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PubMed1992

What is the optimum size for the genetic alphabet?

An important question in biology is why the genetic alphabet is made of just two base pairs (G.C and A.T). This is particularly interesting because of the recent demonstration [Piccirilli, J. A., Krauch, T., Moroney, S. E. & Benner, S. A. (1990) Nature (London) 343, 33-37] that the alphabet can in principle be larger. It is possible to explain the size of the present genetic alphabet as a frozen character state that was an evolutionary optimum in an RNA world when nucleic acids functioned both for storing genetic information and for expressing information as enzymatically active RNA molecules--i.e., ribozymes. A previous model [Szathmáry, E. (1991) Proc. R. Soc. London Ser. B 245, 91-99] has described the principle of this approach. The present paper confirms and extends these results by showing explicitly the ways in which copying fidelity and metabolic efficiency change with the size of the genetic alphabet.

Biological Evolution↗

PubMed1988

Changing the identity of a tRNA by introducing a G-U wobble pair near the 3' acceptor end.

Although the genetic code for protein was established in the 1960's, the basis for amino acid identity of transfer RNA (tRNA) has remained unknown. To investigate the identity of a tRNA, the nucleotides at three computer-identified positions in tRNAPhe (phenylalanine tRNA) were replaced with the corresponding nucleotides from tRNAAla (alanine tRNA). The identity of the resulting tRNA, when examined as an amber suppressor in Escherichia coli, was that of tRNAAla.

Alanine↗

PubMed1991

Gene sequences and comparison of the fimbrial subunits representative of Bacteroides nodosus serotypes A to I: class I and class II strains.

We have determined the nucleotide sequences of the genes encoding the fimbrial subunits representative of the known Bacteroides nodosus serogroups. All of the genes are preceded by a highly conserved region which includes the likely promoter and transcriptional regulator sites as well as the ribosome-biding site, and are followed within a short but variable distance by a sequence with the characteristics of a transcription termination or attenuation signal. Based on sequence and organization, the subunits can be divided into two major classes called I (serogroups A, B, C, E, F, G, and I) and II (serogroups D and H). All contain the same seven-amino-acid positively charged leader sequence and conserved hydrophobic amino-terminal sequence typical of type 4 fibriae. Beyond this point the class II subunits are quite different from class I and share features more in common with those from other type 4 fimbriate bacteria, such as Moraxella bovis and Pseudomonas aeruginosa. The larger class I may be further subdivided into two subsets: (i) [A, E, F)(B, I)) and (ii) (C, G). These proteins exhibit three major clusters of variation, at either end of the presumptive disulphide loop which spans the central third of the protein, and near the carboxy-terimus, with dispersed changes in between. The length of the mature subunits varies from 152-156 amino acids, and the variation includes small insertions or deletions in the variable clusters between more conserved domains. The class II subunits are 149 amino acids in length and contain two pairs of cysteine residues: one is at the end of the amino-terminal conserved region, and the other is at the end of the protein. The major variation occurs in the central region of the molecule, and again small insertions or deletions are required to align adjacent conserved domains. There is also a striking absence of silent codon changes in the 5' coding region of all of these genes, indicating that these sequences have a secondary genetic function, probably in recombinational exchange.

Amino Acid Sequence↗

PubMed2000

DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer.

BACKGROUND AND AIM: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach. METHODS: Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2. RESULTS: Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2. CONCLUSIONS: Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.

Adenoma↗

PubMed1994

Mechanisms of p53 alteration in acute leukemias.

Disruption of normal p53 expression is the most frequent genetic change occurring in various human solid tumors; it is mostly due to sequence alterations of the p53 coding region by missense mutations or to loss of an entire, functional allele of this gene. In the present study, possible mechanisms resulting in a disruption of regulated expression of wild-type p53 were examined in acute leukemias of either lymphoid (ALL) or myeloid (AML) phenotype. p53 transcript accumulation, nucleotide sequence and gene structure were analyzed in primary leukemic cells from 50 patients. p53-specific transcripts were detected in 26/26 cases of ALL and 16/23 cases of AML using reverse transcriptase (RT)-PCR. Sequencing of transcripts did not reveal any point mutations or deletions. Heterozygosity at a polymorphic Bg/II site within intron 1 was found in 4/28 leukemic samples, and loss of one allele was noted in one of these. In addition, a novel, leukemia-associated structural abnormality located within the 5' flanking region of the p53 gene and associated with the loss of heterozygosity was observed in cells from this patient with ALL. The MDM2 gene which inactivates p53 by binding to it was neither amplified nor rearranged in 28 leukemias studied. Thus, disruption of regulated p53 expression resulting in lack of detectable p53 mRNA even by RT-PCR occurs in about 30% of cases of AML; however, p53 alterations typical for human solid tumors are an infrequent event in most types of human acute leukemias.

