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PubMed1989

RNA editing in plant mitochondria.

Comparative sequence analysis of genomic and complementary DNA clones from several mitochondrial genes in the higher plant Oenothera revealed nucleotide sequence divergences between the genomic and the messenger RNA-derived sequences. These sequence alterations could be most easily explained by specific post-transcriptional nucleotide modifications. Most of the nucleotide exchanges in coding regions lead to altered codons in the mRNA that specify amino acids better conserved in evolution than those encoded by the genomic DNA. Several instances show that the genomic arginine codon CGG is edited in the mRNA to the tryptophan codon TGG in amino acid positions that are highly conserved as tryptophan in the homologous proteins of other species. This editing suggests that the standard genetic code is used in plant mitochondria and resolves the frequent coincidence of CGG codons and tryptophan in different plant species. The apparently frequent and non-species-specific equivalency of CGG and TGG codons in particular suggests that RNA editing is a common feature of all higher plant mitochondria.

Amino Acid Sequence↗
PubMed1994

Pharmacogenetics: detecting sensitive populations.

Risk assessment models strive to predict risks to humans from toxic agents. Safety factors and assumptions are incorporated into these models to allow a margin of error. In the case of cancer, substantial evidence shows that the carcinogenic process is a multistage process driven by the interaction of exogenous carcinogenic exposures, genetic traits, and other endogenous factors. Current risk assessment models fail to consider genetic predispositions that make people more sensitive or resistant to exogenous exposures and endogenous processes. Several cytochrome P450 enzymes, responsible for metabolically activating carcinogens and medications, express wide interindividual variation whose genetic coding has now been identified as polymorphic and linked to cancer risk. For example, a restriction fragment-length polymorphism for cytochrome P4501A1, which metabolizes polycyclic aromatic hydrocarbons, and cytochrome P4502E1, which metabolizes N-nitrosamines and benzene, is linked to lung cancer risk. Cytochrome P4502D6, responsible for metabolizing many clinically important medications, also is linked to lung cancer risk. The frequency for each of these genetic polymorphisms vary among different ethnic and racial groups. In addition to inherited factors for the detection of sensitive populations, determining the biologically effective doses for carcinogenic exposures also should quantitatively and qualitatively enhance the risk assessment process. Levels of carcinogen-DNA adducts reflect the net effect of exposure, absorption, metabolic activation, detoxification, and DNA repair. These effects are genetically predetermined, inducibility notwithstanding. The combination of adduct and genotyping assays provide an assessment of risk that reflects recent exogenous exposure as well as one's lifetime ability to activate and detoxify carcinogens.

Carcinogens↗
PubMed1999

Genetic variation and nutrition in relation to coronary artery disease.

There is evidence that coronary artery disease (CAD), hypertension, diabetes mellitus (DM) and hyperlipidemia develop due to interaction of genetic and environmental factors during transition from poverty to affluence. Rapid transition in diet and lifestyle factors may influence heritability of the variant phenotypes that are dependent on the nutrient environment for their expression. We are beginning to recognize the interaction of specific nutrients with the genetic code possessed by all nucleated cells. In the next millennium, the physician may be able to make nutrient intake recommendations not on physical characteristics but on the basis of the individual's phenotypic expression for health while suppressing his phenotypic expression for disease. We have demonstrated an increased susceptibility to CAD, diabetes, central obesity, hyperinsulinemia and lipoprotein(a) excess in Indians in younger age groups indicating a genetic predisposition to these problems due to interaction of gene and environment. Lipoprotein(a) is a genetic risk factor for CAD, diabetes and stroke and it is higher in South Indians than North Indians. Antioxidant vitamins, coenzyme Q10 and n-3 fatty acids may have a beneficial influence whereas linoleic acid, saturated fat and sugars may have adverse effects on phenotypic expression. There is significant evidence that genes are involved in determining enzymes, receptors, cofactors, structural components involved in regulation of blood pressure, the metabolism of lipids, lipoproteins and inflammatory and coagulation factors that are involved in determining an individual's risk. Majority of these genes are polymorphic. While some genes respond to nutritional modulation, others may not indicate any response.

