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PubMed1991

RNA minihelices and the decoding of genetic information.

The rules of the genetic code are determined by the specific aminoacylation of transfer RNAs by aminoacyl transfer RNA synthetase. A straightforward analysis shows that a system of synthetase-tRNA interactions that relies on anticodons for specificity could, in principle, enable most synthetases to distinguish their cognate tRNA isoacceptors from all others. Although the anticodons of some tRNAs are recognition sites for the cognate aminoacyl tRNA synthetases, for other synthetases the anticodon is dispensable for specific aminoacylation. In particular, alanine and histidine tRNA synthetases aminoacylate small RNA minihelices that reconstruct the part of their cognate tRNAs that is proximate to the amino acid attachment site. Helices with as few as six base pairs can be efficiently aminoacylated. The specificity of aminoacylation is determined by a few nucleotides and can be converted from one amino acid to another by the change of only a few nucleotides. These findings suggest that, for a subgroup of the synthetases, there is a distinct code in the acceptor helix of transfer RNAs that determines aminoacylation specificity.

Amino Acyl-tRNA Synthetases↗
PubMed2000

Iceland's plan for genomics research: facts and implications.

The government of Iceland has authorized a private, for-profit firm, deCODE Genetics, to construct a database of the population's medical records as part of a larger plan by deCODE for human genetics research. This article presents the background for genetics research in Iceland, the history of deCODE, and the terms of the law authorizing the database. It then examines five objections to the law, based on commercialization, lack of informed consent, risks to privacy, the effects of other research, and financial unfairness. It concludes that the Icelandic model is not a good precedent for similar research elsewhere.

Confidentiality↗
PubMed2006

Alignment/misalignment hypothesis for tRNA selection by the ribosome.

Transfer RNAs (tRNAs) are the adaptor molecules that allow the ribosome to decode genetic information during protein synthesis. During decoding, the ribosome must chose the tRNA whose anticodon corresponds to the codon inscribed in the messenger RNA to incorporate the correct amino acid into the growing polypeptide chain. Fidelity is improved dramatically by a GTP hydrolysis event. Information about the correctness of the anticodon must be sent from the decoding center to the elongation factor, EF-Tu, where the GTP hydrolysis takes place. A second discrimination event entails the accommodation of the aminoacyl-tRNA into its fully bound A/A state inside the ribosome. Here, we present a hypothesis for a specific mechanism of signal transduction through the tRNA, which operates during GTPase activation and accommodation. We propose that the rigidity of the tRNA plays an important role in the transmission of the decoding signal. While the tRNA must flex during binding and accommodation, its anisotropic stiffness enables precise positioning of the acceptor arm in the A/T state, the A/A state and the accommodation corridor. Correct alignment will result in optimal GTPase activation and accommodation rates. Incorrect tRNAs, however, whose anticodons are misaligned, will also have acceptor arms that are misaligned, resulting in sub-optimal GTPase activation and accommodation rates. In the case of GTPase activation, it is possible that the misalignment of the acceptor arm affects the rate directly, by altering the conformational change of the switch region of EF-Tu, or indirectly, by changing the alignment of EF-Tu with respect to the sarcin-ricin loop (SRL) of the large ribosomal subunit.

Anticodon↗
PubMed2004

Genomic research and data-mining technology: implications for personal privacy and informed consent.

This essay examines issues involving personal privacy and informed consent that arise at the intersection of information and communication technology (ICT) and population genomics research. I begin by briefly examining the ethical, legal, and social implications (ELSI) program requirements that were established to guide researchers working on the Human Genome Project (HGP). Next I consider a case illustration involving deCODE Genetics, a privately owned genetic company in Iceland, which raises some ethical concerns that are not clearly addressed in the current ELSI guidelines. The deCODE case also illustrates some ways in which an ICT technique known as data mining has both aided and posed special challenges for researchers working in the field of population genomics. On the one hand, data-mining tools have greatly assisted researchers in mapping the human genome and in identifying certain "disease genes" common in specific populations (which, in turn, has accelerated the process of finding cures for diseases tha affect those populations). On the other hand, this technology has significantly threatened the privacy of research subjects participating in population genomics studies, who may, unwittingly, contribute to the construction of new groups (based on arbitrary and non-obvious patterns and statistical correlations) that put those subjects at risk for discrimination and stigmatization. In the final section of this paper I examine some ways in which the use of data mining in the context of population genomics research poses a critical challenge for the principle of informed consent, which traditionally has played a central role in protecting the privacy interests of research subjects participating in epidemiological studies.

