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At least 199 records · Page 11Linked to original sources
PubMed2005

Microarray karyotyping of commercial wine yeast strains reveals shared, as well as unique, genomic signatures.

BACKGROUND: Genetic differences between yeast strains used in wine-making may account for some of the variation seen in their fermentation properties and may also produce differing sensory characteristics in the final wine product itself. To investigate this, we have determined genomic differences among several Saccharomyces cerevisiae wine strains by using a "microarray karyotyping" (also known as "array-CGH" or "aCGH") technique. RESULTS: We have studied four commonly used commercial wine yeast strains, assaying three independent isolates from each strain. All four wine strains showed common differences with respect to the laboratory S. cerevisiae strain S288C, some of which may be specific to commercial wine yeasts. We observed very little intra-strain variation; i.e., the genomic karyotypes of different commercial isolates of the same strain looked very similar, although an exception to this was seen among the Montrachet isolates. A moderate amount of inter-strain genomic variation between the four wine strains was observed, mostly in the form of depletions or amplifications of single genes; these differences allowed unique identification of each strain. Many of the inter-strain differences appear to be in transporter genes, especially hexose transporters (HXT genes), metal ion sensors/transporters (CUP1, ZRT1, ENA genes), members of the major facilitator superfamily, and in genes involved in drug response (PDR3, SNQ1, QDR1, RDS1, AYT1, YAR068W). We therefore used halo assays to investigate the response of these strains to three different fungicidal drugs (cycloheximide, clotrimazole, sulfomethuron methyl). Strains with fewer copies of the CUP1 loci showed hypersensitivity to sulfomethuron methyl. CONCLUSION: Microarray karyotyping is a useful tool for analyzing the genome structures of wine yeasts. Despite only small to moderate variations in gene copy numbers between different wine yeast strains and within different isolates of a given strain, there was enough variation to allow unique identification of strains; additionally, some of the variation correlated with drug sensitivity. The relatively small number of differences seen by microarray karyotyping between the strains suggests that the differences in fermentative and organoleptic properties ascribed to these different strains may arise from a small number of genetic changes, making it possible to test whether the observed differences do indeed confer different sensory properties in the finished wine.

Algorithms↗
PubMed2006

Patterns of genetic variation in the hypertension candidate gene GRK4: ethnic variation and haplotype structure.

Association studies using single nucleotide polymorphisms (SNPs) have the potential to help unravel the genetic basis of hypertension. Nevertheless, to date, association studies of hypertension have yielded ambiguous results. It is becoming clear that such association studies must be interpreted within the context of the genetic structure of the populations being studied, and patterns of variation within specific genomic regions. With this in mind we analyzed genetic variation in the G protein-coupled receptor kinase 4 (GRK4) gene, a gene whose product has recently been shown to inhibit the dopamine receptor D1 (DRD1) from increasing sodium excretion. We genotyped three previously identified GRK4 SNPs, as well as ten additional SNPs, over 71.6 kb of the GRK4 locus in four populations: African Americans, Asians, Hispanics and Caucasians. Haplotype structure varied among populations, with Hispanics and Caucasians having the most linkage disequilibrium (LD) among SNPs. African Americans had three shorter haplotype blocks, while patterns of markers in the Asian populations demonstrated less LD among markers, a pattern inconsistent with block structure. We observed limited haplotype diversity in each of the four populations, with differing haplotype frequencies among the ethnic groups. We also found substantial evidence for population differentiation, with the largest differences between the African-American and Asian samples with F(ST) values in the upper 90(th) percentile when compared to a genome-wide distribution. However, for all population comparisons, F(ST) values decreased sharply in the 3' region of the gene. This pattern of differentiation among populations is consistent with selection in this part of the gene maintaining similar patterns of variation among otherwise divergent populations. Our results document not only different allele frequencies between populations, but differences in haplotype structure that may be important in evaluating association studies between hypertension and GRK4.

Black or African American↗
PubMed1999

Genetic control of ventilation: what are we learning from murine models?

