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PubMed2026

Charting host structural variations in cervical cancer by long-read sequencing pinpoints a functional deletion in PIAS1.

Host structural variations (SVs) are critical in cancer development but their landscape and interaction with HPV integration in cervical carcinogenesis remain unclear. In this study, we performed Nanopore long-read sequencing on five HPV-positive cervical cancer tissues and two cell lines to profile host SVs. We identified thousands of SVs and statistically demonstrated their significant enrichment in genomic windows ±25 to ±50 kb from HPV integration sites. Cross-sample analysis revealed 60 shared SVs, including a recurrent deletion within the PIAS1 gene. Multi-omics integration (Hi-C, H3K27ac ChIP-seq, and TCGA data) showed that this deletion is associated with reduced PIAS1 expression, disruption of local topologically associating domains, advanced pathological tumor stage, and poorer overall survival. Functional assays confirmed that PIAS1 deficiency inhibits cervical cancer cell proliferation and migration. Our findings identify a PIAS1 deletion as a candidate driver event, and underscore the pivotal role of host genomic instability in HPV-associated oncogenesis.

Cervical cancer↗
PubMed1990

Immunoglobulin heavy chain gene organization and complexity in the skate, Raja erinacea.

Immunoglobulin heavy chain genes from Raja erinacea have been isolated by cross hybridization with probes derived from the immunoglobulin genes of Heterodontus francisci (horned shark), a representative of a different elasmobranch order. Heavy chain variable (VH), diversity (DH) and joining (JH) segments are linked closely to constant region (CH) exons, as has been described in another elasmobranch. The nucleotide sequence homology of VH gene segments within Raja and between different elasmobranch species is high, suggesting that members of this phylogenetic subclass may share one VH family. The organization of immunoglobulin genes segments is diverse; both VD-J and VD-DJ joined genes have been detected in the genome of non-lymphoid cells. JH segment sequence diversity is high, in contrast to that seen in a related elasmobranch. These data suggest that the clustered V-D-J-C form of immunoglobulin heavy chain organization, including germline joined components, may occur in all subclasses of elasmobranchs. While variation in VH gene structure is limited, gene organization appears to be diverse.

Amino Acid Sequence↗
PubMed1995

Mini-chromosomes in Fusarium sporotrichioides are mosaics of dispersed repeats and unique sequences.

Variations in trichothecene patterns of 26 Fusarium sporotrichioides isolates from different plant and geographic origins showed no correlation with electrophoretic karyotype polymorphisms. When intact chromosomes were examined, interisolate karyotype differences were observed only in the mini-chromosome range. Further polymorphisms were revealed in Notl-digested samples. By summing the Notl fragments the average genome size of F. sporotrichioides was estimated to be 20.4 Mb. Mini-chromosomes shared common sequences with the larger ones; however, clones (RMS-1 and RMS-2) specific to these structures have also been found. These clones contained no coding region and no promising similarities were observed when they were compared to sequences held at GenBank. Mini-chromosomes in F. sporotrichioides constitute a mosaic composed of dispersed repeats and unique sequences. This mosaic structure was maintained in all noninterbreeding, genetically isolated strains examined.

Chromosomes, Fungal↗
PubMed2002

Plant molecular diversity and applications to genomics.

Surveys of nucleotide diversity are beginning to show how genomes have been shaped by evolution. Nucleotide diversity is also being used to discover the function of genes through the mapping of quantitative trait loci (QTL) in structured populations, the positional cloning of strong QTL, and association mapping.

Chromosome Mapping↗
PubMed2026

Cross-kingdom genomic variation in chicken gut microbiomes: insights from China's diverse local breeds.