Computational Biology↗
PubMed2004

"Iceland Inc."?: On the ethics of commercial population genomics.

A detailed analysis of the Icelandic commercial population-wide genomics database project of deCODE Genetics was performed for the purpose of providing ethics insights into public/private efforts to develop genetic databases. This analysis examines the moral differences between the general case of governmental collection of medical data for public health purposes and the centralized collection planned in Iceland. Both the process of developing the database and its design vary in significant ways from typical government data collection and analysis activities. Because of these differences, the database may serve the interests of deCODE more than it serves the interests of the public, undermining the claim that presumed consent for this data collection and its proprietary use is ethical. We believe that there is an evolving consensus that informed consent of participants must be secured for population-based genetics databases and research. The Iceland model provides an informative counterexample that holds key ethics lessons for similar ventures.

Databases, Genetic↗
PubMed2005

A male-specific quantitative trait locus on 1p21 controlling human stature.

BACKGROUND: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. OBJECTIVE: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. METHODS: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. RESULTS: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. CONCLUSIONS: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.

Adult↗
PubMed1992

DNA probes and automation.

Current methods for DNA probe analysis in principle provide access to the total genetic information of any organism and permit applications in health care, for example. In practice, however, greatly improved efficiency of methods for decoding genetic information is required for both research and routine applications. This review describes recent progress towards automated DNA probe assays.

Automation↗
PubMed1998

Population genomics: laying the groundwork for genetic disease modeling and targeting.

The family has proven the most appropriate unit with which to study Mendelian diseases. There are, however, certain limitations on the use of the family as a fundamental unit in the study of common diseases, most of which are complex genetic diseases. The groups that are most likely to yield the genetics of complex diseases are isolated populations with strong founder effects. Therefore, access to such populations is proving to be a precious resource in the work on the genetics of common diseases. The Icelandic population is an excellent population for the study of the genetics of common diseases; it is genetically homogeneous, with founder effects for many traits, and the genealogy of the entire nation is well documented back to the founding days. Furthermore, the nature of the Icelandic national health care system facilitates the assignment of phenotypes in the search for disease genes. Decode Genetics has begun to study of the genetics of 20 of the most common diseases in the Western parts of the world. The company has placed the groundwork for the construction of an encrypted database with information on the health care of the entire nation, genealogy of the entire nation, genotyping information with high density of markers on a large part of the nation (including typing for known disease genes), and resource use in the Icelandic health care system. The plan is to build the database with approval of participating individuals as well as Icelandic government and health care officials. The database will be used to model health care as viewed in the context of genetic predisposition to the development of disease. The database will also be used in the search for drug targets in complex diseases and in the solution of pharmacogenomic problems. Basing the company in Iceland directly benefits the population in terms of employment and return on investment as well as providing the health care system with an information resource which may be used in preventive medicine and in the optimization of health care in Iceland.

Genealogy and Heraldry↗
PubMed1996

Single sequence of a helix-loop peptide confers functional anticodon recognition on two tRNA synthetases.

