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bioRxiv2024

Measuring DNA contents of animal and plant genomes with Gnodes, the long and short of it.

Measurement of DNA contents of genomes is valuable for understanding genome biology, including assessments of genome assemblies, but it is not a trivial problem. Measuring contents of DNA shotgun reads is complicated by several factors: biological contents of genomes at species, individual and tissue or cell levels, laboratory methods, sequencing technology and computational processing for measurement and assembly. This compares, and shares, complications with cytometric (Cym) and related molecular measurements of genome size and contents. There is an obvious discrepancy between cytometric measurements and current long-read genome assemblies (Asm): genome assemblies average 12% below Cym measured sizes, differing in amounts of duplicated content. This report examines five DNA read types to see if they can be used for more precise and reliable discrimination of major genome contents and sizes. The read types are short, accurate Illumina, long Pacific Biosciences, of low and high accuracy, and long Oxford Nanopore Technology of low and high accuracy. Gnodes is the measurement tool used, which maps DNA to assembly, and measures DNA copy numbers for major genome contents of genes, transposons, repeats, and others, using as a measurement unit the single copies of unique conserved genes. Public data of five well studied genomes, human, corn, zebrafish, sorghum and rice, are used for the primary evidence of this work. Results of this are mixed and open to interpretations: In broad terms, all DNA types measure about the same genome contents, at or below 90% agreement, which is a level that the other complications can contribute. For precision above a 90% level, long read types differ in supporting larger cytometric sizes (low accuracy reads), or smaller assembly sizes (high accuracy reads), with accurate short-reads roughly between. The weight of evidence suggests that low accuracy long reads are less biased for genome measurement, that high accuracy long reads have a bias of reduced duplications introduced by computational averaging or filtering. The several complicating factors noted can produce discrepancies larger than this average Cym - Asm difference, and are a problem to control.

genomics↗

bioRxiv2024

Deconstructing evolutionary histories of complex genomic rearrangements in lung malignancies

Somatic genomic rearrangements are hallmarks of cancer. Complex genomic rearrangements (CGRs) involving multiple intertwined structural alterations are often present in tumor genomes. CGRs frequently harbor oncogenic drivers, but their genomic architectures and etiologies are poorly understood. We used deep-coverage optical mapping technology to profile the genomic landscapes of normal lung tissues, benign pulmonary lesions, carcinoma in situ, and advanced carcinomas to examine the patterns of genome disorganization and instability in different stages of carcinogenesis in lung. Large rearrangements and CGRs were prevalent in the carcinomas. We developed omcplR to resolve the architecture of CGRs and predict their genesis from optical mapping data using genome-graph concept. We found that CGRs often arose from hierarchical combinations of multiple, localized simple structural variations, and harbored allelic heterogeneity at the affected loci. Rearrangement patterns and associated genomic signatures suggested that chromoanasynthesis was a likely prevalent mechanism driving complex genomic rearrangements. The early rearrangement junctions in intra-chromosomal CGRs were usually localized within the same chromatin domains, but the late junctions in advanced tumors had more heterogeneous contexts suggesting progressive organizational heterogeneity. The CGRs, especially the late events therein were under positive selection. A composite signature of genomic alterations including the CGRs captured the trajectory of progressive genomic disorganization and instability with carcinogenesis in lung and underscored the extent of genomic structural heterogeneity among the in-situ tumors.

genomics↗

bioRxiv2024

Illumina Complete Long Read Assay yields contiguous bacterial genomes from human gut metagenomes

