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Results for “sequence biases”

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PubMed1989

Chromosome localization-dependent compositional bias of point mutations in Alu repetitive sequences.

The Alu repetitive sequence family originated from a common ancestor. Its members, apparently free from functional constraints, are interspersed throughout primate genomes. We have found that base substitutions occurring during the evolution of primates caused a decrease in the average G + C content of those members of the family that are located in an A + T-rich region of the genome. The family members that are located in a G + C-rich genomic region have not changed their, already high, G + C content. This suggests that the regional differences in G + C content, which are responsible for chromosomal banding, are caused by an accumulation of mutations that, although selectively neutral in the majority, show different compositional bias in different regions of the vertebrate chromosome.

Animals↗

PubMed1985

Structure and genomic organization of the rat aldolase B gene.

The structure of the chromosomal gene encoding rat aldolase isozyme B has been elucidated by sequence analysis of cloned genomic DNA. This gene comprises about 14 X 10(3) base-pairs of DNA, and is separated into nine exons by eight intervening sequences. A presumed transcription-initiation site was assigned by S1 nuclease protection mapping, and T-A-T-A and C-C-A-A-T boxes were found to be 25 and 126 base-pairs, respectively, upstream from this initiation site. There are three characteristic sequences of 100 to 200 base-pairs within the region of 870 base-pairs flanking the 5' side of the gene. These sequences are flanked on either side by direct repeats and terminate with an A-rich stretch of nucleotides. One of them has block homology with a region in an "ID sequence", which is reported to be an element for tissue-specific gene regulation and differentiation. The other two are analogous at the sequence organizational level with a sort of dispersed repeat, the "Alu family". These features suggest that these regions are involved in gene regulation and, also, imply evolutionary events such as duplication or insertion. Comparison of this gene sequence with the rabbit aldolase A complementary DNA sequence revealed some bias in the frequency of nucleotide replacement among the exons, suggesting selective evolutionary conservation of particular exons encoding functional domains. Comparison with the human aldolase B complementary DNA sequence revealed no such tendency; the homology between the two sequences was very high (about 89%), and nucleotide replacements were randomly distributed throughout the protein-coding region.

Animals↗

PubMed2026

Transgene sequence codon optimization and composition determines replication competence of self-amplifying RNA.

Self-amplifying RNA (saRNA) is an emerging RNA therapeutic modality that can facilitate higher magnitude and more durable protein expression at substantially lower doses than nonreplicating mRNA. Unlike conventional messenger RNA (mRNA), alphavirus-derived saRNA must support a replicase-driven RNA amplification step in addition to translation, raising the possibility that transgene coding sequences impose sequence-level constraints on replication. Here, saRNA replication was found to be dependent on the codon composition of the transgene; multiple therapeutic transgenes were replication defective despite an intact Venezuelan Equine Encephalitis Virus (VEEV)-derived saRNA backbone. Replication defects were rescued by synonymous codon re-optimization of the same transgenes, indicating that nucleotide-level features of the coding sequence, rather than the encoded protein, govern replication competence. Comparative compositional analyses identified a distinct signature associated with productive replication, characterized by elevated GC (>53%) and GC3 (>63%) content, higher codon adaptation to human (>0.75), and reduced UpA (<43/kb) and UpU (<41/kb) dinucleotide density. Moreover, deliberate compositional perturbation of an otherwise replication-competent transgene shifted these features and abolished replication, supporting a causal and combinatorial role for sequence composition in defining saRNA replication outcome. These findings define an underappreciated constraint in saRNA therapeutics and motivate saRNA-specific payload design frameworks that incorporate alphavirus-associated compositional biases during transgene sequence optimization.

Codon↗

PubMed1998

Weighting hidden Markov models for maximum discrimination.

MOTIVATION: Hidden Markov models can efficiently and automatically build statistical representations of related sequences. Unfortunately, training sets are frequently biased toward one subgroup of sequences, leading to an insufficiently general model. This work evaluates sequence weighting methods based on the maximum-discrimination idea. RESULTS: One good method scales sequence weights by an exponential that ranges between 0.1 for the best scoring sequence and 1.0 for the worst. Experiments with a curated data set show that while training with one or two sequences performed worse than single-sequence Probabilistic Smith-Waterman, training with five or ten sequences reduced errors by 20% and 51%, respectively. This new version of the SAM HMM suite outperforms HMMer (17% reduction over PSW for 10 training sequences), Meta-MEME (28% reduction), and unweighted SAM (31% reduction). AVAILABILITY: A WWW server, as well as information on obtaining the Sequence Alignment and Modeling (SAM) software suite and additional data from this work, can be found at http://www.cse.ucse. edu/research/compbio/sam.html

Algorithms↗

PubMed1991

Evidence for biased gene conversion in concerted evolution of ribosomal DNA.

