Biomedical subjects

Andrei S Rodin

Publications and source records attributed to Andrei S Rodin.

7 recordsLinked to original sources

PubMed2006

Origin of the genetic code: first aminoacyl-tRNA synthetases could replace isofunctional ribozymes when only the second base of codons was established.

Analysis of the updated compilation of more than 8,000 tRNA gene sequences confirmed our previously reported finding that in pairs of consensus tRNAs with complementary anticodons, their second bases in the acceptor stems are also complementary. This dual complementarity points to the following: (1) the operational code embodied in the acceptor stem, and the classic genetic code embodied in the anticodon could have had the same common ancestor; (2) new tRNAs most likely entered primitive translation in pairs with complementary anticodons; and (3) this process of code expansion was directed by the primordial double-strand coding. However, we did not find the dual complementarity when testing all tRNA pairs in which anticodons were complementary only at the central position, but not complementary at least at one of the flanking two positions. This observation, together with certain additional evidence, suggests that both codes were still being shaped (with only the second base established at the time) when the first protein aminoacyl-tRNA synthetases could have already started replacing their ribozymic precursors.

Amino Acyl-tRNA Synthetases↗

PubMed2006

Partitioning of aminoacyl-tRNA synthetases in two classes could have been encoded in a strand-symmetric RNA world.

The "chicken-or-egg" dilemma dictates that archaic tRNAs be aminoacylated by ribozymic aminoacyl-tRNA synthetases, rAARSs, with protein synthetases (pAARSs) emerging later and, strikingly in two versions. However, the distribution of these two versions among the codons also suggests their involvement in development of the genetic code. Here we propose a solution to this controversy, which relies on a primordial complementarity hypothesis that in a strand-symmetric RNA world both complementary replicas of many genes could encode the first proteins. Accordingly, if one rearranges the code table in a manner that puts complementary codons directly against each other, an almost perfect mirror symmetry in tRNA aminoacylation by the two groups of synthetases is revealed. Specifically, the pairs of complementary anticodons from the same pAARS class tend to contain RR and YY dinucleotides at first and second versus third and second positions, whereas in pairs of pAARSs from the different classes these positions are occupied by YR and RY, including CG, GC, UA, and AU palindromes. The latter are indistinguishable in complementary anticodons, thus leading to erroneous aminoacylation (note that there is no such problem for RR- and YY-containing complementary anticodons). This can be averted by "spreading out" tRNA recognition by two rAARSs away from the anticodons in the opposite directions, giving two complementary rAARSs. The principle of evolutionary continuity suggests that their protein successors also arose on complementary strands. Our analyses support this hypothesis.

Amino Acid Sequence↗

PubMed2005

Mining genetic epidemiology data with Bayesian networks I: Bayesian networks and example application (plasma apoE levels).

MOTIVATION: The wealth of single nucleotide polymorphism (SNP) data within candidate genes and anticipated across the genome poses enormous analytical problems for studies of genotype-to-phenotype relationships, and modern data mining methods may be particularly well suited to meet the swelling challenges. In this paper, we introduce the method of Belief (Bayesian) networks to the domain of genotype-to-phenotype analyses and provide an example application. RESULTS: A Belief network is a graphical model of a probabilistic nature that represents a joint multivariate probability distribution and reflects conditional independences between variables. Given the data, optimal network topology can be estimated with the assistance of heuristic search algorithms and scoring criteria. Statistical significance of edge strengths can be evaluated using Bayesian methods and bootstrapping. As an example application, the method of Belief networks was applied to 20 SNPs in the apolipoprotein (apo) E gene and plasma apoE levels in a sample of 702 individuals from Jackson, MS. Plasma apoE level was the primary target variable. These analyses indicate that the edge between SNP 4075, coding for the well-known epsilon2 allele, and plasma apoE level was strong. Belief networks can effectively describe complex uncertain processes and can both learn from data and incorporate prior knowledge. AVAILABILITY: Various alternative and supplemental networks (not given in the text) as well as source code extensions, are available from the authors. SUPPLEMENTARY INFORMATION: http://bioinformatics.oxfordjournals.org.

Apolipoproteins E↗

PubMed2005

Origins and selection of p53 mutations in lung carcinogenesis.

