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Results for “Genomic Structural Variation”

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At least 19 recordsLinked to original sources
PubMed2006

Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals.

The recent hapmap effort has placed focus on the application of genome-wide SNP analysis to assess the contribution of genetic variability, particularly SNPs, to traits such as disease. Here, we describe the utility of genome-wide SNP analysis in the direct detection of extended homozygosity and structural genomic variation. We use this approach to assess the frequency of genomic alterations resulting from the lymphoblast immortalization and culture processes commonly used in cell repositories. We have assayed 408 804 SNPs in 276 DNA samples extracted from Epstein-Barr virus immortalized cell lines, which were derived from lymphocytes of elderly neurologically normal subjects. These data reveal extended homozygosity (contiguous tracts >5 Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) DNA samples assessed, 66% of which did not overlap with previously described structural variations. Examination of DNA extracted directly from the blood of 30 of these subjects confirmed all examined instances of extended homozygosity (6/6), 75% of structural genomic alteration <5 Mb in size (12/16) and 13% (1/8) of structural genomic alteration >5 Mb in size. These data suggest that structural genomic variation is a common phenomenon in the general population. While a proportion of this variability may be caused or its relative abundance altered by the immortalization and clonal process this will have only a minor effect on genotype and allele frequencies in a large cohort. It is likely that this powerful methodology will augment existing techniques in the identification of chromosomal abnormalities.

Aged↗
PubMed2026

Structural genome variation drives adaptation of the xylose-fermenting yeast Scheffersomyces stipitis to lignocellulosic hydrolysates.

Second-generation (2G) bioethanol from lignocellulosic feedstocks is a sustainable alternative to fossil fuels. However, its production is constrained by the poor performance of industrial microbes in hydrolysates that are generated during biomass pretreatment. Scheffersomyces stipitis is a native xylose fermenting yeast and a promising platform for 2G bioethanol production, and adaptive evolution under hydrolysate stress has yielded strains with enhanced performance. However, the chromosomal basis of this adaptation is unknown. Here, we demonstrate that chromosome scale structural variation, rather than point mutations, underlies the improved phenotype of the evolved strains. By integrating long- and short-read genome sequencing, we identify two major chromosomal rearrangements in the top performing isolate: a reciprocal translocation between chromosomes 1 and 2 that disrupts the NUDIX hydrolase gene YSA1, and the formation of a mitotically stable 175&#xa0;kb minichromosome derived from chromosome 5. Functional analyses show that disruption of YSA1 enhances xylose utilisation and ethanol yield, while the minichromosome contributes to improved performance in hydrolysate conditions. These findings provide direct evidence that balanced rearrangements and minichromosome formation can be selected during prolonged stress and can generate adaptive phenotypes. Taken together, our study establishes genome reorganisation as a key driver of adaptation in S. stipitis.

Xylose↗
PubMed2004

Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2.

Vitamin C (L-ascorbic acid) is an essential co-factor for eight mammalian enzymes and quenches reactive oxygen species. Sodium-dependent vitamin C transport is mediated by two transporters, SVCT 1 and SVCT 2, encoded by SLC23A1 and SLC23A2. We characterized the genomic structures of SLC23A1 and SLC23A2, determined the extent of genetic variation and linkage disequilibrium across each gene, analyzed nucleotide diversity to estimate the effect of selective pressure, and compared sequence variation across species. In SLC23A1, the majority of single nucleotide polymorphisms (SNPs) are population-specific in either African Americans or Caucasians, including three of four non-synonymous SNPs. In contrast, most SNPs in SLC23A2 are shared between African Americans and Caucasians, and there are no non-synonymous SNPs in SLC23A2. Our analysis, combined with previous in vitro and in vivo studies, suggests that non-synonymous variation appears to be tolerated in SLC23A1 but not SLC23A2, and that this may be a consequence of different selective pressures following past gene duplication of the sodium-dependent vitamin C transporters. Genetic association studies of these two genes will need to account for the differences in haplotype structure and the population-specific variants. Our data represent a fundamental step toward the application of genetics to refining nutrient recommendations, specifically for vitamin C, and may serve as a paradigm for other vitamins.

Base Composition↗
PubMed2001

Structural and functional genomics in domestic animals: the way to understand the phenotype.

Molecular approaches to genome analysis in livestock are reviewed by discussing the contribution of molecular genome analysis to the identification of the genetic variation underlying phenotypic variation (structural genome analysis) and to the definition of the trait-associated and environment-affected gene expression (functional genome analysis) as an important prerequisite to understanding the formation of a phenotype. Aspects of using mapped 'quantitative trait loci' (QTL) or gene variants as well as the identified trait-associated and environment-affected gene expression profile in livestock production are expounded.