Metagenomics enables direct investigation of the gene content and potential functions of gut bacteria without isolation and culture. However, metagenome-assembled genomes are often incomplete and have low contiguity due to challenges in assembling repeated genomic elements. Long-read sequencing approaches have successfully yielded circular bacterial genomes directly from metagenomes, but these approaches are low throughput, have high DNA input requirements, and can have high error rates. Illumina has recently launched the Illumina Complete Long Read (ICLR) assay, a new approach for generating kilobase-scale reads with low DNA input requirements and high accuracy. Here, we evaluate the performance of ICLR sequencing for gut metagenomics. We sequenced a microbial mock community and ten human gut microbiome samples with standard, shotgun 2x150 paired-end sequencing, ICLR sequencing, and nanopore long-read sequencing and compared performance in read lengths, assembly contiguity, and bin quality. We find that ICLR human metagenomic assemblies have higher N50 (119.5 {+/-} 24.8 kilobases) than short read assemblies (9.9 {+/-} 4.5 kilobases; p = 0.002), and comparable N50 to nanopore assemblies (91.0 {+/-} 43.8 kilobases; p = 0.32). Additionally, we find that ICLR draft microbial genomes are more complete (94.0% {+/-} 20.6%) than nanopore draft genomes (85.9% {+/-} 23.0%; p[≤] 0.001), and that nanopore draft genomes have truncated gene lengths (924.6 {+/-} 114.7 base pairs) relative to ICLR genomes (954.6 {+/-} 71.5 base pairs; p[≤] 0.001). Overall, we find that ICLR sequencing is a promising method for high-throughput and accurate assembly of microbial genomes from gut metagenomes. ImportanceMetagenomic sequencing allows scientists to directly measure the genome content and structure of microbes residing in complex microbial communities. Traditional short-read metagenomic sequencing methods often yield fragmented genomes, whereas advanced long-read sequencing methods improve genome assembly quality but often suffer from high error rates and are logistically limited due to low throughput and high input requirements. A new method, the Illumina Complete Long Read Assay (ICLR), is capable of generating highly-accurate kilobase-scale sequencing reads with minimal input material. To evaluate the utility of ICLR in metagenomic contexts, we applied short-read, long-read, and ICLR methods to simple and complex microbial communities. We found that ICLR outperforms short-read methods, and yields comparable metagenomic assemblies to standard long-read approaches while requiring less input material. Overall, ICLR represents a high-throughput and efficient solution for assembling complete genomes from complex metagenomes.

genomics↗

bioRxiv2025

BioToken and BioFM - Biologically-Informed Tokenization Enables Accurate and Efficient Genomic Foundation Models

Genomic variation underlies human phenotypic diversity, disease susceptibility, and evolutionary adaptation. Although large-scale genomic sequencing has transformed our ability to map genetic variation, accurately modeling and interpreting this data remains a central challenge; while genomic foundation models (GFMs) are a promising approach, they suffer from fundamental limitations. Current GFMs typically treat DNA simplistically as nucleotide-only sequences, overlooking critical biological context, such as genomic annotations, regulatory elements, and functional contexts central to genomic interpretation. Here, we introduce BioToken, a modular and extendable tokenization framework designed to encode genomic variants and biologically relevant region annotations directly into genomic representations. By utilizing intrinsic inductive biases, BioToken facilitates meaningful representation learning and generalization across diverse molecular phenotypes, such as gene expression, alternative splicing, and variant pathogenicity prediction. Built on BioToken, our genomic foundation model, BioFM, achieves competitive or superior results relative to specialized models (e.g., Enformer, SpliceTransformer) and GFMs up to 7B parameters across a comprehensive suite of genomic benchmarks, including noncoding pathogenicity, expression modulation, sQTL prediction, and long-range genomic interactions. Notably, BioFM achieves state-of-the-art performance with significantly fewer parameters (265M), substantially reducing training costs and computational requirements. Our findings highlight the substantial advantages of integrating biologically-informed inductive biases into genomic foundation modeling, providing a robust and accessible path forward in genomics. We provide our code and model checkpoints to support further research in this direction.

genomics↗

bioRxiv2025

Forty New Genomes Shed Light on Sexual Reproduction and the Origin of Tetraploidy in Microsporidia

Microsporidia are single-celled, obligately intracellular parasites with growing public health, agricultural, and economic importance. Despite this, Microsporidia remain relatively enigmatic, with many aspects of their biology and evolution unexplored. Key questions include whether Microsporidia undergo sexual reproduction, and the nature of the relationship between tetraploid and diploid lineages. While few high-quality microsporidian genomes currently exist to help answer such questions, large-scale biodiversity genomics initiatives, such as the Darwin Tree of Life project, can generate high-quality genome assemblies for microsporidian parasites when sequencing infected host species. Here, we present 40 new microsporidian genome assemblies from infected arthropod hosts that were sequenced to create reference genomes. Out of the 40, 32 are complete genomes, eight of which are chromosome-level, and eight are partial microsporidian genomes. We characterised 14 of these as polyploid and five as diploid. We found that tetraploid genome haplotypes are consistent with autopolyploidy, in that they coalesce more recently than species, and that they likely recombine. Within some genomes, we found large-scale rearrangements between the homeologous genomes. We also observed a high rate of rearrangement between genomes from different microsporidian groups, and a striking tolerance for segmental duplications. Analysis of chromatin conformation capture (Hi-C) data indicated that tetraploid genomes are likely organised into two diploid compartments, similar to dikaryotic cells in fungi, with evidence of recombination within and between compartments. Together, our results provide evidence for the existence of a sexual cycle in Microsporidia, and suggest a model for the microsporidian lifecycle that mirrors fungal reproduction.

