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PubMed2024

Bioinformatics analysis to identify the relationship between human papillomavirus-associated cervical cancer, toll-like receptors and exomes: A genetic epidemiology study.

INTRODUCTION: Genetic variants may influence Toll-like receptor (TLR) signaling in the immune response to human papillomavirus (HPV) infection and lead to cervical cancer. In this study, we investigated the pattern of TLR expression in the transcriptome of HPV-positive and HPV-negative cervical cancer samples and looked for variants potentially related to TLR gene alterations in exomes from different populations. MATERIALS AND METHODS: A cervical tissue sample from 28 women, which was obtained from the Gene Expression Omnibus database, was used to examine TLR gene expression. Subsequently, the transcripts related to the TLRs that showed significant gene expression were queried in the Genome Aggregation Database to search for variants in more than 5,728 exomes from different ethnicities. RESULTS: Cancer and HPV were found to be associated (p<0.0001). TLR1(p = 0.001), TLR3(p = 0.004), TLR4(221060_s_at)(p = 0.001), TLR7(p = 0.001;p = 0.047), TLR8(p = 0.002) and TLR10(p = 0.008) were negatively regulated, while TLR4(1552798_at)(p<0.0001) and TLR6(p = 0.019) were positively regulated in HPV-positive patients (p<0.05). The clinical significance of the variants was statistically significant for TLR1, TLR3, TLR6 and TLR8 in association with ethnicity. Genetic variants in different TLRs have been found in various ethnic populations. Variants of the TLR gene were of the following types: TLR1(5_prime_UTR), TLR4(start_lost), TLR8(synonymous;missense) and TLR10(3_prime_UTR). The "missense" variant was found to have a risk of its clinical significance being pathogenic in South Asian populations (OR = 56,820[95%CI:40,206,80,299]). CONCLUSION: The results of this study suggest that the variants found in the transcriptomes of different populations may lead to impairment of the functional aspect of TLRs that show significant gene expression in cervical cancer samples caused by HPV.

Humans↗
PubMed2002

DNA variation and psychopharmacology of the human serotonin receptor 1B (HTR1B) gene.

One of the neurotransmitter serotonin's receptors, HTR1B, is of interest for many neuropsychiatric traits, illnesses and treatments for multiple reasons, especially its tissue distribution, pharmacological profile and findings from mice lacking the receptor, along with reasons generally implicating serotonin. Eight mutation scans have uncovered sixteen polymorphisms in the coding sequence and surrounding 5'- and 3'-untranslated regions and much is now known of the distribution of these polymorphisms in various ethnic groups and their linkage disequilibrium relationships. Thus far, evidence exists that the uncommon missense T371G (Phe124Cys) and the common promoter region A-161T polymorphisms may exhibit functional effects and possibly that the common synonymous G861C (or more likely a variant in linkage disequilibrium with G861C) does as well. From the eighteen reported population-based case control studies of HTR1B to multiple disorders, several facts stand out. There exists preliminary evidence for association of G861C with i) antisocial alcoholism in the Finnish; ii) alcoholism in the presence of inactive aldehyde dehydrogenase 2 in the Japanese; iii) a history of suicide attempts in European-American personality disorder patients; and iv) minimum lifetime body mass index in Canadian bulimia nervosa patients. From the three reported family-based case control studies of HTR1B to various disorders, one provides preliminary evidence for association of G861C with obsessive compulsive disorder. Although many association studies have been completed, positive results should still be considered preliminary. As these preliminary reports are tested for replication with larger, more powerful samples, there should be increased clarity as to which findings remain robust; in some cases this will require the application of meta-analytic techniques.

Amino Acid Sequence↗
PubMed2005

ProMiner: rule-based protein and gene entity recognition.