Journal Article↗
PubMed1988

Genomic structure and sequence variation of a 3.3-kb repeat DNA element of the kangaroo rat, Dipodomys ordii.

The genomic structure and sequence variation of a 3.3-kb repeat DNA element, representing 5% of the genome of the kangaroo rat Dipodomys ordii, has been investigated. Most of the repeats are arranged in tandem arrays of 50 kb or more. Thirteen randomly selected genomic clones have been mapped with twelve restriction enzymes. The frequency of sequence divergence in the genomic clones is 0.5%. The clone maps and the genomic structure studies have permitted the characterization of a number of variant members of the 3.3-kb repeat family. The genomic organization of the repeat resembles that for repeated DNAs found in large tandem arrays or satellites.

Animals↗
PubMed2025

Generating three-dimensional genome structures with a variational quantum algorithm.

Chromosome conformation capture experiments have revealed the underlying spatial interactions that govern three-dimensional (3D) genome organization and topology. Detecting 3D contacts between genomic loci considerably enhances our understanding of fundamental regulatory processes. Modeling 3D structures from experimental contact matrices can further contextualize the relationship between 3D genome organization and regulation. While classical algorithms have been successful in reconstructing genomic conformations, we investigate the prospect of quantum computation to aid in modeling the conformational space. In this context, we propose a novel variational quantum algorithm (VQA) to model the distribution of 3D genomic structures from experimental contact data. Through rigorous evaluations, we demonstrate the capability of our algorithm to sample ensembles of viable 3D conformations that agree well with experimental and simulated contact data. Furthermore, we extend our methodology to model the conformational space of a single cell or a population of cells. In the advent of sufficient quantum utility, the insights gained from this study can serve as a foundation for investigating high-resolution, large-scale ensembles of genomic conformations through generative VQAs.

Algorithms↗
PubMed2006

Structural variation of the human genome.

There is growing appreciation that the human genome contains significant numbers of structural rearrangements, such as insertions, deletions, inversions, and large tandem repeats. Recent studies have defined approximately 5% of the human genome as structurally variant in the normal population, involving more than 800 independent genes. We present a detailed review of the various structural rearrangements identified to date in humans, with particular reference to their influence on human phenotypic variation. Our current knowledge of the extent of human structural variation shows that the human genome is a highly dynamic structure that shows significant large-scale variation from the currently published genome reference sequence.

Genetic Variation↗
PubMed2025

Chromatin accessibility analysis reveals functional cis-regulatory regions related to fruit development and domestication in tomato.

Non-coding DNA sequences harbor vast regulatory programs that ensure the precise spatiotemporal control of gene expression, which is essential for proper plant development and trait formation. Chromatin accessibility analysis could identify functional DNA regions within the extensive non-coding sequences and infer regulatory elements, serving as a crucial approach to unravel the mysteries of non-coding DNA sequences. Tomato fruit, a fleshy organ, provides a special system for studying fruit development and trait formation. However, the role of cis-accessible chromatin regions (cis-ACRs) during tomato fruit development, particularly in comparison with protein-coding DNA sequences, remains poorly understood. Here, we used ATAC-seq to define the landscape of cis-ACRs during fruit development and domestication in tomato. Temporal differential analysis revealed the dynamic opening and closing of cis-ACRs during fruit development. Comparative analysis of cis-ACRs between cultivated and wild tomatoes highlighted their significant contributions to fruit domestication. Combining analysis with genomic structural variations (SVs) suggested that SVs are likely a key factor in the formation of specific accessible cis-ACRs in cultivated tomatoes. Moreover, using gene editing, we identified a functional cis-ACR within the intron of the MBP3 gene that regulates fruit development and size traits. Overall, our findings provide a comprehensive perspective on the roles of cis-ACRs in tomato fruit development and domestication.

Solanum lycopersicum↗
PubMed2024

Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of &#x223c;2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.

Humans↗
PubMed2000

Genome plasticity in Enterobacteriaceae.

The comparative analysis of multiple representatives of the genomes of particular species are leading us away from a view of bacterial genomes as static, monolithic structures towards the view that they are relatively variable, fluid structures. This plasticity is mainly the result of the rearrangement of genes within the genome and the acquisition of novel genes by horizontal transfer systems, e. g. plasmids, bacteriophages, transposons or gene cassettes. These mechanisms often act in concert thus generating a complex genetic structure. Genomic variations are not a phenomenon at the DNA level alone, they influence the phenotype of a bacterium as well and can render a formerly harmless organism into a hazardous pathogen. This review deals not only with the mechanisms of genome rearrangements and the horizontal transfer of genes in Enterobacteriaceae but also points out that mobile genetic elements themselves are subjected to variation.

Bacteriophages↗
PubMed1995

The gene structure and organization of mouse PG-M, a large chondroitin sulfate proteoglycan. Genomic background for the generation of multiple PG-M transcripts.