genomics↗

bioRxiv2025

Archaic ancestry inference in imputed ancient human genomes

When modern humans expanded from Africa into Eurasia, they interbred with archaic hominins such as Neanderthals and Denisovans. This groundbreaking discovery, made in part possible through the genomic analysis of archaic remains, reshaped our understanding of human origins, and opened new research avenues to study the effects and consequences of archaic introgression. While significant progress has been made in identifying and quantifying archaic introgression, most studies have focused on contemporary individual genomic data. As a result, relatively little is known about the evolution of archaic variants within modern human populations shortly after interbreeding occurred. While analysis of ancient DNA from modern humans offers the potential to address this scientific gap, its poor quality has hindered its exploration. However, recent studies have shown that imputation using contemporary reference panels can accurately infer missing genotypes in ancient genomes. Here, we investigate the feasibility of using imputation to improve both global and local archaic ancestry inference in ancient genomes, by downsampling to different low-coverage values and imputing 20 high-coverage (>10X) ancient genomes, representing individuals from diverse temporal and geographical contexts. We tested the reliability of detecting and quantifying archaic introgression using D-statistics and the f4-ratio. We identified consistent results from the imputed and the original ancient genomes, suggesting that genomic estimates to detect and quantify introgression work well in imputed genomes. Regarding Local Ancestry Inference we find that we can identify more introgressed segments in imputed genomes than in non-imputed genomes. Surprisingly, we find that imputation accuracy is even higher in regions of archaic ancestry compared to other regions of the genome, facilitating the detection of introgressed segments in imputed genomes. Imputation also allows detection of Denisovan segments in Siberian and Alaskan individuals. We show that segments identified even at 0.0625X coverage can be used to reconstruct the history of introgressed haplotypes. For example, comparisons with archaic segments in contemporary humans reveal that the oldest individual analyzed, UstIshim, carried segments that are now found exclusively in either European or East Eurasian populations, indicating that these segments co-occurred in a shared ancestral population. By comparing only ancient individuals, we demonstrate that clustering based solely on the identified archaic segments effectively groups individuals into genetic clusters that correspond to populations defined by geography and time. This analysis shows a clear distinction between individuals with Denisovan introgression and those without, as well as a more detailed separation between Mesolithic and Neolithic Europeans, with the latter closely resembling Central Eurasian individuals. Furthermore, despite the small sample size in this study, we are able to reconstruct the origins of genes identified as candidates for adaptive introgression in contemporary populations, such as the BCN2 gene, which is an adaptively introgressed gene identified in contemporary West Eurasians. Additionally, we identify new candidates for adaptive introgression including LEMD2 and MLN in Europe. In this gene-region, imputation helps resolve the introgressed haplotype, which is closest to the Vindija Neanderthal haplotype.

genomics↗

bioRxiv2025

Massive proliferation of retrotransposons contributes to genome size expansion in species of the Pseudocercospora genus

Genome size expansions are common among eukaryotic lineages. Enlarged genomes can be bioenergetically demanding, and active mobile elements can trigger chromosomal rearrangements and loss of gene function. What triggers genome size expansions remains largely unexplored in many biological clades, particularly within the fungal kingdom. Activation of large transposable elements (TEs), such as long-terminal repeats (LTRs), is a common contributor. Yet the mechanisms of LTR activation remain poorly understood. Here, we focus on the fungal genus Pseudocercospora and closely related species with known variation in genome size. In using an assembly-free approach, we found that TE content is highly variable among species, with species-specific retrotransposon families being the main drivers of independent genome expansions. We further focussed on the two species with the most expanded genomes and reference-quality genomes, P. fijiensis and P. ulei. We found that the P. ulei genome is compartmentalized, with highly variable TE densities among chromosomal regions, and a striking reduction in pathogenicity-associated genes. Overall, our study indicates that species of Pseudocercospora originally had reduced genome sizes, and genome expansions are species-specific, driven by heterogeneous sets of TE families. Furthermore, we found that in the species with the most expanded genome, TE activity might not have ceased yet as indicated by resequencing data analysis of six strains from diverse locations in Colombia. We discuss what might have caused TE activation and subsequent proliferation in the genus, including stress conditions and host adaptation. Surveys of clades with highly dynamic genome sizes are crucial for the investigation of causal factors driving long-term TE dynamics.

