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Results for “Genomic Structural Variation”

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PubMed1996

AF4/FEL, a gene involved in infant leukemia: sequence variations, gene structure, and possible homology with a genomic sequence on 5q31.

The most common chromosome abnormality among infants with acute lymphoblastic leukemia is a t(4;11)(q2l;q23) and patients with this 4;11 translocation have a very poor prognosis. This unique genetic rearrangement fuses the MLL/ALL-1/HRX-Htrx gene at 11q23 with the AF4/FEL gene at 4q21. The resulting chimeric mRNAs presumably encode chimeric proteins which contribute to the leukemogenic state. The AF4 gene remains poorly understood with an unknown function. In this report, we describe the cDNA sequence information from human placental tissue where AF4 mRNA is highly expressed. We identified six intron-exon boundaries in the AF4 genomic structure and discussed more than 30 AF4 cDNA sequence variations reported in the literature. In addition, we identified three overlapping genomic sequences in GenBank entitled the "interleukin growth hormone cluster on chromosome 5q31," which, when aligned and translated, had three regions that suggested homology to the predicted AF4 protein sequence (32% amino acid sequence identity over 314 amino acids, 43% over 63 amino acids, and 50% over 40 amino acids). Of interest, this same chromosome 5q31 region has also been implicated in MLL gene rearrangements in human leukemia.

Amino Acid Sequence↗

PubMed2006

HLA-E, HLA-F, and HLA-G polymorphism: genomic sequence defines haplotype structure and variation spanning the nonclassical class I genes.

Despite several studies that defined the polymorphism of the nonclassical human leukocyte antigen-E (HLA-E), HLA-F, and HLA-G genes, most polymorphisms thus far examined in correlative studies were derived from the coding sequences of these genes. In addition, some discrepancies and ambiguities in the available data have persisted in current databases. To expand the data available and to resolve some of the discrepant data, we have defined protocols that allow for the amplification of 6 to 7 kb of contiguous genomic sequence for each gene, including all of the coding and intron sequences, approximately 2 kb of 5' flanking promoter sequence, and 1 kb of 3' flanking sequence. Using long-range polymerase chain reaction (PCR) protocols, generating either one or two PCR products depending on the locus, amplified genomic DNA was directly sequenced to completion using a set of about 30 primers over each locus to yield contiguous sequence data from both strands. Using this approach, we sequenced 33 genomic DNAs, from Asian, African American, and Caucasian samples. The results of this analysis confirmed several previously reported coding sequence variants, identified several new allelic variants, and also defined extensive variation in intron and flanking sequences. It was possible to construct haplotype maps and to identify tagging single nucleotide polymorphisms that can be used to detect the composite variation spanning all three genes.

Alleles↗

PubMed2006

Plant genome organisation and diversity: the year of the junk!

Having gained a thorough understanding of the structure and organization of model plant genomes, such as those of Arabidopsis thaliana and rice, we have now started to investigate the most interesting aspect of genome structure - its variations. Variation in DNA sequence is responsible for the genetic component of phenotypic variation (i.e. the component upon which both natural and artificial selection act). Recent studies have started to shed light on sequence variation outside of the genic regions, owing mainly to large insertion/deletion (indel) polymorphisms caused by the presence or absence of transposable elements of different classes. In addition to long terminal repeat retrotransposons, DNA transposons have been shown to be responsible for these polymorphisms. These comprise Helitrons, CACTA and Mu-like elements that are capable of acquiring and piecing together fragments of plant genes and are often expressed. Future analyses of the functional roles of intergenic sequence variation will tell us if we will need to pay more attention not only to genes, but also to the 'junk' DNA surrounding them.

DNA, Intergenic↗

PubMed1997

Post-translational modifications of meningococcal pili. Identification of common substituents: glycans and alpha-glycerophosphate--a review.

Neisseria meningitidis elaborate filamentous adhesins, pili or fimbriae, which belong to the type-4 structural group of pili also found on other bacterial pathogens such as Neisseria gonorrhoeae, Pseudomonas aeruginosa, Moraxella bovis and Dichelobacter nodosus. Meningococcal pili readily undergo structural variations which arise as a result of inter- and intra-genomic recombinational events. Structural variations often result in variations in bacterial adhesion mediated by pili. Studies on structure/function relationship of meningococcal pili have shown that pili are post-translationally modified and contain unusual covalently-linked substituents. The presence of glycans was shown by the use of specific carbohydrate labelling, chemical deglycosylation and by introducing galE mutations; the latter studies confirmed the presence of galactose on pili. Mass spectrometric and other analysis of pilin-derived tryptic peptides and linked substituents were used to determine the structure of an unusual O-linked trisaccharide, Gal beta1-4 Gal alpha1-3[2,4-diacetamido-2,4,6-trideoxyhexose]. Similar studies have also identified, perhaps a unique substituent, alpha-glycerophosphate, which is attached to Ser93 by a phosphodiester linkage.

