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Results for “sequence biases”

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PubMed1994

Bias of culture techniques for diagnosing mixed Mycobacterium genavense and Mycobacterium avium infection in AIDS.

Disseminated Mycobacterium avium infection is a common complication in late-stage AIDS. We describe a patient seropositive for human immunodeficiency virus with a disseminated infection caused by mycobacteria. Acid-fast rods were visible by microscopy in stool and bone marrow and in specimens from skin, liver, spleen, lung, and lymph nodes. Using molecular biology techniques and standard culture techniques, we found evidence of a mixed mycobacterial infection with M. genavense and M. avium. We suggest that the prevalence of M. genavense infection in patients with AIDS is underestimated because of the bias toward M. avium when using standard techniques for the detection and identification of mycobacteria.

AIDS-Related Opportunistic Infections↗

PubMed2026

Systematic contextual biases in SegmentNT potentially relevant to other nucleotide transformer models.

Recent advances in large language models have extended to genomic applications, yet model robustness relative to context is unclear. Here, we demonstrate two intrinsic biases (input sequence length and nucleotide position) affecting SegmentNT results, a model included with the Nucleotide Transformer that provides nucleotide-level predictions of biological features. We demonstrate that nucleotide position within the input sequence (beginning, middle, or end) alters the nature of SegmentNT's raw prediction probabilities, which can be standardized to improve prediction consistency. While longer input sequence length improves model performance, diminishing returns suggest a surprisingly small input length of ∼3072 nucleotides might be sufficient for many applications. We further identify a 24-nucleotide periodic oscillation in SegmentNT's prediction probabilities, revealing an intrinsic bias potentially linked to the model's training tokenization (6-mers) and architecture. We identify potential approaches to account for these biases and provide generalizable insights for utilizing nucleotide-resolution functional prediction models.

Nucleotides↗

PubMed2002

Population screening of single-nucleotide polymorphisms exemplified by analysis of 8000 alleles.

The authors describe a method in which the population frequency of single-nucleotide polymorphisms (SNPs) can be efficiently detected and their allele frequencies accurately measured. Selected SNPs in TNFbeta, IL-4, and CTLA-4 were used to demonstrate the method. Blood from 4000 individuals was pooled, DNA was extracted, and target sequences were PCR amplified and analyzed by denaturant capillary electrophoresis. Alleles were separated into peaks based on melting properties of the double DNA helix. Frequencies of the different alleles were determined by calculating the area under the peaks. Allele frequencies and Hardy-Weinberg equilibrium estimated from the pooled data were verified by analyzing 7.5% of the samples randomly selected from the blood donor series. The method herein is equally suitable for single-samples and/or pooled-samples analysis of SNPs, in which sample treatment is kept to a minimum. The potential throughput of the method is beyond obtainable numbers of samples.

Alleles↗

PubMed1995

Population genetics of dinucleotide (dC-dA)n.(dG-dT)n polymorphisms in world populations.

We have characterized eight dinucleotide (dC-dA)n.(dG-dT)n repeat loci located on human chromosome 13q in eight human populations and in a sample of chimpanzees. Even though there is substantial variation in allele frequencies at each locus, at a given locus the most frequent alleles are shared by all human populations. The level of heterozygosity is reduced in isolated or small populations, such as the Pehuenche Indians of Chile, the Dogrib of Canada, and the New Guinea highlanders. On the other hand, larger average heterozygosities are observed in large and cosmopolitan populations, such as the Sokoto population from Nigeria and German Caucasians. Conformity with Hardy-Weinberg equilibrium is generally observed at these loci, unless (a) a population is isolated or small or (b) the repeat motif of the locus is not perfect (e.g., D13S197). Multilocus genotype probabilities at these microsatellite loci do not show departure from the independence rule, unless the loci are closely linked. The allele size distributions at these (CA)n loci do not follow a strict single-step stepwise-mutation model. However, this features does not compromise the ability to detect population affinities, when these loci are used simultaneously. The microsatellite loci examined here are present and, with the exception of the locus D13S197, are polymorphic in the chimpanzees, showing an overlapping distribution of allele sizes with those observed in human populations.

Alleles↗

PubMed2006

Repseek, a tool to retrieve approximate repeats from large DNA sequences.