Antioxidants↗
PubMed1994

Genes coding for the selenocysteine-inserting tRNA species from Desulfomicrobium baculatum and Clostridium thermoaceticum: structural and evolutionary implications.

The genes (selC) coding for the selenocysteine-inserting tRNA species (tRNA(Sec)) from Clostridium thermoaceticum and Desulfomicrobium baculatum were cloned and sequenced. Although they differ in numerous positions from the sequence of the Escherichia coli selC gene, they were able to complement the selC lesion of an E. coli mutant and to promote selenoprotein formation in the heterologous host. The tRNA(Sec) species from both organisms possess all of the unique primary, secondary, and tertiary structural features exhibited by E. coli tRNA(Sec) (C. Baron, E. Westhof, A. Böck, and R. Giegé, J. Mol. Biol. 231:274-292, 1993). The structural and functional properties of the tRNA(Sec) species from prokaryotes analyzed thus far support the notion that tRNA(Sec) may be an evolutionarily conserved structure whose function in the primordial genetic code was to decode UGA with selenocysteine.

Base Sequence↗
PubMed2000

Effects of body size and resource availability on dispersal in a native and a non-native estuarine snail.

I manipulated snail densities of two coexisting species of salt marsh snail, Cerithidea californica Haldeman (native) and Batillaria attramentaria Sowerby (non-indigenous) to investigate how resource levels set by intraspecific competition may influence dispersal rates. I used two distinct size classes of the snails (mature and immature) to determine if the effects of competition on dispersal differed between developmental stages of a consumer. Dispersal attempts were measured within enclosure pens by counting snails climbing the sides of the enclosure. The influence of snail density per se and resource levels (which were set by snail densities) on dispersal rates were separated by comparing responses of snails to density before and after resources became depleted. For large snails of both species, dispersal increased as resource levels decreased, supporting the hypothesis that competition influences dispersal rates. Small snails of both species, in contrast, always dispersed at relatively higher rates than larger individuals, but were not influenced by variation in resource levels. This result corroborates other studies that have shown reduced competition in these species at smaller size, and suggests that another mechanism, such as genetically coded behavior to disperse when young, influences their behavior. Previous experiments demonstrated Batillaria's superior resource conversion efficiency; therefore, I had hypothesized that for any given resource level, Cerithidea would disperse more, because it was more affected by resource availability. Adult Batillaria, however, responded more sensitively to resource levels (i.e., dispersed more at any given resource level) than Cerithidea. This counter-intuitive result illustrates the potential importance of genetic limitations on behavioral responses available to a species. Constraints on behavioral responses may have been accentuated since Batillaria is a non-indigenous species whose evolved behavioral responses are not necessarily adapted to its present, non-native environment.

Journal Article↗
PubMed2026

A Unified Mechanism of +1 Ribosomal Frameshifting.

Ribosomes decode 3-nucleotide codons and move in 1-codon increments to maintain the messenger RNA (mRNA) frame thereby accurately producing the encoded protein. In special cases, including viral genomes and regulatory cellular proteins, frameshifting occurs to expand the coding repertoire of an mRNA to make more than one protein. How these frameshifting events are induced and regulated is an active area of research. Here, we discuss recent progress in the understanding of +1 frameshifting (+1FS), during which the ribosome shifts by 1 mRNA nucleotide in the 3' direction. Structural and biochemical studies yielded insights into +1FS induced by mRNA slippery sequences and transfer RNA (tRNA) stem-loop expansion or modifications. tRNAs with an additional anticodon nucleotide are explored as a biotechnology tool for expanding the genetic code in an approach termed quadruplet decoding. We revisit the challenges of the quadruplet decoding model, discuss +1FS scenarios in bacteria and eukaryotes, and propose a unifying structural mechanism for +1FS.

Frameshifting, Ribosomal↗
PubMed1995

Tryptophanyl-tRNA synthetase crystal structure reveals an unexpected homology to tyrosyl-tRNA synthetase.

