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PubMed2004

Evolving new genetic codes.

Although the genetic code is almost universal, natural variations exist that have caused evolutionary biologists to speculate about codon evolution. There are two predominant hypotheses that specify either a gradual (ambiguous intermediate) or stochastic (codon capture) change in the code. These hypotheses are similar to two biotechnology techniques that have been used to engineer the genetic code: a 'top down' approach, in which the whole organism is evolved for the ability to incorporate unnatural amino acids, and a 'bottom up' approach, in which aminoacyl-tRNA synthetases and their cognate tRNAs are engineered. The biotechnology experiments provide insights into natural codon evolution, and a combination of these approaches should enable the evolution of organisms that can incorporate unnatural amino acids throughout their proteomes.

Journal Article↗
PubMed2001

A model for phylogenetic inference using structural and chemical covariates.

We investigated whether or not evolutionary change in DNA sequence data was homogeneous across different classes of base pairs. DNA sequences for eight protein-coding mitochrondrial genes were obtained for 38 vertebrate taxa from GenBank. Each nucleotide site in the alignment was classified according to a number of covariates, including its codon position, genetic code degeneracy, and hydrophobicity. The evolutionary transition matrix for each base was estimated by tracing implied character changes under parsimony on a known phylogenetic tree. Canonical variates analyses of the inferred transition matrices were performed for each gene to determine whether or not different classes of bases behaved similarly. We found five distinct clusters of transition matrices that could be roughly defined by combinations of codon position and degeneracy. This pattern was consistent among all genes. A stochastic model of rate variation based on the interaction of the covariates was developed to assess the statistical significance of the clusters. The five-group classification was found to explain significantly more sequence variation than did a codon only classification, a codon degeneracy classification, or a codon and degeneracy classification. The same five-group classification was found for all genes tested, suggesting a common process underlying the molecular evolution of the mitochondrial genome. These results confirm that there are classes of base pairs that evolve differently, and suggest that models of sequence evolution that incorporate covariate information may be useful in developing nucleotide substitution models that more accurately reflect evolutionary history.

Animals↗
PubMed2005

Newly sequenced eRF1s from ciliates: the diversity of stop codon usage and the molecular surfaces that are important for stop codon interactions.

The genetic code of nuclear genes in some ciliates was found to differ from that of other organisms in the assignment of UGA, UAG, and UAA codons, which are normally assigned as stop codons. In some ciliate species, the universal stop codons UAA and UAG instead encode glutamine. In some other ciliates, the universal stop codon UGA appears to be translated as cysteine or tryptophan. Eukaryotic release factor 1 (eRF1) is a key protein in stop codon recognition, thus, the protein is believed to play an important role in the stop codon reassignment in ciliates. We have cloned, sequenced, and analyzed the cDNA of eRF1 from four ciliate species of three different classes: Karyorelictea (Loxodes striatus), Heterotrichea (Blepharisma musculus), and Litostomatea (Didinium nasutum, Dileptus margaritifer). Phylogenetic analysis of these eRF1s supports the hypothesis that the genetic code in ciliates has deviated independently several times from the universal genetic code, and that different ciliate eRF1s may have undergone different processes to change the codon specificity. Using computational methods, we have also suggested areas on the surface of eRF1s that are important for stop codon recognition in ciliate eRF1s.

Amino Acid Sequence↗
PubMed1999

Developing a global strategy for cancer.

Over the next 25 years there will be a dramatic increase in the number of people developing cancer. Globally, 10 million new cancer patients are diagnosed each year and this will be 20 million by the year 2020. Cancer is now the public's most feared disease. Billions of dollars are spent annually on cancer research by the drug industry, cancer charities and governments, but a cure for cancer appears elusive. And yet, we are in the midst of a revolution in our ability to image parts of the body, painlessly and in fine detail. We also now understand the intricate workings of the human genome-ultimately responsible for controlling all biological processes in health and disease. By the year 2003 the entire DNA sequence of the human genome will be determined. Powerful computer networks will allow detailed comparisons of genetic structure, so identifying new risk factors. Gene chips will detect minute code changes of considerable relevance. Novel screening technologies will allow us to detect just a few cancer cells in a patient. Robotically guided destructive processes will target abnormal cells in patients long before any cancer-related symptoms develop. And all this is likely by the first quarter of the next century. How are people, society and healthcare systems going to deal with these tremendous technological advances for cancer? Detailed information will be available in every home through easily understandable computer links. Choices now made by professionals will be equally understandable to all. Public education on health will be strengthened allowing a more critical and realistic assessment of media reports on new technologies. But as technology becomes more complex, the gap between the global rich and poor could widen. The export of unhealthy lifestyles--cigarette smoking, dietary habits and sedentary occupations will disproportionately increase cancer in many developing countries, which can least afford the treatment costs. The WHO Cancer Programme is developing a strategy to identify priorities in cancer prevention, detection and treatment in a wide range of epidemiological and economic settings.