BACKGROUND: The gut microbiome possesses substantial genetic diversity that supports microbial adaptation, but the genomic variation patterns across its prokaryotic and viral populations remain incompletely characterized. RESULTS: Through integrated metagenomic and metatranscriptomic analysis of ten indigenous chicken breeds from China, we recovered 1527 representative prokaryotic MAGs, 37,555 representative DNA viral contigs, and 1867 representative RNA viral contigs (primarily comprising Bacillota/Bacteroidota, Uroviricota, and Lenarviricota/Pisuviricota, respectively). By integrating complementary short-read and long-read metagenomics with metatranscriptomics, we identified structural variants (SVs) and single-nucleotide variants (SNVs) in these cross-kingdom genomes. Positive SV-SNV density correlations occurred consistently across all microbial groups, indicating coordinated mutational processes. DNA viruses exhibited the highest variant prevalence (86.9% SNVs, 47.7% SVs), with temperate phages accumulating significantly more variants than virulent phages. Functionally, prokaryotic variants accumulated in carbohydrate metabolism and amino acid metabolism, while viral variants demonstrated broad metabolic hijacking. Horizontal gene transfer (HGT) was characterized by a strong virus-associated signature (69.40% of 536 events) and marked by an asymmetric pattern, with phage-to-bacteria (P-to-B) flow alone constituting 37.50% of all events. Random forest analysis revealed a strong bidirectional predictive relationship between SV and SNV densities across prokaryotic, DNA viral, and RNA viral populations, suggesting coupled genomic instability. Niche breadth emerged as a major driver of SNVs across kingdoms and was positively correlated with variant density. In prokaryotes, HGT events significantly shaped variant patterns. For viruses, genomic GC content was an important factor and consistently showed a negative correlation with SNV density in both DNA and RNA viruses. CONCLUSIONS: These findings demonstrate that coordinated mutational processes and kingdom-specific intrinsic factors drive genomic variation, with viruses serving as key genetic exchange vectors in chicken gut ecosystems. Video Abstract.

Animals↗
PubMed2002

Patterns of positive selection in the complete NBS-LRR gene family of Arabidopsis thaliana.

Plant disease resistance genes have been shown to be subject to positive selection, particularly in the leucine rich repeat (LRR) region that may determine resistance specificity. We performed a genome-wide analysis of positive selection in members of the nucleotide binding site (NBS)-LRR gene family of Arabidopsis thaliana. Analyses were possible for 103 of 163 NBS-LRR nucleotide sequences in the genome, and the analyses uncovered substantial evidence of positive selection. Sites under positive selection were detected and identified for 10 sequence groups representing 53 NBS-LRR sequences. Functionally characterized Arabidopsis resistance genes were in these 10 groups, but several groups with extensive evidence of positive selection contained no previously characterized resistance genes. Amino acid residues under positive selection were identified, and these residues were mapped onto protein secondary structure. Positively selected positions were disproportionately located in the LRR domain (P < 0.001), particularly a nine-amino acid beta-strand submotif that is likely to be solvent exposed. However, a substantial proportion (30%) of positively selected sites were located outside LRRs, suggesting that regions other than the LRR may function in determining resistance specificity. Because of the unusual sequence variability in the LRRs of this class of proteins, secondary-structure analysis identifies LRRs that are not identified by similarity analyses alone. LRRs also contain substantial indel variation, suggesting elasticity in LRR length could also influence resistance specificity.

Amino Acid Sequence↗
PubMed2002

Analysis of the phylogenetic distribution of isochores in vertebrates and a test of the thermal stability hypothesis.

Warm-blooded vertebrates show large-scale variation in G + C content along their chromosomes, a pattern which appears to be largely absent from cold-blooded vertebrates. However, compositional variation in poikilotherms has generally been studied by ultracentrifugation rather than sequence analysis. In this paper, we investigate the compositional properties of coding sequences from a broad range of vertebrate poikilotherms using DNA sequence analysis. We find that on average poikilotherms have lower third-codon position GC contents (GC3) than homeotherms but that some poikilotherms have higher mean GC3 values. We find that most poikilotherms have lower variation in GC3 than homeotherms but that there is a correlation between GC12 and GC3 for some species, indicating that there is systematic variation in base composition across their genomes. We also demonstrate that the GC3 of genes in the zebrafish, Danio rerio, is correlated with that in humans, suggesting that vertebrates share a basic isochore structure. However, we find no correlation between either the mean GC3 or the standard deviation in GC3 and body temperature.