Advances in human and mouse genomes are revolutionizing research in lung biology and pulmonary medicine. Genomic strategies are available that link functional variation to molecular structure, and these approaches are currently being applied to the study of ventilatory control mechanisms. In this review, the author discusses the functional data obtained from inbred murine models in which genetic mutations and polymorphisms play a role in altered breathing. At the conclusion of this review, the author emphasizes the relatively small number of studies that have incorporated the use of genomics to link differential ventilatory function to molecular structure.

Animals↗
PubMed2006

Genome sequence alterations detected upon passage of Burkholderia mallei ATCC 23344 in culture and in mammalian hosts.

BACKGROUND: More than 12,000 simple sequence repeats (SSRs) have been identified in the genome of Burkholderia mallei ATCC 23344. As a demonstrated mechanism of phase variation in other pathogenic bacteria, these may function as mutable loci leading to altered protein expression or structure variation. To determine if such alterations are occurring in vivo, the genomes of various single-colony passaged B. mallei ATCC 23344 isolates, one from each source, were sequenced from culture, a mouse, a horse, and two isolates from a single human patient, and the sequence compared to the published B. mallei ATCC 23344 genome sequence. RESULTS: Forty-nine insertions and deletions (indels) were detected at SSRs in the five passaged strains, a majority of which (67.3%) were located within noncoding areas, suggesting that such regions are more tolerant of sequence alterations. Expression profiling of the two human passaged isolates compared to the strain before passage revealed alterations in the mRNA levels of multiple genes when grown in culture. CONCLUSION: These data support the notion that genome variability upon passage is a feature of B. mallei ATCC23344, and that within a host B. mallei generates a diverse population of clones that accumulate genome sequence variation at SSR and other loci.

Animals↗
PubMed2004

Genomic haplotype blocks may not accurately reflect spatial variation in historic recombination intensity.

Recently, genomic data have revealed a "block-like" structure of haplotype diversity on human chromosomes. This structure is anticipated to facilitate gene mapping studies, because strong associations among loci within a block may allow haplotype variation to be tagged with a limited number of markers. But its usefulness to mapping efforts depends on the consistency of the block structure within and among populations, which in turn depends on how the block structure arises. Recombination hot spots are generally thought to underlie the block structure, but haplotype blocks can also develop stochastically under random recombination, in which case the block structure will show limited consistency among populations. Using coalescent models, which we upscaled to simulate the evolution of haplotypes with many markers at fixed distances, we show that the relationship between block boundaries and historic recombination intensity may be surprisingly weak. The majority of historic recombinations do not leave a footprint in present-day linkage disequilibrium patterns, and the block structure is sensitive to factors that affect the timing of recombination relative to marker mutation events in the genealogy, such as marker frequency bias and historic population size changes. Our results give insight into the potential of stochastic events to affect haplotype block structure, which can limit the usefulness of the block structure to mapping studies.

Animals↗
PubMed1986

Pericentromeric heterochromatin and A-T contents during Robertsonian fusion in the house mouse.

The pericentromeric heterochromatin of meiotic trivalents formed by the Robertsonian (Rb) chromosomes and the two homologous acrocentrics in the house mouse was evaluated by static cytophotometry after selective staining. To reveal pericentromeric heterochromatin specifically, C-banding Giemsa and Hoechst 33258 stains were utilized. Five different Rb chromosomes were investigated and none of them possessed less pericentromeric heterochromatin than the sum of the two homologous acrocentrics. Moreover the total A-T (DAPI) and DNA (PI) content was quantitatively evaluated, by flow cytometry, in G0/G1 nuclei belonging to four different Rb mouse populations, karyotypically characterized by the presence of up to nine Rb chromosomes. Again there were no significant difference, of DAPI and PI content, in the Rb populations nor between any of them and the NMRI/HAN strain with forty acrocentric chromosomes. We conclude that the main consequence of Robertsonian processes (i.e. the rapid variation of the karyotype structure) does not imply detectable quantitative variation in the genome portion involved in the Rb process. We also discuss the possibility that the high rate of Rb exchange in the house mouse could be favoured by the simultaneous effects of undetectable losses of chromosomal material, high repetitiveness of the DNA involved, the presence of the same major type of satellite DNA over each chromosome and the all acrocentric constitution of the karyotype.