The specific aminoacylation of RNA oligonucleotides whose sequences are based on the acceptor stems of tRNAs can be viewed as an operational RNA code for amino acids that may be related to the development of the genetic code. Many synthetases also have direct interactions with tRNA anticodon triplets and, in some cases, these interactions are thought to be essential for aminoacylation specificity. In these instances, an unresolved question is whether interactions with parts of the tRNA outside of the anticodon are sufficient for decoding genetic information. Escherichia coli isoleucyl- and methionyl-tRNA synthetases are closely related enzymes that interact with their respective anticodons. We used binary combinatorial mutagenesis of a 10 amino acid anticodon binding peptide in these two enzymes to identify composite sequences that would confer function to both enzymes despite their recognizing different anticodons. A single peptide was found that confers function to both enzymes in vivo and in vitro. Thus, even in enzymes where anticodon interactions are normally important for distinguishing one tRNA from another, these interactions can be 'neutralized' without losing specificity of amino-acylation. We suggest that acceptor helix interactions may play a role in providing the needed specificity.

Amino Acid Sequence↗
PubMed2003

A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval.

A family ascertained in the United States displays significant evidence of linkage to 17q25.3 (maximum two-point LOD score 6.32). The non-syndromic autosomal-dominant hearing-loss loci DFNA20 and DFNA26 map to this region. The 3-unit support interval and haplotype for this USA kindred falls within the interval for DFNA20 and DFNA26 and reduces the region to 6.05 cM, according to the deCode genetic map. The same gene is probably responsible for both DFNA20/DFNA26. In addition, the USH1G locus maps to this region and could be an allelic variant of the gene responsible for DFNA20/DFNA26. Clinical data is presented for this kindred, where hearing-impaired family members present with sloping audiograms with mid- and high-frequency hearing loss, which progresses to hearing loss that affects all frequencies. The mean age of onset of hearing impairment is 13.2 years of age (standard deviation: 4.6 years).

Adult↗
PubMed2006

Expression genetics and the phenotype revolution.

Genetic analysis of variation demands large numbers of individuals and even larger numbers of genotypes. The identification of alleles associated with Mendelian disorders has involved sample sizes of a thousand or more. Pervasive and common diseases that afflict human populations--cancer, heart disease, diabetes, neurodegeneration, addiction--are all polygenic and are even more demanding of large numbers. DeCode Genetics (http://www.decode.com) has harnessed the human resources of Iceland to unravel genetic and molecular causes of complex disease. The UK BioBank project (http://www.ukbiobank.ac.uk/) will incorporate 500,000 adult volunteers. The murine Collaborative Cross is the experimental equivalent of these human populations and will consist of a panel of approximately 1000 recombinant strains, expandable by intercrossing to much larger numbers of isogenic but heterozygous F(1)s. Massive projects of these types require efficient technologies. We have made enormous progress on the genotyping front, and it is now important to focus energy on devising ultrahigh-throughput methods to phenotype. Molecular phenotyping of the transcriptome has matured, and it is now possible to acquire hundreds of thousands of mRNA phenotypes at a cost matching those of SNPs. Proteomic and cell-based assays are also maturing rapidly. The acquisition of a personal genome along with a personal molecular phenome will provide an effective foundation for personalized medicine. Rodent models will be essential to test our ability to predict susceptibility and disease outcome using SNP data, molecular phenomes, and environmental exposures. These models will also be essential to test new treatments in a robust systems context that accounts for genetic variation.

Animals↗
PubMed2005

Mapping of a novel autosomal recessive nonsyndromic deafness locus (DFNB46) to chromosome 18p11.32-p11.31.

Hereditary nonsyndromic deafness (NSD) is extremely heterogeneous. Autosomal recessive (AR) forms account for approximately 75% of genetic cases. To date, over 40 ARNSD loci have been mapped. A novel locus (DFNB46) for ARNSD was mapped to chromosome 18p11.32-p11.31 in a five-generation Pakistani family. A 10 cM genome-wide scan and fine mapping was carried out using microsatellite markers. A maximum multipoint LOD score of 3.8 was obtained at two markers, D18S481 and D18S1370. The three-unit support interval is flanked by markers D18S59 and D18S391, corresponds to a 17.6 cM region according to the deCode genetic map and spans 5.8 Mb on the sequence-based physical map.