Animals↗
PubMed2003

Sequencing and analysis of the genome of the Whipple's disease bacterium Tropheryma whipplei.

BACKGROUND: Whipple's disease is a rare multisystem chronic infection, involving the intestinal tract as well as various other organs. The causative agent, Tropheryma whipplei, is a Gram-positive bacterium about which little is known. Our aim was to investigate the biology of this organism by generating and analysing the complete DNA sequence of its genome. METHODS: We isolated and propagated T whipplei strain TW08/27 from the cerebrospinal fluid of a patient diagnosed with Whipple's disease. We generated the complete sequence of the genome by the whole genome shotgun method, and analysed it with a combination of automatic and manual bioinformatic techniques. FINDINGS: Sequencing revealed a condensed 925938 bp genome with a lack of key biosynthetic pathways and a reduced capacity for energy metabolism. A family of large surface proteins was identified, some associated with large amounts of non-coding repetitive DNA, and an unexpected degree of sequence variation. INTERPRETATION: The genome reduction and lack of metabolic capabilities point to a host-restricted lifestyle for the organism. The sequence variation indicates both known and novel mechanisms for the elaboration and variation of surface structures, and suggests that immune evasion and host interaction play an important part in the lifestyle of this persistent bacterial pathogen.

Female↗
PubMed2001

10th International Hugo mutation database initiative meeting, 19 April 2001, Edinburgh, Scotland.

The 10th International Mutation Database Initiative Meeting was held on April 19, 2001, in conjunction with the annual Human Genome Meeting in Edinburgh, Scotland. Key points of the meeting are described here. The BiSC WayStation was presented as an operational, viable beginning to the solution for the lack of centralized variation collection structures, with a number of possibilities, notably the BiSC Central Database and HGBASE, as candidates for storing the data. Exploration of new avenues of funding for this project, affiliation with Wiley-Liss, and the establishment of the Mutation Database Initiative (MDI) as a society were also discussed.

Databases, Nucleic Acid↗
PubMed2003

Evidence of a high rate of selective sweeps in African Drosophila melanogaster.

Assessing the rate of evolution depends on our ability to detect selection at several genes simultaneously. We summarize DNA sequence variation data in three new and six previously published data sets from the left arm of the second chromosome of Drosophila melanogaster in a population from West Africa, the presumed area of origin of this species. Four loci [Acp26Aa, Fbp2, Vha68-1, and Su(H)] were previously found to deviate from a neutral mutation-drift equilibrium as a consequence of one or several selective sweeps. Polymorphism data from five loci from intervening regions (dpp, Acp26Ab, Acp29AB, GH10711, and Sos) did not show the characteristic deviation from neutrality caused by local selective sweeps. This genomic region is polymorphic for the In(2L)t inversion. Four loci located near inversion breakpoints [dpp, sos, GH10711, and Su(H)] showed significant structuring between the two arrangements or significant deviation from neutrality in the inverted class, probably as a result of a recent shift in inversion frequency. Overall, these patterns of variation suggest that the four selective events were independent. Six loci were observed with no a priori knowledge of selection, and independent selective sweeps were detected in three of them. This suggests that a large part of the D. melanogaster genome has experienced the effect of positive selection in its ancestral African range.

Africa, Western↗
PubMed2006

Genome-wide analysis of C/D and H/ACA-like small nucleolar RNAs in Leishmania major indicates conservation among trypanosomatids in the repertoire and in their rRNA targets.

Small nucleolar RNAs (snoRNAs) are a large group of noncoding RNAs that exist in eukaryotes and archaea and guide modifications such as 2'-O-ribose methylations and pseudouridylation on rRNAs and snRNAs. Recently, we described a genome-wide screening approach with Trypanosoma brucei that revealed over 90 guide RNAs. In this study, we extended this approach to analyze the repertoire of the closely related human pathogen Leishmania major. We describe 23 clusters that encode 62 C/Ds that can potentially guide 79 methylations and 37 H/ACA-like RNAs that can potentially guide 30 pseudouridylation reactions. Like T. brucei, Leishmania also contains many modifications and guide RNAs relative to its genome size. This study describes 10 H/ACAs and 14 C/Ds that were not found in T. brucei. Mapping of 2'-O-methylations in rRNA regions rich in modifications suggests the existence of trypanosomatid-specific modifications conserved in T. brucei and Leishmania. Structural features of C/D snoRNAs, such as copy number, conservation of boxes, K turns, and intragenic and extragenic base pairing, were examined to elucidate the great variation in snoRNA abundance. This study highlights the power of comparative genomics for determining conserved features of noncoding RNAs.

