Rapid evolution of a large structural polymorphism during a bacterial epidemic.

BackgroundRecent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated.ResultsWe analyzed the whole-genome deep sequencing data (~ 30×) of five native trios from Peninsular Malaysia and North Borneo, and characterized the genomic variants, including single nucleotide variants (SNVs), small insertions and deletions (indels) and copy number variants (CNVs). We discovered approximately 6.9 million SNVs, 1.2 million indels, and 9000 CNVs in the 15 samples, of which 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify de novo variants and estimated the autosomal mutation rates to be 0.81 × 10− 8 – 1.33 × 10− 8, 1.0 × 10− 9 – 2.9 × 10− 9, and ~ 0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example is a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples.ConclusionOur study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia.

Background: Patient-derived cancer models advance therapeutic development and are essential to studies of treatment resistance mechanisms. The Human Cancer Models Initiative (HCMI) has created 665 patient-derived models, including organoids, neurospheres, and conditionally reprogrammed cells, all paired with patient tumors and clinical annotations. This resource provides an opportunity to study genomic conservation and divergence during model development at scale in a large pan-cancer cohort of matched tumor-model pairs. Methods: We characterized the genomes of models and parent tumors, computing allele specific Copy Number Variation (CNV), Single Nucleotide Variants (SNV), small Insertions and Deletions (InDels) and Structural Variations (SV) from bulk whole genome and whole exome Sequencing. We used pyclone to study changes in clonal abundances between tumor and model, MutationTimeR to understand the timing of model specific CNVs and Whole Genome Doubling (WGD), and AmpliconArchitect to identify ecDNA. Results: HCMI models exhibited high concordance with matching tumors when evaluated on SNVs, SVs, InDels and CNVs, with 69% of SNV/InDel drivers and 43% of CNV drivers conserved between tumor and model. Only 2% of investigated models (9/405) showed significantly divergent patterns of aneuploidy and presence of distinct clonal outgrowth in the model. This included two pancreatic cancer models with oncogenic KRAS point mutations that differed from those in the parent tumor. The cohort included models and tumors with ecDNA affecting known oncogenes including EGFR in GBM samples, CCNE1/KRAS in esophageal cancer and MYC in pancreatic cancer. ecDNA were the least conserved aberration type; 20% (50/254) of tumor-detected ecDNA were retained in an associated model while 35% (50/143) of model-detected ecDNA were found in their parent tumors. While the tumors and models generally showed similar WGD states, 10% of models exhibited WGD private to the model, and this model specific WGD generally occurred later in estimated mutational evolution time than models for which the tumor and model were both WGD. Surprisingly, not all models were pure for cancer cells with 19 models, enriched for melanomas, containing more than 20% diploid presumably non-tumor cells. Discussion: HCMI models exhibited high genomic concordance with their matching tumors across all cancer types. We catalogued classes of genomic divergence representing either selection of subclones or evolution during model development. SNVs and InDels exhibited greater conservation compared to CNVs, with ecDNA showing the highest variability between the tumor and the model. Our results provide full visibility into the genomic fidelity of each HCMI model, and enable researchers to select the most relevant HCMI model for their study. Citation Format: Andrew W. McPherson, Seongmin Choi, William F. Hooper, Jennifer M. Shelton, Timothy R. Chu, Dina ElHarouni, Mushriq Al-Jazrawe, Merve Dede, Toshinori Hinoue, Sean A. Misek, Heeju Noh, Luca Zanella, Moony Tseng, Hayley E. Francies, Priya Sridevi, Rachana Agarwal, Cindy W. Kyi, Julyann Perez-Mayoral, Megan J. Stine, Eva Tonsing-Carter, James M. Clinton, The HCMI Network, Peter W. Laird, Calvin J. Kuo, Olivier Elemento, David L. Spector, Andrew D. Cherniack, Kyle Ellrott, Martin L. Ferguson, Rameen Beroukhim, Katherine A. Hoadley, Nicolas Robine, Mathew J. Garnett, David A. Tuveson, Andrea Califano, Paul T. Spellman, Keith L. Ligon, Daniela S. Gerhard, Louis Staudt, Jesse Boehm. Patterns of genomic patient-model conservation and evolution in the Human Cancer Models Initiative (HCMI) next-generation cancer model resource [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3882.