Diet↗
PubMed1999

Developing a global strategy for cancer.

Over the next 25 years there will be a dramatic increase in the number of people developing cancer. Globally, 10 million new cancer patients are diagnosed each year and this will be 20 million by the year 2020. Cancer is now the public's most feared disease. Billions of dollars are spent annually on cancer research by the drug industry, cancer charities and governments, but a cure for cancer appears elusive. And yet, we are in the midst of a revolution in our ability to image parts of the body, painlessly and in fine detail. We also now understand the intricate workings of the human genome--ultimately responsible for controlling all biological processes in health and disease. By the year 2003 the entire DNA sequence of the human genome will be determined. Powerful computer networks will allow detailed comparisons of genetic structure, so identifying new risk factors. Gene chips will detect minute code changes of considerable relevance. Novel screening technologies will allow us to detect just a few cancer cells in a patient. Robotically guided destructive processes will target abnormal cells in patients long before any cancer-related symptoms develop. And all this is likely by the first quarter of the next century. How are people, society and healthcare systems going to deal with these tremendous technological advances for cancer? Detailed information will be available in every home through easily understandable computer links. Choices now made by professionals will be equally understandable to all. Public education on health will be strengthened allowing a more critical and realistic assessment of media reports on new technologies. But as technology becomes more complex, the gap between the global rich and poor could widen. The export of unhealthy lifestyles--cigarette smoking, dietary habits and sedentary occupations will disproportionately increase cancer in many developing countries, which can least afford the treatment costs. The WHO Cancer Programme is developing a strategy to identify priorities in cancer prevention, detection and treatment in a wide range of epidemiological and economic settings.

Female↗
PubMed2004

Epigenetics in human disease and prospects for epigenetic therapy.

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.

DNA Methylation↗
PubMed1997

Gene frequencies of the HPA-1 and HPA-2 platelet antigen alleles among the Amerindians.

BACKGROUND AND OBJECTIVES: Platelet-specific alloantigens are important in neonatal alloimmune thrombocytopenia, posttransfusion purpura, refractoriness to platelet transfusions, and population genetics. Data are scarce on allele frequencies in ethnic groups other than whites and Asians. MATERIALS AND METHODS: Using allele-specific restriction enzyme analysis, we studied the distribution of HPA-1 and HPA-2 alleles in six Brazilian Amazon tribes of Amerindians, belonging to five different language stocks. We compared these with the values obtained for blacks and whites. RESULTS: Only the HPA-1a allele was found among 132 Amerindian chromosomes, compared with a gene frequency of HPA-1b of 0.115 and 0.113, respectively, among blacks and whites. The frequency of HPA-2b among the Amerindians (0.042) is lower than that obtained for blacks and whites (0.148 and 0.100, respectively), and the lowest thus far observed in a population of Asian origin. CONCLUSION: Differences in DNA polymorphisms in Amerindian populations have not only anthropological and genetic interest, but also practical applications when they involve coding regions that may change the functional or immunologic features of the protein.

Alleles↗
PubMed1973

Triple-stranded polynucleotide helix containing only purine bases.

The structure of the complex involving one polyadenylic acid and two polyinosinic acid chains has been determined by x-ray diffraction. The three coaxial, helical chains have conformations like conventional RNA double helices despite the absence of purine-pyrimidine pairing. Formation of hypoxanthine pairs in codon-anticodon interactions therefore requires only trivial changes in the conformation of a standard nucleotide. Evolution of the contemporary genetic code involving purine-pyrimidine complementarity from a primeval code with only adenine-hypoxanthine pairing would have been possible without major discontinuities in molecular geometry.

Adenine Nucleotides↗
PubMed2006

Intrafamilial phenotypic variability in families with RDS mutations: exclusion of ROM1 as a genetic modifier for those with retinitis pigmentosa.

OBJECTIVES: To identify suspected RDS mutations in families in which different people have been identified with either generalised retinal dystrophy or macular dystrophy. METHODS: Two families with a retinal dystrophy were extensively phenotyped and blood was taken for mutation analysis of the RDS (all) and ROM1 (retinitis pigmentosa patients only) genes. RESULTS: A novel p.Trp94X mutation in RDS was found in all three affected members of a two-generation family that was associated with retinitis pigmentosa in the son, pattern dystrophy in the daughter and fundus flavimaculatus in the mother. In the second family, the proband with retinitis pigmentosa carried a p.Arg220Trp mutation. The mother, who was unavailable for mutation screening, had adult vitelliform macular dystrophy. No ROM1 mutations were found in those with retinitis pigmentosa in either family. CONCLUSION: Mutations in RDS can be associated with an intrafamilial variation in retinal disease. The phenotypes range from Stargardt-like macular dystrophy to classic retinitis pigmentosa. CLINICAL RELEVANCE: Intrafamilial phenotypic variation may be due to the presence of environmental or genetic modifying factors. The presence of a modifying-sequence change in the coding region of ROM1 for two people with retinitis pigmentosa from two families with intrafamilial variation in RDS mutation phenotype has been excluded in this study.