Animals↗
PubMed2000

An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes.

Arylamine N:-acetyltransferase (NAT) was first identified as the inactivator of the anti-tubercular drug isoniazid. The enzyme was shown to catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of the hydrazine drug. The rate of inactivation of isoniazid was polymorphically distributed in the population and was one of the first examples of pharmacogenetic variation. NAT was identified recently in Mycobacterium tuberculosis and is a candidate for modulating the response to isoniazid. Genome sequences have revealed many homologous members of this unique family of enzymes. The first three-dimensional structure of a member of the NAT family identifies a catalytic triad consisting of aspartate, histidine and cysteine proposed to form the activation mechanism. So far, all procaryotic NATs resemble the human enzyme which acetylates isoniazid (NAT2). Human NAT2 is characteristic of drug-metabolizing enzymes: it is found in liver and intestine. In humans and other mammals, there are up to three different isoenzymes. If only one isoenzyme is present, it is like human NAT1. Human NAT1 and its murine equivalent specifically acetylate the folate catabolite p-aminobenzoylglutamate. NAT1 and its murine homologue each have a ubiquitous tissue distribution and are expressed early in development at the blastocyst stage. During murine embryonic development, NAT is expressed in the developing neural tube. The proposed endogenous role of NAT in folate metabolism, and its multi-allelic nature, indicate that its role in development should be assessed further.

Animals↗
PubMed2004

A locus contained within a variable region of pneumococcal pathogenicity island 1 contributes to virulence in mice.

We have previously described a 27-kb pathogenicity island of Streptococcus pneumoniae, termed pneumococcal pathogenicity island 1 (PPI1), which contains iron uptake locus piaABCD, required for full virulence in mice, and a further 28 previously uncharacterized genes. We have investigated one of these, Sp1051, which encodes a protein of unknown function. Disruption of Sp1051 does not affect growth in laboratory broth, serum, or blood but impairs virulence in mouse models of infection. When S. pneumoniae capsular serotypes were analyzed by PCR and Southern hybridization, it was found that 33% did not contain Sp1051. Analysis of other genes within PPI1 demonstrated that, compared to the serotype 4 genome published by The Institute for Genome Research (TIGR), the genomes of many strains contain deletions of a variable number of genes between Sp1046 and Sp1064, conforming to one of six different patterns. Amplification by PCR of this PPI1 variable region from a capsular serotype 17 strain and comparison of the sequence to TIGR serotype 4 strain sequence showed that Sp1051 is contained within an 11.3-kb segment of DNA flanked by 7-bp direct repeats within the serotype 4 strain which is not present in the serotype 17 strain. Further comparison of the sequences of this region between the three published S. pneumoniae genomes demonstrated that serotype 19F and strain R6 contain novel complements of genes not present in the serotype 4 strain. These data indicate that there is striking variation in gene content and structure of the 3' region of PPI1 among strains and that this region includes at least one virulence determinant. Gene variation within horizontally acquired DNA such as that of PPI1 may be one factor modulating differences in virulence among strains.

ATP-Binding Cassette Transporters↗
PubMed2000

[Increased variability of (TCC)n microsatelline loci in populations of the parthenogenetic lizard Lacerta unisexualis Darevsky].

In four isolated populations of parthenogenetic Caucasian rock lizard Lacerta unisexualis, variability of (TCC)n loci was examined using multilocus DNA fingerprinting. Unexpectedly high variability of (TCC)n microsatellites was found in all four populations. The mean similarity index was 0.825, which is higher than similarity estimates obtained for other mini- and microsatellite loci in L. unisexualis and parthenogenetic species L. dahli and L. armeniaca studied earlier. The high variation level of (TCC)n loci was shown to be at least partially associated with the presence of a diverged (TCC)n sequence fraction in the L. unisexualis genome. Mutations at some other genetically unstable (TCC)n loci may cause their structural diversity in populations of L. unisexualis.

