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PubMed1999

Codon bias and mutability in HIV sequences.

A survey of the patterns of synonymous codon preference in the HIV env gene reveals a correlation between the codon bias and the mutability requirements of different regions of the protein. At hypervariable regions in gp120 one finds a greater proportion of codons that tend to mutate nonsynonymously, but to a target that is similar in hydrophobicity and volume. We argue that this strategy results from a compromise between the selective pressure placed on the virus by the induced immune response, which favors amino acid substitutions in the complementarity determining regions, and the negative selection against missense mutations that violate structural constraints of the env protein.

Codon↗
PubMed2005

Protein database searches using compositionally adjusted substitution matrices.

Almost all protein database search methods use amino acid substitution matrices for scoring, optimizing, and assessing the statistical significance of sequence alignments. Much care and effort has therefore gone into constructing substitution matrices, and the quality of search results can depend strongly upon the choice of the proper matrix. A long-standing problem has been the comparison of sequences with biased amino acid compositions, for which standard substitution matrices are not optimal. To address this problem, we have recently developed a general procedure for transforming a standard matrix into one appropriate for the comparison of two sequences with arbitrary, and possibly differing compositions. Such adjusted matrices yield, on average, improved alignments and alignment scores when applied to the comparison of proteins with markedly biased compositions. Here we review the application of compositionally adjusted matrices and consider whether they may also be applied fruitfully to general purpose protein sequence database searches, in which related sequence pairs do not necessarily have strong compositional biases. Although it is not advisable to apply compositional adjustment indiscriminately, we describe several simple criteria under which invoking such adjustment is on average beneficial. In a typical database search, at least one of these criteria is satisfied by over half the related sequence pairs. Compositional substitution matrix adjustment is now available in NCBI's protein-protein version of blast.

Algorithms↗
PubMed2004

Bias explorer: measurements of compositional bias in EMBL and GenBank sequence files.

A Windows application for compositional analysis of sequenced genomes (EMBL or GenBank flat files) is available as freeware. The application allows the user to quantify word bias using Markov chain analysis and it allows the user to generate sliding window data for GC-skew, AT-skew, purine excess, keto excess and discrete word counts. The mathematical routines reside in a dynamic link library (DLL), which can be used independently by other applications. The software is available for download at http://www.dfuni.dk/~anfu/Bioinformatics/Main.htm.

Bias↗
PubMed2001

Detecting the impact of sequencing errors on SAGE data.

UNLABELLED: SAGE data are obtained by sequencing short DNA tags. Due to the mistakes in DNA sequencing, SAGE data contain errors. We propose a new approach to identify tags whose abundance is biased by sequencing errors. This approach is based on a concept of neighbourhood: abundant tags can contaminate tags whose sequence is very close. The application of our approach reveals that moderately abundant tags can be generated by sequencing errors uniquely. It also allows for detecting correct rare tags. AVAILABILITY: Software is available only to non-profit entities and for non-commercial purposes upon request.

Gene Expression Profiling↗
PubMed1993

Unbiased analysis of the frequency of beta-thalassemia point mutations in a population of African-American newborns.

OBJECTIVE: To determine frequency of specific beta-thalassemia alleles in the African-American population prospectively, using newborn screening specimens, and to evaluate the need for including these alleles in screening follow-up programs. DESIGN: Allele-specific oligonucleotide tests were developed and used to analyze African-American newborn screening specimens for beta-thalassemia point mutations to determine their frequency. Direct sequencing of amplified DNA from the dried blood specimens was used to confirm the presence of point mutations. POPULATION: African-American newborns in Texas. RESULTS: Allele-specific oligonucleotides identified five newborn specimens carrying beta-thalassemia point mutations among 471 specimens from African-American neonates. Direct sequencing of DNA from the dried blood specimens confirmed that these individuals had a normal and a mutant allele. Five newborn screening specimens in which the results of screening and DNA tests were in disagreement (four with FS by screening and AS by DNA, and one with FC by screening and AC by DNA) were analyzed for these beta-thalassemia point mutations and in each case were found to be S/beta-thalassemia or C/beta-thalassemia compound heterozygotes, respectively. CONCLUSIONS: Allele-specific oligonucleotides accurately identified newborn specimens carrying beta-thalassemia point mutations. Direct sequencing from dried blood specimens confirmed these results. The A(-29)G allele frequency was 0.003, and the C(-88)T frequency was 0.002. These alleles also were observed among positive samples in a neonatal hemoglobinopathy screening program. Therefore, any newborn screening program with a molecular genetic follow-up component must include testing for these beta-thalassemia alleles to assure timely and appropriate management for affected infants.

Alleles↗
PubMed2004

Genome-scale phylogeny and the detection of systematic biases.