UNLABELLED: Chromosomes or other long DNA sequences contain many highly similar repeated sub-sequences. While there are efficient methods for detecting strict repeats or detecting already characterized repeats, there is no software available for detecting approximate repeats in large DNA sequences allowing for weighted substitutions and indels in a coherent statistical framework. Here, we present an implementation of a two-steps method (seed detection followed by their extension) that detects those approximate repeats. Our method is computationally efficient enough to handle large sequences and is flexible enough to account for influencing factors, such as sequence-composition biases both at the seed detection and alignment levels. AVAILABILITY: http://wwwabi.snv.jussieu.fr/public/RepSeek/

Algorithms↗

PubMed2006

A novel insertion of a rearranged L1 element in exon 44 of the dystrophin gene: further evidence for possible bias in retroposon integration.

L1 elements are mammalian retrotransposons contributing to genome evolution and causing rare mutations in human. We describe a de novo insertion of an L1 element into the dystrophin gene resulting in skipping of exon 44 and causing Duchenne muscular dystrophy in a boy. The L1 element was rearranged due to the twin-priming mechanism, but contrary to all described L1 rearrangements the 5' region of the inverted L1 sequence ended within the poly(A) tail of the element. Furthermore, the target site for the insertion was located only 87 bp from the insertion site in another patient described previously. These findings can contribute to the understanding of the mechanisms of L1 element rearrangement, and may support the notion that some subregions of the human genome could be preferred targets for retroelements using the L1 enzymatic machinery.

Base Sequence↗

PubMed1994

Evaluation of an automated DNA profiling system employing multiplex amplification of four tetrameric STR loci.

We have examined the performance and reproducibility of an automated DNA profiling system which is based on the multiplex amplification of 4 tetrameric STR loci-HUMVWFA31/A. HUMTH01, HUMF13A1 and HUMFES/FPS. The system was able to type 100 pg of purified, undegraded, genomic DNA. At lower concentrations of DNA (below 100 pg), allelec drop-out occurred due to stochastic differences in allele copy number. Minor variation of individual PCR reagent concentrations or cycling temperatures did not result in a significant effect on the efficiency of amplification of any of the 4 loci in the quadruplex system. More substantial variation of reagent concentrations or cycling temperatures outside the optimum range of the system resulted in a reduction or complete loss of signal for one or more loci. This was also observed at high ionic strength or extreme pH. However, under all reagent concentrations and conditions studied, no artefact bands that could potentially result in the mistyping of a sample were apparent within the read region (130-240 bases) of the gel. Evaluation of both native and denaturing polyacrylamide gels revealed that, although native gels displayed faster run times, the sizing precision of such gels for certain STR loci was lower than that of denaturing gels. Also, artefact bands may be present within the read region of native gels. In conclusion the quadruplex amplification system described, coupled with automated fluorescence-based detection on denaturing polyacrylamide gels, appeared to be a robust and reliable system for individual identification.

Alleles↗

PubMed2003

A new model of sheep Ig diversification: shifting the emphasis toward combinatorial mechanisms and away from hypermutation.

The current model of Ig repertoire development in sheep focuses on the rearrangement of a small number (approximately 20) of Vlambda gene segments. It is believed that this limited combinatorial repertoire is then further diversified through postrearrangement somatic hypermutation. This process has been reported to introduce as many as 110 mutations/1000 nucleotides. In contrast, our data have that indicated somatic hypermutation may diversify the preimmune repertoire to a much lesser extent. We have identified 64 new Vlambda gene segments within the rearranged Ig repertoire. As a result, many of the unique nucleotide patterns thought to be the product of somatic hypermutation are actually hard-coded within the germline. We suggest that combinatorial rearrangement makes a much larger contribution, and somatic hypermutation makes a much smaller contribution to the generation of diversity within the sheep Ig repertoire than is currently acknowledged.

Aging↗

PubMed1997

Retroviral oligonucleotide distributions correlate with biased nucleotide compositions of retrovirus sequences, suggesting a duplicative stepwise molecular evolution.