Molecular epidemiologists usually consider the spectrum of p53 mutations found in human tumors to be a signature of the corresponding environmental carcinogen(s). In lung cancer, this signature is the spectrum of G --> T transversions, presumably induced by polycyclic aromatic hydrocarbons (PAH) from cigarette smoke. What complicates the situation, however, is that in the p53 gene the same codons are preferential targets for not only mutagenesis but also tumorigenic selection. In this review, we compare the G --> T spectra induced by PAH o-quinones and diol epoxides with those in lung cancer and show that the main "shaper" of the latter is selection, not mutagenesis. In addition, we propose the approach that allows to distinguish selection and mutagenesis components of the p53 spectra and, therefore, to test the suspect carcinogens for their "in vivo" mutagenic involvement. Collectively, the reviewed basic premises, concepts and data are consistent with the increasing recognition of environmental cancer risk conditions as selecting rather than inducing tumorigenic mutations.

Humans↗

PubMed2005

Repositioning-dependent fate of duplicate genes.

Gene duplication is the main source of evolutionary novelties. However, the problem with duplicates is that the purifying selection overlooks deleterious mutations in the redundant sequence, which therefore, instead of gaining a new function, often degrades into a functionless pseudogene. This risk of functional loss instead of gain is much higher for small populations of higher organisms with a slow and complex development. We propose that it is the epigenetic tissue/stage-complementary silencing of duplicates that makes them exposable to the purifying selection, thus saving them from pseudogenization and opening the way towards new function(s). Our genome-wide analyses of gene duplicates in several eukaryotic species combined with the phylogenetic comparison of vertebrate alpha- and beta-globin gene clusters strongly support this epigenetic complementation (EC) model. The distinctive condition for a new duplicate to survive by the EC mechanism seems to be its repositioning to an ectopic site, which is accompanied by changes in the rate and direction of mutagenesis. The most distinguished in this respect is the human genome. In this review, we extend and discuss the data on the EC- and repositioning-dependent fate of gene duplicates with the special emphasis on the problem of detecting brief postduplication period of adaptive evolution driven by positive selection. Accordingly, we propose a new CpG-focused measure of selection that is insensitive to translocation-caused biases in mutagenesis.

Animals↗

PubMed2004

On the excess of G --> T transversions in the p53 gene in lung cancer cell lines. Reply to Pfeifer and Hainaut.

Our recent retrospective analysis of the lung cancer-associated p53 mutation data [Mutat. Res. 508 (2002) 1] showed the possibility of (i) inhibiting action of tobacco smoke on repair of G --> T primary lesions in the non-transcribed strand of the p53 gene and (ii) the origin of new p53 mutations, predominantly G --> T transversions, in lung cancer cell lines apparently unexposed to tobacco smoke. In summary, our arguments suggest that (i) in addition to polycyclic aromatic hydrocarbons (PAH)-DNA adducts there exist other lung cancer-specific, rather than smoke-specific sources of G --> T transversions and (ii) a direct mutagenic action is not the only smoke-associated cause of the prevalence of this class of p53 mutations in lung cancer. In the subsequent critical commentary [Mutat. Res. 526 (2003) 39], Pfeifer and Hainaut suggested our arguments to be "incompatible with available evidence". We would like to address their critique, and appreciate the editors of Mutation Research giving us an opportunity to do so.

Humans↗

PubMed2004

Defining relationships between the known members of the cytochrome P450 3A subfamily, including five putative chimpanzee members.

An analysis of the cytochrome P450 3A subfamily (CYP3A) was undertaken in order to define relationships across species among subfamily members. Some members were excluded due to incomplete sequences, while others were held in abeyance because of their almost complete homology. This is the first publication of five chimpanzee CYP3A genes-CYP3A4, CYP3A5, CYP3A7, CYP3A43, and CYP3A67. This project utilized two approaches for characterizing possible relationships-phylogenetic analysis and genomic structure. For the phylogenetic analysis, both nucleotide and amino acid sequences were aligned in silico using the CLUSTAL algorithm, and then visually inspected for accuracy. Three different computer software packages were utilized: MEGA 2.1, TREECON 1.3b, and PHYLIP 3.5. Multiple methods were used: neighbor-joining (NJ), minimum evolution (ME), maximum parsimony (MP), and maximum likelihood (ML). The resulting topologies were compared against each other to define the consensus topology. In addition, the chimpanzee, human, mouse, and rat genome databases were searched for intron/exon information pertaining to the included genes. Both methods suggest the same conclusion, defining orthologs is plausible between similar species (i.e., mouse and rat), but is less useful between species of different orders (i.e., primate and rodent) or classes (i.e., mammal and avian).

Animals↗