Concerted evolution is the production and maintenance of homogeneity within repeated families of DNA. Two mechanisms--unequal crossing over and biased gene conversion--have been the principal explanations of concerted evolution. Concerted evolution of ribosomal DNA (rDNA) arrays is thought to be largely the result of unequal crossing over. However, concerted evolution of rDNA in parthenogenetic lizards of hybrid origin is strongly biased toward one of two parental sequences, which is consistent with biased gene conversion as the operative mechanism. The apparent gene conversions are independent of initial genome dosage and result in homogenization of rDNA arrays across all nucleolar organizer regions.

Animals↗

PubMed2006

Analyses of expressed sequence tags from apple.

The domestic apple (Malus domestica; also known as Malus pumila Mill.) has become a model fruit crop in which to study commercial traits such as disease and pest resistance, grafting, and flavor and health compound biosynthesis. To speed the discovery of genes involved in these traits, develop markers to map genes, and breed new cultivars, we have produced a substantial expressed sequence tag collection from various tissues of apple, focusing on fruit tissues of the cultivar Royal Gala. Over 150,000 expressed sequence tags have been collected from 43 different cDNA libraries representing 34 different tissues and treatments. Clustering of these sequences results in a set of 42,938 nonredundant sequences comprising 17,460 tentative contigs and 25,478 singletons, together representing what we predict are approximately one-half the expressed genes from apple. Many potential molecular markers are abundant in the apple transcripts. Dinucleotide repeats are found in 4,018 nonredundant sequences, mainly in the 5'-untranslated region of the gene, with a bias toward one repeat type (containing AG, 88%) and against another (repeats containing CG, 0.1%). Trinucleotide repeats are most common in the predicted coding regions and do not show a similar degree of sequence bias in their representation. Bi-allelic single-nucleotide polymorphisms are highly abundant with one found, on average, every 706 bp of transcribed DNA. Predictions of the numbers of representatives from protein families indicate the presence of many genes involved in disease resistance and the biosynthesis of flavor and health-associated compounds. Comparisons of some of these gene families with Arabidopsis (Arabidopsis thaliana) suggest instances where there have been duplications in the lineages leading to apple of biosynthetic and regulatory genes that are expressed in fruit. This resource paves the way for a concerted functional genomics effort in this important temperate fruit crop.

Arabidopsis↗

PubMed2005

Tag-based approaches for transcriptome research and genome annotation.

With the increasing number of whole genome sequences available, genomic research has shifted toward the annotation of functional elements and transcribed regions. Thus, the related field of transcriptome research requires accurate methods for the profiling of genes that are not biased by known sequence information, and that also allow for the identification of promoter regions. Starting with serial analysis of gene expression (SAGE), methods making use of short sequencing tags have greatly contributed to transcriptome studies. Here we review recent developments in the use of short sequencing tags in expression profiling, gene discovery and genome annotation. These tags are obtained from the 5' end of mRNAs, both terminal ends of mRNAs, or genomic regions. The 5' end-specific tags, with their ability to identify transcripts along with their transcriptional start sites, will be of particular interest for gene network studies and may become one of the most important approaches in systems biology.

Animals↗

PubMed2005

openSputnik--a database to ESTablish comparative plant genomics using unsaturated sequence collections.

The public expressed sequence tag collections are continually being enriched with high-quality sequences that represent an ever-expanding range of taxonomically diverse plant species. While these sequence collections provide biased insight into the populations of expressed genes available within individual species and their associated tissues, the information is conceivably of wider relevance in a comparative context. When we consider the available expressed sequence tag (EST) collections of summer 2004, most of the major plant taxonomic clades are at least superficially represented. Investigation of the five million available plant ESTs provides a wealth of information that has applications in modelling the routes of plant genome evolution and the identification of lineage-specific genes and gene families. Over four million ESTs from over 50 distinct plant species have been collated within an EST analysis pipeline called openSputnik. The ESTs were resolved down into approximately one million unigene sequences. These have been annotated using orthology-based annotation transfer from reference plant genomes and using a variety of contemporary bioinformatics methods to assign peptide, structural and functional attributes. The openSputnik database is available at http://sputnik.btk.fi.

Cluster Analysis↗

PubMed2005

Multiple sequence alignment accuracy and evolutionary distance estimation.

