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PubMed2026

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

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

Tyto alba↗

PubMed2026

Haplotype-resolved genome of Forsythia suspensa reveals the reticulate evolution in Oleaceae and a novel gene cluster regulating stamen development.

The olive family (Oleaceae) comprises numerous species of economic, horticultural, and medicinal importance. Despite its significance, the evolutionary history of this complex family remains enigmatic. Here, we generated a high-quality haplotype-resolved genome of Forsythia suspensa, a distylous species that occupies a key phylogenetic position in Oleaceae. The 2 haplotypes exhibit significant allelic divergence with potential allele-specific regulation. We reconstructed the polyploidization history of Oleaceae by confirming and precisely dating a shared whole-genome triplication and an independent whole-genome duplication event. We revealed a complex reticulate evolution that gave rise to the tribe Oleeae: an initial hybridization between Forsythieae (♂) and Jasmineae (♀), a subsequent backcrossing event, and a final whole-genome duplication. We identified a novel tandemly duplicated pectin methylesterase inhibitor gene cluster that regulates filament length and pollen size via restricting cell elongation in the long-styled morph. Dosage augmentation via stepwise cluster formation (0.99 to 3.83 Mya) may contribute to maintaining stamen traits of the long-styled morph. These FsPMEIs are co-expressed with many cell wall-related genes, suggesting a functional link in cell wall modification. Our study reveals the reticulate evolution in Oleaceae and a novel gene cluster controlling stamen development in F. suspensa and provides valuable haplotype-resolved genomic resources for heterostylous species, offering novel framework and molecular pathways to understand plant adaptive evolution.

Forsythia↗

PubMed2025

Investigations of HLA-F and HLA-G 3'UTR Polymorphisms in Preeclampsia and Fetal Growth Restriction Indicate a Possible Role of HLA-F-HLA-G Haplotypes and Diplotypes.

HLA-F and HLA-G may be involved in the pathogeneses of preeclampsia and fetal growth restriction (FGR). However, the functions of HLA-F and HLA-G in placental dysfunction remain unclear. The aim was to investigate differences in the prevalence of specific HLA-F and HLA-G gene allelic polymorphisms, genotypes, haplotypes, and diplotypes between controls and cases with preeclampsia or FGR. In total, blood samples from 365 pregnant females (controls, n = 192; preeclampsia, n = 164; FGR, n = 19) in their second and third trimester, and corresponding cordial blood samples (reflecting newborns, n = 160) were obtained after delivery. Genomic DNA was sequenced with a focus on the specific gene polymorphisms in the HLA-F gene locus, especially the single nucleotide polymorphisms (SNPs) rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G), as well as the rs371194629 (14-bp ins/del) in the 3'UTR of HLA-G. Haplotype and diplotype distributions were obtained using PHASE v2.1, and linkage disequilibrium analyses were performed. SNPs in the HLA-F gene locus and the 3'UTR of HLA-G were not associated with the risk of preeclampsia or FGR. The SNPs did not correlate with fetal-placental weight ratio, deviation of birth weight at gestational age, and placental weight. However, a trend towards an absence of certain HLA-F-HLA-G extended diplotypes in preeclampsia was observed. The current study does not support associations of the investigated HLA-F SNPs with preeclampsia or FGR. However, further studies are needed to evaluate the possible role of certain fetal HLA-F-HLA-G extended haplotypes and diplotypes in preeclampsia.

Humans↗

PubMed2025

Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer.

BACKGROUND: Immune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs. METHODS: We carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6-8 weeks after ICI initiation. Findings were validated in two external cohorts. RESULTS: We identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8), OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade ≥2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade ≥2 (OR 3.02; 95% CI 1.83 to 5.02; p<0.001), grade ≥3 (OR 3.59; 95% CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95% CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group. CONCLUSIONS: Novel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

Humans↗

PubMed2025

Unraveling the complex genetic landscape of OTOF-related hearing loss: a deep dive into cryptic variants and haplotype phasing.