Acute Disease↗

PubMed1977

The code of the scientist and its relationship to ethics.

Scientist's norms (principally honesty, objectivity, tolerance, doubt of certitude, and unselfish engagement) are in danger of serious distortion unless broadened to apply to the relations between scientists and nonscientists. Also needing supplementation is an ethic of development appropriate to a fast-changing society and advanced as an approach to the more effective and humane regulation of cultural and technological development. Because of their genetic relationships the code of the scientist and the ethic of development are probably complementary and together may overcome the shortcomings of each taken separately. Taken together, furthermore, they indicate the possibility of a humane world order based on the cooperation of a community of scientists and its public.

Codes of Ethics↗

PubMed1990

Genetic code 1990. Outlook.

The genetic code is evolving as shown by 9 departures from the universal code: 6 of them are in mitochondria and 3 are in nuclear codes. We propose that these changes are preceded by disappearance of a codon from coding sequences in mRNA of an organism or organelle. The function of the codon that disappears is taken by other, synonymous codons, so that there is no change in amino acid sequences of proteins. The deleted codon then reappears with a new function. Wobble pairing between anticodons and codons has evolved, starting with a single UNN anticodon pairing with 4 codons. Directional mutation pressure affects codon usage and may produce codon reassignments, especially of stop codons. Selenocysteine is coded by UGA, which is also a stop codon, and this anomaly is discussed. The outlook for discovery of more changes in the code is favorable, and open reading frames should be compared with actual sequential analyses of protein molecules in this search.

Anaerobiosis↗

PubMed2003

Genetic diversity: frameshift mechanisms alter coding of a gene (Epstein-Barr virus LF3 gene) that contains multiple 102-base-pair direct sequence repeats.

Frameshift mutations provide recognized mechanisms for changing the coding potential of an organism. Here, multiple frameshifts are identified in repetitive sequences within an Epstein-Barr virus unspliced early gene, LF3, which is associated with the viral replicative cycle and also transcriptionally expressed in many virally associated tumors. On the DNA strand encoding LF3, there are three open reading frames, only one of which contains an initiation codon. Most (>95%) of the gene consists of numerous (>20, varying with cell source) GC-rich copies of a 102-bp direct repeat (called IR 4) flanked by small unique sequences. LF3 may express a protein if its initiation and termination codons reside in the same reading frame, but this is not always the case. Frameshifting events, occurring in short runs of pyrimidines (mainly C residues) in the repeats, give rise to mutations which may provide a mechanism for escape of an LF3 function from host surveillance. Sequence studies link these frameshifts to DNA replication errors. Notably, the number of sites in LF3 at which such mutations can occur permits a very large amount of diversity in this gene. Our data also suggest a second degeneracy mechanism within the protein itself, which influences its stability and may reflect a host defense mechanism. LF3 thus provides a potentially important model for studying the quest for supremacy between a virus and its host.

Amino Acid Sequence↗

PubMed1994

Consistency and stability of recombinant fermentations.

Production of proteins of consistent quality in heterologous, genetically-engineered expression systems is dependent upon identifying the manufacturing process parameters which have an impact on product structure, function, or purity, validating acceptable ranges for these variables, and performing the manufacturing process as specified. One of the factors which may affect product consistency is genetic instability of the primary product sequence, as well as instability of genes which code for proteins responsible for post-translational modification of the product. Approaches have been developed for mammalian expression systems to assure that product quality is not changing through mechanisms of genetic instability. Sensitive protein analytical methods, particularly peptide mapping, are used to evaluate product structure directly, and are more sensitive in detecting genetic instability than is direct genetic analysis by nucleotide sequencing of the recombinant gene or mRNA. These methods are being employed to demonstrate that the manufacturing process consistently yields a product of defined structure from cells cultured through the range of cell ages used in the manufacturing process and well beyond the maximum cell age defined for the process. The combination of well designed validation studies which demonstrate consistent product quality as a function of cell age, and rigorous quality control of every product lot by sensitive protein analytical methods provide the necessary assurance that product structure is not being altered through mechanisms of mutation and selection.