Amino Acid Sequence↗

PubMedDate not supplied

Repeated sequences in bacterial chromosomes and plasmids: a glimpse from sequenced genomes.

To gain insight into the extent of exact DNA repeats in sequenced bacterial genomes and their plasmids, we analyzed the collection of completely sequenced bacterial genomes available at GenBank using the program Miropeats. This program draws graphical representations of exact DNA repeats in whole genomes. In this work, we present maps showing the extent and type (inverted or direct) of exact DNA repeats longer than 300 bp for the whole collection. These repeats may participate in a variety of events relevant for bacterial genome plasticity, such as amplifications, deletions, inversions, and translocations (via homologous recombination), as well as transposition. Additionally, we review recent data showing that high-frequency architectural variations in genomic structure occur at both the interspecies and interstrain levels.

Bacteria↗

PubMed2026

Optimizing GRIDSS for clinical use: A targeted NGS filtering strategy for germline structural variant detection.

Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS addresses this gap by integrating paired-end mapping, split-read analysis, and assembly-based approaches. However, its use in targeted sequencing and diagnostic workflows remains complex. NGS panel data from 9726 patients with suspected hereditary cancer were analyzed using GRIDSS. A filtering strategy was developed to prioritize clinically relevant germline SVs. Multiple parameter settings were tested to optimize performance. The initial dataset of 1,307,592 variants was reduced to 89 candidates after applying the selected filtering strategy. Of these, 24 had been previously detected by routine callers and were not further analyzed. Among the remaining 65, 13 were considered likely true positives after visual inspection using IGV. Experimental validation was performed by Sanger/Nanopore long-read sequencing for these variants, all of which were confirmed. Eight were classified as (likely) pathogenic, including two frameshift duplications in MSH6, one splicing variant in BARD1, and five mobile element insertions in APC, BRCA2, and PALB2. Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.

Humans↗

PubMed2025

Complex de novo structural variants are an underestimated cause of rare disorders.

Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conduct a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, obtained as part of the UK 100,000 Genomes Project. We identify 1,870 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n = 158; 8.4%) emerge as the third most common type of SV, following simple deletions and duplications. We classify 65% of these complex dnSVs into 11 subtypes. Among probands with dnSVs (n = 1,696), 9% exhibit exon-disrupting pathogenic dnSVs associated with the probands' phenotype. Notably, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or whole-exome sequencing methods are found to be complex dnSVs. We also find distinct genomic properties of de novo deletions depending on the parent of origin. This study highlights the importance of complex dnSVs in the cause of rare disorders and demonstrates the necessity of specific genomic analysis to avoid overlooking these variants.

Humans↗

PubMed2026

De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes.

Three-dimensional genome organization plays a critical role in gene regulation, and disruptions can lead to developmental disorders by altering the contact between genes and their distal regulatory elements. Structural variants (SVs) can disturb local genome organization, such as the merging of topologically associating domains upon boundary deletion. Testing large numbers of SVs experimentally for their effects on chromatin structure and gene expression is time and cost prohibitive. To address this, we propose a computational approach to predict SV impacts on genome folding, which can help prioritize causal hypotheses for functional testing. We develop a weighted scoring method that measures chromatin contact changes specifically affecting regions of interest, such as regulatory elements or promoters, and implement it in the SuPreMo-Akita software. With this tool, we rank hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings based on predicted disruptions to nearby neuronal regulatory interactions. This reveals that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings. We prioritize candidate variants that disrupt ASD CREints and validate our top-ranked locus using isogenic excitatory neurons with and without the dnSV, confirming accurate predictions of disrupted chromatin contacts. This study suggests that disrupted genome folding is a potential genetic mechanism in a subset of ASD cases and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions across tissues.

Humans↗

PubMed2025

Aplf/Dna2 variants drive chromosomal fission and accelerate speciation in zokors.

Chromosomal fissions and fusions are common, yet the molecular mechanisms and implications in speciation remain poorly understood. Here, we confirm a fission event in one zokor species through multiple-omics and functional analyses. We traced this event to a mutation in a splicing enhancer of the DNA repair gene Aplf in the fission-bearing species, which caused exon skipping and produced a truncated protein that disrupted DNA repair. An intronic deletion in Dna2, known to facilitate neo-telomere formation when knocked out, reduced gene activity. These variants collectively drove chromosomal fission in this zokor species. The newly formed chromosome became fixed due to carrying essential genes and strong selective pressure. While geographic isolation likely initiated the divergence of this species and the sister one, the fission event and associated decline at the chromosome level in gene flow probably exacerbated the speciation process. Our work elucidates the genetic basis of chromosomal fission and underscores its role in speciation dynamics.

