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PubMed2003

Governing population genomics: law, bioethics, and biopolitics in three case studies.

Existing scholarship on population genomics has only superficially addressed issues of power and political process. Accordingly, questions of politics and governance pervade the analysis of three population genomics case studies that follow: the Human Genome Diversity Project, Iceland's Health Sector Database, and "Clinical Genomics" as defined by the Beth Israel-Ardais collaboration. An examination of these case studies reveals that the common law, U.S. regulatory law, and international law have not developed the political sophistication to make the traditional promises of biomedical ethics--respect for autonomy, justice, and beneficence--come to fruition. Further, comparisons of these projects illuminate three areas ripe for reframing--informed consent, expert ethical oversight, and commercial benefits. Four avenues of reform are suggested.

Advisory Committees↗
PubMed1999

Effect of mutations in the A site of 16 S rRNA on aminoglycoside antibiotic-ribosome interaction.

Decoding of genetic information occurs upon interaction of an mRNA codon-tRNA anticodon complex with the small subunit of the ribosome. The ribosomal decoding region is associated with highly conserved sequences near the 3' end of 16 S rRNA. The decoding process is perturbed by the aminoglycoside antibiotics, which also interact with this region of rRNA. Mutations of certain nucleotides in rRNA reduce aminoglycoside binding affinity, as previously demonstrated using a model RNA oligonucleotide system. Here, predictions from the oligonucleotide system were tested in the ribosome by mutation of universally conserved nucleotides at 1406 to 1408 and 1494 to 1495 in the decoding region of plasmid-encoded bacterial 16 S rRNA. Phenotypic changes range from the benign effect of U1406-->A or A1408-->G substitutions, to the highly deleterious 1406G and 1495 mutations that assemble into 30 S subunits but are defective in forming functional ribosomes. Changes in the local conformation of the decoding region caused by these mutations were identified by chemical probing of isolated 30 S subunits. Ribosomes containing 16 S rRNA with mutations at positions 1408, 1407+1494, or 1495 had reduced affinity for the aminoglycoside paromomycin, whereas no discernible reduction in affinity was observed with 1406 mutant ribosomes. These data are consistent with prior NMR structural determination of aminoglycoside interaction with the decoding region, and further our understanding of how aminoglycoside resistance can be conferred.

Anti-Bacterial Agents↗
PubMed1994

[Knowledge and destiny or longevity and old age: the heritage of Homo sapiens].

Several theories have been proposed to explain ageing: limitation of the number of cell divisions or Hayflick's limit, the genetic theory, the action of free radicals, immune deficiency, etc. All of these theories share several points in common: their genetic determinism or repercussions which appear to be part of the heritage of complex organisms. Progress in genetics with chromosome decoding to localise genes and genetic manipulations or control of gene expression will probably allow an increased life expectancy, perhaps in the near future.

Aged↗
PubMed1998

The Human Genome Diversity Project: medical benefits versus ethical concerns.

By the year 2005 the entire human genome should have been sequenced and the genes identified. But the resulting genomic sequence, although a marvelous accomplishment, will be a composite of just a handful of individuals selected at random. The Human Genome Diversity Project was proposed as a means to overcome these limitations by obtaining genetic information from many diverse populations of the world. This would give medical geneticists a handle on the variations in susceptibility to disease among different populations, as well as being of anthropological value. But would such a project risk exploiting the indigenous populations involved?

Bioethics↗
PubMedDate not supplied

Human tissue research in the genomic era of medicine: balancing individual and societal interests.

Advances in DNA sequencing technology and in our understanding of the human genome are ushering in a new era of genomic medicine, one with dramatic potential to not only benefit society through research involving human tissue, but also to cause economic or psychosocial harms to tissue donors and their families. This delicate situation requires that the needs of tissue donors be carefully considered and balanced with those of the medical research community, especially on issues concerning confidentiality, consent, and compensation. We analyzed the tensions between tissue donors and researchers over the research use of human tissue. We also reviewed several approaches, including the establishment of tissue-trustee infrastructures at academic medical centers, aimed at achieving a more equitable balance between individual donor protection and societal benefits derived from tissue-based research. Arch Intern Med. 2000;160:3377-3384.

Academic Medical Centers↗
PubMed2004

Genetically modified mice: tools to decode the functions of connexins in the heart-new models for cardiovascular research.

It has long been known that gap junctions are required for the propagation of electrical impulse in the heart. A good deal later, the connexins (Cxs), which are probably exclusive components of the junctional channels that constitute the gap junctions, were identified. More recently, the in vivo functions of cardiac Cxs have been investigated by the analysis of genetically modified mice. These studies have confirmed that Cxs are involved in cardiac impulse conduction, and, unexpectedly, in heart morphogenesis. In addition, cardiac abnormalities described in mice genetically modified for Cx genes, and those observed in certain human cardiac diseases, have been proven to be similar.

Animals↗
PubMed2005

Recent progress of structural biology of tRNA processing and modification.

