Biomedical subjects

Edward N Trifonov

Publications and source records attributed to Edward N Trifonov.

At least 19 recordsLinked to original sources

PubMed2006

Protein modules conserved since LUCA.

Universal scale of the sequence conservation has been recently introduced based on omnipresence of the protein sequence motifs across species. A large spectrum of short sequences, up to eight residues has been found to reside in all or almost all prokaryotic organisms. By this discovery a principally novel quantitative approach is introduced to the problem of reconstruction of the last universal common ancestor (LUCA). The most conserved elements (protein modules) with defined structures and sequences harboring the omnipresent motifs are outlined in this work, by combining the sequence and protein crystal structure data. The structurally conserved modules involve 25-30 amino acid residues and have appearance of closed loops, loop-n-lock structures. This confirms earlier conclusions on the loop-fold structure of globular proteins. Many of the topmost conserved modules represent the primary closed loop prototypes, that have been derived by whole genome sequence searches. The data presented, thus, make a basis for further developments toward the earliest stages of protein evolution.

Amino Acid Sequence↗

PubMed2006

Specific selection pressure at the third codon positions: contribution to 10- to 11-base periodicity in prokaryotic genomes.

Prokaryotic sequences are responsible for more than just protein coding. There are two 10- to 11-base periodical patterns superimposed on the protein coding message within the same sequence. Positional auto- and cross-correlation analysis of the sequences shows that these two patterns are a short-range counter-phase oscillation of AA and TT dinucleotides and a medium-range in-phase oscillation of the same dinucleotides, spanning distances of up to approximately 30 and approximately 100 bases, respectively. The short-range oscillation is encoded by the amino acid sequences themselves, apparently, due to the presence of amphipathic alpha-helices in the proteins. The medium-range oscillation, related to DNA folding in the cell, is created largely by a special choice of the bases in the third positions of the codons. Interestingly, the amino acid sequences do contribute to that signal as well. That is, the very amino acid sequences are, to some extent, degenerate to serve the same oscillating pattern that is associated with the degenerate third codon positions.

Amino Acid Sequence↗

PubMed2006

Walking through protein sequence space.

Following the original idea of Maynard Smith on evolution of the protein sequence space, a novel tool is developed that allows the "space walk", from one sequence to its likely evolutionary relative and further on. At a given threshold of identity between consecutive steps, the walks of many steps are possible. The sequences at the ends of the walks may substantially differ from one another. In a sequence space of randomized (shuffled) sequences the walks are very short. The approach opens new perspectives for protein evolutionary studies and sequence annotation.

ATP-Binding Cassette Transporters↗

PubMed2006

The features of Drosophila core promoters revealed by statistical analysis.

BACKGROUND: Experimental investigation of transcription is still a very labor- and time-consuming process. Only a few transcription initiation scenarios have been studied in detail. The mechanism of interaction between basal machinery and promoter, in particular core promoter elements, is not known for the majority of identified promoters. In this study, we reveal various transcription initiation mechanisms by statistical analysis of 3393 nonredundant Drosophila promoters. RESULTS: Using Drosophila-specific position-weight matrices, we identified promoters containing TATA box, Initiator, Downstream Promoter Element (DPE), and Motif Ten Element (MTE), as well as core elements discovered in Human (TFIIB Recognition Element (BRE) and Downstream Core Element (DCE)). Promoters utilizing known synergetic combinations of two core elements (TATA_Inr, Inr_MTE, Inr_DPE, and DPE_MTE) were identified. We also establish the existence of promoters with potentially novel synergetic combinations: TATA_DPE and TATA_MTE. Our analysis revealed several motifs with the features of promoter elements, including possible novel core promoter element(s). Comparison of Human and Drosophila showed consistent percentages of promoters with TATA, Inr, DPE, and synergetic combinations thereof, as well as most of the same functional and mutual positions of the core elements. No statistical evidence of MTE utilization in Human was found. Distinct nucleosome positioning in particular promoter classes was revealed. CONCLUSION: We present lists of promoters that potentially utilize the aforementioned elements/combinations. The number of these promoters is two orders of magnitude larger than the number of promoters in which transcription initiation was experimentally studied. The sequences are ready to be experimentally tested or used for further statistical analysis. The developed approach may be utilized for other species.