ColoSeq Provides Comprehensive Lynch and Polyposis Syndrome Mutational Analysis Using Massively Parallel Sequencing

Introduction: Currently NGS techniques are being widely used as a tool in routine oncology workflows. Majority of labs use either DNA based small hotspots panels or two separate DNA and RNA panel. Unfortunately, this methodology can lead to an incomplete mutation profile because it lacks comprehensive tumor screening for theranostics. Many heterogeneous tumors carry multiple mutations and gene function can be altered by several types of variations including SNVs, CNV’s, Indels, SV’s and GF’s. Recently, it has been shown by various studies that TMB and MSI can correlate with a cancer patient’s responsiveness to checkpoint inhibitor immunotherapy. These findings have stimulated a widespread interest in the development of cost-effective assays that accurately measure TMB and MSI along with somatic variants. Here we assess whether TMB measured through NGS of a 1.9 MB-523-gene panel correlates with that determined through Foundation one CDx panel. We also assess and compare the accuracy of determining the MSI status of multiple cancers through sequencing a 523-gene targeted DNA panel vs MSI by PCR or MMR by immunohistochemistry. The assay is a targeted next-generation sequencing (NGS) assay designed to detect genetic alterations in 523 genes for SNVs, CNV’s, Indels, and SV’s & 55 genes for fusion and splice variant detection. Assessment of GF’s, SV’s, SNVs, CNV’s, TMB and MSI in one assay using DNA and RNA creates efficiencies in sample usage, time, and cost. Methods: The validation was guided by the joint consensus recommendation for validation of NGS assays by the AMP, CAP & NYSDOH. The validation included evaluations of precision, analytic sensitivity, analytic specificity, accuracy, reportable range, and reference range. RNA and DNA from of 100 samples (mixture of known patient specimens, known CAP proficiency specimens as well as known synthetic reference standards {Accormetrix hotspot DNA panel Seracare CNV DNA panel, & Seracare fusion V2 panel}) was used. These clinical samples were earlier tested on gold standard orthogonal methods like PCR, FISH, CDx NGS, and karyotype ( n=100 clinical and reference materials formalin-fixed, paraffin-embedded (FFPE) tumor samples from lung, GI, skin, CNS, breast, kidney, uterus, ovarian, salivary, thyroid gland tumors, soft tissue & bone cancer etc. Libraries for were prepared using the Illumina TruSight Oncology 500 (TSO500+) kit and sequenced on NextSeq 550. Sequencing analysis, variant, TMB and MSI calling were performed using software provided by illumina. Results: We were able to validate manufacture's analytical claims for all the variants groups including TMB and MSI in our validation. Conclusions: DNA and RNA libraries are prepared in parallel, sequenced, and analyzed simultaneously for efficient assessment of numerous types of somatic variants. We anticipate that this approach of obtaining high-resolution data from an FFPE samples at reduced sequencing cost, will facilitate testing in different malignancies which was not previously possible especially for determination of TMB and MSI. Note: This abstract was not presented at the meeting. Citation Format: Ravindra Kolhe, Pankaj Ahluwalia, Saleh Heneidi, Sudha Ananth, Vamsi Kota, Ashis Mondal. Guideline adherent clinical validation of a comprehensive DNA/RNA panel (523 genes-TruSight Oncology 500) for determination of single nucleotide variants (SNV’s), small insertions or deletions (Indels), copy number variations (CNV’s), splice variations (SV’s), gene fusions (GF’s), tumor mutation burden (TMB) and micro-satellite instability (MSI) on anext-generation sequencing (NGS)platform in a CLIA setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-227.

