Genomic Structural Variation Research Articles

Duplicated Copy Number Variant of the Maize 9-Lipoxygenase ZmLOX5 Improves 9,10-KODA-Mediated Resistance to Fall Armyworms.

Extensive genome structure variations, such as copy number variations (CNVs) and presence/absence variations, are the basis for the remarkable genetic diversity of maize; however, the effect of CNVs on maize herbivory defense remains largely underexplored. Here, we report that the naturally occurring duplication of the maize 9-lipoxygenase gene ZmLOX5 leads to increased resistance of maize to herbivory by fall armyworms (FAWs). Previously, we showed that ZmLOX5-derived oxylipins are required for defense against chewing insect herbivores and identified several inbred lines, including Yu796, that contained duplicated CNVs of ZmLOX5, referred to as Yu796-2×LOX5. To test whether introgression of the Yu796-2×LOX5 locus into a herbivore-susceptible B73 background that contains a single ZmLOX5 gene is a feasible approach to increase resistance, we generated a series of near-isogenic lines that contained either two, one, or zero copies of the Yu796-2×LOX5 locus in the B73 background via six backcrosses (BC6). Droplet digital PCR (ddPCR) confirmed the successful introgression of the Yu796-2×LOX5 locus in B73. The resulting B73-2×LOX5 inbred line displayed increased resistance against FAW, associated with increased expression of ZmLOX5, increased wound-induced production of its primary oxylipin product, the α-ketol, 9-hydroxy-10-oxo-12(Z),15(Z)-octadecadienoic acid (9,10-KODA), and the downstream defense hormones regulated by this molecule, 12-oxo-phytodienoic acid (12-OPDA) and abscisic acid (ABA). Surprisingly, wound-induced JA-Ile production was not increased in B73-2×LOX5, resulting from the increased JA catabolism. Furthermore, B73-2×LOX5 displayed reduced water loss in response to drought stress, likely due to increased ABA and 12-OPDA content. Taken together, this study revealed that the duplicated CNV of ZmLOX5 quantitively contributes to maize antiherbivore defense and presents proof-of-concept evidence that the introgression of naturally occurring duplicated CNVs of a defensive gene into productive but susceptible crop varieties is a feasible breeding approach for enhancing plant resistance to herbivory and tolerance to abiotic stress.

Landscape of genomic structural variations in Indian population-based cohorts: Deeper insights into their prevalence and clinical relevance

Structural variations (SV) are large (> 50 bp) genomic rearrangements comprising deletions, duplications, insertions, inversions, and translocations. Studying SVs is important because they play active and critical roles in regulating gene expression, determining disease predispositions, and identifying population-specific differences among individuals of diverse ancestries. However, SV discoveries in the Indian population using whole-genome sequencing (WGS) has been limited. In this study, using short-read WGS having an average 42X depth of coverage, we identify and characterize 36,210 SVs from 529 individuals enrolled in population-based cohorts in India. These SVs include 24,574 deletions, 2913 duplications, 8710 insertions, and 13 inversions. 1.26% (456 out of 36,210) of the identified SVs can potentially impact the coding regions of genes. Furthermore, 56 of these SVs are highly intolerant to loss-of-function changes to the mapped genes, and five SVs impacting ADAMTS17, CCDC40, and RHCE are common in our study individuals. Seven rare SVs significantly impact dosage sensitivity of genes known to be associated with various clinical phenotypes. Most of the SVs in our study are rare and heterozygous. This fine-scale SV discovery in the under-represented Indian population provides valuable insights that extends beyond Euro-centric human genetic studies.

Abstract 2337: Accelerated optical genome mapping analysis with Stratys Compute and Guided Assembly