Adult↗
PubMed1970

Science and man.

Explore the source record for details and available documents.

Communication↗
PubMed1987

The genetic relatedness of a number of individual cognate genes of viruses in the bluetongue and closely related serogroups.

Genome segments 2, 4, 6, 7, 8, 9, and 10 of bluetongue virus (BTV) serotype 10 were cloned in pBR322. The 2926-bp S2 gene, which codes for the serotype-specific antigen, was cloned as two overlapping 2.4-kb inserts. The relatedness of cognate S2 genes among different isolates of BTV10 was investigated by hybridization, restriction enzyme mapping, and sequencing of the terminal ends. Hybridization under high stringency conditions indicated a genetic diversity between isolates of BTV10 from South Africa and the United States. This was confirmed by a comparison of the restriction map of the cloned S2 gene of a BTV10 isolate from South Africa to that of the S2 gene of the BTV10 strain of the United States which has been cloned and sequenced by Purdy et al. (1985). The part of the genome that was sequenced indicated, however, that this variation was confined to an approximately 10% sequence divergence in the coding region. Very few of the nucleotide substitutions resulted in an amino acid change. The genetic variation of cognate BTV genes within the BTV serogroup as well as among different members of closely related serogroups was also investigated. DNA probes from cloned BTV10 segments were hybridized to dsRNA from 24 different BTV serotypes. Genome segments S2 and S6 were found to be almost equally serotype specific. The stringency of the wash solutions after hybridization can be manipulated to determine an order of relatedness of different cognate genes. This was illustrated by the hybridization of a sensitive RNA probe of S7 to different BTV serotypes as well as to dsRNA from closely related orbiviruses. The results confirmed a relatedness between BTV and members of the epizootic hemorrhagic disease virus (EHDV) serogroups.

Amino Acid Sequence↗
PubMed2000

Frequency and molecular analysis of hprt mutations induced by estradiol in Chinese hamster V79 cells.

The natural hormone estradiol (E2) induces tumors in rodents and various types of DNA damage in vitro and in vivo, but has not been mutagenic in bacterial or mammalian assays. Recent reports of chromosomal and genetic lesions induced by E2 has led us to re-examine the mutation frequency and molecular alterations of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene in Chinese hamster V79 cells. E2 at both physiological and pharmacological concentrations (10-11, 10-10, and 10-7, 10-6 M) significantly increased the mutation frequency of the hprt gene by 2. 57-, 3.45-, 2.63-, and 8.78-fold, respectively, compared to the controls, while 10-13, 10-12, 10-9, or 10-8 M E2 induced little change (< or =0.93-fold). PCR and a molecular analysis of the hprt coding sequence identified genetic lesions in the cDNA and/or genomic DNA in 15 of the 21 picked E2-induced mutants (71%). Simple base substitutions, such as Tright curved arrow G or Tright curved arrow A transversions, were the most common mutations (8/21 or 38%) and frequently occurred at 122 bp or 407 bp of the hprt coding sequence. Deletion mutations were detected in 6 of the 21 clones (29%). An Aright curved arrow G and a Cright curved arrow T transition and a four-base insertion (TATT) were identified each in one mutant clone. A RT-PCR analysis demonstrated an abundant expression of the estrogen receptor-alpha (ERalpha). However, ICI 182,780, an antagonist of ERalpha, acted in an additive manner with E2 and increased the hprt mutation frequency. In conclusion, E2 induces a low frequency of mutations (deletions and point mutations) in V79 cells, which is consistent with the weak carcinogenic activity of this hormone. The mutagenic effects of E2 in V79 cells are not mediated by the ERalpha.

Animals↗
PubMed2005

[Therapeutic implications of polymorphisms in cytochromes and drug transporters].

There is great heterogeneity in the way individuals respond to drug therapy. Reasons for this variability include pathophysiological or environmental factors, drug interactions or genetic influences. Among those influences are polymorphisms in drug-metabolizing enzymes, such as Cytochrom-P-450 (CYP) 2D6, CYP2C9 or CYP2C19 or genetic variants in enzymes coding for drug transporters, such as P-Glycoprotein. Polymorphisms might cause changes in drug pharmacokinetics and consequently drug efficacy after administration of recommended standard drug doses. Reduced enzyme activity can either result in a higher percentage of drug side-effects, or an augmented drug response due to increased target site concentrations. Conversely, intensified catalytic enzymatic activity might lead to subtherapeutic drug concentrations. In the future, genetic screening by genotyping before the initiation of pharmacotherapy might help to identify responders or non-responders and might it offer individualized therapies to select patient populations.

