8 eliminate the expression of ABD-BI in neuromeres 10-13, inclusive, and that mutants in iab-9 eliminate expression of ABD-BII in neuromere 14. ABD-B expression is also analyzed in homozygotes for (i) loss-of-function mutants involving the iab-5, iab-6 and iab-7 regions, (ii) gain-of-function mutants Miscadastral pigmentation (Mcp) and Superabdominal (Sab), and (iii) a trans-regulator, Polycomb (Pc). ABD-B expression along the antero-posterior axis is colinear with the chromosomal order of the cis-regulatory regions. The behavior of rearrangement-associated iab-6 and iab-7 mutants suggests that the enhancer-like region, iab-5, and possibly also iab-6, may be shared between the abd-A and Abd-B domains. Such sharing is proposed as a factor that tends to keep gene complexes intact during evolution.

Abdomen↗

PubMed2005

Reverse engineering genetic networks using evolutionary computation.

This paper proposes an improved evolutionary method for constructing the underlying network structure and inferring effective kinetic parameters from the time series data of gene expression using decoupled S-system formalism. We employed Trigonometric Differential Evolution (TDE) as the optimization engine of our algorithm for capturing the dynamics in gene expression data. A more effective fitness function for attaining the sparse structure, which is the hallmark of biological networks, has been applied. Experiments on artificial genetic network show the power of the algorithm in constructing the network structure and predicting the regulatory parameters. The method is used to evaluate interactions between genes in the SOS signaling pathway in Escherichia coli using gene expression data.

Algorithms↗

PubMed1996

Evolution of heart rate variability in cardiac transplant recipients: a clinical study.

OBJECTIVES: To investigate in cardiac transplant patients whether post-transplantation time, graft arteriosclerosis, allograft rejection, or earlier cytomegalovirus infection affect the neural regulatory mechanisms of the donor heart. DESIGN: A consecutive series of heart transplant patients during a 12-month period. SETTING: A university hospital in Finland. SUBJECTS: Consecutive cardiac transplant recipients (n = 38) attending the hospital for their annual clinical examination were studied. Their mean (SD) age was 45.4 (11.5) years, 37 were male, and the median (range) time since transplantation was 36 (12-72) months. INTERVENTIONS: Power spectral analysis of R-R intervals (during 5 min of controlled breathing, the Valsalva manoeuvre, and deep breathing), routine coronary arteriography, cytomegalovirus serology. RESULTS: R-R interval (r = 0.67; P < 0.001), the root mean square difference of successive R-R intervals (r = 0.38; P < 0.05), the total R-R interval power (r = 0.45; P < 0.01), the power of the very low frequency (0.0-0.07 Hz) component (r = 0.53; P < 0.01), and the power of the nonrespiratory (0.0-0.15 Hz) component (r = 0.49; P < 0.01) were related to the length of time since the operation. Patients having had a transplantation 3 years ago or more had significantly greater median (range) total R-R interval power than those having had the operation less than 3 years ago (59 [10-265] vs. 20 [3-113] ms2; P = 0.02). There was also a difference between the two groups in the very low frequency component (18 [1-226] vs. 5 [0-45] ms2; P = 0.01), in the nonrespiratory component (30[1-227] vs. 9 [0-53]ms2; P = 0.02), and in the Valsalva ratio (0.995 [0.955-1.065] vs. 1.020 [0.975-1.155]; P = 0.03). Patients with and without graft arteriosclerosis, episodes of rejection, or earlier cytomegalovirus infection showed no difference in the power spectral measures. CONCLUSIONS: The donor heart rate variability increases with post-transplantation time. Heart rate variability in transplant recipients is not related to the extent of graft arteriosclerosis, episodes of allograft rejection, or earlier cytomegalovirus infection.

Adult↗

PubMed1999

Biogenesis and evolution of photosynthetic (thylakoid) membranes.

Work in molecular phylogeny during the past few years has documented that the biogenesis, maintenance, adaptation, and controlled resorption of thylakoid (photosynthetic) membranes are by far more complex than the requirements for maintaining their function, especially in plants (eukaryotic photoautotrophs). Plants, due to their genome compartmentation that originated in a cohabitation of cells (endosymbiotic events), have evolved an exquisite set of regulatory mechanisms for their energy-transducing organelles. These operate in concert with basically ancient regulatory circuits originating in the organelle ancestors. It appears that the biogenesis of thylakoid membranes, as that of chloroplasts in general, cannot be understood without knowledge of the history of the cells.