BACKGROUND: Identification of gene and protein names in biomedical text is a challenging task as the corresponding nomenclature has evolved over time. This has led to multiple synonyms for individual genes and proteins, as well as names that may be ambiguous with other gene names or with general English words. The Gene List Task of the BioCreAtIvE challenge evaluation enables comparison of systems addressing the problem of protein and gene name identification on common benchmark data. METHODS: The ProMiner system uses a pre-processed synonym dictionary to identify potential name occurrences in the biomedical text and associate protein and gene database identifiers with the detected matches. It follows a rule-based approach and its search algorithm is geared towards recognition of multi-word names. To account for the large number of ambiguous synonyms in the considered organisms, the system has been extended to use specific variants of the detection procedure for highly ambiguous and case-sensitive synonyms. Based on all detected synonyms for one abstract, the most plausible database identifiers are associated with the text. Organism specificity is addressed by a simple procedure based on additionally detected organism names in an abstract. RESULTS: The extended ProMiner system has been applied to the test cases of the BioCreAtIvE competition with highly encouraging results. In blind predictions, the system achieved an F-measure of approximately 0.8 for the organisms mouse and fly and about 0.9 for the organism yeast.

Computational Biology↗
PubMed1997

Investigation of the dynamics of the spread of human immunodeficiency virus to brain and other tissues by evolutionary analysis of sequences from the p17gag and env genes.

The time of spread of human immunodeficiency virus type 1 (HIV-1) from lymphoid to nonlymphoid tissues in the course of infection was investigated by sequence comparisons of variants infecting a range of lymphoid and nonlymphoid tissues from three individuals with AIDS in the pl7gag gene and regions flanking the V1/V2 hypervariable regions. Phylogenetic analysis in both regions revealed several lineages in each individual that contained sequences from both lymphoid and nonlymphoid tissues such as the brain. This observation contrasts strongly with the previously described organ-specific sequences in the V3 region in this study population and other investigations. Although individual pairwise comparisons of relatively short sequences such as p17gag are subject to considerable stochastic error, we found that the diversity of gag sequences in variants from lymphoid tissue was consistently lower than that found among variants amplified from the brain. By estimating mean synonymous pairwise distances in the p17gag region, we were able to make an approximate calculation of the ages of populations in different tissues. Those from lymphoid tissue ranged from 2.65 to 5.6 years in the three study subjects, compared with 4.1 to 6.2 years for variants in the brain. Indeed, variants infecting the brain were no more closely related to each other than they were to variants infecting other tissues in the body. In two of the three individuals, these times of divergence indicate that infection of the brain may have occurred as an early event in the progression to disease, preceding the onset of AIDS by several years. This study is the first in which it was possible to estimate times of diversification in different tissues in vivo and is of importance in understanding the dynamics of the spread of HIV-1 into nonlymphoid tissues and its possible adaptation for replication in different cell types.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Synonymous SNPs provide evidence for selective constraint on human exonic splicing enhancers.

The human SNP database was used to detect selection on 238 hexamers previously identified as exonic splicing enhancers (ESEs). We compared the distribution of the 238 putative ESEs in biallelic and triallelic SNPs within five different functional categories of the SNP database: synonymous, nonsynonymous, introns, UTRs, and nongenic SNPs. Since true ESEs do not function outside of exons, SNPs that disrupt ESE motifs were expected to be more common in nonexonic portions of the genome. Our results supported this expectation: ESEs were least prevalent within synonymous SNPs and most common in nongenic SNPs. There were approximately 11% fewer ESEs within synonymous biallelic SNPs than expected under no selective constraint. We also compared the frequency of neutral SNPs, those where neither allele was an ESE, with deleterious SNPs, those where one or more alleles was an ESE, across the five different functional classes of SNPs. In comparison with the other functional classes of SNPs, synonymous SNPs contained an excess of neutral variants (+1.64% and +6.04% for biallelic and triallelic SNPs, respectively) and a dearth of deleterious variants (-13.11% and -52.39% for biallelic and triallelic SNPs, respectively). The observed patterns were consistent with purifying selection on the 238 hexamers to maintain their function as ESEs. However, in contrast to previous work, we did not find evidence for selection to maintain ESE function at nonsynonymous SNPs because selection at the protein level probably obscured any difference at the level of ESE function.

Alternative Splicing↗
PubMed2025

Revisiting the question: When is a centromere not a kinetochore?