Transfer RNA (tRNA) is a key molecule to decode the genetic information on mRNA to amino aicds (protein), in a ribosome. For tRNA to fulfill its adopter function, tRNA should be processed into the standard length, and be post-transcriptionally modified. This modification step is essential for the tRNA to maintain the canonical L-shaped structure, which is required for the decoding function of tRNA. Otherwise, it has recently been proposed that modification procedure itself contributes to the RNA (re)folding, where the modification enzymes function as a kind of RNA chaperones. Recent genome analyses and post-genome (proteomics and transcriptomics) analyses have identified genes involved in the tRNA processings and modifications. Furthermore, post-genomic structural analysis has elucidated the structural basis for the tRNA maturation mechanism. In this paper, the recent progress of the structural biology of the tRNA processing and modification is reviewed.

Amino Acyl-tRNA Synthetases↗
PubMed1990

Suppression and the code: beyond codons and anticodons.

Specificity and accuracy in the decoding of genetic information during mRNA-programmed, ribosome-dependent polypeptide synthesis (translation) involves more than just hydrogen bonding between two anti-parallel trinucleotides, the mRNA codon and the tRNA anticodon. Other macromolecules are also involved, and translational suppression has been and continues to be an appropriate and effective way to identify them, as well as other parts of mRNA and tRNA, and to elucidate the structural determinants of their functions and interactions. Experimental results are presented that bear upon codon context effects, the role of tRNA structural features in aminoacyl-tRNA selection and in codon selection (reading-frame maintenance), determinants of tRNA identity, elongation factor suppressor mutants, and termination codon recognition by the ribosomal RNA of the small subunit. The examples presented illustrate the complexity of the decoding process and the interconnectedness of translational macromolecules in achieving specificity and accuracy in polypeptide synthesis.

Anticodon↗
PubMed2003

Association of an aminoacyl-tRNA synthetase with a putative metabolic protein in archaea.

Aminoacyl-tRNA synthetases are essential enzymes that catalyze attachment of amino acids to tRNAs for decoding of genetic information. In higher eukaryotes, several synthetases associate with non-synthetase proteins to form a high-molecular mass complex that may improve the efficiency of protein synthesis. This multi-synthetase complex is not found in bacteria. Here we describe the isolation of a non-synthetase protein from the archaeon Methanocaldococcus jannaschii that was copurified with prolyl-tRNA synthetase (ProRS). This protein, Mj1338, also interacts with several other tRNA synthetases and has an affinity for general tRNA, suggesting the possibility of forming a multi-synthetase complex. However, unlike the non-synthetase proteins in the eukaryotic complex, the protein Mj1338 is predicted to be a metabolic protein, related to members of the family of H(2)-forming N(5),N(10)-methylene tetrahydromethanopterin (5,10-CH(2)-H(4)MP) dehydrogenases that are involved in the one-carbon metabolism of the archaeon. The association of Mj1338 with ProRS, and with other components of the protein synthesis machinery, thus suggests the possibility of a closer link between metabolism and decoding in archaea than in eukarya or bacteria.

Amino Acid Sequence↗
PubMed1985

[Formation and genetic structure of polylysogens for lambda and phi 80 and their lambda att80 hybrid infecting wild-type Escherichia coli].

The frequency of polylysogeny and the genetic structure of polylysogens were studied for phages lambda, phi 80 and lambda att80. For none of these phages does frequency of polylysogeny vary by more than a factor of 2 within a wide range of multiplicities of infection (from 10(-3) up to 10) but the relative location of the prophages on the host chromosome is different. In the case of lambda, polylysogens are formed with a high frequency (0.20-0.41) and the prophages are inserted in tandem into the primary (normal) att site. In the case of phi 80 and lambda att80, polylysogens occur about 10 times less frequently and usually have one prophage inserted into the primary attachment site and another (sometimes, also a third) in one of the secondary ones. Wild-type Escherichia coli was shown to possess at least four secondary att80 sites, two of which (close to the his and tolC loci) are preferred. The frequency of secondary integration of phi 80 and lambda att80 does not differ significantly in the wild-type host and in cells deleted for the primary att site (0.041 and 0.045, respectively, among surviving cells at MOI 10). Certain properties of the phi 80 lysogens make it more difficult to decode their genetic structure.

Attachment Sites, Microbiological↗
PubMed2000

Lessons from knockout and transgenic mice for infertility in men.

This review concentrates on the clear cases where knocking out a gene in mice has caused male infertility and thus comes near to proving that the gene plays a role in the development of sperm. Knockout mice have been created with primary defects at every stage of spermatogenesis thus creating a framework for decoding the genetic hierarchy that causes male germ cell differentiation. As well as defining essential genes in vivo experiments have defined promoter and untranslated sequences responsible for the expression of proteins at all the spermatogenic stages. In conclusion knockout mice remain the ultimate test of spermatogenic hypotheses as well as providing detailed information about this complex process.

Animals↗