We previously showed not only the presence of multiple RNA transcripts of different sizes encoding the core protein of mouse PG-M, but also their tissue-dependent expression. Major causes for the multiple forms were found to be due to alternative usage of the two different chondroitin sulfate attachment domains (alpha and beta). In this study, genomic DNA analysis has revealed that these domains are encoded by two large exons, exon VII (2880 base pairs) and exon VIII (5229 base pairs). The splice sites of these two exons were consistent with the occurrence of alternative splicing without frameshift. Furthermore, the mouse PG-M gene was shown to have four distinct polyadenylation signals and three candidates for the transcription initiation site as well. These genomic structural variations may contribute to the multiplicity of PG-M transcripts. Northern hybridization analysis showed that at least three different transcripts were generated by different usage of the distinct polyadenylation signals.

Alternative Splicing↗
PubMed2025

Sawfish: improving long-read structural variant discovery and genotyping with local haplotype modeling.

MOTIVATION: Structural variants (SVs) play an important role in evolutionary and functional genomics but are challenging to characterize. High-accuracy, long-read sequencing can substantially improve SV characterization when coupled with effective calling methods. While state-of-the-art long-read SV callers are highly accurate, further improvements are achievable by systematically modeling local haplotypes during SV discovery and genotyping. RESULTS: We describe sawfish, an SV caller for mapped high-quality long reads incorporating systematic SV haplotype modeling to improve accuracy and resolution. Assessment against the draft Genome in a Bottle (GIAB) SV benchmark from the T2T-HG002-Q100 diploid assembly shows that sawfish has the highest accuracy among state-of-the-art long-read SV callers across every tested SV size group. Additionally, sawfish maintains the highest accuracy at every tested depth level from 10- to 32-fold coverage, such that other callers required at least 30-fold coverage to match sawfish accuracy at 15-fold coverage. Sawfish also shows the highest accuracy in the GIAB challenging medically relevant genes benchmark, demonstrating improvements in both comprehensive and medically relevant contexts.When joint-genotyping seven samples from CEPH-1463, sawfish has over 9000 more pedigree-concordant calls than other state-of-the-art SV callers, with the highest proportion of concordant SVs (81%). Sawfish's quality model enables selection for an even higher proportion of concordant SVs (88%), while still calling nearly 5000 more pedigree-concordant SVs than other callers. These results demonstrate that sawfish improves on the state-of-the-art for long-read SV calling accuracy across both individual and joint-sample analyses. AVAILABILITY AND IMPLEMENTATION: Sawfish source code, pre-compiled Linux binaries, and documentation are released on GitHub: https://github.com/PacificBiosciences/sawfish.

Haplotypes↗
PubMed2026

needLR: long-read structural variant annotation with population-scale frequency estimation.

SUMMARY: We present needLR, a structural variant (SV) annotation tool that can be used for filtering and prioritization of candidate pathogenic SVs from long-read sequencing data using population allele frequencies, annotations for genomic context, and gene-phenotype associations. When using population data from 500 presumably healthy individuals to evaluate nine test cases with known pathogenic SVs, needLR assigned allele frequencies to over 97.5% of all detected SVs and reduced the average number of novel genic SVs to 121 per case while retaining all known pathogenic variants. AVAILABILITY AND IMPLEMENTATION: needLR is implemented in bash with dependencies including Truvari v4.2.2, BEDTools v2.31.1, and BCFtools v1.19. Source code, documentation, and pre-computed population allele frequency data are freely available at https://github.com/jgust1/needLR under an MIT license and archived on Zenodo at https://zenodo.org/records/19463479.

Software↗
PubMed2026

The value of structural variants to conservation genomics in the pangenome era.

Structural variants (SVs) comprise an axis of genetic diversity with strong consequences for phenotype and fitness, making them a potentially important target for conservation genomics. Here, we review how and why SVs can play a role in conservation genomics; the different types of SVs and how they can affect phenotype; and how pangenomes and long-read sequencing are illuminating their evolution in populations, including small populations and those of conservation concern. SVs comprise multinucleotide mutations including insertions, deletions, transpositions, inversions, and other multinucleotide mutations, often overlapping genes and other functional genome regions. As a result, SVs often play important roles in phenotypic evolution and local adaptation and can contribute substantially to genetic load in inbred populations. However, our understanding of the factors influencing SV diversity in populations is still in its infancy and is complicated by the vast range of sizes, effects, and mechanisms of formation of these mutations. We argue that SVs are an important axis of genetic diversity which should be characterized alongside more traditional metrics of genetic diversity in conservation contexts. There are a number of analytical challenges to detecting and studying SVs, but analyses aimed at understanding the role of SVs in inbreeding load and population health are rapidly becoming realizable goals, accelerated by new technologies and analytical approaches. New tools, including population-scale long-read sequencing and pangenome approaches, are beginning to make SVs accessible in ways which can be readily applied in conservation settings.