Centromeres have been the focus of extensive research for almost a century, so it may come as a surprise that a consistent definition and nomenclature for these structures remains elusive. In recent times, centromeric chromatin is most frequently defined by the presence of nucleosomes containing the H3 variant CENP-A and is typically synonymous with the site of the inner-kinetochore. However, crucial mammalian centromere proteins including CENP-B and INCENP have well defined distributions that show very little overlap with CENP-A. Additional protein localisations spanning the primary constriction or forming a band below CENP-A chromatin have been reported. Together, these observations suggest a complex and multi-layered chromatin organisation that is not well served by the canonical dichotomy of 'centromeric' and 'pericentromeric' chromatin. Strikingly, this is not a new observation but was made soon after the discovery of CENP proteins, including in a 1991 publication titled 'When is the centromere not a kinetochore?'. Here we revisit this question, which has become more pertinent following technical innovations in long-read sequencing and super-resolution microscopy. We present a model of centromere organisation for monocentromeres that incorporates additional complexity. We then use this model to reconceptualise diverse centromere forms in other eukaryotes including regional centromeres, holocentromeres and centromeres that lack key proteins including CENP-A. In this way, we hope to move towards a unified understanding of centromeric chromatin.

Centromere↗
PubMed1999

Associations between amino acids in the evolution of HIV type 1 protease sequences under indinavir therapy.

Significant diversity exists in amino acid sequences encoding HIV-1 protease in individuals naive for protease inhibitors, which could influence the rate of evolution of resistance. High-level resistance to indinavir requires multiple substitutions among at least 11 amino acid sites, and no single substitution was observed in all of 29 resistant isolates obtained from patients on long-term indinavir monotherapy. We have analyzed the evolution of PR in these sequences. The divergence from the baseline amino acid sequence by week 24 was 4%, increasing more than 7% by week 60. The mean difference between sequences from different patients at baseline was 6% (3-9%), rising to 10% after 40 weeks (3-16%), although at all time points nonsynonymous substitutions were less frequent than synonymous nucleotide changes. Analysis of associations between variants at different amino acid sites using a mutual information statistic revealed four pairs of sites to be significantly associated. In three cases these associations included residue 82. Clusters of baseline and week 24 amino acid sequences identified by maximum parsimony did not correlate significantly with the IC95 to indinavir, although a weak correlation of baseline clusters with phenotype at the week 24 time point was suggested.

Amino Acid Sequence↗
PubMed2005

The variation of the novel allele HLA-B*0739 suggests low alloreactivity when mismatched with HLA-B*0702.

We here report the identification of a new HLA-B*07 allele in a male Caucasian. The new allele was initially typed as B*0713 by sequence-specific primed PCR. Because of the infrequence of that allele, a sequencing-based typing was performed to confirm that result. This yielded the detection of the novel allele. It is closest to B*070201, while it differs from B*0713 in 12 positions in exon 2. Compared to B*070201, the new variant is characterized by a non-synonymous nucleotide exchange (C-->T) at nucleotide position 118 of exon 2. Previously, this was considered a constant position, suggesting that it is likely to be caused by a single-point mutation. It results in the amino acid exchange Ala-->Val at position 40 of the mature polypeptide. As this position is located in an outer loop of the HLA molecule, it is highly unlikely to affect peptide binding or T-cell receptor interaction. Thus, the newly found allele should have a low alloreactive potential in case of a mismatch to the most common HLA-B allele B*0702.

Alleles↗
PubMed2004

Identification of some charcoal-black-pigmented CDC fermentative coryneform group 4 isolates as Rothia dentocariosa and some as Corynebacterium aurimucosum: proposal of Rothia dentocariosa emend. Georg and Brown 1967, Corynebacterium aurimucosum emend. Yassin et al. 2002, and Corynebacterium nigricans Shukla et al. 2003 pro synon. Corynebacterium aurimucosum.