Multiomics↗

PubMed2002

The mosaic structure of variation in the laboratory mouse genome.

Most inbred laboratory mouse strains are known to have originated from a mixed but limited founder population in a few laboratories. However, the effect of this breeding history on patterns of genetic variation among these strains and the implications for their use are not well understood. Here we present an analysis of the fine structure of variation in the mouse genome, using single nucleotide polymorphisms (SNPs). When the recently assembled genome sequence from the C57BL/6J strain is aligned with sample sequence from other strains, we observe long segments of either extremely high (approximately 40 SNPs per 10 kb) or extremely low (approximately 0.5 SNPs per 10 kb) polymorphism rates. In all strain-to-strain comparisons examined, only one-third of the genome falls into long regions (averaging >1 Mb) of a high SNP rate, consistent with estimated divergence rates between Mus musculus domesticus and either M. m. musculus or M. m. castaneus. These data suggest that the genomes of these inbred strains are mosaics with the vast majority of segments derived from domesticus and musculus sources. These observations have important implications for the design and interpretation of positional cloning experiments.

Albinism↗

PubMed2025

Integrative Genotyping and Analysis of Canine Structural Variation Using Long-read and Short-read Data.

Structural variation makes an important contribution to canine evolution and phenotypic differences. Although recent advances in long-read sequencing have enabled the generation of multiple canine genome assemblies, most prior analyses of structural variation have relied on short-read sequencing. To offer a more complete assessment of structural variation in canines, we performed an integrative analysis of structural variants present in 12 canine samples with available long-read and short-read sequencing data along with genome assemblies. Use of long-reads permits the discovery of heterozygous variation that is absent in existing haploid assembly representations while offering a marked increase in the ability to identify insertion variants relative to short-read approaches. Examination of the size spectrum of structural variants shows that dimorphic LINE-1 and SINE variants account for over 45% of all deletions and identified 1,410 LINE-1s with intact open reading frames that show presence-absence dimorphism. Using a graph-based approach, we genotype newly discovered structural variants in an existing collection of 1,879 resequenced dogs and wolves, generating a variant catalog containing a 56.5% increase in the number of deletions and 705% increase in the number of insertions previously found in the analyzed samples. Examination of allele frequencies across admixture components present across breed clades identified 283 structural variants evolving with a signature of selection.

Animals↗

PubMed1996

Sequence variation in 5' termini of rubella virus genomes: changes affecting structure of the 5' proximal stem-loop.

Variation within a 523 nucleotide region proximal to the 5' terminus of seven rubella virus strains has been analysed. Compared to the Therien strain twenty sites of nucleotide variation have been identified, three of which are in the 5' untranslated region. Individual strains have between three and nine nucleotide differences, only three of which result in amino acid substitutions. TO-336 has a serine for threonine at amino acid (aa) 42 and CM arginine for histidine at aa 159. RA27/3 has arginine for lysine at aa 3 and serine for threonine at aa 42. Nucleotide differences which affect a stem-loop structure reported to be important for binding of host cell proteins have been identified.

Amino Acid Substitution↗

PubMed2026

A chromosome-level, haplotype-resolved genome assembly for the barn owl, Tyto alba.

Recent advances in long-read sequencing have enabled near telomere-to-telomere (T2T) assemblies across diverse taxa. However, avian genomes remain challenging due to numerous microchromosomes, small, typically < 20Mb, DNA molecules that are gene-, GC-, and repeat-rich. As a consequence, microchromosomes are often missing from genome assemblies. Here, we present a chromosome-level, haplotype-resolved genome assembly for the Western barn owl (Tyto alba). Using a trio-binning strategy with Illumina parental reads combined with PacBio HiFi and Oxford Nanopore Technologies data, we generated two phased contig sets. These were scaffolded into 40 linkage groups using a linkage map. Comparative analyses identified unplaced HiFi scaffolds corresponding to microchromosomes, which we integrated into six additional microchromosomes using long reads information. The two assemblies present 46 chromosomes, matching the karyotype of the species. They exhibit strong synteny between parental haplotypes, except for a ∼38 Mb complex region on chromosome 7 containing nested inversions. This high-quality reference provides a haplotype-resolved and chromosome-level genome for Strigiformes, enabling fine-scale studies of structural variation and avian genome evolution.

Tyto alba↗

PubMed2000

Intraspecific variation in gamma-radiation resistance and genomic structure in the filamentous fungus Alternaria alternata: a case study of strains inhabiting Chernobyl reactor no. 4.

This is probably the first report on intraspecific variation in radiation resistance for filamentous fungi. It was revealed that natural ("field") strains of the filamentous fungus Alternaria alternata are extremely variable in response to gamma-irradiation ranging from supersensitive to highly resistant to radiation. At the same time nearly all strains originating from the highly radiation-polluted reactor of the Chernobyl (Ukraine) Nuclear Power Plant possessed high radiation resistance. The genome structure of strains studied by universally primed polymerase chain reaction (UP-PCR) was found to be well conserved in "reactor" but not in "control" strains. The "reactor" strains appear to be genetically adapted to this high radiation habitat by means of selection, thus providing a natural source of genetically homogeneous fungal lineages.