Abstract Background Optical genome maps (OGM) from Bionano enable the detection of genomic structural and copy number variants that cannot be detected by next-generation sequencing (NGS) technologies and are often missed by conventional cytogenetic techniques. Bionano has developed bioinformatics pipelines for calling structural and copy number variants including the Bionano Solve de novo assembly pipeline for constitutional analysis and the Rare Variant Analysis (RVA) pipeline for low-allele-fraction cancer applications. Both pipelines are computationally intensive and currently take 5-10 hours on the latest generation of the Bionano Saphyr® Compute which is deployed as a four-node compute cluster and requires significant IT resources. Methods To increase throughput and simplify the deployment of the compute resources needed to support the Stratys™ optical genome mapping instrument, Bionano has developed Stratys™ Compute. Stratys Compute improves both compute and analytical performance by adapting compute-intensive stages in the Solve pipeline to run on GPUs and by developing the Guided Assembly pipeline. Stratys Compute is powered by state-of-the-art NVIDIA RTX 6000 Ada generation cards and CUDA-optimized refinement, alignment, and structural variation detection kernels to accelerate OGM analysis. Stratys Compute is a standalone workstation placed adjacent to Stratys instrument. This will minimize the IT footprint and bypass the integration with the customer site’s data center. We have incorporated these optimizations into the new Guided Assembly pipeline, which aims to combine the low-allele fraction detection capability of the RVA pipeline with the whole genome coverage and ability to detect smaller structural variants enabled by the de novo assembly pipeline. The Guided Assembly pipeline uses the reference genome as an initial seed followed by extension, refinement, and structural variant calling. This new analysis method has been evaluated through comparison to previous results from both existing pipelines and standard benchmarking datasets used to estimate structural variant calling performance and is deployed on Stratys Compute for both constitutional and low allele-fraction applications. Results Guided Assembly has been adapted to run on GPU hardware in a simplified compute tower that can be deployed to a lab along with the Stratys instrument without the need for a dedicated server room. We found concordance between the guided assembly results and our previous de novo and RVA pipeline results. We also found increased sensitivity at low allele fractions for detecting insertion variants smaller than 5 kb and larger than 200 kb while finding equivalent performance for other variant types with the updated methods. The accelerated Guided Assembly for constitutional and low-allele-fraction applications will be available to early access customers in Q4 2023 with full commercial release in Q2 2024. Citation Format: Damla Senol Cali, Thomas Anantharaman, Martin Muggli, Samer Al-Saffar, Charles Schoonover, Neil Miller. Accelerated optical genome mapping analysis with Stratys Compute and Guided Assembly [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2337.

The Complex Landscape of Structural Divergence Between the Drosophila pseudoobscura and D. persimilis Genomes.

Structural genomic variants are key drivers of phenotypic evolution. They can span hundreds to millions of base pairs and can thus affect large numbers of genetic elements. Although structural variation is quite common within and between species, its characterization depends upon the quality of genome assemblies and the proportion of repetitive elements. Using new high-quality genome assemblies, we report a complex and previously hidden landscape of structural divergence between the genomes of Drosophila persimilis and D. pseudoobscura, two classic species in speciation research, and study the relationships among structural variants, transposable elements, and gene expression divergence. The new assemblies confirm the already known fixed inversion differences between these species. Consistent with previous studies showing higher levels of nucleotide divergence between fixed inversions relative to collinear regions of the genome, we also find a significant overrepresentation of INDELs inside the inversions. We find that transposable elements accumulate in regions with low levels of recombination, and spatial correlation analyses reveal a strong association between transposable elements and structural variants. We also report a strong association between differentially expressed (DE) genes and structural variants and an overrepresentation of DE genes inside the fixed chromosomal inversions that separate this species pair. Interestingly, species-specific structural variants are overrepresented in DE genes involved in neural development, spermatogenesis, and oocyte-to-embryo transition. Overall, our results highlight the association of transposable elements with structural variants and their importance in driving evolutionary divergence.

Investigating structural variant, indel and single nucleotide polymorphism differentiation between locally adapted Atlantic salmon populations.

Genomic structural variants (SVs) are now recognized as an integral component of intraspecific polymorphism and are known to contribute to evolutionary processes in various organisms. However, they are inherently difficult to detect and genotype from readily available short-read sequencing data, and therefore remain poorly documented in wild populations. Salmonid species displaying strong interpopulation variability in both life history traits and habitat characteristics, such as Atlantic salmon (Salmo salar), offer a prime context for studying adaptive polymorphism, but the contribution of SVs to fine-scale local adaptation has yet to be explored. Here, we performed a comparative analysis of SVs, single nucleotide polymorphisms (SNPs) and small indels (<50 bp) segregating in the Romaine and Puyjalon salmon, two putatively locally adapted populations inhabiting neighboring rivers (Québec, Canada) and showing pronounced variation in life history traits, namely growth, fecundity, and age at maturity and smoltification. We first catalogued polymorphism using a hybrid SV characterization approach pairing both short- (16X) and long-read sequencing (20X) for variant discovery with graph-based genotyping of SVs across 60 salmon genomes, along with characterization of SNPs and small indels from short reads. We thus identified 115,907 SVs, 8,777,832 SNPs and 1,089,321 short indels, with SVs covering 4.8 times more base pairs than SNPs. All three variant types revealed a highly congruent population structure and similar patterns of F ST and density variation along the genome. Finally, we performed outlier detection and redundancy analysis (RDA) to identify variants of interest in the putative local adaptation of Romaine and Puyjalon salmon. Genes located near these variants were enriched for biological processes related to nervous system function, suggesting that observed variation in traits such as age at smoltification could arise from differences in neural development. This study therefore demonstrates the feasibility of large-scale SV characterization and highlights its relevance for salmonid population genomics.