Genomic Structural Variation↗
PubMed2025

Temperature and Pressure Shaped the Evolution of Antifreeze Proteins in Polar and Deep Sea Zoarcoid Fishes.

Antifreeze proteins (AFPs) have enabled teleost fishes to repeatedly colonize polar seas. Four AFP types have convergently evolved in several fish lineages. AFPs inhibit ice crystal growth and lower tissue freezing point. In lineages with AFPs, species inhabiting colder environments may possess more AFP copies. Elucidating how differences in AFP copy number evolve is challenging due to the genes' tandem array structure and consequently poor resolution of these repetitive regions. Here, we explore the evolution of type III AFPs (AFP III) in the globally distributed suborder Zoarcoidei, leveraging six new long-read genome assemblies. Zoarcoidei has fewer genomic resources relative to other polar fish clades while it is one of the few groups of fishes adapted to both the Arctic and Southern Oceans. Combining these new assemblies with additional long-read genomes available for Zoarcoidei, we conducted a comprehensive phylogenetic test of AFP III evolution and modeled the effects of thermal habitat and depth on AFP III gene family evolution. We confirm a single origin of AFP III via neofunctionalization of the enzyme sialic acid synthase B. We also show that AFP copy number increased under low temperature but decreased with depth, potentially because pressure lowers freezing point. Associations between the environment and AFP III copy number were driven by duplications of paralogs that were translocated out of the ancestral locus at which AFP III arose. Our results reveal novel environmental effects on AFP evolution and demonstrate the value of high-quality genomic resources for studying how structural genomic variation shapes convergent adaptation.

Animals↗
PubMed2026

Mechanistic Perspectives From Genomics and Pangenomics of Medicinal and Aromatic Plants: Linking Genome Architecture to Phytochemical Diversity.

Medicinal and aromatic plants (MAPs) produce a remarkable diversity of specialized metabolites with significant pharmaceutical, nutraceutical, and industrial value. Although advances in long-read sequencing, chromosome-scale genome assembly, and pangenomics have greatly expanded genomic resources, the mechanistic links between genome architecture and phytochemical diversity remain incompletely understood. The present review synthesizes current evidence describing how structural genomic variation may contribute to phytochemical diversity, while acknowledging that many proposed genome-to-metabolite relationships require further experimental validation. Examples illustrate how genome architecture is associated with specialized-metabolite biosynthesis through multiple regulatory processes. However, the strength of supporting evidence varies considerably among MAP species. Moreover, relatively few genome-to-metabolite relationships have been confirmed through direct functional validation. We further discuss how pangenomics, multiomics integration, genome editing, synthetic biology, and artificial intelligence support the discovery, validation, and engineering of specialized metabolic pathways. Casual conclusions are evaluated according to the strength of available evidence, highlighting where causal relationships have been experimentally established and where conclusions remain primarily association-based. Overall, this review provides an integrated conceptual and evidence-based perspective summarizing proposed relationships between genome architecture and phytochemical diversity and outlines future priorities for functional genomics, precision breeding, metabolic engineering, and sustainable utilization of MAPs.

artificial intelligence↗
PubMed2006

Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome.

The structural diversity of the human genome is much higher than previously assumed although its full extent remains unknown. To investigate the association between segmental duplications that display constitutive copy number differences (CNDs) between humans and the great apes and those which exhibit polymorphic copy number variations (CNVs) between humans, we analysed a BAC array enriched with segmental duplications displaying such CNDs. This study documents for the first time that in addition to human-specific gains common to all humans, these duplication clusters (DCs) also exhibit polymorphic CNVs > 40 kb. Segmental duplication is known to have been a frequent event during human genome evolution. Importantly, among the CNV-associated genes identified here, those involved in transcriptional regulation were found to be significantly overrepresented. Complex patterns of variation were evident at sites of DCs, manifesting as inter-individual differentially sized copy number alterations at the same genomic loci. Thus, CNVs associated with segmental duplications do not simply represent insertion/deletion polymorphisms, but rather constitute a wide variety of rearrangements involving differential amplification and partial gains and losses with high inter-individual variability. Although the number of CNVs was not found to differ between Africans and Caucasians/Asians, the average number of variant patterns per locus was significantly lower in Africans. Thus, complex variation patterns characterizing segmental duplications result from relatively recent genomic rearrangements. The high number of these rearrangements, some of which are potentially recurrent, together with differences in population size and expansion dynamics, may account for the greater diversity of CNV in Caucasians/Asians as compared with Africans.

Animals↗