BACKGROUND: Tryptophanyl-tRNA synthetase (TrpRS) catalyzes activation of tryptophan by ATP and transfer to tRNA(Trp), ensuring translation of the genetic code for tryptophan. Interest focuses on mechanisms for specific recognition of both amino acid and tRNA substrates. RESULTS: Maximum-entropy methods enabled us to solve the TrpRS structure. Its three parts, a canonical dinucleotide-binding fold, a dimer interface, and a helical domain, have enough structural homology to tyrosyl-tRNA synthetase (TyrRS) that the two enzymes can be described as conformational isomers. Structure-based sequence alignment shows statistically significant genetic homology. Structural elements interacting with the activated amino acid, tryptophanyl-5'AMP, are almost exactly as seen in the TyrRS:tyrosyl-5'AMP complex. Unexpectedly, side chains that recognize indole are also highly conserved, and require reorientation of a 'specificity-determining' helix containing a conserved aspartate to assure selection of tryptophan versus tyrosine. The carboxy terminus, which is disordered and therefore not seen in TyrRS, forms part of the dimer interface in TrpRS. CONCLUSIONS: For the first time, the Bayesian statistical paradigm of entropy maximization and likelihood scoring has played a critical role in an X-ray structure solution. Sequence relatedness of structurally superimposable residues throughout TrpRS and TyrRS implies that they diverged more recently than most aminoacyl-tRNA synthetases. Subtle, tertiary structure changes are crucial for specific recognition of the two different amino acids. The conformational isomerism suggests that movement of the KMSKS loop, known to occur in the TyrRS transition state for amino acid activation, may provide a basis for conformational coupling during catalysis.

Amino Acid Sequence↗
PubMed1994

DNA mapping in growth and developmental disorders.

DNA mapping techniques are being increasingly applied to familial and acquired disorders affecting growth and development. To understand the potential applications of these techniques, one must first have a good understanding of the components and basic structure of DNA, the genetic code, the basic structure of genes and the roles that various components of gene structure play in regulating gene expression. Following review of this basic information, a variety of DNA mapping techniques including in situ hybridization, Southern blotting, polymerase chain reaction amplification, DNA sequencing and linkage analysis will be covered. Applications of these techniques can enable mapping of unknown genes by detection of loss of allelic heterozygosity or use of linkage analysis and genetic maps. With increasing ease, mutations such as deletions, expansions, rearrangements and point mutations can be detected in diseases such as congenital adrenal hyperplasia, cystic fibrosis, diabetes insipidus, growth hormone deficiency, fragile X syndrome, Laron dwarfism and Turner syndrome. From this discussion, a better understanding of methods of gene localization, uses of genetic maps and rapid, convenient methods to detect a variety of molecular derangements causing familial disorders affecting growth and development will be gained.

Blotting, Southern↗
PubMed2002

Omnipotent decoding potential resides in eukaryotic translation termination factor eRF1 of variant-code organisms and is modulated by the interactions of amino acid sequences within domain 1.

In eukaryotes, a single translational release factor, eRF1, deciphers three stop codons, although its decoding mechanism remains puzzling. In the ciliate Tetrahymena thermophila, UAA and UAG codons are reassigned to Gln codons. A yeast eRF1-domain swap containing Tetrahymena domain 1 responded only to UGA in vitro and failed to complement a defect in yeast eRF1 in vivo at 37 degrees C. This finding demonstrates that decoding specificity of eRF1 from variant code organisms resides at domain 1. However, the wild-type eRF1 hybrid fully restored the growth of eRF1-deficient yeast at 30 degrees C. Tetrahymena eRF1 contains a variant sequence, KATNIKD, at the tip of domain 1. The TASNIKD variant of hybrid eRF1 rendered the eRF1-nullified yeast viable, although in an in vitro assay, the same hybrid eRF1 responded only to UGA. Nevertheless, the yeast eRF1 bearing the KATNIKD motif instead of the TASNIKS heptapeptide present in higher eukaryotes remains omnipotent in vivo. Collectively, these data suggest that variant genetic code organisms like Tetrahymena have an intrinsic potential to decode three stop codons in vivo, and that interaction within domain 1 between the KAT tripeptide and other sequences modulates the decoding specificity of Tetrahymena eRF1.