A computer-assisted analysis was made of 24 complete nucleotide sequences selected from the vertebrate retroviruses to represent the ten viral groups. The conclusions of this analysis extend and strengthen the previously made hypothesis on the Moloney murine leukemia virus: The evolution of the nucleotide sequence appears to have occurred mainly through at least three overlapping levels of duplication: (1) The distributions of overrepresented (3-6)-mers are consistent with the universal rule of a trend toward TG/CT excess and with the persistence of a certain degree of symmetry between the two strands of DNA. This suggests one or several original tandemly repeated sequences and some inverted duplications. (2) The existence of two general core consensuses at the level of these (3-6)-mers supports the hypothesis of a common evolutionary origin of vertebrate retroviruses. Consensuses more specific to certain sequences are compatible with phylogenetic trees established independently. The consensuses could correspond to intermediary evolutionary stages. (3) Most of the (3-6)-mers with a significantly higher than average frequency appear to be internally repeated (with monomeric or oligomeric internal iterations) and seem to be at least partly the cause of the bias observed by other researchers at the level of retroviral nucleotide composition. They suggest a third evolutionary stage by slippage-like stepwise local duplications.

Animals↗

PubMed2000

Computational identification of cis-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiae.

AlignACE is a Gibbs sampling algorithm for identifying motifs that are over-represented in a set of DNA sequences. When used to search upstream of apparently coregulated genes, AlignACE finds motifs that often correspond to the DNA binding preferences of transcription factors. We previously used AlignACE to analyze whole genome mRNA expression data. Here, we present a more detailed study of its effectiveness as applied to a variety of groups of genes in the Saccharomyces cerevisiae genome. Published functional catalogs of genes and sets of genes grouped by common name provided 248 groups, resulting in 3311 motifs. In conjunction with this analysis, we present measures for gauging the tendency of a motif to target a given set of genes relative to all other genes in the genome and for gauging the degree to which a motif is preferentially located in a certain distance range upstream of translational start sites. We demonstrate improved methods for comparing and clustering sequence motifs. Many previously identified cis-regulatory elements were found. We also describe previously unidentified motifs, one of which has been verified by experiments in our laboratory. An extensive set of AlignACE runs on randomly selected sets of genes and on sets of genes whose upstream regions contain known transcription factor binding sites serve as controls.

Algorithms↗

PubMed1993

Computer-assisted prediction, classification, and delimitation of protein binding sites in nucleic acids.

We present a method to determine the location and extent of protein binding regions in nucleic acids by computer-assisted analysis of sequence data. The program ConsIndex establishes a library of consensus descriptions based on sequence sets containing known regulatory elements. These defined consensus descriptions are used by the program ConsInspector to predict binding sites in new sequences. We show the programs to correctly determine the significant regions involved in transcriptional control of seven sequence elements. The internal profile of relative variability of individual nucleotide positions within these regions paralleled experimental profiles of biological significance. Consensus descriptions are determined by employing an anchored alignment scheme, the results of which are then evaluated by a novel method which is superior to cluster algorithms. The alignment procedure is able to include several closely related sequences without biasing the consensus description. Moreover, the algorithm detects additional elements on the basis of a moderate distance correlation and is capable of discriminating between real binding sites and false positive matches. The software is well suited to cope with the frequent phenomenon of optional elements present in a subset of functionally similar sequences, while taking maximal advantage of the existing sequence data base. Since it requires only a minimum of seven sequences for a single element, it is applicable to a wide range of binding sites.

Algorithms↗

PubMed1992

Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene.