Alternaria↗

PubMed2001

Genome screen for quantitative trait loci underlying normal variation in femoral structure.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib-pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10 of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

Adult↗

PubMed2025

Reproductive Isolation due to Divergent Ecological Selection Is Accompanied by Vast Genomic Instability in Experimentally Evolved Yeast Populations.

Populations evolving independently in divergent environments accumulate genetic differences and potentially evolve reproductive isolation as a by-product of divergence. The speed and mechanisms underlying this process are difficult to investigate because we rarely get the opportunity to witness them in natural settings, and histories of selection and gene flow between populations are often unknown. Here, we experimentally evolved yeast for 1000 generations of evolution in both divergent and parallel environments. At regular time points during experimental evolution, we made crosses between parallel- and divergent-evolving populations to measure postzygotic reproductive isolation (gamete viability). We used whole genome population sequencing to determine the mutational load, the number and types of structural variation, and other genomic features of the parent, F1 and F2 intraspecific hybrids. We found evidence for large-scale phenotypic and genome-wide differentiation in response to divergent laboratory selection. Divergent-selected populations produced hybrids with reduced gamete viability-a classic signature of postzygotic reproductive isolation in the form of hybrid breakdown. Parallel-selected populations, on the other hand, remained more reproductively compatible (with exceptions). We found that F2 hybrid genomes contained vast genomic instability, that is, new structural variants (especially insertions, deletions and interchromosomal translocations) that were not observed in parent and F1 genomes, which is likely a result of chromosome missegregation and recombination errors in hybrid meiosis. Our results provide phenotypic and genomic evidence that partial reproductive isolation evolved due to adaptation to divergent environments, consistent with predictions of ecological speciation theory.

Reproductive Isolation↗

PubMed2006

Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation.

The last 2 years have seen much excitement in the field of genetics with the identification of a formerly unappreciated level of "structural variation" within the normal human genome. Genetic structural variants include deletions, duplications, and inversions in addition to the recently discovered, copy number variants. Single nucleotide polymorphisms are the most extensively evaluated variant within the genome to date. Combining our knowledge from these studies with our rapidly accumulating understanding of structural variants, it is apparent that the extent of genetic dissimilarity between any 2 individuals is considerable and much greater than that which was previously recognized. Clearly, this more diverse view of the genome has significant implications for allogeneic hematopoietic stem cell transplantation, not least in the generation of transplant antigens but also in terms of individual susceptibility to transplant-related toxicities. With advances in DNA sequencing technology we now have the capacity to perform genome-wide analysis in a high throughput fashion, permitting a detailed genetic analysis of patient and donor prior to transplantation. Understanding the significance of this additional genetic information and applying it in a clinically meaningful way will be one of the challenges faced by transplant clinicians in the future.

Genetic Predisposition to Disease↗

PubMed1987

The human growth hormone gene locus: structure, evolution, and allelic variations.

Genomic clones containing the closely related genes for human growth hormone (hGH) and chorionic somatomammotropin (hCS) were obtained from genomic bacteriophage lambda and cosmid libraries. The entire GH/CS chromosomal locus was reconstructed utilizing overlapping restriction fragments characterized from the isolated clones. The hGH/hCS locus contains two GH genes and three CS genes spanning 48 kb of DNA in the order: 5'-(hGH-1/hCS-5/hCS-1/hGH-2/hCS-2)-3', confirming analysis of cosmid clones obtained from a different human library (Barsh et al., 1983). To complete the characterization of the hCS genes, the nucleotide sequence of the hCS-5 gene was determined. Sequence analysis revealed a mutation of the 5' splice site at the exon II-intron B boundary, suggesting that the hCS-5 gene is a pseudogene. The nucleotide sequence of an allelic variant of the hCS-2 gene was determined and found to contain a single amino acid substitution and the deletion of a single codon. The hGH/hCS gene locus was further characterized by the localization of at least 27 Alu-type repetitive sequences and identification of three unique sequences in the vicinity of several hGH and hCS genes which define the probable breakpoints of the evolutionary duplication units. These data, combined with the nucleotide sequences of all five GH and CS genes, indicate that the hGH/hCS gene locus has evolved by duplication mechanisms. Evidence for the occurrence of at least one gene conversion event involving the hCS-1 gene precursor and the hCS-2 gene was found, indicating that the hGH/hCS gene locus has evolved by concerted mechanisms. The structure of the hCS genes is discussed in light of recent studies of CS genes from other mammalian species.

Alleles↗