BACKGROUND: Pathogenic variants in OTOF are a major cause of auditory synaptopathy. However, challenges remain in interpreting OTOF variants, including difficulties in confirming haplotype phasing using traditional short-read sequencing (SRS) due to the large gene size, the potential incomplete penetrance of certain variants, and difficulties in assessing variants at non-canonical splice sites. This study aims to revisit the genetic landscape of OTOF variants in a Taiwanese non-syndromic auditory neuropathy spectrum disorder (ANSD) cohort using a combination of sequencing technologies, predictive tools, and experimental validations. METHODS: We performed SRS to analyze OTOF variants in 65 unrelated Taiwanese patients diagnosed with non-syndromic ANSD, complemented by long-read sequencing (LRS) for haplotype phasing. A prediction-to-validation pipeline was implemented to assess the pathogenicity of cryptic variants using SpliceAI software and minigene assays. RESULTS: Biallelic pathogenic OTOF variants were identified in 33 patients (50.8%), while monoallelic variants were found in five patients. Three novel variants, c.3864G > A (p.Ala1288 =), c.4501G > A (p.Ala1501Thr), and c.5813 + 2T > C, were detected. The pathogenicity of two non-canonical mis-splicing variants, c.3894 + 5G > C and c.3864G > A (p.Ala1288 =), was confirmed by minigene assays. LRS-based haplotype phasing revealed that the common missense variant c.5098G > C (p.Glu1700Gln) and the novel variant c.5975A > G (p.Lys1992Arg) are in cis and form a founder pathogenic allele in the Taiwanese population. CONCLUSIONS: Our study highlights the genetic heterogeneity of DFNB9 and emphasizes the importance of population-specific variant interpretation. The integration of advanced sequencing technologies, predictive algorithms, and functional validation assays will improve the accuracy of molecular diagnosis and inform personalized treatment strategies for individuals with DFNB9.

Humans↗

PubMed1979

Haplotype analysis of the linkage group HLA-A: HLA-B : Bf in Japanese.

Three hundred four HLA-A : HLA-B : Bf haplotypes of the Japanese population as deduced by family analysis are described. Several linkage disequilibriums were observed in the following two-factor haplotypes: HLA-A and HLA-B, HLA-A and Bf, and HLA-B and Bf. Positive linkage disequilibriums between HLA-A and HLA-B noted in the present study seem to be Japanese specific when compared with the results obtained from other ethnic groups reported so far. The striking finding is that three HLA-B : Bf haplotypes, namely B12-BfF, B15-BfF, and B7-BfS, are common and show linkage disequilibrium in both Japanese and European Caucasians (German). This finding not only confirms the proximity of the HLA-B and Bf loci but also suggests that the interaction of the two genes plays an important role in the maintenance of stable linkage disequilibrium.

Gene Frequency↗

PubMed1979

Genetic segregation of multiple sclerosis and histocompatibility (HLA) haplotypes.

The possibility that a gene determining susceptibility to multiple sclerosis (MSS) may be closely linked to the major histocompatibility locus (HLA) is suggested by observation of a loose association between multiple sclerosis (MS) and certain HLA determinants. In the present study, the possible association was analyzed by studying the segregation of MS and the HLA haplotypes in families with more than one case of MS. Analysis of 48 published families revealed that the haplotype shared by those with MS within the family was also shared by those without clinical signs of MS at close to the 50% frequency expected by chance. Thus, we were unable to demonstrate that MS is associated with one HLA defined parental haplotype. We discussed reasons for this apparent failure to demonstrate existence of an MSS gene using available multiplex MS families.

HLA Antigens↗

PubMed1979

DNA fragments of the Mus musculus beta globin haplotypes Hbbs and Hbbd.

Two alternative haplotypes at the complex locus controlling hemoglobin beta chain synthesis in Mus musculus were compared at the DNA level. As expected, Hbbd homozygotes--which as adults synthesize two species of beta chain--have two genes for beta globin. Adult mice homozygous for the Hbbs haplotype make only a single type of beta polypeptide, yet they also have two beta globin genes. Apparently the two Hbbs genes encode identical proteins, or one of the two genes is not detectably expressed. The Hbbs and Hbbd haplotypes are thus more similar at the DNA level than studies of their polypeptide products have indicated.

Animals↗

PubMed1979

Influence of major histocompatibility haplotype on autoimmune disease varies in different inbred families of chickens.

Three partially inbred substrains of Obese strain chickens were studied for the spontaneous development of autoimmune thyroiditis. The influence of the major histocompatibility complex (B haplotype) was marked in one, less marked but still significant in a second, and barely detectable and transient in a third substrain. These differences in the effect of B haplotype may be due to the overriding action of genes other than those within the B haplotype.

Animals↗

PubMed1979

HLA haplotypes and hayfever: a possible protective role.