BACKGROUND: Sequence alignment is a common tool in bioinformatics and comparative genomics. It is generally assumed that multiple sequence alignment yields better results than pair wise sequence alignment, but this assumption has rarely been tested, and never with the control provided by simulation analysis. This study used sequence simulation to examine the gain in accuracy of adding a third sequence to a pair wise alignment, particularly concentrating on how the phylogenetic position of the additional sequence relative to the first pair changes the accuracy of the initial pair's alignment as well as their estimated evolutionary distance. RESULTS: The maximal gain in alignment accuracy was found not when the third sequence is directly intermediate between the initial two sequences, but rather when it perfectly subdivides the branch leading from the root of the tree to one of the original sequences (making it half as close to one sequence as the other). Evolutionary distance estimation in the multiple alignment framework, however, is largely unrelated to alignment accuracy and rather is dependent on the position of the third sequence; the closer the branch leading to the third sequence is to the root of the tree, the larger the estimated distance between the first two sequences. CONCLUSION: The bias in distance estimation appears to be a direct result of the standard greedy progressive algorithm used by many multiple alignment methods. These results have implications for choosing new taxa and genomes to sequence when resources are limited.

Algorithms↗

PubMed1983

Influence of local nucleotide sequence on substitution of 2-aminopurine for adenine during deoxyribonucleic acid synthesis in vitro.

Three highly purified DNA polymerases, Escherichia coli polymerase I (enzyme A) and the polymerases induced by wild-type T4 phage and by T4 phage mutant L141 (antimutator phenotype), have been examined with respect to their tendency to incorporate the deoxyribonucleotide of 2-aminopurine [(AP)] for deoxyadenylate at specific sites in deoxyribonucleic acid (DNA). Using phi X174 phage DNA as a template and selected phi X174 restriction fragments as specific primers, we synthesized short sequences of phi X174 DNA in vitro by the polymerase of interest, with the 5'-triphosphate of 2-aminopurine deoxyriboside and dATP at equimolar concentration. The relative incorporation of (AP) at the various adenine sites was determined by providing the newly synthesized DNA fragment with a specific terminal radioactive label, subjecting the DNA fragment to thermal depurination as a DNA cleavage reaction highly selective for (AP), and analyzing the resulting radioactive fragments by denaturing gel electrophoresis, autoradiography, and microdensitometry. The L141 polymerase shows very pronounced site-dependent variations in (AP) incorporation. For the wild-type T4 polymerase, the pattern of (AP) incorporation follows the biases seen for the L141 enzyme, although in a less pronounced form. Sequence preferences for (AP) incorporation are least marked for E. coli polymerase I (enzyme A); in several instances, they run counter to the sequence biases observed with the T4 enzymes. For the enzyme showing the most pronounced sequence effects, L141 polymerase, the extent of (AP) incorporation was determined at 57 different sites. No simple principle governing the sequence dependence of (AP) incorporation could be deduced from these results.

2-Aminopurine↗

PubMed1990

Cleavage-site motifs in mitochondrial targeting peptides.

Although mitochondrial targeting peptides lack a common consensus sequence, a certain bias in the positional distribution of amino acids has recently been found. These patterns seem to be associated with cleavage of the precursor proteins by matrix processing proteases. We have extended the previous studies and found new sequence motifs that are conserved within subgroups of mitochondrial targeting peptides. These motifs have certain common themes, indicating that they are associated with cleavage by one single protease. Two of the conserved patterns have a high predictive value, but even for sequences that do not possess these patterns, a fairly accurate prediction of the cleavage site is shown to be possible. We also suggest that a well-conserved RXY decreases (S/A) pattern may be used to engineer efficiently recognized cleavage sites into uncleaved or artificial mitochondrial targeting peptides.

Amino Acid Sequence↗

PubMed2003

Structural dynamics of individual Holliday junctions.

The four-way DNA (Holliday) junction is the central intermediate of genetic recombination, but the dynamic aspects of this important structure are presently unclear. Although transitions between alternative stacking conformers have been predicted, conventional kinetic studies are precluded by the inability to synchronize the junction in a single conformer in bulk solution. Using single-molecule fluorescence methodology we have been able to detect these transitions. The sequence dependence, the influence of counterions and measured energetic barriers indicate that the conformer transition and branch migration processes share the unstacked, open structure as the common intermediate but have different rate-limiting steps. Relative rates indicate that multiple conformer transitions occur at each intermediate step of branch migration, allowing the junction to reach conformational equilibrium. This provides a mechanism whereby the sequence-dependent conformational bias could determine the extent of genetic exchange upon junction resolution.

Base Sequence↗

PubMed2001

Correlation between sequence conservation of the 5' untranslated region and codon usage bias in Mus musculus genes.