Animals↗

PubMed2006

Primordia vita. Deconvolution from modern sequences.

Evolution of the triplet code is reconstructed on the basis of consensus temporal order of appearance of amino acids. Several important predictions are confirmed by computational sequence analyses. The earliest amino acids, alanine and glycine, have been encoded by GCC and GGC codons, as today. They were succeeded, respectively, by A- and G-series of amino acids, encoded by pyrimidine-central and purine-central codons. The length of the earliest proteins is estimated to be 6-7 residues. The earliest mRNAs were short G+C-rich molecules. These short sequences could have formed hairpins. This is confirmed by analysis of modern prokaryotic mRNA sequences. Predominant size of detected ancient hairpins also corresponds to 6-7 amino acids, as above. Vestiges of last common ancestor can be found in extant proteins in form of entirely conserved short sequences of size six to nine residues present in all or almost all sequenced prokaryotic proteomes (omnipresent motifs). The functions of the topmost conserved octamers are not involved in the basic elementary syntheses. This suggests an initial abiotic supply of amino acids, bases and sugars.

Base Sequence↗

PubMed2006

Self-inflicted fear of evolution.

Commonly calculated zero probabilities for synthesis of a given protein sequence by chance are that small because the sizes of the proteins taken for the calculations are too large (over 100 residues). Same estimate for 20-30 residue chains makes the chance close to 1.

Evolution, Molecular↗

PubMed2006

Three sequence rules for chromatin.

Extensive DNA sequence analysis of three eukaryotes, S. cerevisiae, C. elegans, and D. melanogaster, reveals two different AA/TT periodical patterns associated with the nucleosome positioning. The first pattern is the counter-phase oscillation of AA and TT dinucleotides, which has been frequently considered as the nucleosome DNA pattern. This represents the sequence rule I for chromatin structure. The second pattern is the in-phase oscillation of the AA and TT dinucleotides with the same nucleosome DNA period, 10.4 bases. This pattern apparently corresponds to curved DNA, that also participates in the nucleosome formation, and represents the sequence rule II for chromatin. The positional correlations of AA and TT dinucleotides also indicate that the nucleosomes are separated by specific linker sizes (preferably 8, 18, ... bases), dictated by the steric exclusion rules. Thus, the sequence positions of the neighboring nucleosomes are correlated, and this represents the sequence rule III.

Animals↗

PubMed2006

Sequence structure of human nucleosome DNA.

Positional distributions of various dinucleotides in experimentally derived human nucleosome DNA sequences are analyzed. Nucleosome positioning in this species is found to depend largely on GG and CC dinucleotides periodically distributed along the nucleosome DNA sequence, with the period of 10.4 bases. The GG and CC dinucleotides oscillate counterphase, i.e., their respective preferred positions are shifted about a half-period from one another, as it was observed earlier for AA and TT dinucleotides. Other purine-purine and pyrimidine-pyrimidine dinucleotides (RR and YY) display the same periodical and counterphase pattern. The dominance of oscillating GG and CC dinucleotides in human nucleosomes and the contribution of AG(CT), GA(TC), and AA(TT) suggest a general nucleosome DNA sequence pattern - counterphase oscillation of RR and YY dinucleotides. AA and TT dinucleotides, commonly accepted as major players, are only weak contributors in the case of human nucleosomes.

Humans↗

PubMed2006

Tracing ancient mRNA hairpins.

From recent developments of the early evolution theory it follows that the earliest mRNAs were short ( approximately 20 nt) (G+C)-rich polynucleotides. These short sequences could form hairpins, which would be of high evolutionary advantage because of stability and uniqueness of their conformations. Due to mutations accumulated during billions of years of evolution, the speculated earliest hairpins would largely lose the initial complementarities. Some of the original complementary base-to-base contacts, however, may have survived. Computational analysis of modern prokaryotic mRNA sequences reveals excess population of the expected short range complementarities. The derived earliest mRNA hairpin size fully corresponds to the predicted size of ancient coding duplexes. The repertoire of the surviving hairpins traced in modern mRNA confirms duplex structure of the earliest mRNA, suggested by the early molecular evolution theory.

Bacteria↗

PubMed2005

Conserved sequences of prokaryotic proteomes and their compositional age.