The HLA haplotype frequencies of European asthmatic children and their immediate families were studied, and a disassociation between haplotype A1-B8 and skin sensitivity to grass pollens was found, suggesting that within this allergic population, possession of the haplotype A1-B8 conferred possible protection against grass pollinosis. There was no association between A1-B8 and clinical asthma or between it and skin sensitivity to the house dust mite.

Dust↗

PubMed1979

HLA-B17 and the HLA-A1, B17 haplotype in acute myelogenous leukemia.

Seventy-nine Caucasians with acute myelogenous leukemia (AML) were genotyped to determine whether AML, the induction of remission or patient survival were associated with particular HLA phenotypes or haplotypes. HLA-B17 and B27 were increased in AML patients over 40 years of age. Combined analysis of four independent studies indicates that HLA-B17 is significantly but weakly associated with AML, relative risk = 1.48 (.01 less than P less than .025). The A1, B17 and Aw24, Bw35 haplotypes occurred more frequently in the AML group as compared to racial and geographic controls (uncorrected P = 0.0068 and 0.0098, respectively Fisher's Exact Test). Induction of remission occurred less frequently in patients with the B17 phenotype as compared to patients lacking this antigen (P = 0.047). Patient survival was associated with remission status (P = 0.002) but was not significantly associated with particular HLA phenotypes or haplotypes. These results indicate that a gene or genes in the HLA-B region of the major histocompatibility complex can influence susceptibility to AML and also the response to chemotherapy.

Adolescent↗

PubMed2026

Haplotype-aware long-read error correction.

Error correction of long reads is an important initial step in genome assembly workflows. For organisms with ploidy greater than one, it is important to preserve haplotype-specific variation during read correction. This challenge has driven the development of several haplotype-aware correction methods. However, existing methods are based on either ad-hoc heuristics or deep learning approaches. In this paper, we introduce a rigorous formulation for this problem. Our approach builds on the minimum error correction framework used in reference-based haplotype phasing. We prove that the proposed formulation for error correction of reads in de novo context, i.e., without using a reference genome, is NP-hard. To make our exact algorithm scale to large datasets, we introduce practical heuristics. Experiments using PacBio HiFi sequencing datasets from human and plant genomes show that our approach achieves accuracy comparable to state-of-the-art methods. Implementation: https://github.com/at-cg/HALE .

Clustering↗

PubMed2024

Haplotype-resolved genome assembly and implementation of VitExpress, an open interactive transcriptomic platform for grapevine.

Haplotype-resolved genome assemblies were produced for Chasselas and Ugni Blanc, two heterozygous Vitis vinifera cultivars by combining high-fidelity long-read sequencing and high-throughput chromosome conformation capture (Hi-C). The telomere-to-telomere full coverage of the chromosomes allowed us to assemble separately the two haplo-genomes of both cultivars and revealed structural variations between the two haplotypes of a given cultivar. The deletions/insertions, inversions, translocations, and duplications provide insight into the evolutionary history and parental relationship among grape varieties. Integration of de novo single long-read sequencing of full-length transcript isoforms (Iso-Seq) yielded a highly improved genome annotation. Given its higher contiguity, and the robustness of the IsoSeq-based annotation, the Chasselas assembly meets the standard to become the annotated reference genome for V. vinifera. Building on these resources, we developed VitExpress, an open interactive transcriptomic platform, that provides a genome browser and integrated web tools for expression profiling, and a set of statistical tools (StatTools) for the identification of highly correlated genes. Implementation of the correlation finder tool for MybA1, a major regulator of the anthocyanin pathway, identified candidate genes associated with anthocyanin metabolism, whose expression patterns were experimentally validated as discriminating between black and white grapes. These resources and innovative tools for mining genome-related data are anticipated to foster advances in several areas of grapevine research.

Vitis↗

PubMed2025

Deletion of the HLA-B Gene in One of the Inherited Haplotypes in a Northern European Family.

Targeted next generation sequencing-based HLA typing of a 17-year-old female transplant patient showed homozygosity for the HLA-B allele. The segregation analysis of HLA haplotypes of family members only allowed the conclusion that the B-allele was deleted in the haplotype inherited from the father and accordingly paternal grandfather, resulting in false homozygous genotyping. The subsequent whole-genome sequencing of the patient and her father confirmed an approximately 85 kb deletion at 6p21.33 from the 5' end of the HLA-B to the 3' end of the HLA-C gene extending telomeric to HLA-C.