Phylogenetic inference from sequences can be misled by both sampling (stochastic) error and systematic error (nonhistorical signals where reality differs from our simplified models). A recent study of eight yeast species using 106 concatenated genes from complete genomes showed that even small internal edges of a tree received 100% bootstrap support. This effective negation of stochastic error from large data sets is important, but longer sequences exacerbate the potential for biases (systematic error) to be positively misleading. Indeed, when we analyzed the same data set using minimum evolution optimality criteria, an alternative tree received 100% bootstrap support. We identified a compositional bias as responsible for this inconsistency and showed that it is reduced effectively by coding the nucleotides as purines and pyrimidines (RY-coding), reinforcing the original tree. Thus, a comprehensive exploration of potential systematic biases is still required, even though genome-scale data sets greatly reduce sampling error.

Genome, Fungal↗
PubMed1989

The sequence asymmetry of the Escherichia coli chromosome appears to be independent of strand or function and may be evolutionarily conserved.

I have examined potential determinants of the asymmetric distribution of nucleotide sequences in the genome of Escherichia coli as cataloged in GenBank release 44. I have used the frequency of occurrence of all possible tetranucleotides in a given sequence catalog or derivative as a comparative measure of asymmetry. The GenBank-cataloged strand and its complement show statistically similar (not complementary) distributions. The distribution is statistically similar in comparisons between the protein coding subset and the total genome, the coding subset and selected non-coding genes, the coding subset and the remainder of the DNA, and the coding subset and stable RNA sequences. I have compared the distribution in the genome of E. coli with the distributions found in the cataloged genomes of Salmonella typhimurium, Bacillus subtilis, and of coliphages lambda and T7. The distribution summed in both strands of the cataloged DNA differs statistically only in comparisons with lytic bacteriophage T7 because only the two strands of T7 show statistically dissimilar distributions. Despite similarities in tetranucleotide distribution, the pattern of codon complementarity in B. subtilis is different than that documented for E. coli. Thus, sequence asymmetry does not seem related to specific DNA function or to documented similarities or differences in codon bias. The sequence asymmetry of the E. coli genome may thus reflect a hitherto unsuspected pattern impressed on both strands of DNA which is or can be packaged into bacterial genomes.

Bacillus subtilis↗
PubMed1994

An automated film reader for DNA sequencing based on homomorphic deconvolution.

An automated reader for electrophoresis based DNA sequencing methods is described that provides fast and accurate sequence determination. Digitized sequencing lanes are processed with homomorphic blind deconvolution in preparation for peak detection, interlane alignment, peak refinement and base calling. Initial reads from direct blot sequencing films have error rates of about 1% at the rate of 5 nucleotides/s. Typical read lengths are 500-600 nucleotides. The described reader is a significant improvement over existing readers and could be an essential component in the sequencing efforts of the Human Genome Project.

Base Sequence↗
PubMed1993

Sequence of the novel joints present in the amplified DNA of N-phosphonacetyl-L-aspartate resistant Drosophila cells: implication on the mechanisms of amplification in these cells.

We have previously shown the presence, in the amplified DNA of a Drosophila cell line resistant to N-phosphonacetyl-L-aspartate (PALA), of two units of 150 kb and 120 kb respectively duplicated and amplified. The two joints (J1 and J2) linking these units as well as their respective wild-type counterparts have been sequenced. Sequence analysis indicates that a region of the Drosophila genome which corresponds to the proximal boundary of the 150 kb unit is common to both joints. In addition to this common region, the J1 junction possesses a 26-nucleotide sequence belonging to the J2 junction. This indicates that the J2 junction was the first formed, and that J1, therefore, results from recombination between J2 and a region of the wild-type genome 120 kb distal to J2. Sequence analysis also reveals that the joints result from illegitimate recombination between unrelated regions. AT-rich sequences, strand bias composition and putative topoisomerase I and II sites were found in at least one of the two parental sequences involved in the formation of the joints. On the basis of these results we can hypothesize that after two illegitimate recombinations between sister chromatids, leading first to J2 and then to J1, the amplification may have arisen by a series of homologous (unequal crossing-over) or illegitimate recombinations, or by an intrachromosomal rolling circle.

Animals↗
PubMed1995

Gene conversion during vector insertion in embryonic stem cells.

Recombination of an insertion vector into its chromosomal homologue is a conservative event in that both the chromosomal and the vector sequences are preserved. However, gene conversion may accompany homologous recombination of an insertion vector. To examine gene conversion in more detail we have determined the targeting frequencies and the structure of the recombinant alleles generated with a series of vectors which target the hprt gene in embryonic stem cells. We demonstrate that gene conversion of the introduced mutation does not significantly limit homologous recombination and that gene conversion occurs without a sequence specific bias for five different mutations. The frequency of the loss of a vector mutation and the gain of a chromosomal sequence is inversely proportional to the distance between the vector mutation and the double-strand break. The loss of a chromosomal sequence and the gain of a vector mutation occurs at a low frequency.

Alleles↗
PubMed2000

Gene structure prediction by spliced alignment of genomic DNA with protein sequences: increased accuracy by differential splice site scoring.