genomics↗

bioRxiv2025

Genomic resources of Ascidiella aspersa and comparative analysis across tunicates reveal conserved class-level features and evolutionary diversification

BackgroundAscidiella aspersa is an invasive tunicate and one of the closest relatives of vertebrates. Despite its ecological nuisance, A. aspersa is anticipated to be a valuable model organism for developmental studies due to its remarkably transparent embryos. However, annotated genome assemblies and transcriptomic resources have not yet been fully established. Although several tunicate genomes have been sequenced, most lack annotations, and a comprehensive analysis across tunicates has not yet been conducted. ResultsWe performed de novo genome assembly and transcriptome analysis of A. aspersa, producing a high-quality 306.5 Mb genome assembly. The transcriptome was derived from nine different organs of adults and embryos at six developmental stages. Ab initio and homology-based gene predictions identified 24,504 genes with a BUSCO score of 92.2%. Functional annotation was added for 18,636 genes in the model. To understand the relative features of this species among tunicates, we conducted genome-wide comparative analysis using publicly available data from 35 other tunicate genomes across three classes, five orders, and 12 families, thus constructing gene models for 27 species with BUSCO scores >80%. Overall, phylogenetic analysis revealed a new hypothesis regarding the relationships among Phlebobranchia and Aplousobranchia families. Gene duplication analysis showed distinct contractions of gene families in some taxa with losses of specific DNA repair related genes that were shared among Thaliacea--these may have contributed to their evolutionary diversification. Tunicate genomes exhibited a high level of variation in genomic GC content (28.0%-42.7%). A. aspersa has the highest GC content in coding regions and the third position of codons among tunicate species, with changes in codon usage bias differing from other Ascidiidae species. We also constructed an online comparative tunicate genome database (TUNOME), that provides functional annotations of gene models and ortholog analyses based on these genomic and transcriptomic data. ConclusionsWe constructed genomic resources for A. aspersa and another 35 tunicate gene models. Comparative analysis reveals a variety in tunicate species genomes and characterizes class-level features. Our resources are expected to be a foundation for experimental studies involving non-model tunicates and for comparative analysis among tunicate species.

genomics↗

bioRxiv2025

Genome assembly and diagnostic DNA markers for sex of the largest freshwater fish in North America, the white sturgeon (Acipenser transmontanus).

Sturgeon and paddlefish represent some of the most early diverging branches of ray-finned fishes and have undergone at least one global and several lineage-specific whole genome duplication events. White sturgeon (Acipenser transmontanus), the largest freshwater fish in North America, have experienced at least two rounds of whole genome duplication, and may exhibit both di- and multi-valent meiotic segregation. Moreover, they exhibit contemporary ploidy variants due to spontaneous autopolyploidy, particularly in aquaculture. Nonetheless, as a species with several population segments that exhibit chronic recruitment failure, conservation aquaculture is an important part of their management. To facilitate the development of genetic tools to aid white sturgeon conservation, as well as a basis to understand how ploidy changes and variation historically and contemporarily shape the evolution of this species, we present a genome assembly for a white sturgeon from the Snake River, Idaho, USA. Analysis of sequence data used for assembly indicated a haploid genome size of approximately 1.5Gbp, implying tetraploidy (4N), while analysis of heterozygous k-mers from 21 to 41 bp suggest the genome reflects both 4N and 8N variants. The final genome assembly, scaffolded using linkage maps constructed from Fraser River and Snake River F1 families, contained 6.26Gbp in 832,145 scaffolds, consistent with published genome size estimates. Conserved ortholog completeness for this genome (90.5%; 22.8% single-copy and 67.7% duplicated) was similar to the putatively diploid sterlet sturgeon, and the largest linkage map-based scaffold was 55.2Gbp, though the N50 for this assembly was only 416Kbp, indicating the assembly remains fragmented. We demonstrate the utility of this assembly by identifying genomic regions significantly associated with sex. Genetic markers, designed for inclusion in an amplicon genotyping panel, predicted sex 96.6% and 81.5% correctly in females and males, respectively, providing a strong overall association ({square}2 p-value < 2.7x10-37) with some variation by geographic region. Article summaryFunctional polysomes (more than two chromosomes that pair in meiosis) are rare among vertebrates. White sturgeon, the largest freshwater fish in North America, are tetraploid and occasionally hexaploid. Several populations of this species are stagnant or declining, requiring aquaculture to bolster reproduction. We analyzed whole genomic data and assembled the genome of an individual from the unique Snake River, Idaho, population. Results indicate most genetic variants are consistent with tetraploidy, and the genome assembly, while fragmented, is largely complete. We demonstrate its utility by designing genetic markers for sex for use in conservation and commercial aquaculture.