The genomic landscape of transposable elements in yeast hybrids is shaped by structural variation and genotype-specific modulation of transposition rate.

Transposable elements (TEs) are major contributors to structural genomic variation by creating interspersed duplications of themselves. In return, structural variants (SVs) can affect the genomic distribution of TE copies and shape their load. One long-standing hypothesis states that hybridization could trigger TE mobilization and thus increase TE load in hybrids. We previously tested this hypothesis (Hénault et al., 2020) by performing a large-scale evolution experiment by mutation accumulation (MA) on multiple hybrid genotypes within and between wild populations of the yeasts Saccharomyces paradoxus and Saccharomyces cerevisiae. Using aggregate measures of TE load with short-read sequencing, we found no evidence for TE load increase in hybrid MA lines. Here, we resolve the genomes of the hybrid MA lines with long-read phasing and assembly to precisely characterize the role of SVs in shaping the TE landscape. Highly contiguous phased assemblies of 127 MA lines revealed that SV types like polyploidy, aneuploidy, and loss of heterozygosity have large impacts on the TE load. We characterized 18 de novo TE insertions, indicating that transposition only has a minor role in shaping the TE landscape in MA lines. Because the scarcity of TE mobilization in MA lines provided insufficient resolution to confidently dissect transposition rate variation in hybrids, we adapted an in vivo assay to measure transposition rates in various S. paradoxus hybrid backgrounds. We found that transposition rates are not increased by hybridization, but are modulated by many genotype-specific factors including initial TE load, TE sequence variants, and mitochondrial DNA inheritance. Our results show the multiple scales at which TE load is shaped in hybrid genomes, being highly impacted by SV dynamics and finely modulated by genotype-specific variation in transposition rates.

Ethnic and functional differentiation of copy number polymorphisms in Tunisian and HapMap population unveils insights on genome organizational plasticity

Admixture mapping has been useful in identifying genetic variations linked to phenotypes, adaptation and diseases. Copy number variations (CNVs) represents genomic structural variants spanning large regions of chromosomes reaching several megabases. In this investigation, the “Canary” algorithm was applied to 102 Tunisian samples and 991 individuals from eleven HapMap III populations to genotype 1279 copy number polymorphisms (CNPs). In this present work, we investigate the Tunisian population structure using the CNP makers previously identified among Tunisian. The study revealed that Sub-Saharan African populations exhibited the highest diversity with the highest proportions of allelic CNPs. Among all the African populations, Tunisia showed the least diversity. Individual ancestry proportions computed using STRUCTURE analysis revealed a major European component among Tunisians with lesser contribution from Sub-Saharan Africa and Asia. Population structure analysis indicated the genetic proximity with Europeans and noticeable distance from the Sub-Saharan African and East Asian clusters. Seven genes harbouring Tunisian high-frequent CNPs were identified known to be associated with 9 Mendelian diseases and/or phenotypes. Functional annotation of genes under selection highlighted a noteworthy enrichment of biological processes to receptor pathway and activity as well as glutathione metabolism. Additionally, pathways of potential concern for health such as drug metabolism, infectious diseases and cancers exhibited significant enrichment. The distinctive genetic makeup of the Tunisians might have been influenced by various factors including natural selection and genetic drift, resulting in the development of distinct genetic variations playing roles in specific biological processes. Our research provides a justification for focusing on the exclusive genome organization of this population and uncovers previously overlooked elements of the genome.

Integrating Dynamic 3D Chromatin Architecture and Gene Expression Alterations Reveal Heterosis in Brassica rapa.