Adenine↗
PubMed2005

Comparative interactomics.

The behavior, morphology and response to stimuli in biological systems are dictated by the interactions between their components. These interactions, as we observe them now, are therefore shaped by genetic variations and selective pressure. Similar to what has been achieved by comparing genome structures and protein sequences, we hope to obtain valuable information about systems' evolution by comparing the organization of interaction networks and by analyzing their variation and conservation. Equally, significantly we can learn whether and how to extend the network information obtained experimentally in well-characterized model systems to different organisms. We conclude from our analysis that, despite the recent completion of several high throughput experiments aimed at the description of complete interactomes, the available interaction information is not yet of sufficient coverage and quality to draw any biologically meaningful conclusion from the comparison of different interactomes. Thus, the transfer of network information obtained from simple organism to evolutionary distant species should be carried out and considered with caution. By using smaller higher-confidence datasets, a larger fraction of interactions is shown to be conserved; this suggests that with the development of more accurate experimental and informatic approaches, we will soon be in the position to study the network evolution.

Animals↗
PubMed2005

Pharmacogenetics of the serotonin transporter.

Response to psychopharmacologic drugs is genetically complex, results from an interplay of multiple genomic variations with environmental influences, and depends on the structure or functional expression of gene products, which are direct drug targets or indirectly modify the development and synaptic plasticity of neural networks critically involved in their effects. During brain development, the serotonin (5HT) system, which is commonly targeted by antidepressant, anxiolytic, and antipsychotic drugs, controls neuronal specification, differentiation, and phenotype maintenance. While formation and integration of these neural networks is dependent on the action of multiple proteins, converging lines of evidence indicate that genetically controlled variability in the expression of the 5HT transporter (5HTT) is critical to the development and plasticity of distinct neurocircuits. The most promising finding to date indicate an association between the response time as well as overall response to serotonin reuptake inhibitors (SSRIs) and a common polymorphism (5HTTLPR) within the transcriptional control region of the 5HTT gene (SLC6A4) in patients with depressive disorders. The formation and maturation of serotonergic and associated systems, in turn, are influencing the efficacy of serotonergic compounds in a variety of psychiatric conditions. Based on the notion that complex gene x gene and gene x environment interactions in the regulation of brain plasticity are presumed to contribute to individual differences in psychopharmacologic drug response, the concept of developmental psychopharmacogenetics is emerging.

Animals↗
PubMed2025

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗
PubMed1997

Tissue culture adaptation of foot-and-mouth disease virus selects viruses that bind to heparin and are attenuated in cattle.

Isolates of foot-and-mouth disease virus (FMDV) exist as complex mixtures of variants. Two different serotype O1 Campos preparations that we examined contained two variants with distinct plaque morphologies on BHK cells: a small, clear-plaque virus that replicates in BHK and CHO cells, and a large, turbid-plaque virus that only grows in BHK cells. cDNAs encoding the capsids of these two variants were inserted into a genome-length FMDV type A12 infectious cDNA and used to produce chimeric viruses that exhibited the phenotype of the original variants. Analyses of these viruses, and hybrids created by exchanging portions of the capsid gene, identified codon 56 in VP3 (3056) as the critical determinant of both cell tropism and plaque phenotype. Specifically, the CHO growth/clear-plaque phenotype is dependent on the presence of the highly charged Arg residue at 3056, and viruses with this phenotype and genotype were selected during propagation in tissue culture. The genetically engineered Arg 3056 virus was highly attenuated in bovines, but viruses recovered from animals inoculated with high doses of this virus had lost the ability to grow in CHO cells and contained either an uncharged residue at 3056 or a negatively charged Glu substituted for a Lys at a spatially and antigenically related position on VP2 (2134). Comparison of these animal-derived viruses to other natural and engineered viruses demonstrated that positively charged residues are required at both 2134 and 3056 for binding to heparin. Taken together, these results indicate that in vitro cultivation of FMDV type O selects viruses that bind to heparin and that viruses with the heparin-binding phenotype are attenuated in the natural host.

Adaptation, Physiological↗
PubMed2006

Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1).