Germline mutations cause or predispose to most disease. Hemophilia B is a useful model for studying the underlying pattern of recent germline mutations in humans because the observed pattern of mutation in factor IX more closely reflects the underlying pattern of mutation than the observed pattern for many other genes. In addition, it is possible to identify and correct for biases inherent in ascertaining only those mutations that cause hemophilia. Aspects of the pattern of germline mutation in the factor IX gene are becoming clear: 1) in the United States, two-thirds of mutations causing mild disease arose from three founders whereas almost all the mutations resulting in either moderate or severe disease arose independently, generally within the past 150 years; 2) direct estimates of the rates of mutation in humans indicate that transitions are more frequent than transversions, which in turn are more frequent than deletions and insertions; 3) transitions at CpG are elevated approximately 24-fold relative to transitions at non-CpG dinucleotides; 4) transversions at CpG are elevated approximately eightfold relative to transversions at non-CpG dinucleotides; 5) the sum total of the dinucleotide mutation rates produces a bias against G and C bases that would be sufficient to maintain the G+C content of the factor IX gene at its evolutionarily conserved level of 40%; and 6) the pattern of mutation is similar for Caucasians residing in the United States and for Asians residing in Asia. Two ideas emerge from this and from an analysis of the pattern of recent deleterious mutations compared with ancient neutral mutations that have been fixed during evolution into the factor IX gene. First, the bulk of germline mutations are likely to arise from endogenous processes rather than environmental mutagens. Second, the factor IX protein is composed mostly of two classes of amino acids: critical residues in which all single-base missense changes will disrupt protein function, and "spacer" residues in which the precise nature of the residue is unimportant but the peptide bond is necessary to keep the critical residues in register. More work is necessary to assess the veracity and generality of these ideas.

Amino Acid Sequence↗

PubMed2002

B-vitamin intake, metabolic genes, and colorectal cancer risk (United States).

OBJECTIVE: This population-based case-control study was designed to investigate the interrelationships between polymorphisms in the methylenetetrahydrofolate (MTHFR C677T and A1298C) gene and other genes (MTR A2756G; MTRR A66G and CBS 844ins68), intake of B-vitamins and colorectal cancer risk (CRC). METHODS: We interviewed 727 CRC cases of Japanese, Caucasian, or Native Hawaiian origin and 727 controls matched on sex, age, and ethnicity. RESULTS: Compared to the homozygous wild-type genotype, the odds ratios for subjects with one or two MTHFR 677T variant alleles were 0.8 (0.6-1.1) and 0.7 (0.5-1.1), respectively (p for gene-dosage effect: 0.04). The TT genotype was associated with a 50-60% decrease in CRC risk among subjects with high intake of folate or vitamin B6, compared to those with the CC genotype and low levels of intake. The MTHFR 1298C and CBS8 44ins68 variant alleles were also found to be weakly protective against CRC and to act jointly with the 677T allele. CONCLUSIONS: This study provides additional evidence for a decreased CRC risk for subjects with the MTHFR 677T allele, particularly at high levels of folate and vitamin B6 intake. Our data also suggest that the relationships between CRC and the MTHFR A1298C and CBS 844ins68 polymorphisms warrant further study.

Age Distribution↗

PubMed2000

Selection of functional tRNA primers and primer binding site sequences from a retroviral combinatorial library: identification of new functional tRNA primers in murine leukemia virus replication.

Retroviral reverse transcription is initiated from a cellular tRNA molecule and all known exogenous isolates of murine leukemia virus utilise a tRNA(Pro)molecule. While several studies suggest flexibility in murine leukemia virus primer utilisation, studies on human immunodeficiency virus and avian retro-viruses have revealed evidence of molecular adapt-ation towards the specific tRNA isoacceptor used as replication primer. In this study, murine leukemia virus tRNA utilisation is investigated by in vivo screening of a retroviral vector combinatorial library with randomised primer binding sites. While most of the selected primer binding sites are complementary to the 3'-end of tRNA((Pro)), we also retrieved PBS sequences matching four other tRNA molecules and demonstrate that Akv murine leukemia virus vectors may efficiently replicate using tRNA(Arg(CCU)), tRNA(Phe(GAA))and a hitherto unknown human tRNA(Ser(CGA)).

3T3 Cells↗

PubMed2004

MSCAN: identification of functional clusters of transcription factor binding sites.

Identification of functional transcription factor binding sites in genomic sequences is notoriously difficult. The critical problem is the low specificity of predictions, which directly reflects the low target specificity of DNA binding proteins. To overcome the noise produced in predictions of individual binding sites, a new generation of algorithms achieves better predictive specificity by focusing on locally dense clusters of binding sites. MSCAN is a leading method for binding site cluster detection that determines the significance of observed sites while correcting for local compositional bias of sequences. The algorithm is highly flexible, applying any set of input binding models to the analysis of a user-specified sequence. From the user's perspective, a key feature of the system is that no reference data sets of regulatory sequences from co-regulated genes are required to train the algorithm. The output from MSCAN consists of an ordered list of sequence segments that contain potential regulatory modules. We have chosen the features in MSCAN such that sequence and matrix retrieval is highly facilitated, resulting in a web server that is intuitive to use. MSCAN is available at http://mscan.cgb.ki.se/cgi-bin/MSCAN.