Heterosis plays a significant role in enhancing variety, boosting yield, and raising economic value in crops, but the molecular mechanism is still unclear. We analyzed the transcriptomes and 3D genomes of a hybrid (F1) and its parents (w30 and 082). The analysis of the expression revealed a total of 485 specially expressed genes (SEGs), 173 differentially expressed genes (DEGs) above the parental expression level, more actively expressed genes, and up-regulated DEGs in the F1. Further study revealed that the DEGs detected in the F1 and its parents were mainly involved in the response to auxin, plant hormone signal transduction, DNA metabolic process, purine metabolism, starch, and sucrose metabolism, which suggested that these biological processes may play a crucial role in the heterosis of Brassica rapa. The analysis of 3D genome data revealed that hybrid F1 plants tend to contain more transcriptionally active A chromatin compartments after hybridization. Supplementaryly, the F1 had a smaller TAD (topologically associated domain) genome length, but the number was the highest, and the expression change in activated TAD was higher than that of repressed TAD. More specific TAD boundaries were detected between the parents and F1. Subsequently, 140 DEGs with genomic structural variants were selected as potential candidate genes. We found two DEGs with consistent expression changes in A/B compartments and TADs. Our findings suggested that genomic structural variants, such as TADs and A/B chromatin compartments, may affect gene expression and contribute to heterosis in Brassica rapa. This study provides further insight into the molecular mechanism of heterosis in Brassica rapa.

The Identification of Goat KCNJ15 Gene Copy Number Variation and Its Association with Growth Traits.

(1) Background: Copy number variation (CNV) is a critical component of genome structural variation and has garnered significant attention. High-throughput screening of the KCNJ15 gene has revealed a correlation between the CNV region and the growth traits of goats. We aimed to identify the CNV of the KCNJ15 gene in five goat breeds and analyze its association with growth characteristics. (2) Methods: We utilized 706 goats from five breeds: Guizhou black goat (GZB), Guizhou white goat (GZW), Bohuai goat (BH), Huai goat (HH), and Taihang goat (TH). To evaluate the number of copies of the KCNJ15 gene using qPCR, we analyzed the correlation between the CNV and growth characteristics and then used a universal linear model. The findings revealed variations in the distribution of different copy number types among the different goat breeds. (3) Results: Association analysis revealed a positive influence of the CNV in the KCNJ15 gene on goat growth. In GZB, individuals with duplication types exhibited superior performance in terms of cannon bone circumference (p < 0.05). In HH, individuals with duplication types exhibited superior performance in terms of body slanting length (p < 0.05). Conversely, normal TH demonstrated better body height and body weight (p < 0.05), while in GZW, when CN = 3, it performed better than other types in terms of body weight and chest circumference (p < 0.05). However, in BH, it had no significant effect on growth traits. (4) Conclusions: We confirmed that the CNV in the KCNJ15 gene significantly influences the growth characteristics of four distinct goat breeds. The correlation between KCNJ15 gene CNVs and goat growth traits offers valuable insights to breeders, enabling them to employ precise and efficient breeding methods that enhance livestock welfare, productivity, and overall economic benefits in the industry.

46, XX disorder of sexual development associated with mixed germ cell tumor of the prostate: a rare case report

BackgroundExtragonadal germ cell tumors originating from the prostate are exceptionally rare. To the best of our knowledge, there have been no reported cases of mixed germ cell tumors in individuals with 46 XX disorder of sex development. In this study, we conducted a comprehensive analysis using whole genome sequencing to investigate the clinicopathological and molecular genetic characteristics of a submitted case, with the objective of elucidating its underlying pathogenesis.Case presentationA 40-year-old male patient was diagnosed with a combination of 46, XX disorder of sex development and a primary prostate mixed germ cell tumor with yolk sac tumor and teratoma components. Whole-genome sequencing revealed that the tumor cells had a high somatic mutational load. Analysis of genomic structural variations and copy number variants confirmed the patient's karyotype as 46, XX (SRY +). Additionally, the patient exhibited short stature, small bilateral testes, slightly enlarged breasts, elevated serum alpha-fetoprotein concentrations, elevated follicle-stimulating hormone and luteinizing hormone levels, and low testosterone levels.DiscussionA case of 46, XX disorder of sex development, along with a primary prostatic mixed germ cell tumor, was diagnosed. This diagnosis has contributed to advancing our understanding of the genetic and phenotypic profile of the disease and may provide some insights for its treatment.