Gene identification in genomic DNA from eukaryotes is complicated by the vast combinatorial possibilities of potential exon assemblies. If the gene encodes a protein that is closely related to known proteins, gene identification is aided by matching similarity of potential translation products to those target proteins. The genomic DNA and protein sequences can be aligned directly by scoring the implied residues of in-frame nucleotide triplets against the protein residues in conventional ways, while allowing for long gaps in the alignment corresponding to introns in the genomic DNA. We describe a novel method for such spliced alignment. The method derives an optimal alignment based on scoring for both sequence similarity of the predicted gene product to the protein sequence and intrinsic splice site strength of the predicted introns. Application of the method to a representative set of 50 known genes from Arabidopsis thaliana showed significant improvement in prediction accuracy compared to previous spliced alignment methods. The method is also more accurate than ab initio gene prediction methods, provided sufficiently close target proteins are available. In view of the fast growth of public sequence repositories, we argue that close targets will be available for the majority of novel genes, making spliced alignment an excellent practical tool for high-throughput automated genome annotation.

Algorithms↗
PubMed2006

Prediction of non-coding and antisense RNA genes in Escherichia coli with Gapped Markov Model.

A new mathematical index was developed to identify and characterize non-coding RNA (ncRNA) genes encoded within the Escherichia coli (E. coli) genome. It was designated the GMMI (Gapped Markov Model Index) and used to evaluate sequence patterns located at the separate positions of consensus sequences, codon biases and/or possible RNA structures on the basis of the Markov model. The GMMI was able to separate a set of known mRNA sequences from a mixture of ncRNAs including tRNAs and rRNAs. Consequently, the GMMI was employed to predict novel ncRNA candidates. At the beginning, possible transcription units were extracted from the E. coli genome using consensus sequences for the sigma70 promoter and the rho-independent terminator. Then, these units were evaluated by using the GMMI. This identified 133 candidate ncRNAs, which contain 29 previously annotated small RNA genes and 46 possible antisense ncRNAs. Furthermore 12 transcripts (including five antisense RNAs) were confirmed according to the expression analysis. These data suggests that the expression of small antisense RNAs might be more common than previously thought in the E. coli genome.

Computational Biology↗
PubMed1998

Recombination in the 5' leader of murine leukemia virus is accurate and influenced by sequence identity with a strong bias toward the kissing-loop dimerization region.

Retroviral recombination occurs frequently during reverse transcription of the dimeric RNA genome. By a forced recombination approach based on the transduction of Akv murine leukemia virus vectors harboring a primer binding site knockout mutation and the entire 5' untranslated region, we studied recombination between two closely related naturally occurring retroviral sequences. On the basis of 24 independent template switching events within a 481-nucleotide target sequence containing multiple sequence identity windows, we found that shifting from vector RNA to an endogenous retroviral RNA template during minus-strand DNA synthesis occurred within defined areas of the genome and did not lead to misincorporations at the crossover site. The nonrandom distribution of recombination sites did not reflect a bias for specific sites due to selection at the level of marker gene expression. We address whether template switching is affected by the length of sequence identity, by palindromic sequences, and/or by putative stem-loop structures. Sixteen of 24 sites of recombination colocalized with the kissing-loop dimerization region, and we propose that RNA-RNA interactions between palindromic sequences facilitate template switching. We discuss the putative role of the dimerization domain in the overall structure of the reverse-transcribed RNA dimer and note that related mechanisms of template switching may be found in remote RNA viruses.

3T3 Cells↗
PubMed2000

Guilt by association: the arginine case revisited.

If the genetic code arose in an RNA world, present codon assignments may reflect primordial RNA-amino acid affinities. Whether aptamers selected from random pools to bind free amino acids do so using the cognate codons at their binding sites has been controversial. Here we defend and extend our previous analysis of arginine binding sites, and propose a model for the maintenance of codon-amino acid interactions through the evolution of amino acids from ribozyme cofactors into the building blocks of proteins.

Anticodon↗
PubMed1996

Site-specific codon bias in bacteria.

Sequences of the gapA and ompA genes from 10 genera of enterobacteria have been analyzed. There is strong bias in codon usage, but different synonymous codons are preferred at different sites in the same gene. Site-specific preference for unfavored codons is not confined to the first 100 codons and is usually manifest between two codons utilizing the same tRNA. Statistical analyses, based on conclusions reached in an accompanying paper, show that the use of an unfavored codon at a given site in different genera is not due to common descent and must therefore be caused either by sequence-specific mutation or sequence-specific selection. Reasons are given for thinking that sequence-specific mutation cannot be responsible. We are unable to explain the preference between synonymous codons ending in C or T, but synonymous choice between A and G at third sites is largely explained by avoidance of AG-G (where the hyphen indicates the boundary between codons). We also observed that the preferred codon for proline in Enterobacter cloacea has changed from CCG to CCA.

Bacterial Outer Membrane Proteins↗