Evolution, Molecular↗

PubMed1997

The single MyoD family gene of Ciona intestinalis encodes two differentially expressed proteins: implications for the evolution of chordate muscle gene regulation.

A MyoD family gene was identified in the ascidian Ciona intestinalis and designated CiMDF (Ciona intestinalis Muscle Determination Factor). Expression of CiMDF was restricted to the muscle cells of the developing embryo and the body-wall muscle of adults. Northern blots showed that two differentially regulated CiMDF transcripts were expressed during development. A 1.8 kb transcript (CiMDFa) appeared first and was gradually replaced by a 2.7 kb transcript (CiMDFb). These transcripts encoded essentially identical MyoD family proteins with the exception of a 68 amino acid C-terminal sequence present in CiMDFb that was absent from CiMDFa. Although both CiMDFa and CiMDFb contained the cysteine-rich/basic-helix loop helix domain (Cys-rich/bHLH) present in all MyoD family proteins, only CiMDFb contained the region near the C terminus (Domain III) characteristic of this gene family. Genomic Southern blots showed that C. intestinalis has only one MyoD family gene, suggesting that CiMDFa and CiMDFb result from differential processing of primary transcripts. The existence of two MyoD family proteins that are differentially expressed during ascidian embryogenesis has novel parallels to vertebrate muscle development and may reflect conserved myogenic regulatory mechanisms among chordates.

Amino Acid Sequence↗

PubMed1989

Molecular biology of enzyme adaptations in higher eukaryotes.

Multicellular eukaryotes have evolved complex homeostatic mechanisms that buffer the majority of their cells from direct interaction with the external environment. Thus, in these organisms long-term adaptations are generally achieved by modulating the developmental profile and tissue specificity of gene expression. Nevertheless, a subset of eukaryotic genes are still involved in direct responses to environmental fluctuations. It is the adaptative responses in the expression of these genes that buffers many other genes from direct environmental effects. Both microevolutionary and macroevolutionary patterns of change in the structure and regulation of such genes are illustrated by the sequences encoding alpha-amylases. The molecular biology and evolution of alpha-amylases in Drosophila and other higher eukaryotes are presented. The amylase system illustrates the effects of both long-term and short-term natural selection, acting on both the structural and regulatory components of a gene--enzyme system. This system offers an opportunity for linking evolutionary genetics to molecular biology, and it allows us to explore the relationship between short-term microevolutionary changes and long-term adaptations.

Adaptation, Biological↗

PubMed2026

Evolutionary architecture and lineage-specific diversification of Forkhead box transcription factors in Perna viridis.

The Forkhead box (Fox) transcription factors are evolutionarily conserved regulators of development, cell cycle, and apoptosis across metazoans. This study provides the first comprehensive genome-wide analysis of the Fox gene family in the Asian green mussel (Perna viridis). We identified 28 Fox genes distributed across 10 chromosomes. Comparative analysis reveals the absence of the FoxI, FoxQ1, FoxR and FoxS subfamily, consistent with other bivalves and indicative of lineage-specific gene loss during molluscan evolution. Notably, gene duplications in the FoxAB, FoxD, FoxH, FoxN1-4, FoxQ2 and FoxQD subfamilies may reflect functional diversification associated with environmental adaptation. Exon-intron structural variability, including intron loss in several paralogues, suggests structural diversification and potential regulatory variation. Phylogenetic reconstruction confirmed the monophyly of core Fox classes while highlighting divergent expansion patterns in lophotrochozoans. Selection analyses showed strong purifying selection across duplicated Fox paralogs, supporting functional conservation after lineage-specific expansion. Gene Ontology enrichment linked Fox genes to stress response, apoptosis, and transcriptional regulation. By integrating phylogenetic, structural, and transcriptomic analyses, this study provides a genomic framework for understanding Fox gene organisation, evolution, and tissue-associated expression patterns in Perna viridis and establishes a comparative resource for future functional studies in bivalves.

Animals↗

PubMed1996

Transcriptional control of Hox genes in the vertebrate nervous system.

The identification, in transgenic mice, of Hox gene DNA regulatory elements that can recapitulate certain aspects of the endogenous gene expression pattern has proceeded with great success. Perfect reproduction of the correct expression pattern, however, is uncommon, even when large genomic fragments spanning neighboring genes are analyzed, suggesting that important regulatory regions may be located at large distances from the genes they control or that their specific context may be important. Four classes of transcriptional regulators have been identified recently that have been shown to directly regulate Hox gene expression in the murine nervous system: retinoic acid receptors, Krox20, the Pbx/exd family, and the Hox genes themselves.

Animals↗