The codon adaptation index (CAI) values of all protein-coding sequences of the full-length cDNA libraries of Mus musculus were computed based on the RIKEN mouse full-length cDNA library. We have also computed the extent of consensus in flanking sequences of the initiator ATG codon based on the 'relative entropy' values of respective nucleotide positions (from -20 to +12 bp relative to the initiator ATG codon) for each group of genes classified by CAI values. With regard to the two nucleotides positions (-3 and +4) known to be highly conserved in Kozak's consensus sequence, a clear correlation between CAI values and relative entropy values was observed at position -3 but this was not significant at position +4, although a significant correlation was found at position -1 of the consensus sequence. Further, although no correlation was observed at any additional positions, relative entropy values were very high at positions -4, -6, and -8 in genes with high CAI values. These findings suggest that the extent of conservation in the flanking sequence of the initiator ATG codon including Kozak's consensus sequence was an important factor in modulation of the translation efficiency as well as synonymous codon usage bias particularly in highly expressed genes.

5' Untranslated Regions↗

PubMed2001

Genome-scale compositional comparisons in eukaryotes.

We examined dinucleotide relative abundances and their biases in recent sequences of eukaryotic genomes and chromosomes, including human chromosomes 21 and 22, Saccharomyces cerevisiae, Arabidopsis thaliana, and Drosophila melanogaster. We found that dinucleotide relative abundances are remarkably constant across human chromosomes and within the DNA of a particular species. The dinucleotide biases differ between species, providing a genome signature that is characteristic of the bulk properties of an organism's DNA. We detail the relations between species genome signatures and suggest possible mechanisms for their origin and maintenance.

Animals↗

PubMed1993

Identification of the nuclear-encoded chloroplast ribosomal protein L12 of the monocotyledonous plant Secale cereale and sequencing of two different cDNAs with strong codon bias.

Two different cDNA clones (SCL12-1 and SCL12-2) encoding precursors of a chloroplast ribosomal protein with homology to L12 from Escherichia coli were isolated from rye leaf cDNA libraries and sequenced. The corresponding polypeptide of rye chloroplast ribosomes was identified. The sequences for the mature proteins of M(r) 13,447 and 13,609 share 85% amino acid identity. The mature polypeptide of clone SCL12-1 has an amino acid identity of 71%, 72% or 44%, respectively, relative to L12 proteins from spinach, tobacco, or E. coli. Codon usage of the rye L12 cDNAs shows a high preference (97% and 82%) for G or C in the third base position.

Amino Acid Sequence↗

PubMed1995

An investigation of conservation-biased gap-penalties for multiple protein sequence alignment.

Sequence conservation in a multiple sequence alignment (or profile) is often used to influence the alignment of further sequences onto the profile. Most methods, however, have considered only the opening of a gap at a single point and not what is contained in the inserted segment of one sequence (or profile) or what terminates the 'broken' ends of the other. An alignment algorithm is described that incorporates these aspects and the relative importance of the contribution from the insert and the 'broken' ends has been assessed. The approach was tested on families of very remotely related sequences using a novel protocol that was developed to quantify both the stability and generality of the solution.

Algorithms↗

PubMed1987

Database bias and the identification of protein coding sequences.

A simple quantitative test for the probability that an open reading frame actually codes for a protein has been described by Tramontano and Macchiato (1986). However, their test is only valid for the special case in which both coding and noncoding sequences are represented equally. We present a generalized adaptation of their method that uses estimates for the relative proportions of coding and noncoding sequences to provide a more accurate prediction.

Amino Acid Sequence↗

PubMed2004

RELIC--a bioinformatics server for combinatorial peptide analysis and identification of protein-ligand interaction sites.

Phage display technology provides a versatile tool for exploring the interactions between proteins, peptides and small molecule ligands. Quantitative analysis of peptide population sequence diversity and bias patterns has the power to significantly enhance the impact of these methods [1, 2]. We have developed a suite of computational tools for the analysis of peptide populations and made them accessible by integrating fifteen software programs for the analysis of combinatorial peptide sequences into the REceptor LIgand Contacts (RELIC) relational database and web-server. These programs have been developed for the analysis of statistical properties of peptide populations; identification of weak consensus sequences within these populations; and the comparison of these peptide sequences to those of naturally occurring proteins. RELIC is particularly suited to the analysis of peptide populations affinity selected with a small molecule ligand such as a drug or metabolite. Within this functional context, the ability to identify potential small molecule binding proteins using combinatorial peptide screening will accelerate as more ligands are screened and more genome sequences become available. The broader impact of this work is the addition of a novel means of analyzing peptide populations to the phage display community.

Algorithms↗