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M Borodovsky

Publications and source records attributed to M Borodovsky.

25 records · Page 2Linked to original sources

Detection of new genes in a bacterial genome using Markov models for three gene classes.

We further investigated the statistical features of the three classes of Escherichia coli genes that have been previously delineated by factorial correspondence analysis and dynamic clustering methods. A phased Markov model for a nucleotide sequence of each gene class was developed and employed for gene prediction using the GeneMark program. The protein-coding region prediction accuracy was determined for class-specific Markov models of different orders when the programs implementing these models were applied to gene sequences from the same or other classes. It is shown that at least two training sets and two program versions derived for different classes of E. coli genes are necessary in order to achieve a high accuracy of coding region prediction for uncharacterized sequences. Some annotated E. coli genes from Class I and Class III are shown to be spurious, whereas many open reading frames (ORFs) that have not been annotated in GenBank as genes are predicted to encode proteins. The amino acid sequences of the putative products of these ORFs initially did not show similarity to already known proteins. However, conserved regions have been identified in several of them by screening the latest entries in protein sequence databases and applying methods for motif search, while some other of these new genes have been identified in independent experiments.

Algorithms↗

Intrinsic and extrinsic approaches for detecting genes in a bacterial genome.

The unannotated regions of the Escherichia coli genome DNA sequence from the EcoSeq6 database, totaling 1,278 'intergenic' sequences of the combined length of 359,279 basepairs, were analyzed using computer-assisted methods with the aim of identifying putative unknown genes. The proposed strategy for finding new genes includes two key elements: i) prediction of expressed open reading frames (ORFs) using the GeneMark method based on Markov chain models for coding and non-coding regions of Escherichia coli DNA, and ii) search for protein sequence similarities using programs based on the BLAST algorithm and programs for motif identification. A total of 354 putative expressed ORFs were predicted by GeneMark. Using the BLASTX and TBLASTN programs, it was shown that 208 ORFs located in the unannotated regions of the E. coli chromosome are significantly similar to other protein sequences. Identification of 182 ORFs as probable genes was supported by GeneMark and BLAST, comprising 51.4% of the GeneMark 'hits' and 87.5% of the BLAST 'hits'. 73 putative new genes, comprising 20.6% of the GeneMark predictions, belong to ancient conserved protein families that include both eubacterial and eukaryotic members. This value is close to the overall proportion of highly conserved sequences among eubacterial proteins, indicating that the majority of the putative expressed ORFs that are predicted by GeneMark, but have no significant BLAST hits, nevertheless are likely to be real genes. The majority of the putative genes identified by BLAST search have been described since the release of the EcoSeq6 database, but about 70 genes have not been detected so far. Among these new identifications are genes encoding proteins with a variety of predicted functions including dehydrogenases, kinases, several other metabolic enzymes, ATPases, rRNA methyltransferases, membrane proteins, and different types of regulatory proteins.

Amino Acid Sequence↗

Deriving non-homogeneous DNA Markov chain models by cluster analysis algorithm minimizing multiple alignment entropy.

Non-homogeneous Markov chain models can represent biologically important regions of DNA sequences. The statistical pattern that is described by these models is usually weak and was found primarily because of strong biological indications. The general method for extracting similar patterns is presented in the current paper. The algorithm incorporates cluster analysis, multiple alignment and entropy minimization. The method was first tested using the set of DNA sequences produced by Markov chain generators. It was shown that artificial gene sequences, which initially have been randomly set up along the multiple alignment panels, are aligned according to the hidden triplet phase. Then the method was applied to real protein-coding sequences and the resulting alignment clearly indicated the triplet phase and produced the parameters of the optimal 3-periodic non-homogeneous Markov chain model. These Markov models were already employed in the GeneMark gene prediction algorithm, which is used in genome sequencing projects. The algorithm can also handle the case in which the sequences to be aligned reveal different statistical patterns, such as Escherichia coli protein-coding sequences belonging to Class II and Class III. The algorithm accepts a random mix of sequences from different classes, and is able to separate them into two groups (clusters), align each cluster separately, and define a non-homogeneous Markov chain model for each sequence cluster.

Algorithms↗

Characteristic features of the nucleotide sequences of yeast mitochondrial ribosomal protein genes as analyzed by computer program GeneMark.

The nucleotide sequence data for yeast mitochondrial ribosomal protein (MRP) genes were analyzed by the computer program GeneMark which predicts the presence of likely genes in sequence data by calculating statistical biases in the appearance of consecutive nucleotides. The program uses a set of standard sequence data for this calculation. We used this program for the analysis of yeast nucleotide sequence data containing MRP genes, hoping to obtain information as to whether they share features in common that are different from other yeast genes. Sequence data sets for ordinary yeast genes and for 27 known MRP genes were used. The MRP genes were nicely predicted as likely genes regardless of the data sets used, whereas other yeast genes were predicted to be likely genes only when the data set for ordinary yeast genes was used. The assembled sequence data for chromosomes II, III, VIII and XI as well as the segmented data for chromosome V were analyzed in a similar manner. In addition to the known MRP genes, eleven ORF's were predicted to be likely MRP genes. Thus, the method seems very powerful in analyzing genes of heterologous origins.

Base Sequence↗

Recognition of genes in DNA sequence with ambiguities.

The search for genes in a newly sequenced DNA is a well known problem. Among other factors, the gene-searching process is hampered by a number of ambiguities which may remain unresolved experimentally for a long time. A computer method that is able to predict genes in a DNA sequence containing ambiguities has been developed, based on the non-homogeneous Markov chain technique. The reliability of the method has been tested using a set of sequences generated by a Monte-Carlo procedure and a set of 425 E. coli sequences with ambiguities introduced artificially.

DNA↗

First and second moment of counts of words in random texts generated by Markov chains.

An exact expression for the variance of random frequency that a given word has in text generated by a Markov chain is presented. The result is applied to periodic Markov chains, which describe the protein-coding DNA sequences better than simple Markov chains. A new solution to the problem of word overlap is proposed. It was found that the expected frequency and overlapping properties determine most of the variance. The expectation and variance of counts for triplets are compared with experimental counts in Escherichia coli coding sequences.

Algorithms↗