Amino Acid Sequence↗
PubMed1994

Nucleotide sequence of the cox3 gene from Chondrus crispus: evidence that UGA encodes tryptophan and evolutionary implications.

We present the nucleotide sequence of the gene encoding subunit 3 of cytochrome c oxidase in Chondrus crispus, the first report on a mitochondrial gene from a red alga. Amino acid alignment with homologous proteins shows that tryptophan is specified by UGA, as in the mitochondrial code of most organisms other than green plants. However, phylogenetic analyses of cox3 amino acid and nucleotide sequences indicate that C. crispus COX3 is related to the green-plant mitochondrial lineage. No RNA editing was detected on the corresponding transcript. As the only known photosynthetic eukaryotes that both share an immediate mitochondrial ancestor with green plants and exhibit features characteristic of non-plant mitochondria, ie, a small-sized mitochondrial genome and a modified genetic code, rhodophytes may be thought of as an intermediate evolutionary link at the root of the green-plant mitochondrial lineage.

Amino Acid Sequence↗
PubMed1994

Analysis of directional mutation pressure and nucleotide content in mitochondrial cytochrome b genes.

We present a new approach for analyzing directional mutation pressure and nucleotide content in protein-coding genes. Directional mutation pressure, the heterogenicity in the likelihood of different nucleotide substitutions, is used to explain the increasing or decreasing guanine-cytosine content (GC%) in DNA and is represented by microD, in agreement with Sueoka (1962, Proc Natl Acad Sci USA 48:582-592). The new method uses simulation to facilitate identification of significant A+T or G+C pressure as well as the comparison of directional mutation pressure among genes, even when they are translated by different genetic codes. We use the method to analyze the evolution of directional mutation pressure and nucleotide content of mitochondrial cytochrome b genes. Results from a survey of 110 taxa indicate that the cytochrome b genes of most taxa are subjected to significant directional mutation pressure and that the gene is subject to A+T pressure in most cases. Only in the anseriform bird Cairina moschata is the cytochrome b gene subject to significant G+C pressure. The GC% at nonsynonymous codon sites decreases proportionately with increasing A+T pressure, and with a slope less than one, indicating a presence of selective constraints. The cytochrome b genes of insects, nematodes, and eumycotes are subject to extreme A+T pressures (microD = 0.123, 0.224, and 0.130) and, in parallel, the GC% of the nonsynonymous codon sites has decreased from about 0.44 in organisms that are not subjected to A+T or G+C pressure to about 0.332, 0.323, and 0.367, respectively. The distribution of taxa according to the GC% at nonsynonymous codon sites and directional mutation pressure supports the notion that variation in these parameters is a phylogenetic component.

Biological Evolution↗
PubMed1999

The prospects for antisense therapy.

The use of short spans of nucleic acid--DNA or RNA--to disrupt the expression of disease-related genetic code is an idea potentially applicable to a vast number of illnesses, including most neoplasms. On several fronts, including hematologic malignancies, the concept has reached clinical trials--where appreciation of the in vivo hurdles is leading to new approaches for delivery of this new magic bullet.

Antisense Elements (Genetics)↗
PubMed2004

Reproducible sequence generation in random neural ensembles.

Little is known about the conditions that neural circuits have to satisfy to generate reproducible sequences. Evidently, the genetic code cannot control all the details of the complex circuits in the brain. In this Letter, we give the conditions on the connectivity degree that lead to reproducible and robust sequences in a neural population of randomly coupled excitatory and inhibitory neurons. In contrast to the traditional theoretical view we show that the sequences do not need to be learned. In the framework proposed here just the averaged characteristics of the random circuits have to be under genetic control. We found that rhythmic sequences can be generated if random networks are in the vicinity of an excitatory-inhibitory synaptic balance. Reproducible transient sequences, on the other hand, are found far from a synaptic balance.