Purpose Circulating cell-free tumor DNA (ctDNA) is rapidly gaining attention as a valuable biosource for the detection and diagnosis of multiple types of cancer. ctDNA can be easily obtained through a minimally invasive liquid biopsy. Multiple NGS-based methods have been developed specifically for application in liquid biopsies. Before such methods can be implemented in clinical care, they need to be technically validated through measurement of independent reference standards. In the current project we technically validated the Roche AVENIO ctDNA Assay, which is based on the CAPP-seq technology [Newman AM, et al. Nat Biotechnol. 2016;34:547-55]. Its Targeted Kit interrogates 17 genes for Single Nucleotide Variants (SNVs), Insertions and Deletions (InDels), Copy Number Variations (CNVs) and gene fusions in a single workflow. Methods The detection of SNVs, CNVs, Indels and gene fusions was evaluated as follows: - SeraCare Seraseq ctDNA Complete was analyzed in four replicates at 2.5%, 0.5% and 0.1% mutant allele frequency (AF), and at 50ng and 10ng input. This material contains SNVs, InDels, CNVs and gene fusions. - An in-house characterized reference pool of patient plasma, containing SNVs and InDels at various AF (0.07% - 5.51%), was analyzed in four replicates at 50ng and 10ng input. - Plasma and serum samples obtained from patients with tissue confirmed presence of CNV were used to validate the robustness of CNV detection. Twelve samples were selected to represent a range of background DNA (serum had 2-4 times higher wildtype DNA levels compared to plasma), amplification levels (CNV levels 1.4-fold to 4.2-fold by ddPCR) and total input (10-50ng cfDNA input). - Plasma obtained from five patients with EML4-ALK gene fusion confirmed on tissue was used to further validate fusion detection. Sequencing was performed on an Illumina NextSeq on High Output mode with sixteen samples per run (20-33M read pairs per sample). Results Sensitivity for detection of SNVs and InDels was 100% for all variants down to 0.18% AF when using 50ng input, and 50% for variants at 0.10% AF. For 10ng input the variants were detected down to 0.60% AF with sensitivity of 92%. For variants with AF between 0.07% and 0.53%, sensitivity was 67%. Results from twelve plasma and serum samples obtained from patients with EGFR CNV were 100% concordant with ddPCR results. These results were confirmed in SeraCare samples at 10ng and 50ng input. Sensitivity of fusion detection in SeraCare material was 100% for AF of 0.5% and 50ng input, and 38% for input of 10ng. No fusions were detected at 50ng or 10ng input for AF of 0.1%. We furthermore confirmed 3 out of the 5 fusions found in tissue. Conclusions We have determined the lower limits of detection for SNVs, CNVs and gene fusions. Sensitivity was dependent on DNA input with performance optimized at 50ng. Our results confirm the feasibility of in-house use of the AVENIO ctDNA Targeted Kit for broad molecular profiling in liquid biopsies. Citation Format: Daan C. Vessies, Theodora C. Linders, Kalpana L. Ramkisoensing, Petra M. Nederlof, Gerrit A. Meijer, Kim Monkhorst, Daan van den Broek. Technical validation of Roche AVENIO sequencing platform for liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1381.