The occurrence, inheritance, and segregation of complex genomic structural variation in synthetic Brassica napus

“Synthetic” allopolyploids recreated by interspecific hybridization play an important role in providing novel genomic variation for crop improvement. Such synthetic allopolyploids often undergo rapid genomic structural variation (SV). However, how such SV arises, is inherited and fixed, and how it affects important traits, has rarely been comprehensively and quantitively studied in advanced generation synthetic lines. A better understanding of these processes will aid breeders in knowing how to best utilize synthetic allopolyploids in breeding programs. Here, we analyzed three genetic mapping populations (735 DH lines) derived from crosses between advanced synthetic and conventional Brassica napus (rapeseed) lines, using whole-genome sequencing to determine genome composition. We observed high tolerance of large structural variants, particularly toward the telomeres, and preferential selection for balanced homoeologous exchanges (duplication/deletion events between the A and C genomes resulting in retention of gene/chromosome dosage between homoeologous chromosome pairs), including stable events involving whole chromosomes (“pseudoeuploidy”). Given the experimental design (all three populations shared a common parent), we were able to observe that parental SV was regularly inherited, showed genetic hitchhiking effects on segregation, and was one of the major factors inducing adjacent novel and larger SV. Surprisingly, novel SV occurred at low frequencies with no significant impacts on observed fertility and yield-related traits in the advanced generation synthetic lines. However, incorporating genome-wide SV in linkage mapping explained significantly more genetic variance for traits. Our results provide a framework for detecting and understanding the occurrence and inheritance of genomic SV in breeding programs, and support the use of synthetic parents as an important source of novel trait variation.

A sequence-aware merger of genomic structural variations at population scale

Merging structural variations (SVs) at the population level presents a significant challenge, yet it is essential for conducting comprehensive genotypic analyses, especially in the era of pangenomics. Here, we introduce PanPop, a tool that utilizes an advanced sequence-aware SV merging algorithm to efficiently merge SVs of various types. We demonstrate that PanPop can merge and optimize the majority of multiallelic SVs into informative biallelic variants. We show its superior precision and lower rates of missing data compared to alternative software solutions. Our approach not only enables the filtering of SVs by leveraging multiple SV callers for enhanced accuracy but also facilitates the accurate merging of large-scale population SVs. These capabilities of PanPop will help to accelerate future SV-related studies.

Structural genomic variation in the inbred Scandinavian wolf population contributes to the realized genetic load but is positively affected by immigration.

When populations decrease in size and may become isolated, genomic erosion by loss of diversity from genetic drift and accumulation of deleterious mutations is likely an inevitable consequence. In such cases, immigration (genetic rescue) is necessary to restore levels of genetic diversity and counteract inbreeding depression. Recent work in conservation genomics has studied these processes focusing on the genetic diversity of single nucleotide polymorphisms. In contrast, our knowledge about structural genomic variation (insertions, deletions, duplications and inversions) in endangered species is limited. We analysed whole-genome, short-read sequences from 212 wolves from the inbred Scandinavian population and from neighbouring populations in Finland and Russia, and detected >35,000 structural variants (SVs) after stringent quality and genotype frequency filtering; >26,000 high-confidence variants remained after manual curation. The majority of variants were shorter than 1 kb, with a distinct peak in the length distribution of deletions at 190 bp, corresponding to insertion events of SINE/tRNA-Lys elements. The site frequency spectrum of SVs in protein-coding regions was significantly shifted towards rare alleles compared to putatively neutral variants, consistent with purifying selection. The realized genetic load of SVs in protein-coding regions increased with inbreeding levels in the Scandinavian population, but immigration provided a genetic rescue effect by lowering the load and reintroducing ancestral alleles at loci fixed for derived SVs. Our study shows that structural variation comprises a common type of in part deleterious mutations in endangered species and that establishing gene flow is necessary to mitigate the negative consequences of loss of diversity.

