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PubMed2026

Protocol for haplotype-resolved structural variant detection via long-read sequencing using cuteHap.

Long-read sequencing technologies have revolutionized human genome exploration at an unparalleled resolution, particularly facilitating the analysis of structural variation (SV) at haplotype resolution. Here, we present a protocol for using cuteHap, a robust framework for haplotype-aware SV detection through phased alignment reads generated by diverse long-read sequencing platforms. We describe procedures for single-nucleotide variant (SNV) calling, read phasing, SV calling, and genotyping. We also establish a benchmarking pipeline to evaluate the detected SV callsets. For complete details on the use and execution of this protocol, please refer to Cao et al.1.

Bioinformatics↗

PubMed1978

The phenotypic variability of diastrophic dysplasia.

To determine the relationship between so-called "diastrophic variant" and diastrophic dysplasia, four patients considered to have the variant condition were studied in detail and compared to 67 patients (including 17 sets of affected sibs) considered to have classical diastrophic dysplasia. Analysis of the combined clinical, radiographic, histologic, and genetic data indicates that there is wide variability in the phenotypic expression of diastrophic dysplasia, even within sibships, and that those individuals previously labeled as having "diastrophic variant" appear to have mild diastrophic dysplasia.

Adult↗

PubMed1985

Bone marrow findings in systemic mastocytosis.

The neoplastic proliferation of tissue mast cells constitutes a group of rare diseases that have localized and systemic variants. The cytologic (n = 7) and histologic (n = 38) findings in bone marrow from a total of 45 patients with systemic mastocytosis were evaluated. Three distinct histologic patterns of marrow involvement were distinguished. In 21 cases a patchy or focal infiltration pattern was encountered. Mast cell aggregates were located predominantly in peritrabecular and perivascular areas. The adjacent trabeculae were thickened. A dense network of reticulin fibers and foci of lymphocytes accompanied the mast cell infiltrates. Increased numbers of eosinophils frequently demarcated the mast cell infiltrates from the surrounding tissue. In the noninfiltrated marrow areas hematopoiesis and the distribution of fat cells appeared to be normal. This histologic pattern, designated type 1, was observed exclusively in patients showing primary involvement of the skin, indistinguishable from urticaria pigmentosa. In 14 additional cases peritrabecular and perivascular sheets of mast cells, with concomitant fibrosis and osteosclerosis, were also present. Unlike the findings in type 1, however, the noninfiltrated marrow areas showed marked reductions in fat cell content and markedly increased granulocytopoiesis or increased numbers of blast cells (infiltration pattern type 2). On the basis of the hematologic and clinical findings, chronic myeloid leukemia was diagnosed in six of these cases, myelomonocytic leukemia in three cases, and acute myeloid leukemia in two cases. The bone marrow of three patients was diffusely infiltrated by atypical mast cells, leading to marked hypoplasia of fat cells and blood cell precursors. These histologic features were identified as infiltration pattern type 3. The diagnosis of mast cell leukemia was confirmed in all three cases by the presence of numerous mast cells in the blood. The prognosis for patients with the type 1 marrow infiltration pattern and primary skin involvement was favorable (actuarial survival rate five years after diagnosis, 0.75). This variant was called benign systemic mastocytosis. Primary skin involvement did not occur in the patients with type 2 or 3 infiltration patterns. The prognosis for these patients was poor (actuarial survival five years after diagnosis, 0.17 for type 2 and 0.00 for type 3). These two forms were accordingly designated malignant systemic mastocytosis.

Adult↗

PubMed2001

Decoding the language of var genes and Plasmodium falciparum sequestration.

Sequestration and rosetting are key determinants of Plasmodium falciparum pathogenesis. They are mediated by a large family of variant proteins called P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 proteins are multispecific binding receptors that are transported to parasite-induced, 'knob-like' binding structures at the erythrocyte surface. To evade immunity and extend infections, parasites clonally vary their expressed PfEMP1. Thus, PfEMP1 are functionally selected for binding while immune selection acts to diversify the family. Here, we describe a new way to analyse PfEMP1 sequence that provides insight into domain function and protein architecture with potential implications for malaria disease.

Amino Acid Sequence↗

PubMed1996

Mammary fibroadenoma and some phyllodes tumour stroma are composed of CD34+ fibroblasts and factor XIIIa+ dendrophages.