Diagnosis of lysosomal disorders (LDs) may be hampered by their clinical heterogeneity, phenotypic overlap, and variable age at onset. Conventional biological diagnostic procedures are based on a series of sequential investigations and require multiple sampling. Early diagnosis may allow for timely treatment and prevent clinical complications. In order to improve LDs diagnosis, we developed a capture-based next generation sequencing (NGS) panel allowing the detection of single nucleotide variants (SNVs), small insertions and deletions, and copy number variants (CNVs) in 51 genes related to LDs. The design of the LD panel covered at least coding regions, promoter region, and flanking intronic sequences for 51 genes. The validation of this panel consisted in testing 21 well-characterized samples and evaluating analytical and diagnostic performance metrics. Bioinformatics pipelines have been validated for SNVs, indels and CNVs. The clinical output of this panel was tested in five novel cases. This capture-based NGS panel provides an average coverage depth of 474× which allows the detection of SNVs and CNVs in one comprehensive assay. All the targeted regions were covered above the minimum required depth of 30×. To illustrate the clinical utility, five novel cases have been sequenced using this panel and the identified variants have been confirmed using Sanger sequencing or quantitative multiplex PCR of short fluorescent fragments (QMPSF). The application of NGS as first-line approach to analyze suspected LD cases may speed up the identification of alterations in LD-associated genes. NGS approaches combined with bioinformatics analyses, are a useful and cost-effective tool for identifying the causative variations in LDs.

Whole Genome Sequencing On Donor Cell Leukemia in a Patient with Multiple Myeloma Identified Gene Mutations That May Provide Insights to Leukemogenesis.

Emerging evidence demonstrates the clinical utility of genomic applications in newborn intensive care unit (NICU) patients with strong indications of Mendelian etiology. However, such applications' diagnostic yield and utility remain unclear for NICU cohorts with minimal phenotype selection. In this study, focused medical exome sequencing was used as a first-tier, singleton-focused diagnostic tool for 2303 unrelated sick neonates. Integrated analysis of single nucleotide variants (SNVs), small insertions and deletions (Indels), and large copy number variants (CNVs) was performed. The diagnostic rate in this NICU cohort is 12.3% (284/2303), with 190 probands with molecular diagnoses made from SNV/Indel analyses (66.9%), 93 patients with diagnostic aneuploidy/CNVs findings (32.8%), and 1 patient with both SNV and CNV (0.4%). In addition, 54 (2.3%) of patients had a reportable incidental finding. Multiple organ involvements, craniofacial abnormalities, and dermatologic abnormalities were the strongest positive predictors for a molecular diagnosis. Among the 190 cases with SNV/Indel defects, direct impacts on medical management were observed in 46.8% of patients after the results were reported. In this study, we demonstrate that focused medical exome sequencing is a powerful first-line diagnostic tool for NICU patients. Significant number of diagnosed NICU patients can benefit from more focused medical management and long-term care.