Cis-acting genetic variations can affect the amount and structure of mRNA/protein. Genomic surveys indicate that polymorphisms affecting transcription and mRNA processing, including splicing and turnover, may account for the main share of genetic factors in human phenotypic variability; however, most of these polymorphisms remain yet to be discovered. We use allelic expression imbalance (AEI) as a quantitative phenotype in the search for functional cis-acting polymorphisms in many genes, including ABCB1 (multidrug resistance 1 gene, MDR1, Pgp). Previous studies have shown that ABCB1 activity correlates with a synonymous polymorphism, C3435T; however, the functional polymorphism and molecular mechanism underlying this clinical association remained unknown. Analysis of allele-specific expression in liver autopsy samples and in vitro expression experiments showed that C3435T represents a main functional polymorphism, accounting for 1.5- to 2-fold changes in mRNA levels. The mechanism appears to involve increased mRNA turnover, probably as a result of different folding structures calculated for mRNA with the Mfold program. Other examples of the successful application of AEI analysis for studying functional polymorphism include 5-HTT (serotonin transporter, SLC6A4) and OPRM1 (mu opioid receptor). AEI is therefore a powerful approach for detecting cis-acting polymorphisms affecting gene expression and mRNA processing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Haplotype block structures show significant variation among populations.

Recent studies suggest that haplotypes tend to have block-like structures throughout the human genome. Several methods were proposed for haplotype block partitioning and for tagging single-nucleotide polymorphism (SNP) identification. In population genetics studies, several research groups compared block structures across human populations. However, the measures used to quantify population similarity are either less than satisfactory or nonexistent. In this article, we propose several similarity measures to facilitate the comparisons of haplotype structures, namely block boundaries and tagging SNPs, across populations. With these measures, we can more objectively compare haplotype block structures and tagging SNP sets between different populations. In addition, these measures allow us to compare the results of different methods for block partition and tagging SNP identification. When we applied these measures to a real data set on chromosome 10 in 16 worldwide populations, we found that in this genome region: 1) haplotype block boundaries vary among populations, with European and some African populations showing similar boundaries but other populations showing other patterns; 2) tagging SNP sets are generally similar for populations with similar haplotype block structures but differ if the block structures differ; and 3) all but one of the block finding methods we tested yield consistent results, although variations exist regarding consistency. Our tentative results show that at least in the genome region studied, it is unlikely that a common haplotype pattern exists for all human populations: many populations, even in the same geographical region, may have different haplotype patterns.

Chromosome Mapping↗
PubMed2003

Improving the Arabidopsis genome annotation using maximal transcript alignment assemblies.

The spliced alignment of expressed sequence data to genomic sequence has proven a key tool in the comprehensive annotation of genes in eukaryotic genomes. A novel algorithm was developed to assemble clusters of overlapping transcript alignments (ESTs and full-length cDNAs) into maximal alignment assemblies, thereby comprehensively incorporating all available transcript data and capturing subtle splicing variations. Complete and partial gene structures identified by this method were used to improve The Institute for Genomic Research Arabidopsis genome annotation (TIGR release v.4.0). The alignment assemblies permitted the automated modeling of several novel genes and >1000 alternative splicing variations as well as updates (including UTR annotations) to nearly half of the approximately 27 000 annotated protein coding genes. The algorithm of the Program to Assemble Spliced Alignments (PASA) tool is described, as well as the results of automated updates to Arabidopsis gene annotations.

Algorithms↗
PubMed2026

Dual-dimensional profiling of host genomic variations and HPV integration in PD-L1-stratified cervical cancer via Oxford Nanopore Technology.