genomics↗

bioRxiv2025

A Near Telomere-to-Telomere Reference Genome for Drakensberger Cattle Achieved Through Trio-Binned Long-Read Sequencing

Drakensberger cattle is indigenous to South Africa and represent a unique genetic resource which is known for its quality beef production and adapted to the harsh climatic conditions. Despite its significance within the beef industry, no high-quality chromosomal level genome has been reported for this breed, limiting genomic selection and conservation efforts. Although there is a bovine genome reference, we need a breed specific reference to identify breed-unique alleles and structural variants that might not be explained by a distant reference. To address this, we generated a haplotype resolved assembly for Drakensberger cattle using a trio-binning where we employed PacBio HiFi reads for sire and dam, a combination of PacBio HiFi reads, Oxford Nanopore Technologies reads and Omni-C reads for the offspring. The assembled diploid genome size is 2.89 Gb with a scaffold N50 of 111 Mb and contig N50 of 61 Mb. The consensus accuracy was exceptionally high (QV = 70.23) and a genome completeness of 97.5 %, as analysed by the Benchmarking Universal Single-Copy Orthologs (BUSCO). The k-mer profiling suggested one of the strong haplotype separation for livestock with the paternity assembly containing 97.1% and maternity with 99.0%, combined diploid genome recovered 99.46% of all the solid read k-mers. We identified 14 telomeric ends across 13 scaffolds. The final genome encompassed a total of 22,854 protein-coding genes. This is the first high-quality, haplotype resolved genome assembly of the Drakensberger breed. This assembly high accuracy, contiguity and completeness place the genome among the highest-quality cattle genomes produced to date. This genomic resource is essential in designing programs to studies for breed evolution, adaptation, genomic selection and for conservation of the South African indigenous resources.

genomics↗

bioRxiv2018

Ultrasensitive capture of human herpes simplex virus genomes directly from clinical samples reveals extraordinarily limited evolution in cell culture

Herpes simplex viruses (HSV) are difficult to sequence due to their large DNA genome, high GC content, and the presence of repeats. To date, most HSV genomes have been recovered from culture isolates, raising concern that these genomes may not accurately represent circulating clinical strains. We report the development and validation of a DNA oligonucleotide hybridization panel to recover near complete HSV genomes at abundances up to 50,000-fold lower than previously reported. Using copy number information on herpesvirus and host DNA background via quantitative PCR, we developed a protocol for pooling for cost-effective recovery of more than 50 HSV-1 or HSV-2 genomes per MiSeq run. We demonstrate the ability to recover >99% of the HSV genome at >100X coverage in 72 hours at viral loads that allow whole genome recovery from latently-infected ganglia. We also report a new computational pipeline for rapid HSV genome assembly and annotation. Using the above tools and a series of 17 HSV-1-positive clinical swabs sent to our laboratory for viral isolation, we show limited evolution of HSV-1 during viral isolation in human fibroblast cells compared to the original clinical samples. Our data indicate that previous studies using low passage clinical isolates of herpes simplex viruses are reflective of the viral sequences present in the lesion and thus can be used in phylogenetic analyses. We also detect superinfection within a single sample with unrelated HSV-1 strains recovered from separate oral lesions in an immunosuppressed patient during a 2.5-week period, illustrating the power of direct-from-specimen sequencing of HSV.\n\nImportanceHerpes simplex viruses affect more than 4 billion people across the globe, constituting a large burden of disease. Understanding global diversity of herpes simplex viruses is important for diagnostics and therapeutics as well as cure research and tracking transmission among humans. To date, most HSV genomics has been performed on culture isolates and DNA swabs with high quantities of virus. We describe the development of wet-lab and computational tools that enable the accurate sequencing of near-complete genomes of HSV-1 and HSV-2 directly from clinical specimens at abundances >50,000-fold lower than previously sequenced and at significantly reduced cost. We use these tools to profile circulating HSV-1 strains in the community and illustrate limited changes to the viral genome during the viral isolation process. These techniques enable cost-effective, rapid sequencing of HSV-1 and HSV-2 genomes that will help enable improved detection, surveillance, and control of this human pathogen.