Chromosome Mapping↗
PubMed2024

Genome-Wide Association Study of Accessory Atrioventricular Pathways.

IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias. DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. EXPOSURES: Sequence variants. MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs. RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

Humans↗
PubMed1983

Possible mechanism for origin of chiral specificity during origins of life.

We have earlier (Origins of Life 10 (1980), 15-30) proposed a conformational theory for the origin of nucleic acid-directed adaptor-mediated ordered and proliferative synthesis of proteins and hence origin of life. Conjunction of L-amino acids and beta-D-ribonucleotides emerges as a natural consequence of a template fitting interaction in this theory of the origin of the genetic decoding apparatus. Here we propose an interesting new concept for the origin of chiral specificity, by showing that two autonomously developing systems of protein-synthesizing machinery, one manufacturing L-peptides (L-system) and the other, D-peptides (D-system) could have arisen and during early stages of evolution L-system could have developed a killer enzyme to destroy the D-system, causing the presently existing chiral specificity in all the evolved organisms on Earth. It would be interesting to look for such 'killer enzymes' in the present-day organisms. Of course, the existence of D-amino acid-containing antibiotics gives some credence to this theory.

Genetic Code↗
PubMed2000

Prevalence and inheritance of hip osteoarthritis in Iceland.

The purpose of this study was to: (I) assess the prevalence of hip osteoarthritis (OA) in Iceland and compare it with that in Southern Scandinavia, (II) determine the incidence of total hip replacement (THR) for primary OA in Iceland, (III) compare two different methods for defining radiographic hip OA, (IV) assess in a population-wide study in Iceland the genetic contribution t hip OA leading to THR, and (V) perform a genome-wide scan of a large Icelandic family to identify a chromosomal susceptibility locus for hip OA leading to THR. many Icelandic patients with hip OA have been well aware that this disease "goes in the family". by examining a large proportion of all Icelandic colon radiographs taken 1990-1996 the prevalence of radiographic hip OA in Iceland was found to be at least five-fold higher compared to Swedish and Danish studies that have used the same methods. A comparison of two methods for estimating hip OA from colon radiographs showed that a simple quantitative method of measuring joint space was more reliable than a qualitative method. The age-standardized incidence of THR for primary hip OA in Iceland between 1982 and 1996 was estimated and found to be about 50 percent higher than for Sweden. The higher Icelandic prevalence of hip OA may explain most of this difference. To investigate the contribution of heritability to hip OA leading to THR, information from two population-wide database in Iceland was combined: A national registry of THR between 1972 and 1996, and a genealogy database of all Icelandic genealogy records for the last 11 centuries made available by deCode Genetics. The genetic contribution to THR for OA was assessed by (a) identifying familial clusters of THR for OA, (b) applying the minimum founder test (MFT) to estimate the minimum number of ancestors to account for all patients with THR for OA, compared to the average number of founders for control lists, (c) calculating an average pairwise kinship coefficient (KC) for the patient and control lists, (d) estimating the relative risk (RR) for relatives of patients with THR for OA. A large number of familial clusters of patients with THR for OA were identified. MFT showed that OA patients descended from fewer founders than the control groups. The average pairwise KC among patients with OA was greater than in the population. RR for siblings of THR for OA patients was 3.05 (2.52, 3.10). Icelandic patients with THR for OA are thus significantly more related to each other than are matched controls. These findings support a significant genetic contribution to a common form of OA and encourages the search for genes conferring an increased susceptibility to OA. New techniques now make it possible to search the whole human genome for chromosomal susceptibility loci associating with OA. A genome wide scan was done to identify susceptibility loci for hip OA leading to THR, using DNA from a large Icelandic family with a very high prevalence of primary hip OA. A genome locus with a lod score of 2.58 was identified on chromosome 16p. A similar locus has been reported on from England. This is the first instance where what may be the same susceptibility locus for OA is independently described in two different populations with hip OA. We have identified other families with hip OA which link to the studied family and are continuing an expanded genome-wide scan. Continued studies of the kind outlined here will clarify the complex genetic background of OA and identify genetic variation associated with the disease. In addition to improving our understanding of the pathogenesis of OA and identifying new molecular targets for treatment, this will allow a better insight into the interactions between genetic background and environmental factors that initiate and drive OA.