A full repertoire of octapeptides which are present in at least 30 bacterial proteomes of total 131 currently available is computationally derived and filtered. An original search technique is used that, in terms of computational time and memory, is similar to the Suffix tree method. The presence of a given sequence in a large number of proteomes qualifies it as a conserved sequence. The larger the number of proteomes where it is found, the higher is the conservation. The concept of compositional age of the amino acid sequences ("compositional clock") is introduced for the first time. The compositional age is calculated on the basis of the consensus temporal order of appearance of amino acids in early evolution. The correlation between the compositional age and the sequence conservation is established.

Amino Acid Sequence↗

PubMed2005

Gene splice sites correlate with nucleosome positions.

Gene sequences in the vicinity of splice sites are found to possess dinucleotide periodicities, especially RR and YY, with the period close to the pitch of nucleosome DNA. This confirms previously reported findings about preferential positioning of splice junctions within the nucleosomes. The RR and YY dinucleotides oscillate counter-phase, i.e., their respective preferred positions are shifted about half-period from one another, as it was observed earlier for AA and TT dinucleotides. Species specificity of nucleosome positioning DNA pattern is indicated by the predominant use of the periodical GG(CC) dinucleotides in human and mouse genes, as opposed to predominant AA(TT) dinucleotides in Arabidopsis and C. elegans.

Alternative Splicing↗

PubMed2005

Sequence structure of van der Waals locks in proteins.

Recent works has suggested that proteins in early evolution have gone through a stage of closed loop elements with a typical contour size of 25-35 residues. These closed loops are still the elementary protein units to these days, and can be used to spell out protein sequence/structure relationship through a relatively small number of protein prototypes. In this study we aimed to identify the sequences that are used to lock the loop ends to one another, and to show how an extensive dictionary of such locking pairs can be created using positional correlation data from a large proteome database, and structural data from PDB databases. Such a dictionary can be used in reconstructing the evolutionary pathway the modern proteins have gone through, and in identifying closed loop elements in modern proteins with yet unknown 3D structure.

Amino Acid Motifs↗

PubMed2005

Closed loops of TIM barrel protein fold.

The closed loops within the proteins of the TIM-barrel fold family are analyzed and compared sequence- and structure-wise. The size distribution of the closed loops of the TIM-barrels confirms universal preference to the standard size of 25-30 residues. 3D structural RMSD comparisons of the closed loops and presentation of their sequences in binary form suggest that the TIM-barrel proteins are built from descendants of several types of basic closed loop prototypes. Comparison of these prototypes points to a likely common ancestor--the alpha helix containing closed loops of 28 amino acids. The presumed ancestor is characterized by specific binary consensus sequence.

Amino Acid Sequence↗

PubMed2005

Yeast nucleosome DNA pattern: deconvolution from genome sequences of S. cerevisiae.

Positional correlation analysis for the complete genome of Saccharomyces cerevisiae is performed with the aim to reveal possible chromatin-related sequence features. A strong periodicity with the period 10.4 bases is detected in the distance histograms for the dinucleotides AA and TT, with the characteristic decay distance of approximately 50 base pairs. The oscillations are observed as well in the distributions of other dinucleotides. However, the respective amplitudes are small, consistent with secondary effects, due to dominant periodicity of AA and TT. The observations are in accord with earlier data on the chromatin sequence periodicities and nucleosome DNA sequence patterns. The autocorrelations of AA and TT dinucleotides in yeast include also a counter-phase component. A tentative DNA sequence pattern for the yeast nucleosomes is suggested and verified by comparison of its autocorrelation plots with the respective natural autocorrelations. The nucleosome mapping guided by the pattern is in accord with experimental data on the linker length distribution in yeast.

Algorithms↗

PubMed2004

Sequence periodicity of Escherichia coli is concentrated in intergenic regions.

BACKGROUND: Sequence periodicity with a period close to the DNA helical repeat is a very basic genomic property. This genomic feature was demonstrated for many prokaryotic genomes. The Escherichia coli sequences display the period close to 11 base pairs. RESULTS: Here we demonstrate that practically only ApA/TpT dinucleotides contribute to overall dinucleotide periodicity in Escherichia coli. The noncoding sequences reveal this periodicity much more prominently compared to protein-coding sequences. The sequence periodicity of ApC/GpT, ApT and GpC dinucleotides along the Escherichia coli K-12 is found to be located as well mainly within the intergenic regions. CONCLUSIONS: The observed concentration of the dinucleotide sequence periodicity in the intergenic regions of E. coli suggests that the periodicity is a typical property of prokaryotic intergenic regions. We suppose that this preferential distribution of dinucleotide periodicity serves many biological functions; first of all, the regulation of transcription.