Biotechnology↗

PubMed1998

Polymorphisms of thymidine kinase gene in herpes simplex virus type 1: analysis of clinical isolates from herpetic keratitis patients and laboratory strains.

Drug-resistance of herpes simplex virus (HSV) is caused most frequently by mutation of the viral thymidine kinase (TK) gene. To elucidate the significance of detecting nucleotide changes of the TK gene for screening drug-resistant viruses, the frequency and variation of the genetic polymorphisms in the whole coding region of the TK gene were studied in 14 acyclovir-susceptible HSV type 1 (HSV-1) clinical isolates from 14 patients with epithelial herpetic keratitis. Two reference HSV-1 laboratory strains, McKrae and PH, and two acyclovir-resistant variants of the PH strain were also studied as controls. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing detected nucleotide differences at 24 positions, and amino acid substitutions at 12 codons in the TK gene of the examined viruses. Nucleotide diversity of 0.0029 per base (the average number of nucleotide substitutions of 3.3 per 1,131 base pairs) in the TK gene in the clinical isolates was comparable to 0.0037 per base of the whole HSV-1 genome in Japanese isolates reported previously. PCR-SSCP analysis of the acyclovir-resistant strains easily detected aberrantly shifted bands by comparing them with those of the parental strain, followed by the quick determination of mutated sequences. These results suggest that detection of nucleotide changes of the TK gene is useful for serial observation of persistent or recurrent HSV infection as observed in immunocompromised hosts, but that it is not useful for screening drug-resistant viruses from nonepidemic clinical isolates because of the comparable genetic polymorphisms in the TK gene as in the whole HSV-1 genome.

Acyclovir↗

PubMed1999

Human delta-opioid receptor gene and susceptibility to heroin and alcohol dependence.

In the present study, we tested the hypothesis that addictive behavior may be influenced by genetic variation in the human delta-opioid receptor gene. We investigated the contribution of a silent T to C change in the coding region to the development of heroin and alcohol dependence using large case-control and family-based association samples. Presence of the C allele was previously reported to significantly increase the risk for heroin dependence. In the present study, however, we did not find statistically significant differences between patients and controls nor did we find preferential transmission of the C allele from parents to affected offspring. Our results, therefore, do not support an association between genetic variation of the delta-opioid receptor and addictive behavior in man.

Adult↗

PubMed1997

Chromosomal mapping and mutational analysis of the coding region of the glycogen synthase kinase-3alpha and beta isoforms in patients with NIDDM.

Activation of glycogen synthesis in skeletal muscle in response to insulin results from the combined inactivation of glycogen synthase kinase-3 (GSK-3) and activation of the protein phosphatase-1, changing the ratio between the inactive phosphorylated state of the glycogen synthase to the active dephosphorylated state. In a search for genetic defects responsible for the decreased insulin stimulated glycogen synthesis seen in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their glucose-tolerant first-degree relatives we have performed mutational analysis of the coding region of the 2 isoforms of GSK-3alpha and GSK-3beta in 72 NIDDM patients and 12 control subjects. No structural changes were detected apart from a few silent mutations. Mapping of the GSK-3alpha to chromosome 19q13.1-13.2 and the GSK-3beta to chromosome 3q13.3-q21 outside known genetic loci linked to NIDDM further makes it unlikely that these genes are involved in the pathogenesis of common forms of NIDDM.

Alleles↗

PubMed2005

Thermosynthesis as energy source for the RNA World: a model for the bioenergetics of the origin of life.

The thermosynthesis concept, biological free energy gain from thermal cycling, is combined with the concept of the RNA World. The resulting overall origin of life model suggests new explanations for the emergence of the genetic code and the ribosome. It is proposed that the first protein named pF(1) obtained the energy to support the RNA World by a thermal variation of F(1) ATP synthase's binding change mechanism. It is further proposed that this pF(1) was the single translation product during the emergence of the genetic machinery. During thermal cycling pF(1) condensed many substrates with broad specificity, yielding NTPs and randomly constituted protein and RNA libraries that contained self-replicating RNA. The smallness of pF(1) permitted the emergence of the genetic machinery by selection of RNA that increased the fraction of pF(1)s in the protein library: (1) an amino acids concatenating progenitor of rRNA bound to (2) a chain of 'positional tRNAs' linked by mutual recognition, and yielded a pF(1) (or its main motif); this positional tRNA set gradually evolved to a set of regular tRNAs functioning according to the genetic code, with concomitant emergence of (3) an mRNA coding for pF(1).