Sixty-three clinical isolates of charcoal-black-pigmented, gram-positive coryneform rods were received for identification by the Centers for Disease Control and Prevention (CDC) and were provisionally designated CDC fermentative coryneform group 4 (FCG4). Forty-five of these were characterized by morphological, physiologic, antimicrobial susceptibility, cellular fatty acids, 16S rRNA gene sequencing, and DNA-DNA hybridization analyses. Nitrate reduction, cellular fatty acid analysis, 16S rRNA gene sequencing, and DNA-DNA hybridization studies segregated these strains into two groups: FCG4a (8 strains) and FCG4b (37 strains). The FCG4a strains, only one of which was from a female genitourinary source, produced cellular fatty acid and biochemical profiles similar to those observed with reference strains of Rothia dentocariosa and Rothia mucilaginosa, while the FCG4b strains were similar to Corynebacterium species. DNA-DNA hybridization analysis demonstrated species-level relatedness among six FCG4a tested strains and showed that they were a charcoal-black-pigmented variant of R. dentocariosa. Sixteen isolates of the FCG4b group, mainly from female genitourinary tract specimens, as well as the type strains of two recently named species, Corynebacterium aurimucosum and Corynebacterium nigricans, were shown by DNA-DNA hybridization analysis and the sequencing of the 16S rRNA gene to be related at the species level and unrelated to the type strain of R. dentocariosa; therefore, the Corynebacterium-like strains were classified as a charcoal-black-pigmented variant of C. aurimucosum, because this name has nomenclatural priority over C. nigricans. These findings indicate that FCG4 represents a heterogeneous group that contains pigmented variants of both R. dentocariosa and C. aurimucosum; hence, the descriptions of both R. dentocariosa and C. aurimucosum have been amended to include charcoal-black-pigmented variants, and C. nigricans is a pro synonym of C. aurimucosum.

Centers for Disease Control and Prevention, U.S.↗
PubMed2005

Four new mutations in the BCHE gene of human butyrylcholinesterase in a Brazilian blood donor sample.

The genetic variation of human butyrylcholinesterase has been associated with height, body mass index, Alzheimer's disease, and response to xenobiotic agents. The present study reports four new mutations, found in the exon 2 of the BCHE gene, in a sample from 3001 Brazilian blood donors. The three nonsynonymous mutations and one synonymous mutation detected are: 223G-->C, G75R; 270A-->C, E90 D; 297T-->G, I99 M; 486T-->C, A162 A, respectively. All these variants are rare: 0.093+/-0.093% for the missense mutations and 0.137+/-0.137% for the synonymous mutation. A table with the 58 non-usual variants of butyrylcholinesterase is also presented.

Blood Donors↗
PubMed2000

The effects of Hill-Robertson interference between weakly selected mutations on patterns of molecular evolution and variation.

Associations between selected alleles and the genetic backgrounds on which they are found can reduce the efficacy of selection. We consider the extent to which such interference, known as the Hill-Robertson effect, acting between weakly selected alleles, can restrict molecular adaptation and affect patterns of polymorphism and divergence. In particular, we focus on synonymous-site mutations, considering the fate of novel variants in a two-locus model and the equilibrium effects of interference with multiple loci and reversible mutation. We find that weak selection Hill-Robertson (wsHR) interference can considerably reduce adaptation, e.g., codon bias, and, to a lesser extent, levels of polymorphism, particularly in regions of low recombination. Interference causes the frequency distribution of segregating sites to resemble that expected from more weakly selected mutations and also generates specific patterns of linkage disequilibrium. While the selection coefficients involved are small, the fitness consequences of wsHR interference across the genome can be considerable. We suggest that wsHR interference is an important force in the evolution of nonrecombining genomes and may explain the unexpected constancy of codon bias across species of very different census population sizes, as well as several unusual features of codon usage in Drosophila.

Alleles↗
PubMed1997

The origin of hepatitis C virus genotypes.