Background: The high-grade transformation of chronic lymphocytic leukemia (CLL), also called Richter's Syndrome (RS), carries a dismal prognosis. RS shares the histological characteristics with diffuse large B-cell lymphoma (DLBCL), but it has a distinct molecular profile compared to de novo DLBCL. Heterogeneous mutational profiles characterize RS, but studies report 90% of the tumours to involve molecular lesions in at least one of the TP53, CDKN2A, MYC or NOTCH1 genes. Being chemotherapy resistant, RS remains an area of high unmet clinical need. Aims: Our aim was to perform an integrative analysis of paired CLL and RS phases using a combination of coding and non-coding single nucleotide variants (SNVs), small insertions and deletions (InDels) and copy number variants (CNVs) detected by whole genome sequencing (WGS). Genes and pathways implicated in transformation were interrogated by RNA expression profiling of 800 cancer-related genes. Methods: We performed WGS on paired CLL and RS phase samples from 17 patients enrolled in our phase II trial of ofatumumab, cyclophosphamide, doxorubin, vincristine and prednisolone (O-CHOP). Through integrated analysis of SNVs, InDels and CNVs, we searched for differences in the somatic mutation spectrum between the two disease phases. We also employed targeted DNA and RNA expression profiling (NanoString) on an extended patient cohort (n = 38) to confirm our findings. Results: A significantly larger mutation burden (SNVs and InDels) was detected in RS (31.2 (±22.5) variants/subject) compared to CLL phase (20.8 (±12.7) variants/subject) (p = 0.031) and significantly more genes were mutated in RS (n = 457 genes; 29.6 (±21.3) mutated genes/subject) compared to CLL phase (n = 306 genes; 19.8 (±12.4) mutated genes/subject) (p = 0.022). Most mutated genes and variants detected were missense mutations and non-recurrent (i.e. detected in a single subject/phase). As in previous studies, lesions in the TP53, NOTCH1 and CDKN2A genes were common. We also detected mutations in XPO1 (35.3%) and TRAF3 (35.3%) genes more frequently than previously reported in RS. We next investigated the combined impact of mutated genes on cellular pathways and found MAPK pathway gene lesions to be enriched in RS vs CLL phase. Lesions in at least one MAPK pathway gene were detected in 9 (52.9%) CLL and 15 (88.2%) RS samples. In addition, at least one PI3K pathway gene lesion was detected in 10 (58.8%) CLL and 14 (82.4%) RS samples. Analysis of clonal evolution across different pathways demonstrated a high expansion probability for clones containing MAPK mutations. Next, we performed RNA expression profiling and pathway enrichment analysis, showing the JAK-STAT, PI3K and P53 pathways were the most likely to harbor differentially expressed genes. Five pathways (PI3K, cell cycle and apoptosis, RAS, PANC Drivers and MAPK) had 10 or more differentially expressed genes. Finally, we explored the evolution in the mutation landscape of non-coding regions during transformation finding 5 patients that carried mutation clusters in a region previously characterized as a functionally active PAX5 enhancer in CLL. Three of these occurred in the RS phase only. Expanded analysis on all filtered mutations in the entire PAX5 enhancer region showed 10 samples each with 1–8 mutations, of which 6 had mutations only in the RS phase. Summary/Conclusion: In conclusion, we show that integrated analysis of WGS combined with RNA expression profiling identifies a number of directly targetable pathways that merit clinical evaluation in RS.

Williams-Beuren syndrome (WBS) is a severe congenital disorder that presents challenges in prenatal diagnosis due to the atypical or incomplete phenotypes exhibited by affected fetuses. This study investigated the relationship between genotype and complex phenotype in WBS fetuses using ultrasound, SNP array, and whole exome sequencing. Chromosomal microarray analysis (CMA) and whole genome sequencing (WES) were conducted on pregnant women undergoing prenatal diagnosis. We analyzed genome-wide copy number variants (CNVs), regions of homozygosity (ROH), single nucleotide variants (SNVs), small insertions and deletions, and splice sites. A deletion at 7q11.23 was identified in 7 out of 6,718 prenatal diagnostic samples (1 in 960). Ultrasound findings varied: two fetuses exhibited cardiovascular anomalies; one presented with persistent left superior vena cava and intrauterine growth retardation (IUGR), while two others displayed polycystic kidney dysplasia, one accompanied by mild tricuspid regurgitation, and the remaining two fetuses showed no apparent ultrasound abnor-malities. Genetic analysis revealed CNVs ranging in size from 1.43 to 1.66 megabase pairs (Mb), affecting 34 to 41 genes. On average, one additional CNV larger than 100 kilobase pairs (Kb) of unknown significance and 0.43 ROH larger than 5 Mb were identified in these cases. Although pathogenic or likely pathogenic SNV or splice sites related to renal development and cardiovascular development were found, none correlated with the fetal phenotype observed. The phenotypes of WBS fetuses are often atypical and complex. Future research should focus on integrating advanced genetic technologies and improved imaging modalities to enhance our understanding of the intricate genotype-phenotype relationships associated with WBS.