genomics↗

bioRxiv2018

A Hybrid de novo Assembly of the Sea Pansy (Renilla muelleri) Genome

BackgroundOver 3,000 species of octocorals (Cnidaria, Anthozoa) inhabit an expansive range of environments, from shallow tropical seas to the deep-ocean floor. They are important foundation species that create coral \"forests\" which provide unique niches and three-dimensional living space for other organisms. The octocoral genus Renilla inhabits sandy, continental shelves in the subtropical and tropical Atlantic and eastern Pacific Oceans. Renilla is especially interesting because it produces secondary metabolites for defense, exhibits bioluminescence, and produces a luciferase that is widely used in dual-reporter assays in molecular biology. Although several cnidarian genomes are currently available, the majority are from hexacorals. Here, we present a de novo assembly of the R. muelleri genome, making this the first complete draft genome from an octocoral.\n\nFindingsWe generated a hybrid de novo assembly using the Maryland Super-Read Celera Assembler v.3.2.6 (MaSuRCA). The final assembly included 4,825 scaffolds and a haploid genome size of 172 Mb. A BUSCO assessment found 88% of metazoan orthologs present in the genome. An Augustus ab initio gene prediction found 23,660 genes, of which 66% (15,635) had detectable similarity to annotated genes from the starlet sea anemone, Nematostella vectensis, or to the Uniprot database. Although the R. muelleri genome is smaller (172 Mb) than other publicly available, hexacoral genomes (256-448 Mb), the R. muelleri genome is similar to the hexacoral genomes in terms of the number of complete metazoan BUSCOs and predicted gene models.\n\nConclusionsThe R. muelleri hybrid genome provides a novel resource for researchers to investigate the evolution of genes and gene families within Octocorallia and more widely across Anthozoa. It will be a key resource for future comparative genomics with other corals and for understanding the genomic basis of coral diversity.

genomics↗

bioRxiv2019

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are still limited. In addition to the limited inclusion of these populations in genetic studies, these populations have more complex linkage disequilibrium structure that may reduce the number of variants associated with a phenotype. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with commercial genome-wide genotyping array data. We demonstrate that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhances gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3 to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels, respectively. Impressively, even for extremely rare variants with sample minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~20,000 self-identified African descent individuals and ~23,000 self-identified Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC (p=8.1x10-12) in African populations, rs11549407 with lower HGB (p=1.59x10-12) and HCT (p=1.13x10-9) in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of TOPMed imputation reference panel for identification of novel associations between rare variants and complex traits not previously detected in similar sized genome-wide studies of under-represented African and Hispanic/Latino populations.\n\nAuthor summaryAdmixed African and Hispanic/Latino populations remain understudied in genome-wide association and fine-mapping studies of complex diseases. These populations have more complex linkage disequilibrium (LD) structure that can impair mapping of variants associated with complex diseases and their risk factors. Genotype imputation represents an approach to improve genome coverage, especially for rare or ancestry-specific variation; however, these understudied populations also have smaller relevant imputation reference panels that need to be expanded to represent their more complex LD patterns. In this study, we leveraged >100,000 phased sequences generated from the multi-ethnic NHLBI TOPMed project to impute in admixed cohorts encompassing ~20,000 individuals of African ancestry (AAs) and ~23,000 Hispanics/Latinos. We demonstrated substantially higher imputation quality for low frequency and rare variants in comparison to the state-of-the-art reference panels (1000 Genomes Project and Haplotype Reference Consortium). Association analyses of ~35 million (AAs) and ~27 million (Hispanics/Latinos) variants passing stringent post-imputation filtering with quantitative hematological traits led to the discovery of associations with two rare variants in the HBB gene; one of these variants was replicated in an independent sample, and the other is known to cause anemia in the homozygous state. By comparison, the same HBB variants would not have been genome-wide significant using other state-of-the-art reference panels due to lower imputation quality. Our findings demonstrate the power of the TOPMed whole genome sequencing data for imputation and subsequent association analysis in admixed African and Hispanic/Latino populations.

genomics↗

bioRxiv2019

Unusual genome expansion and transcription suppression in ectomycorrhizal Tricholoma matsutake by repetitive insertions of transposable elements