Animals↗
PubMed1995

tRNAs are imported into mitochondria of Trypanosoma brucei independently of their genomic context and genetic origin.

The mitochondrial genome of Trypanosoma brucei does not encode any identifiable tRNAs. Instead, mitochondrial tRNAs are synthesized in the nucleus and subsequently imported into mitochondria. In order to analyse the signals which target the tRNAs into the mitochondria, an in vivo import system has been developed: tRNA variants were expressed episomally and their import into mitochondria assessed by purification and nuclease treatment of the mitochondrial fraction. Three tRNA genes were tested in this system: (i) a mutated version of the trypanosomal tRNA(Tyr); (ii) a cytosolic tRNA(His) of yeast; and (iii) a human cytosolic tRNA(Lys). The tRNAs were expressed in their own genomic context, or containing various lengths of the 5'-flanking sequence of the trypanosomal tRNA(Tyr) gene. In all cases efficient import of each of the tRNAs was observed. We independently confirmed the mitochondrial import of the yeast tRNA(His), since in organello [alpha-32P]ATP-labelling of the 3'-end of the tRNA was inhibited by carboxyatractyloside, a highly specific inhibitor of the mitochondrial adenine nucleotide translocator. Import of heterologous tRNAs in their own genomic contexts supports the conclusion that no specific targeting signals are necessary to import tRNAs into mitochondria of T. brucei, but rather that the tRNA structure itself is sufficient to specify import.

Animals↗
PubMed1992

Molecular cloning and nucleotide sequence of a pestivirus genome, noncytopathic bovine viral diarrhea virus strain SD-1.

Genomic RNA of noncytopathic (NCP) bovine viral diarrhea virus (BVDV) strain SD-1 was extracted directly from serum obtained from a persistently infected animal. cDNA was synthesized and amplified by polymerase chain reaction (PCR) before cloning. The complete genomic nucleotide sequence was determined by sequencing at least two different clones from independent PCR reactions. The 5' and 3' end sequences of the SD-1 genome was determined from 5'-3' ligation clones. The complete genome sequence was comprised of 12,308 nucleotides containing one large open reading frame which encodes an amino acid sequence of 3898 residues with a calculated molecular weight of 438 kDa. In contrast to cytopathic (CP) BVDV strain NADL, which contains a cellular RNA insert of 270 nucleotides and CP BVDV strain Osloss, which has an inserted ubiquitin RNA sequence of 228 nucleotides, the NCP strain SD-1 had no insertion along the genome. Sequence comparison with other pestiviruses revealed that the overall nucleotide sequence homologies of SD-1 are 88.6% with NADL, 78.3% with Osloss, 67.1% with HoCV Alfort, and 67.2% with HoCV Brescia. The overall deduced amino acid sequence homologies of SD-1 are 92.7% with NADL, 86.2% with Osloss, 72.5% with HoCV Alfort, and 71.2% with HoCV Brescia. The most conserved nucleotide and amino acid sequences are located in the 5' untranslated region (5'UTR) and nonstructural protein p80 region, respectively. The viral glycoproteins, particularly gp53, and nonstructural proteins p54 and p58 have the lowest homology comparing both nucleotide and amino acid sequences between SD-1 and other pestiviruses. Extensive analyses of amino acid sequences for the viral structural proteins and nonstructural protein p54 regions from five pestiviruses led to the identification of four conserved domains (designated as C1, C2, C3, C4) and three highly variable domains (designated as V1, V2, V3) within this region. The C1, C2, and C3 domains are located in the capsid protein p14, glycoprotein gp48, and gp25, respectively. The C4 domain is located in the junction between gp53 and p54. Interestingly, out of three variable domains, two (V1, V2) are located in the same glycoprotein gp53. The third variable domain is located in the nonstructural protein p54.

Amino Acid Sequence↗