For many RNA viruses, relatively recent times of origin of extant viruses are implied by the high rate of substitution observed in longitudinal studies. However, extrapolation of short-term rates of substitution can give misleading estimates of times of divergence. We show here that the common ancestor of different types of hepatitis C virus (HCV) is older than previously thought. The rate of HCV sequence change was measured amongst a cohort of individuals infected following administration of anti-D immunoglobulin. Virus sequences were obtained in the E1 and NS5B genes and compared with each other and with sequences from an infective batch. Taking account of the bias towards synonymous transition substitutions, the time of divergence of variants of subtype 1b is estimated to have occurred 70-80 years ago. The numerous subtypes of HCV are proposed to derive from more than 300 years of endemic infection in certain geographical regions, with recent spread of some subtypes to other parts of the world. Estimation of the time of origin of the major HCV genotypes (types 1-6) is problematic, but our data and analogy with other viruses suggest that divergence occurred at least 500-2000 years ago.

Antibodies, Anti-Idiotypic↗
PubMed1996

Intratype variation in 12 human papillomavirus types: a worldwide perspective.

In this study, we have examined intratype human papillomavirus (HPV) sequence variation in a worldwide collection of cervical specimens. Twelve different HPV types including HPV-18, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-58, HPV-59, HPV-68 (ME180), MM9/PAP238A (recently designated HPV-73), and a novel partial genomic HPV sequence designated MM4/Wl3B were analyzed in this study. Cervical specimens were collected as part of epidemiological investigations conducted in New Mexico and an international study of invasive cervical cancer (IBSCC). Specimens from several countries including Argentina, Brazil, Bolivia, Benin, Cuba, Colombia, Chile, Germany, Mali, Panama, Paraguay, Spain, Algeria, Uganda, Guinea, Tanzania, Indonesia, Philippines, Thailand, and the United States were evaluated. Specimen DNAs were subjected to amplification with the MY09/11 L1 consensus PCR system. The PCR products were cloned, and an approximately 410-bp region in the L1 open reading frame was sequenced from 146 specimens (approximately 60,000 bp). Within a single HPV type, nucleotide diversity varied between 0.2 and 2.9% (i.e., between any pair of variants) and the majority of nucleotide changes were synonymous (amino acid conserving). These data provide information pertinent to HPV diagnostic probe development and are potentially relevant to future rational vaccine strategies. Similarly, amino acid diversity varied between 0 and 5.1%. Some of these amino acid changes may represent markers of intertype evolutionary relationships. Presuming that HPVs have evolved under the same constraints as their corresponding hosts, the limited genetic diversity observed for all HPVs studied to date may reflect an evolutionary bottleneck occurring in both virus and host populations.

Amino Acid Sequence↗
PubMed2004

Mitochondrial cytochrome B DNA variation in the high-fecundity atlantic cod: trans-atlantic clines and shallow gene genealogy.

An analysis of sequence variation of 250 bp of the mitochondrial cytochrome b gene of 1278 Atlantic cod Gadus morhua ranging from Newfoundland to the Baltic shows four high-frequency (>8%) haplotypes and a number of rare and singleton haplotypes. Variation is primarily synonymous mutations. Natural selection acting directly on these variants is either absent or very weak. Common haplotypes show regular trans-Atlantic clines in frequencies and each of them reaches its highest frequency in a particular country. A shallow multifurcating constellation gene genealogy implies young age and recent turnover of polymorphism. Haplotypes characterizing populations at opposite ends of the geographic distribution in Newfoundland and the Baltic are mutationally closest together. The haplotypes are young and have risen rapidly in frequency. Observed differentiation among countries is due primarily to clinal variation. Hypotheses of historical isolation and polymorphisms balanced by local selection and gene flow are unlikely. Instead the results are explained by demic selection of mitochondria carried by highly fit females winning reproductive sweepstakes. By inference the Atlantic cod, a very high-fecundity vertebrate, is characterized by a high variance of offspring number and strong natural selection that leads to very low effective to actual population sizes.

Analysis of Variance↗
PubMed1983

[Biological essence of the squamous-cell structures in 2-component endometrial cancer].