Analysis of five near-complete genome assemblies of the tomato pathogen Cladosporium fulvum uncovers additional accessory chromosomes and structural variations induced by transposable elements effecting the loss of avirulence genes

BackgroundFungal plant pathogens have dynamic genomes that allow them to rapidly adapt to adverse conditions and overcome host resistance. One way by which this dynamic genome plasticity is expressed is through effector gene loss, which enables plant pathogens to overcome recognition by cognate resistance genes in the host. However, the exact nature of these loses remains elusive in many fungi. This includes the tomato pathogen Cladosporium fulvum, which is the first fungal plant pathogen from which avirulence (Avr) genes were ever cloned and in which loss of Avr genes is often reported as a means of overcoming recognition by cognate tomato Cf resistance genes. A recent near-complete reference genome assembly of C. fulvum isolate Race 5 revealed a compartmentalized genome architecture and the presence of an accessory chromosome, thereby creating a basis for studying genome plasticity in fungal plant pathogens and its impact on avirulence genes.ResultsHere, we obtained near-complete genome assemblies of four additional C. fulvum isolates. The genome assemblies had similar sizes (66.96 to 67.78 Mb), number of predicted genes (14,895 to 14,981), and estimated completeness (98.8 to 98.9%). Comparative analysis that included the genome of isolate Race 5 revealed high levels of synteny and colinearity, which extended to the density and distribution of repetitive elements and of repeat-induced point (RIP) mutations across homologous chromosomes. Nonetheless, structural variations, likely mediated by transposable elements and effecting the deletion of the avirulence genes Avr4E, Avr5, and Avr9, were also identified. The isolates further shared a core set of 13 chromosomes, but two accessory chromosomes were identified as well. Accessory chromosomes were significantly smaller in size, and one carried pseudogenized copies of two effector genes. Whole-genome alignments further revealed genomic islands of near-zero nucleotide diversity interspersed with islands of high nucleotide diversity that co-localized with repeat-rich regions. These regions were likely generated by RIP, which generally asymmetrically affected the genome of C. fulvum.ConclusionsOur results reveal new evolutionary aspects of the C. fulvum genome and provide new insights on the importance of genomic structural variations in overcoming host resistance in fungal plant pathogens.

Progress and clinical prospect of genomic structural variants investigation

Progress and clinical prospect of genomic structural variants investigation

P1196 Genomic structural variation and polygenic risk score for Inflammatory Bowel Disease

Abstract Background Genome-wide association studies (GWAS) of patients with inflammatory bowel disease (IBD) have identified multiple single-nucleotide polymorphisms (SNPs) and genetic variants involving structural changes in the DNA sequence. SNPs and structural variants (SVs) can play a crucial role in IBD pathogenesis. In this study, we evaluated large deletions induced by SVs in patients with IBD. Additionally, we evaluated the ethnic contribution to a polygenic risk score (PRS) for IBD. Methods Seventy-five Patients with IBD of Korean ancestry from Seoul National University Bundang Hospital (SNUBH) were subjected to whole-genome sequencing (49 patients with UC and 26 patients with CD). SVs involving large deletions were detected and analyzed by using the Genome Aggregation Database (gnomAD) and AnnotSV. The SVs were prioritized based on a list of 241 IBD-associated SNPs identified in the previous GWAS. The prediction performance of European- and Korean-derived PRSs for IBD was also evaluated. For calculating PRS, we applied previously published models derived from the European and Korean populations, respectively, and used Korean Genome and Epidemiology Study (KoGES) database as the Korean controls. Results We found a total of 146 SVs involving large deletions in the IBD cohort. Among them, 10 SVs were annotated as likely pathogenic, according to AnnotSV and American College of Medical Genetics and Genomics guidelines; 24 SVs had the probability of being loss-of-function intolerant (pLI ≥ 0.9). We found that the frequency of large deletions that overlapped with the regions coding NOTCH1, HGF, PTPN2, and SENP7 were rare in the IBD cohort compared to the gnomAD population (Table). The large deletions that overlapped with the regions coding IL2RA, ITGA4, BANK1, and STAT3 were identified in the IBD cohort but not in the gnomAD population. The PRS for IBD in the IBD cohort was significantly higher than that in the Korean controls under the Korean- or European-derived model (Figure A). However, the PRSs for CD or UC were not able to distinguish patients with CD and UC in the IBD cohort (Figure B and C). Conclusion Our finding suggests that SVs involving large deletion may be an important genomic variability in predicting the development of IBD. The PRS for IBD can predict IBD development without ethnic specificity.

Genome-wide detection of structural variation in some sheep breeds using whole-genome long-read sequencing data.