Base Composition↗

PubMed2003

Dinucleosome DNA of human K562 cells: experimental and computational characterizations.

Dinucleosome formation is the first step in the organization of the higher order chromatin structure. With the ultimate aim of elucidating the dinucleosome structure, we constructed a library of human dinucleosome DNA. The library consists of PCR-amplifiable DNA fragments obtained by treatment of nuclei of erythroid K562 cells with micrococcal nuclease followed by extraction of DNA and adaptor ligation to the blunt-ended DNA fragments. The library was then cloned using a plasmid vector and the sequences of the clones were determined. The dominating clones containing the Alu elements were removed. A total of 1002 clones, which comprised a dinucleosome database, contained 84 and 918 clones from the clones before and after removing Alu elements, respectively. Approximately 70% of the clones were between 300 and 400 bp in size and they were distributed to various locations of all chromosomes except the Y chromosome. The clones containing A(2)N(8)A(2)N(8)A(2) or T(2)N(8)T(2)N(8)T(2) sequences were classified into three types, Type I (N shape), Type II (V shape) and Type III (M shape) according to DNA curvature plots. The locations of experimentally determined curved DNA segments matched well with the calculated ones though the clones of Types I and III showed additional curved DNA segments as revealed by the curvature plots. The distributions of complementary dinucleotides in the nucleosome DNA, at the ends of the dinucleosome DNA clones, allowed us to predict the positions of the nucleosome dyad axis, and estimate the size of the nucleosome core DNA, 125nt. The distributions of AA and TT dinucleotides, as well as other RR and YY dinucleotides, showed a periodicity with an average period of 10.4 bases, close to the values observed before. Mapping of nucleosome positions in the dinucleosome database based on the observed periodicity revealed that the nucleosomes were separated by a linker of 7.5+ approximately 10 x n nt. This indicates that the nucleosome-nucleosome orientations are, typically, halfway between parallel and antiparallel. Also an important finding is that the distributions of AA/TT and other RR/YY dinucleotides, apparently, reflect both DNA curvature and DNA bendability, cooperatively contributing to the nucleosome formation.

Base Sequence↗

PubMed2003

Hidden messages in the nef gene of human immunodeficiency virus type 1 suggest a novel RNA secondary structure.

The coexistence of multiple codes in the genome of human immunodeficiency virus type 1 (HIV-1) was analyzed. We explored factors constraining the variability of the virus genome primarily in relation to conserved RNA secondary structures overlapping coding sequences, and used a simple combination of algorithms for RNA secondary structure prediction based on the nearest-neighbor thermodynamic rules and a statistical approach. In our previous study, we applied this combination to a non- redundant data set of env nucleotide sequences, confirmed the conservative secondary structure of the rev-responsive element (RRE) and found a new RNA structure in the first conserved (C1) region of the env gene. In this study, we analyzed the variability of putative RNA secondary structures inside the nef gene of HIV-1 by applying these algorithms to a non-redundant data set of 104 nef sequences retrieved from the Los Alamos HIV database, and predicted the existence of a novel functional RNA secondary structure in the beta3/beta4 regions of nef. The predicted RNA fold in the beta3/beta4 region of nef appears in two forms with different loop sizes. The loop of the first fold consists of seven nucleotides (positions 494-500), with consensus UCAAGCU appearing in 79% of sequences. The other has a five-base loop (positions 495-499) with consensus CAAGC. The difference in size between these two loops may reflect the difference between respective counterparts in the hairpin recognition. This may also have an adaptive biological significance.

Algorithms↗

PubMed2003

Evolutionary aspects of protein structure and folding.

The traditional reconstruction of molecular events of the past based on sequence conservation becomes very vague beyond one to two billion years ago. There are certain molecular features, however, such as polymer flexibility and loop closure, that are conserved merely because of their physical nature. This allows one to penetrate the earliest stages of protein evolution.

Amino Acid Sequence↗