BACKGROUND: The integration of human papillomavirus (HPV) DNA into the host genome is a key step in the development of HPV-associated cervical cancer (CC). However, the genomic characteristics of host genomic variations and HPV integration within the context of programmed death-ligand 1 (PD-L1) expression stratification have not been systematically investigated. METHODS: Whole-genome sequencing was performed using Oxford Nanopore Technology (ONT) on six samples (three from the high PD-L1 expression group and three from the low PD-L1 expression group). The characteristics of host genomic variations under different PD-L1 expression stratifications were explored, including structural variations (SV), copy number variations (CNV), single nucleotide polymorphisms (SNP), and insertion-deletions (Indel). Subsequently, the distribution features of HPV integration sites were analyzed, different integration types were identified, and pathway analysis was conducted. RESULTS: Whole-genome SV analysis revealed that the total number of SVs and the composition of mutation types were similar between the high and low PD-L1 expression groups, with insertions (INS) and deletions (DEL) predominating in both. These variations were primarily enriched in intergenic regions and introns. In the low PD-L1 expression group, integration events were observed at multiple chromosomal loci, with the most frequent integration occurring in the KLF5 gene region on chromosome 13. No frequently integrated loci were identified in the high PD-L1 expression group. Additionally, four distinct HPV integration breakpoint patterns were preliminarily identified and analyzed. CONCLUSION: PD-L1 expression stratification did not significantly alter the overall genomic instability of the host. However, differences were observed in the distribution patterns of HPV integration sites. These findings provide new insights into the genomic heterogeneity of CC under different PD-L1 expression backgrounds and may lay the groundwork for future research exploring stratified immunotherapy based on HPV integration features.

Humans↗
PubMed2005

Impact of natural variation in bacterial F17G adhesins on crystallization behaviour.

Since the introduction of structural genomics, the protein has been recognized as the most important variable in crystallization. Recent strategies to modify a protein to improve crystal quality have included rationally engineered point mutations, truncations, deletions and fusions. Five naturally occurring variants, differing in 1-18 amino acids, of the 177-residue lectin domain of the F17G fimbrial adhesin were expressed and purified in identical ways. For four out of the five variants crystals were obtained, mostly in non-isomorphous space groups, with diffraction limits ranging between 2.4 and 1.1 A resolution. A comparative analysis of the crystal-packing contacts revealed that the variable amino acids are often involved in lattice contacts and a single amino-acid substitution can suffice to radically change crystal packing. A statistical approach proved reliable to estimate the compatibilities of the variant sequences with the observed crystal forms. In conclusion, natural variation, universally present within prokaryotic species, is a valuable genetic resource that can be favourably employed to enhance the crystallization success rate with considerably less effort than other strategies.

Adhesins, Bacterial↗
PubMed1980

Analyses of variable antigen gene rearrangements in Trypanosoma brucei.

For the purpose of investigating the genetic basis of antigenic variation in Trypanosoma brucei, we have analyzed the structure of the genome surrounding the gene coding for one T. brucei variable antigen (ILTat 1.2) in several T. brucei clones expressing this and other variable antigens. In each case there are two copies of the gene. We found no evidence of an extra copy associated with the expression of this gene. Differences were found between the two copies in a single clone, and between the copies in different clones. The differences could be explained by insertion and deletion of various lengths of DNA in a region beyond the C-terminal end of the gene. Differences in genomic structure were found even between clones expressing the same antigen, whether ILTat 1.2 or another. Thus, no feature of the rearrangements observed can be correlated with the expression of a particular antigen.

Animals↗
PubMed2003

Conservation of a gene conversion mechanism in two distantly related paralogues of Anaplasma marginale.

Anaplasmataceae, the causative agents of anaplasmosis and ehrlichiosis, persist in the bloodstream of their mammalian hosts, allowing acquisition and transmission by tick vectors. Anaplasma marginale establishes persistent infection characterized by sequential cycles of rickettsaemia in which new antigenic variants emerge. The two most immunodominant outer membrane proteins, MSP2 and MSP3, are paralogues, each encoded by a distinct family of related genes. This study demonstrates that, although the two gene families have diverged substantially, each has maintained a similar mechanism to generate structurally and antigenically polymorphic surface antigens. Like MSP2, MSP3 is expressed from a single locus in which variation of the expressed msp3 gene is generated by recombination using msp3 pseudogenes. Each of the msp3 pseudogenes encodes a unique central variable region (CVR) flanked by conserved 5' and 3' regions. Changes in the CVR of the expressed msp3, concomitant with invariance of the pseudogenes, indicate that expression site variation is generated using gene conversion. A. marginale thus maintains two large, separate systems within its small genome to generate antigenic variation of its surface proteins, while analogous structural elements indicate a common mechanism.

Acute Disease↗