Action Potentials↗
PubMed1979

[Cellular differentiation and malignant transformation (author's transl)].

The mechanisms and determination of differentiation of normal and cancer cells were compared by distinguishing them from the phenomena of regulation, retrodifferentiation and maturation. Reference is made to the laws of order in time and space which are superimposed on the common genetic code during the various types of differentiation. In conclusion, the particular mechanisms of malignant differentiation are discussed by taking melanoma and tumor formation by papova-viruses as examples.

Animals↗
PubMed1998

Preponderance of slightly deleterious polymorphism in mitochondrial DNA: nonsynonymous/synonymous rate ratio is much higher within species than between species.

We estimated synonymous (dN) and nonsynonymous (dS) substitution rates for protein-coding genes of the mitochondrial genome from two individuals each of the species human, chimpanzee, and gorilla. The genes were analyzed both separately and in a combined data set. Pairwise sequence comparisons suggest that the dN/dS rate ratios are about 5-10 times higher in within-species comparisons than in between-species comparisons. This result is confirmed by a more rigorous likelihood ratio test, which rejected the null hypothesis that the dN/dS rate ratios are identical within and between species. The likelihood models account for the genetic code structure, transition/transversion rate ratio, and codon usage bias and are expected to produce more reliable results than the commonly used contingency test. Separate analyses of different genes show that the dN/dS rate ratios are higher within species than between species for all 13 mitochondrial genes, with the difference being statistically significant for all except three small or slowly evolving genes. Furthermore, in conserved genes, nonsynonymous rates within species tend to be higher than the between-species rates by a greater proportion than in fast-changing genes. Our findings confirm and extend earlier results obtained from smaller data sets and suggest the operation of slightly deleterious mutations throughout the mitochondrial genome in the hominoids. Implications of the results for evolutionary studies and, in particular, for studies of the origin of modern humans, are discussed.

Adenosine Triphosphatases↗
PubMed2007

Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia.

The goal of genetic association studies is to identify common (>5%) risk factors in complex disease traits. Herein we describe the first replicable 'functional' risk allele for Parkinson's disease. The leucine-rich repeat kinase 2 (Lrrk2) G2385R substitution is associated with familial parkinsonism, late-, and early-onset Parkinson's disease in ethnic Chinese Taiwanese. Crucially, we provide evidence of identity-by-descent and suggest that Lrrk2 G2385R carriers originate from one ancestor some 4800 years ago, at the start of Chinese civilization. Moreover, our findings demonstrate that common genetic coding variants contribute to Parkinson's disease in a population specific manner which may have important implications for future genome-wide association studies.

Aged↗
PubMed1989

Presence of the hypermodified nucleotide N6-(delta 2-isopentenyl)-2-methylthioadenosine prevents codon misreading by Escherichia coli phenylalanyl-transfer RNA.

The overall structure of transfer RNA is optimized for its various functions by a series of unique post-transcriptional nucleotide modifications. Since many of these modifications are conserved from prokaryotes through higher eukaryotes, it has been proposed that most modified nucleotides serve to optimize the ability of the tRNA to accurately interact with other components of the protein synthesizing machinery. When a cloned synthetic Escherichia coli tRNAPhe gene was transfected into a bacterial host that carried a defective phenylalanine tRNA-synthetase gene, tRNAPhe was overexpressed by 11-fold. As a result of this overexpression, an undermodified tRNAPhe species was produced that lacked only N6-(delta 2-isopentenyl)-2-methylthioadenosine (ms2i6A), a hypermodified nucleotide found immediately 3' to the anticodon of all major E. coli tRNAs that read UNN codons. To investigate the role of ms2i6A in E. coli tRNA, we compared the aminoacylation kinetics and in vitro codon-reading properties of the ms2i6A-lacking and normal fully modified tRNAPhe species. The results of these experiments indicate that while ms2i6A is not required for normal aminoacylation of tRNAPhe, its presence stabilizes codon-anticodon interaction and thereby prevents misreading of the genetic code.

Adenosine↗