Introduction: Targeted cancer therapies rely on the identification of biomarkers specific to the tumors. Next generation sequencing (NGS) based genomic profiling has informed clinical decision making by identifying somatic alterations such as single nucleotide variants (SNVs), small insertion and deletion mutations (indels), structural variations, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Here, we describe an integrative approach to characterize the genomic complexity of solid tumors using whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing (RNAseq), and tumor only panel sequencing. Methods: We report on WES for 84 paired tumor normal samples in a variety of tumor types including breast, colon, head and neck, melanoma, cervical, thyroid, glioblastoma, lung, pancreatic, prostate, appendiceal, cholangiocarcinoma, and kidney. A subset of these samples were also sequenced with high depth tumor only gene panel. WGS and RNAseq data were included in the analysis for additional 14 tumor normal pairs. Somatic alteration assessments included SNV, indels, MSI status, TMB, mutational signatures, copy number variations, gene fusions and structural variations. Results: Analysis using tumor normal WES and RNAseq identified both clinically relevant genes as well as mutational processes. We found a high percentage of germline mutations were misidentified as somatic variants using tumor only panels, further highlighting the importance of paired tumor normal sequencing. In some cases, the putative driver gene or the variant in a cancer gene identified by WES was not included in panel sequencing. For example, mutations in FOXA1 gene were recently implicated as clinically relevant resistance and metastasis marker. Exome wide mutational signature analysis also identified BRCA (Cosmic sig 3) signature in tumors with no alterations in BRCA1/2 genes. WGS analysis and fusion gene detection revealed novel fusion genes as well as important structural alterations. Examples include a novel BRAF fusion in a cholangiocarcinoma devoid of other known driver mutations, a novel NTRK3 fusion partner in a glioblastoma tumor, and numerous tandem duplications in an ovarian cancer. Conclusion: In contrast to tumor only gene panels, tumor and matched normal whole exome assay examines the entire coding portion of the genome without the limitations of a predefined gene list. This allows for detection of mutations in recently identified cancer drivers, ability to reliably distinguish somatic variants from clonal hematopoiesis or other germline variants, calculate genome wide mutational patterns including TMB, MSI, and identify the underlying mutational processes such as genomic signatures. The addition of WGS sequencing allows the identification of clinically relevant genomic rearrangements and novel structural variations. Citation Format: Corine K. Lau, Alena S. Harley, Paul Choppa, Janine Cooc, Ainura Kyshtoobayeva, Natalia Jun, Mark Dayrit, Wayne Delport, Mark Saldivar, Yop Jun, Raaj Trivedi, Alexandra E. Gylfe, Travis R. Lacey, Ezra Cohen, Kenneth Bloom, Eve Shinbrot. Integrative tumor profiling beyond panel sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3420.

A multi-laboratory assessment of clinical exome sequencing for detection of hereditary disease variants: 4441 ClinVar variants for clinical genomic test development and validation

41 - Detection of Exon-Centric Copy Number Changes and Mutations with Customizable Target Enrichment

High-throughput sequencing technologies have offered in recent years new opportunities to study genome variations. These studies have mostly focused on single nucleotide polymorphisms, small insertions or deletions and on copy number variants. Other structural variants, such as large insertions or deletions, tandem duplications, translocations, and inversions are less well-studied, despite that some have an important impact on phenotypes. In the present study, we performed a large-scale survey of structural variants in cattle. We report the identification of 6,426 putative structural variants in cattle extracted from whole-genome sequence data of 62 bulls representing the three major French dairy breeds. These genomic variants affect DNA segments greater than 50 base pairs and correspond to deletions, inversions and tandem duplications. Out of these, we identified a total of 547 deletions and 410 tandem duplications which could potentially code for CNVs. Experimental validation was carried out on 331 structural variants using a novel high-throughput genotyping method. Out of these, 255 structural variants (77%) generated good quality genotypes and 191 (75%) of them were validated. Gene content analyses in structural variant regions revealed 941 large deletions removing completely one or several genes, including 10 single-copy genes. In addition, some of the structural variants are located within quantitative trait loci for dairy traits. This study is a pan-genome assessment of genomic variations in cattle and may provide a new glimpse into the bovine genome architecture. Our results may also help to study the effects of structural variants on gene expression and consequently their effect on certain phenotypes of interest.

Identification and Interpretation of Clinically Relevant Somatic Variants from Whole-Genome Sequencing Data