Genomic structural variants (SVs) constitute a significant proportion of genetic variation in the genome. The rapid development of long-reads sequencing has facilitated the detection of long-fragment SVs. There is no published study to detect SVs using long-read data from sheep. We applied a long-read mapping approach to detect SVs and characterized a total of 30,771 insertions, deletions, inversions and translocations. We identified 716, 916, 842 and 303 specific SVs in Southdown sheep, Alpine merino sheep, Qilian White Tibetan sheep and Oula sheep, respectively. We annotated these SVs and found that these SV-related genes were primarily enriched in the well-established pathways involved in the regulation of the immune system, growth and development and environmental adaptability. We detected and annotated SVs based on NGS resequencing data to validate the accuracy based on third-generation detection. Moreover, five candidate SVs were verified using the PCR method in 50 sheep. Our study is the first to use a long-reads sequencing approach to construct a novel structural variation map in sheep. We have completed a preliminary exploration of the potential effects of SVs on sheep.

Monitoring Genomic Structural Rearrangements Resulting from Gene Editing.

The cytogenomics-based methodology of directional genomic hybridization (dGH) enables the detection and quantification of a more comprehensive spectrum of genomic structural variants than any other approach currently available, and importantly, does so on a single-cell basis. Thus, dGH is well-suited for testing and/or validating new advancements in CRISPR-Cas9 gene editing systems. In addition to aberrations detected by traditional cytogenetic approaches, the strand specificity of dGH facilitates detection of otherwise cryptic intra-chromosomal rearrangements, specifically small inversions. As such, dGH represents a powerful, high-resolution approach for the quantitative monitoring of potentially detrimental genomic structural rearrangements resulting from exposure to agents that induce DNA double-strand breaks (DSBs), including restriction endonucleases and ionizing radiations. For intentional genome editing strategies, it is critical that any undesired effects of DSBs induced either by the editing system itself or by mis-repair with other endogenous DSBs are recognized and minimized. In this paper, we discuss the application of dGH for assessing gene editing-associated structural variants and the potential heterogeneity of such rearrangements among cells within an edited population, highlighting its relevance to personalized medicine strategies.

Detection of Genomic Structural Variations Associated with Drug Sensitivity and Resistance in Acute Leukemia.

Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate of patients is typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for patients cause significant side effects. Understanding the evolution of leukemia to identify novel targets and, therefore, drug treatment regimens is a significant medical need. Genomic rearrangements and other structural variations (SVs) have long been known to be causative and pathogenic in multiple types of cancer, including leukemia. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual patients may help guide therapeutic options. Here, we show the utilization of optical genome mapping (OGM) to detect known and novel SVs in the samples of patients with leukemia. Importantly, this technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and allows for the unbiased detection of novel SVs, which may be relevant to disease pathogenesis and/or drug resistance. Coupled with the chemosensitivities of these samples to FDA-approved oncology drugs, we show how an impartial integrative analysis of these diverse datasets can be used to associate the detected genomic rearrangements with multiple drug sensitivity profiles. Indeed, an insertion in the gene MUSK is shown to be associated with increased sensitivity to the clinically relevant agent Idarubicin, while partial tandem duplication events in the KMT2A gene are related to the efficacy of another frontline treatment, Cytarabine.

Genomic structural variation is associated with hypoxia adaptation in high-altitude zokors.

Zokors, an Asiatic group of subterranean rodents, originated in lowlands and colonized high-elevational zones following the uplift of the Qinghai-Tibet plateau about 3.6 million years ago. Zokors live at high elevation in subterranean burrows and experience hypobaric hypoxia, including both hypoxia (low oxygen concentration) and hypercapnia (elevated partial pressure of CO2). Here we report a genomic analysis of six zokor species (genus Eospalax) with different elevational ranges to identify structural variants (deletions and inversions) that may have contributed to high-elevation adaptation. Based on an assembly of a chromosome-level genome of the high-elevation species, Eospalax baileyi, we identified 18 large inversions that distinguished this species from congeners native to lower elevations. Small-scale structural variants in the introns of EGLN1, HIF1A, HSF1 and SFTPD of E. baileyi were associated with the upregulated expression of those genes. A rearrangement on chromosome 1 was associated with altered chromatin accessibility, leading to modified gene expression profiles of key genes involved in the physiological response to hypoxia. Multigene families that underwent copy-number expansions in E. baileyi were enriched for autophagy, HIF1 signalling and immune response. E. baileyi show a significantly larger lung mass than those of other Eospalax species. These findings highlight the key role of structural variants underlying hypoxia adaptation of high-elevation species in Eospalax.