Algorithms↗

PubMed1994

Biased representation of immunoglobulin heavy chain variable region subgroups in chronic lymphocytic leukemia.

The distribution of three immunoglobulin heavy chain variable region gene subgroups (VH1, 3 and 5) was investigated, using the polymerase chain reaction technique, in 53 patients with chronic lymphocytic leukemia. Thirty-seven patients displayed rearrangements of one of the above three gene segments. Over-representation of the VH5 subgroup was observed relative to its small size.

Antigens, CD↗

PubMed2005

iMARS--mutation analysis reporting software: an analysis of spontaneous cII mutation spectra.

The sensitivity of any mutational assay is determined by the level at which spontaneous mutations occur in the corresponding untreated controls. Establishing the type and frequency at which mutations occur naturally within a test system is essential if one is to draw scientifically sound conclusions regarding chemically induced mutations. Currently, mutation-spectra analysis is laborious and time-consuming. Thus, we have developed iMARS, a comprehensive mutation-spectrum analysis package that utilises routinely used methodologies and visualisation tools. To demonstrate the use and capabilities of iMARS, we have analysed the distribution, types and sequence context of spontaneous base substitutions derived from the cII gene mutation assay in transgenic animals. Analysis of spontaneous mutation spectra revealed variation both within and between the transgenic rodent test systems Big Blue Mouse, MutaMouse and Big Blue Rat. The most common spontaneous base substitutions were G:C-->A:T transitions and G:C-->T:A transversions. All Big Blue Mouse spectra were significantly different from each other by distribution and nearly all by mutation type, whereas the converse was true for the other test systems. Twenty-eight mutation hotspots were observed across all spectra generally occurring in CG, GA/TC, GG and GC dinucleotides. A mutation hotspot at nucleotide 212 occurred at a higher frequency in MutaMouse and Big Blue Rat. In addition, CG dinucleotides were the most mutable in all spectra except two Big Blue Mouse spectra. Thus, spontaneous base-substitution spectra showed more variation in distribution, type and sequence context in Big Blue Mouse relative to spectra derived from MutaMouse and Big Blue Rat. The results of our analysis provide a baseline reference for mutation studies utilising the cII gene in transgenic rodent models. The potential differences in spontaneous base-substitution spectra should be considered when making comparisons between these test systems. The ease at which iMARS has allowed us to carry out an exhaustive investigation to assess mutation distribution, mutation type, strand bias, target sequences and motifs, as well as predict mutation hotspots provides us with a valuable tool in helping to distinguish true chemically induced hotspots from background mutations and gives a true reflection of mutation frequency.

Animals↗

PubMed1995

The contribution of slippage-like processes to genome evolution.

Simple sequences present in long (> 30 kb) sequences representative of the single-copy genome of five species (Homo sapiens, Caenorhabditis elegans, Saccharomyces cerevisiae, E. coli, and Mycobacterium leprae) have been analyzed. A close relationship was observed between genome size and the overall level of sequence repetition. This suggested that the incorporation of simple sequences had accompanied increases of genome size during evolution. Densities of simple sequence motifs were higher in noncoding regions than in coding regions in eukaryotes but not in eubacteria. All five genomes showed very biased frequency distributions of simple sequence motifs in all species, particularly in eukaryotes where AAA and TTT predominated. Interspecific comparisons showed that noncoding sequences in eukaryotes showed highly significantly similar frequency distributions of simple sequence motifs but this was not true of coding sequences. ANOVA of the frequency distributions of simple sequence motifs indicated strong contributions from motif base composition and repeat unit length, but much of the variation remained unexplained by these parameters. The sequence composition of simple sequences therefore appears to reflect both underlying sequence biases in slippage-like processes and the action of selection. Frequency distributions of simple sequence motifs in coding sequences correlated weakly or not at all with those in noncoding sequences. Selection on coding sequences to eliminate undesirable sequences may therefore have been strong, particularly in the human lineage.

Animals↗