Cytochrome P-450 Enzyme System↗
PubMed1997

[The topological structure of the genetic code].

On the basis of the topological concept of the vicinity of the point, graphs of connectedness for four nitrous bases (L and D tetrahedra) and the topological patterns of doublet and triplet genetic codes were constructed. These topological patterns were isomorphic to Boolean hypercubes B4 and B6, respectively. The resultant structures of the genetic code resembled those obtained earlier in terms of the rhombic variant of the genetic code table, which was constructed on the basis of complementarity of the coding doublets. Specifically, both models assumed the following: (1) when two groups of doublets and quartets of triplets that coded for one amino acid or two amino acids each were transformed into each other according to Rumer's rule (C <--> A, G <--> U), they retained C2 symmetry, and (2) single transitions of nitrous bases changed the structures of the encoded amino acids to the minimum possible extent. A possible mechanism for the origin of the genetic code and the possibility of using the characteristics of the obtained structures to develop the algorithm of prediction of the supermolecular protein structure, read genetic "texts", and refine the functions of amino acids as molecular modules are discussed in terms of the results obtained.

Algorithms↗
PubMed2006

Variation in evolutionary processes at different codon positions.

Evolutionary studies commonly model single nucleotide substitutions and assume that they occur as independent draws from a unique probability distribution across the sequence studied. This assumption is violated for protein-coding sequences, and we consider modeling approaches where codon positions (CPs) are treated as separate categories of sites because within each category the assumption is more reasonable. Such "codon-position" models have been shown to explain the evolution of codon data better than homogenous models in previous studies. This paper examines the ways in which codon-position models outperform homogeneous models and characterizes the differences in estimates of model parameters across CPs. Using the PANDIT database of multiple species DNA sequence alignments, we quantify the differences in the evolutionary processes at the 3 CPs in a systematic and comprehensive manner, characterizing previously undescribed features of protein evolution. We relate our findings to the functional constraints imposed by the genetic code, protein function, and the types of mutation that cause synonymous and nonsynonymous codon changes. The results increase our understanding of selective constraints and could be incorporated into phylogenetic analyses or gene-finding techniques in the future. The methods used are extended to an overlapping reading frame data set, and we discover that overlapping reading frames do not necessarily cause more stringent evolutionary constraints.

Base Sequence↗
PubMed2006

Genetics, development and evolution of adaptive pigmentation in vertebrates.

The study of pigmentation has played an important role in the intersection of evolution, genetics, and developmental biology. Pigmentation's utility as a visible phenotypic marker has resulted in over 100 years of intense study of coat color mutations in laboratory mice, thereby creating an impressive list of candidate genes and an understanding of the developmental mechanisms responsible for the phenotypic effects. Variation in color and pigment patterning has also served as the focus of many classic studies of naturally occurring phenotypic variation in a wide variety of vertebrates, providing some of the most compelling cases for parallel and convergent evolution. Thus, the pigmentation model system holds much promise for understanding the nature of adaptation by linking genetic changes to variation in fitness-related traits. Here, I first discuss the historical role of pigmentation in genetics, development and evolutionary biology. I then discuss recent empirically based studies in vertebrates, which rely on these historical foundations to make connections between genotype and phenotype for ecologically important pigmentation traits. These studies provide insight into the evolutionary process by uncovering the genetic basis of adaptive traits and addressing such long-standing questions in evolutionary biology as (1) are adaptive changes predominantly caused by mutations in regulatory regions or coding regions? (2) is adaptation driven by the fixation of dominant mutations? and (3) to what extent are parallel phenotypic changes caused by similar genetic changes? It is clear that coloration has much to teach us about the molecular basis of organismal diversity, adaptation and the evolutionary process.

Adaptation, Biological↗
PubMed1991

[Carrier detection of Glanzmann's thrombasthenia by Taq I restriction fragment length polymorphism of GPIIIa gene].

Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder in which platelets fail to aggregate in second hemostasis due to qualitative and/or quantitative defect in their GPIIb/IIIa complex. In the present study, both phenotypic and genotypic assays were performed by Western blot and Southern blot techniques in 13 members of 3 GT families. 2 GT carriers of 3 probable carriers whose clinical features and GPIIb/IIIa protein were essentially normal were determined by Taq I/5' GPIIIa RFLP. There were no major deletion or insertion in GPIIIa gene in 4 patients with GT. Thus, the genetic defects in these patients is most likely due to a small change or point mutation in the nucleotide sequence of GPIIIa coding region.

Adolescent↗