Adolescent↗

PubMed2026

Evolution and domestication-trait associations of ultra-long centromere haplotypes in pepper plants.

Centromeric and pericentromeric regions of most eukaryotic genomes are highly repetitive and strongly recombination-suppressed, confounding efforts to resolve genetic variation, population structure and phenotypic associations. Pepper (Capsicum annuum) centromeres are nearly devoid of satellite repeats, facilitating assembly and population-level comparison of centromeric regions. Here we integrate 9 near-complete genome assemblies, CENH3 ChIP-seq profiles from 26 diverse accessions, and resequencing and phenotypic data from ~400 cultivated and wild accessions to investigate population-level diversity and phenotypic relevance of pepper peri/centromeric regions. Functional centromere positions are largely fixed on 8 of 12 chromosomes, whereas the remaining 4 carry distinct centromeric epialleles shaped mainly by centromere repositioning and pericentromeric inversions. Pepper centromeres are embedded within ultra-long centromere-spanning haplotype (cenhap) blocks, ranging from 29.8 to 112.9 Mb and collectively covering 23.96% of the genome; each block contains only 1-4 major haplotypes. Some cenhaps may act as supergene-like units and are strongly associated with fruit traits, probably because recombination-suppressed intervals harbour multiple fruit-related genes, including OFP and F-box genes. F2 segregation assays further reveal transmission distortion of chromosomes carrying alternative cenhaps. Together, these findings highlight peri/centromeric regions as underrecognized reservoirs of agronomically important variation.

Centromere↗

PubMed2026

The Soifua Manuia reference panel with 2,570 Samoan haplotypes improves genotype imputation quality among Samoans.

Genotype imputation is fundamental to association studies, and yet even gold standard panels like TOPMed are limited in the populations for which they yield good imputation. Specifically, Pacific Islanders are poorly represented in extant panels. To address this, we used whole-genome sequencing from 1,285 Samoan individuals combined with 1000 Genomes Project (1KGP) individuals to construct an imputation reference panel that better represents Pacific Islander, specifically Samoan, genetic variation. Here we show that this panel yielded up to two times more well-imputed (r2 ≥ 0.80) variants than TOPMed-R3 and 1KGP and was enriched for moderate and high impact variants. There was improved imputation accuracy across the minor allele frequency (MAF) spectrum; accuracy (r2) was greater for population-specific variants (high fixation index, FST) and those from larger haplotypes (high LD score). However, the gain in accuracy over TOPMed-R3 was largest for small haplotypes, reflecting the Samoan panel's ability to capture variation not well tagged by other panels.

Haplotypes↗

PubMed2025

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

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

Haplotypes↗

PubMed2024

Fabry disease in female monozygotic twins with complex intronic haplotype variants: a case report.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disease caused by the impairment of α-galactosidase A. The complex intronic haplotype (CIH) variants, located in promoter and intronic regulatory lesions, has been found in patients with classical forms of Fabry disease. We present a case of Fabry disease in female monozygotic twins exhibiting the CIH mutation and classical manifestations. CASE PRESENTATION: A 61-year-old woman with a history of stroke, carotid artery occlusion, hypertrophic cardiomyopathy, and chronic kidney disease was referred to the nephrology clinic for management of her chronic kidney disease. Her monozygotic twin sister also presented with hypertrophic cardiomyopathy, atrial flutter, carotid stenosis, and proteinuria. Clinical symptoms and a comprehensive family history strongly suggested the presence of Fabry disease. Genetic analysis revealed the presence of 5 variants within a complex intronic haplotype (CIH): c.-10 C > T, c.369 + 990 C > A, c.370 - 81_370-77delCAGCC, c.640-16 A > G, and c.1000-22 C > T. We conducted a review of the patient's previous kidney biopsy findings, which demonstrated the presence of lamellated inclusion bodies in electron microscopy. Remarkably, both the monozygotic twin sister and her son exhibited the same genetic mutation. Enzyme replacement therapy was initiated for the patient. Her kidney function decreased throughout a thorough 2-year follow-up period, while there was a slight decrease in the left ventricular mass index. CONCLUSIONS: This is the first reported case of female monozygotic twins with the CIH variants representing cardiac, cerebrovascular, and renal manifestations suggestive of Fabry disease.

Humans↗