Adult↗
PubMed2006

Interrupted genes in extremophilic archaea: mechanisms of gene expression in early organisms.

Extremophilic Archaea populate biotopes previously considered inaccessible for life. This feature, and the possibility that they are the extant forms of life closest to the last common ancestor, make these organisms excellent candidates for the study of evolution on Earth and stimulate the exobiological research in planets previously considered totally inhospitable. Among the other aspects of the physiology of these organisms, the study of the molecular genetics of extremophilic Archaea can give hints on how the genetic information is transmitted and propagated in ancient forms of life. We review here the expression of interrupted genes in a recently discovered nanoarchaeon and the mechanisms of reprogrammed genetic decoding in Archaea.

Amino Acid Sequence↗
PubMed1997

The ternary complex of EF-Tu and its role in protein biosynthesis.

The past year has seen a breakthrough in our structural understanding of how aminoacyl-tRNAs are selected and transported to the ribosomal A-site in order to decode genetic information contained in messenger RNA. All aminoacyl-tRNAs are recognized by the elongation factor EF-Tu in prokaryotes or EF-1alpha in eukaryotes. The recent determination of the structure of the ternary complex of aminoacyl-tRNA, EF-Tu and a GTP analogue shows how the CCA end of all aminoacyl-tRNA structures can be accommodated in a specific binding site on EF-Tu-GTP, and how part of the T-helix can be recognized by EF-Tu in a non-sequence-specific way. Furthermore, the structure of the ternary complex shows striking structural similarity to the structure of another prokaryotic elongation factor, EF-G, the tRNA translocase, in its GDP or empty form. This observation has led to the proposal of a general macromolecular mimicry of RNA and protein, which predicts elements of RNA-like structures will occur in other translation factors, such as initiation factors and release factors, that interact with similar sites on the ribosome.

Peptide Elongation Factor Tu↗
PubMed1999

tRNA discrimination at the binding step by a class II aminoacyl-tRNA synthetase.

Aminoacyl-tRNA synthetases preserve the fidelity of decoding genetic information by accurately joining amino acids to their cognate transfer RNAs. Here, tRNA discrimination at the level of binding by Escherichia coli histidyl-tRNA synthetase is addressed by filter binding, analytical ultracentrifugation, and iodine footprinting experiments. Competitive filter binding assays show that the presence of an adenylate analogue 5'-O-[N-(L-histidyl)sulfamoyl]adenosine, HSA, decreased the apparent dissociation constant (K(D)) for cognate tRNA(His) by more than 3-fold (from 3.87 to 1.17 microM), and doubled the apparent K(D) for noncognate tRNA(Phe) (from 7.3 to 14.5 microM). By contrast, no binding discrimination against mutant U73 tRNA(His) was observed, even in the presence of HSA. Additional filter binding studies showed tighter binding of both cognate and noncognate tRNAs by G405D mutant HisRS [Yan, W., Augustine, J., and Francklyn, C. (1996) Biochemistry 35, 6559], which possesses a single amino acid change in the C-terminal anticodon binding domain. Discrimination against noncognate tRNA was also observed in sedimentation velocity experiments, which showed that a stable complex was formed with the cognate tRNA(His) but not with noncognate tRNA(Phe). Footprinting experiments on wild-type versus G405D HisRS revealed characteristic alterations in the pattern of protection and enhancement of iodine cleavage at phosphates 5' to tRNA nucleotides in the anticodon and hinge regions. Together, these results suggest that the anticodon and core regions play major roles in the initial binding discrimination between cognate and noncognate tRNAs, whereas acceptor stem nucleotides, particularly at position 73, influence the reaction at steps after binding of tRNA.

Adenosine↗