Combined comparative study of anatomo-histological features, proliferative activity, content of X-chromatin, and ploidy of the nuclei of epithelial structures of 7 adenoacanthomas, 8 glandular-squamous cell carcinomas, and 7 adenocarcinomas (control group) of the endometrium was carried out. Microspectrophotometry of DNA revealed heterogeneity in DNA content and polyploidy typical of malignant growth in all cell populations, including squamous cell component of adenoacanthomas. The correlation between reduced degree of histological differentiation, depth of invasion, and decreased number of nuclei containing X-chromatin bodies as well as the occurrence of histological transitions suggest that adenoacanthomas and glandular-squamous cell carcinomas should be regarded as one group of two-component endometrial tumors and the terms used for their designations as synonyms. Within this group, highly and poorly differentiated variants may be distinguished which is of prognostic importance.

Adenocarcinoma↗
PubMed1998

SAPHIRE International: a tool for cross-language information retrieval.

The world's foremost medical literature is written in English, yet much of the world does not speak English as a primary language. This has led to increasing research interest in cross-language information retrieval, where textual databases are queried in languages other than the one in which they are written. We describe enhancements to the SAPHIRE concept-retrieval system, which maps free-text documents and queries to concepts in the UMLS Metathesaurus, that allow it to accept text input and provide Metathesaurus concept output in any of six languages: English, German, French, Russian, Spanish, and Portuguese. An example of the use of SAPHIRE International is shown in the CliniWeb catalogue of clinically-oriented Web pages. A formative evaluation of German terms shows that additional work is required in handling plural and other suffix variants as well as expanding the breadth of synonyms in the UMLS Metathesaurus.

Clinical Medicine↗
PubMed2005

Human papillomavirus type 16 E2 and E6/E7 variants.

OBJECTIVES: Polymorphisms in human papillomavirus (HPV) type 16 have been shown to be related to geographic areas and are broadly classified as European (E), African (Af), Asian (As), or Asian-American (AA). Certain variants have been reported as being more likely to cause cervical disease; our objectives were to identify new HPV16 polymorphisms, to determine the linkage of the E2 and E6/E7 regions and to determine the minimum sequence necessary to classify variants. METHODS: We sequenced the complete E2, E6, and E7 regions in all HPV16-positive cervical samples identified in a case-control study of pre-invasive cervical disease. RESULTS: In the 100 samples analyzed, only one new polymorphism was identified, a synonymous change, T3205A, in region E2. The frequency distribution of variants in the sample set was 37 European prototypes and 27 E-G350, 16 AA, 5 Af1, 2 Af2, 8 E-C109G, 3 E-G131G, and 2 As. As shown by others, region E7 varied much less than E6 and E2. CONCLUSIONS: In each case, E2 changes were linked to the expected E6/E7 changes, and there was no evidence for recombination. The linkage between E2 and E6/E7 allows variant classification to be based on a short E6 sequence (nt 109-350).

Base Sequence↗
PubMed1998

Long-term evolution of the hypervariable region of hepatitis C virus in a common-source-infected cohort.

The long-term evolution of the hepatitis C virus hypervariable region (HVR) and flanking regions of the E1 and E2 envelope proteins have been studied in a cohort of women infected from a common source of anti-D immunoglobulin. Whereas virus sequences in the infectious source were relatively homogeneous, distinct HVR variants were observed in each anti-D recipient, indicating that this region can evolve in multiple directions from the same point. Where HVR variants with dissimilar sequences were present in a single individual, the frequency of synonymous substitution in the flanking regions suggested that the lineages diverged more than a decade previously. Even where a single major HVR variant was present in an infected individual, this lineage was usually several years old. Multiple lineages can therefore coexist during long periods of chronic infection without replacement. The characteristics of amino acid substitution in the HVR were not consistent with the random accumulation of mutations and imply that amino acid replacement in the HVR was strongly constrained. Another variable region of E2 centered on codon 60 shows similar constraints, while HVR2 was relatively unconstrained. Several of these features are difficult to explain if a neutralizing immune response against the HVR is the only selective force operating on E2. The impact of PCR artifacts such as nucleotide misincorporation and the shuffling of dissimilar templates is discussed.

Amino Acid Sequence↗