Genome sequence of Tricholoma matsutake was revealed as the one of the large fungal genomes published up to date at 189.0 Mbp with 15,305 predicted genes. The unusual size of this fungal genome contained frequent colonization of transposable elements (TEs) occupying more than half of the entire genome. We identified that 702 genes were surrounded by TEs and 83.2% of those genes were never transcribed at any development stage. This observation corroborated that the insertion of transposable elements alters the transcription of the genes neighboring TEs.\n\nRepeat-induced point mutation such as C to T hypermutation with a bias over CpG dinucleotides was also recognized in this genome, representing a typical defense mechanism against TEs during evolution. Many transcription factor genes were activated in both primordia and fruiting body, which indicates that many regulatory processes are shared during developmental stages. Small secreted protein genes (<300 aa) were dominantly transcribed in hyphae, where symbiotic interactions occur with hosts. Comparative analysis with 37 Agaricomycetes genomes revealed that IstB-like domain (PF01695) was conserved in taxonomically diverse mycorrhizal genomes, where the T. matsutake genome contained four copies of this domain. Three of the IstB-like genes were overexpressed in hyphae. In the CAZyme analysis, reduced CAZyme genes were found as other ectomycorrhizal genomes including a lot of loss of glycoside hydrolase genes. Also, auxiliary activity genes were dominantly transcribed in primordia. The T. matsutake genome sequence provides insight into the large genome size and clues to understand unusual fungal genome expansion.

genomics↗

bioRxiv2019

The Bovine Genome Variation Database (BGVD): Integrated Web-database for Bovine Sequencing Variations and Selective Signatures

Next-generation sequencing has yielded a vast amount of cattle genomic data for the global characterization of population genetic diversity and the identification of regions of the genome under natural and artificial selection. However, efficient storage, querying and visualization of such large datasets remain challenging. Here, we developed a comprehensive Bovine Genome Variation Database (BGVD, http://animal.nwsuaf.edu.cn/BosVar) that provides six main functionalities: Gene Search, Variation Search, Genomic Signature Search, Genome Browser, Alignment Search Tools and the Genome Coordinate Conversion Tool. The BGVD contains information on genomic variations comprising [~]60.44 M SNPs, [~]6.86 M indels, 76,634 CNV regions and signatures of selective sweeps in 432 samples from modern cattle worldwide. Users can quickly retrieve distribution patterns of these variations for 54 cattle breeds through an interactive source of breed origin map using a given gene symbol or genomic region for any of the three versions of the bovine reference genomes (ARS-UCD1.2, UMD3.1.1, and Btau 5.0.1). Signals of selection are displayed as Manhattan plots and Genome Browser tracks. To further investigate and visualize the relationships between variants and signatures of selection, the Genome Browser integrates all variations, selection data and resources from NCBI, the UCSC Genome Browser and AnimalQTLdb. Collectively, all these features make the BGVD a useful archive for in-depth data mining and analyses of cattle biology and cattle breeding on a global scale.

genomics↗

bioRxiv2026

Chromosome-level reference genome of the beach false foxglove, Agalinis fasciculata (Orobanchaceae)

Orobanchaceae is the largest family of parasitic plants, encompassing a full spectrum of parasitic strategies, ranging from autotrophic to holoparasitic. Agalinis is a genus of facultative hemiparasites comprising about 70 species distributed throughout the Americas, including several endemic and rare taxa. Agalinis fasciculata, the beach false foxglove, is a widely distributed species across southeastern North America. Here, we use PacBio HiFi, Omni-C, and RNA-seq data to generate the first high-quality reference genome for the genus. The nuclear genome is 2.29 Gb in size, with most sequences anchored to 14 pseudochromosomes and an N50 of 162 Mb. BUSCO analyses indicate high completeness (98.4%). Structural genome annotation identified 34,133 protein-coding genes and 39,266 transcripts, most of which have at least one functional annotation. The plastid and mitochondrial genomes were also assembled. We further examined genetic diversity and demographic history in A. fasciculata, revealing low genome-wide heterozygosity and evidence of inbreeding. This reference genome is an important resource for understanding the evolutionary history of the genus and the evolutionary patterns of parasitism within Orobanchaceae. SignificanceThis high-quality genome is the first chromosome-level assembly for Agalinis, a hemiparasitic genus in the plant family Orobanchaceae. It improves the taxon sampling within Orobanchaceae, representing an important resource for investigating patterns of genome evolution in parasitic lineages. Furthermore, Agalinis has served as a focal genus for studies of the anatomy of haustorial development, and genome annotation incorporated RNA from multiple tissues, enabling the identification of genes expressed in different tissues, including roots and haustoria. This genome also serves as a reference for evolutionary studies of other Agalinis species, many of which are endemic and of conservation concern in North and South America. Overall, the beach false foxglove genome will support studies of the evolutionary history of Agalinis and genome evolution across Orobanchaceae.