Energy Metabolism↗

PubMed2004

Epigenetics and cancer: implications for drug discovery and safety assessment.

It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment.

Acetylation↗

PubMed2004

Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences.

EYA1 mutations cause branchio-oto-renal (BOR) syndrome. These mutations include single nucleotide transitions and transversions, small duplications and deletions, and complex genomic rearrangements. The last cannot be detected by coding sequence analysis of EYA1. We sought to refine the clinical diagnosis of BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. Based on genotype-phenotype analyses, we propose new criteria for the clinical diagnosis of BOR syndrome. We found that in approximately 40% of persons meeting our criteria, EYA1 mutations were identified. Of these mutations, 80% were coding sequence variants identified by SSCP, and 20% were complex genomic rearrangements identified by a semiquantitative PCR-based screen. We conclude that genetic testing of EYA1 should include analysis of the coding sequence and a screen for complex rearrangements.

Branchio-Oto-Renal Syndrome↗

PubMed1966

Genetic code: aspects of organization.

The pattern of organization of the genetic code decreases to a minimum the phenotypic effects of mutation and of base-pairing errors in protein synthesis. Single base changes, especially transitions, usually cause either no amino acid change or the change to a chemically similar amino acid. The degree of degeneracy of the codons for an amino acid is correlated with their guanine-cytosine content. The code gives greater protection (by both degeneracy and guaninecytosine content of codons) to those amino acids that appear more frequently in proteins. Increased reliability of the protein-synthesis system afforded by this pattern of organization nay have determined the fitness of the present code.

Amino Acid Sequence↗

PubMed1975

RNA processing and RNA tumor virus origin and evolution.

The results of molecular hybridization experiments with high-molecular-weight RNA isolated from RNA tumor viruses and DNA from normal cells suggest that RNA tumor virus genomes originate from cell genes. Some RNA tumor viruses (here called class 1) appear to have been generated in recent times in that their RNA is closely related in nucleotide sequence to certain cell genes (class 1 genes). A second class of RNA tumor viruses (here called class 2) is more distantly related to genomic information of normal cells. Structural properties of the RNA of RNA tumor viruses lead us to propose that the tumor virus RNA is originated when RNA transcripts of class 1 genes are processed by a mechanism we call "paraprocessing." We postulate that RNA paraprocessing is normally used only at particular times during differentiation and is characterized by the cytoplasmic appearance of high-molecular-weight RNA chains containing terminal polyadenylic acid (200 residues). Paraprocessing of class 1 gene transcripts in committed or differentiated cells is considered to be aberrant in transcription that can lead to the generation of an RNA tumor virus genome. If the paraprocessed class 1 gene transcript codes for a reverse transcriptase, replication of the RNA becomes possible. Transfer of the replicating RNA to a new cell can result in genetic change such that the virus genome mutates, differing from the original progenitor genes. We propose that this genetic change causes class 1 viruses to become class 2. These ideas are applied to evidence concerning the biology of infection of RNA tumor viruses and concerning the involvement of RNA tumor viruses in human cancer. Genetic change can also occur during the origination of an RNA tumor virus genome by repeated reverse transcription and recombination (45) or by genetic alteration of particularly changeable cell genes ("hot spots") (43).

Animals↗

PubMed1998

Position effect in human genetic disease.

The spatially, temporally and quantitatively correct expression of a gene requires the presence not only of intact coding sequence, free of adverse nucleotide changes, but also correctly functioning regulatory control. With the identification of an increasing number of disease-related genes, the molecular defect in many cases has been defined. It is becoming clear that it is not always the transcription unit that bears the defect: there are a number of cases where the regulation of gene expression has been compromised. Cases associated with chromosomal rearrangement outside the transcription and promoter regions are categorized as position effects. A number of different mechanisms may explain their aetiology. Here, we examine the human disorders where such position effects are implicated. Further study of such cases may lead to important insights into mechanisms of gene regulation and transcriptional control.

Animals↗