genomics↗

bioRxiv2026

A Translocation within the Ogataea Species Complex Alters Local Subtelomeric Chromatin while Maintaining Overall Genome Organization

Eukaryotic genomic DNA is packaged in the nucleus as chromatin - a DNA-protein aggregate regulating genome function, including transcription. Chromatin is classified as either active euchromatin or silent heterochromatin, with each marked by distinct histone post-translational modifications (PTMs). Chromatin composition also mediates genome organization, including how heterochromatin aggregates at the nuclear periphery while euchromatin localizes to the nucleus center. In fungi, heterochromatic loci cluster, including independent centromere and telomere clusters that form the Rabl chromosome conformation. However, it is unknown if chromatin composition and genome organization are conserved in closely related fungi, and how these features are impacted by large-scale chromosomal rearrangements. Here, we examined differences in histone PTM deposition, gene expression, and genome organization in two yeast species from the order Pichiales, which diverged from the common ancestor shared with Saccharomyces cerevisiae more than 200 million years ago. We focused on Ogataea polymorpha, which is used for industrial protein production, and Ogataea haglerorum, an isolate of which harbors a translocation between chromosomes 1 and 6. We show that the enrichment of three activating PTMs - the trimethylation of lysine 4 of histone H3 (H3K4me3) and the acetylation of lysine 9 of histone H3 (H3K9ac) or lysine 16 of histone H4 (H4K16ac) - are similar genome-wide yet gene orthologs have distinct chromatin and expression patterns. While both Ogataea genomes organize into a Rabl conformation, the O. haglerorum translocation alters subtelomeric chromatin composition and expression of genes affected by the translocation. Our work highlights the genome function differences that occur on a microevolutionary scale. Article SummaryTo assess changes in chromatin - the DNA-protein aggregate controlling genome function - between closely related species of fungi, we compared histone modifications, gene expression, and DNA folding in two yeasts in the same species complex, Ogataea polymorpha and Ogataea haglerorum. Globally, we found similar patterns of chromatin composition, transcription, and genome folding, with distinct differences in individual genes. Further, a large genome rearrangement in O. haglerorum alters histone mark deposition and gene expression at affected chromosome ends. Our results provide insights into functional genome changes that occur over short evolutionary time scales and in response to large chromosomal changes.

genomics↗

bioRxiv2026

Adaptive sampling-based enrichment enables genome reconstruction of intracellular symbionts despite host background and reference divergence

Recovering genomes of intracellular microbes from host-dominated samples remains a major challenge in microbial genomics, due to low target abundance, overwhelming host DNA, and the inability to culture these organisms independently. Despite extensive interest in Wolbachia, efficient genome recovery directly from host tissues remains limited by the inefficiency of host-dominated sequencing and the constraints of existing enrichment strategies. Here, we demonstrate that Oxford Nanopore adaptive sampling (AS) enables efficient, real-time enrichment of target DNA directly from complex host tissues, providing a culture-free approach for genome recovery in such systems. To our knowledge, this represents the first application of enrichment-mode adaptive sampling to achieve de novo reconstruction of an intracellular endosymbiont genome in a mosquito system. Using Aedes aegypti mosquitoes infected with a locally derived wAlbB-like strain, we applied enrichment-mode AS to selectively sequence Wolbachia DNA. This resulted in an increase from <1% Wolbachia reads in conventional shotgun data to [~]90% under adaptive sampling. De novo assembly of AS-enriched long reads yielded a near-complete genome ([~]1.5 Mb) in two contigs with >96-99% completeness. Comparative analyses revealed multiple large-scale chromosomal rearrangements relative to the reference wAlbB genome, demonstrating that adaptive sampling does not impose reference-dependent genome structure. Annotation further identified three prophage-associated regions, including two strain-specific expansions absent from the reference genome. Notably, cytoplasmic incompatibility genes (cifA and cifB) were identified adjacent to one of these regions, consistent with their known genomic association with prophage elements. Importantly, adaptive sampling remained effective despite substantial structural divergence between the reference and target genomes, revealing an unexpectedly robust application of this approach beyond its presumed operating conditions. Together, these results establish enrichment-mode adaptive sampling as a robust and scalable strategy for genome-resolved analysis of intracellular bacteria in host-associated systems.

genomics↗