Fibroadenomas and mammary phyllodes tumour arise by proliferation of mammary stroma and epithelial elements. However, it is the stromal element that determines the biology of these biphasic tumours. Normal mammary stroma, like most collagenous connective tissue, contains resident populations of CD34+ dendritic interstitial cells and scattered factor XIIIa+ collagen-associated dendrophages. Actin+myofibroblasts are usually absent from mammary stroma in non-disease states. To determine whether CD34+ and factor XIIIa+ cells proliferate in fibroadenomas and phyllodes tumours, and to study myofibroblastic differentiation in these lesions, we examined 19 fibroadenomas in 14 patients along with five low grade and two high grade phyllodes tumours. We employed antibodies against the human progenitor cell antigen CD34, coagulation factor XIIIa and HHF-35 actin. In three fibroadenomas and two phyllodes tumours, we used Ki-67 antigen to study cell proliferation and oestrogen and progesterone receptors to study possible hormonal influence on stromal cells. In all fibroadenomas, CD34 strongly stained interlobular, pericanalicular and intracanalicular fibroblasts with collagenous and/or myxoid features. Four low grade phyllodes tumours also had CD34+ fibroblasts as did one high grade tumour. Actin reactivity varied and was most pronounced in six fibroadenomas resembling the so-called cellular variant, while seven regular fibroadenomas had no actin+stromal cells and six had only focal and weak actin+stromal cells. Factor XIIIa+ cells were prominently admixed in the stroma of all tumours studied comprising from 5% to 20% in fibroadenomas and, focally, up to 50% in phyllodes tumours. Oestrogen and progesterone receptors were expressed only in glandular elements. Ki-67 index in stromal cells was 1% to 3% in fibroadenoma, 10% to 20% in low grade, and 20% to 40% in high grade phyllodes tumour. We conclude that fibroadenomas and some phyllodes tumours are composed of CD34+ fibroblasts that show varying myxoid, collagenous or myofibroblastic differentiation. The fibroblasts are accompanied by a subset of dendritic histiocytes that express factor XIIIa. Fibroadenoma variants show prominent collagenous actin+myofibroblastic differentiation of CD34+ stromal cells, sometimes with a gradient of CD34 down-regulation. Fine-needle or limited stereotactic core biopsy of these biphasic tumours, if they yield only stromal cells, must be distinguished from other CD34+ stromal tumours. Increased factor XIIIa+ dendrophage populations were seen in phyllodes tumours, especially in two high grade tumours that had malignant fibrous histiocytoma-like features, suggesting clonal evolution toward the fibrohistiocytic final pathway. Further study of CD34 and factor XIIIa+ mammary stromal cells in larger numbers of phyllodes tumours might ascertain whether increasing factor XIIIa reactivity correlates with differentiation and increased tumour aggressiveness.

Adult↗

PubMed1992

Alloalbuminemia in Sweden: structural study and phenotypic distribution of nine albumin variants.

Plasma samples exhibiting alloalbuminemia on electrophoresis at pH 8.6 were requested from clinical laboratories throughout Sweden. Nine variants, each representing a different single point mutation, were found in 100 apparently unrelated Swedes. The overall prevalence of alloalbuminemia was estimated at 1:1700. Mutations were identified by protein-structural analysis followed by allele-specific DNA hybridization to verify the most common types. Slightly retarded (+1) mobility was seen in 80 cases. Of these, 71 had the Arg(-2)----Cys proalbumin variant previously called Malmö I proalbumin. Thirteen examples of the second most frequent type, the substitution Lys313----Asn and a mobility change of -1 charge unit, were found, as well as six cases of Glu570----Lys (albumin B) and a single case of Arg-1----Gln (proalbumin Christchurch). Five previously unreported types of alloalbuminemia were identified: four instances of Glu376----Gln, which is the second known mutation at this site; two examples of Asp550----Ala, the second mutation reported at this site; and one example each of Asp63----Asn, Gln268----Arg, and Asn318----Lys. Other mutations were identified among eight subjects of foreign descent. The high frequency and relatively uniform geographic distribution of the Arg-2----Cys mutation suggest that it may have occurred in a founder individual many generation ago in Sweden.

Amino Acid Sequence↗

PubMed1986

Plasma cell infiltrates in atherosclerotic abdominal aortic aneurysms.

Thirty-one of 156 abdominal aortic resection specimens containing atherosclerotic aneurysm wall had an inflammatory infiltrate with a prominent plasma cell component of the media or of plaque replacing the media. The specimens in general were not examples of the so-called "inflammatory variant" of atherosclerotic aneurysm. No association between the infiltrate and syphilis, collagen vascular disease, furosemide exposure, chronic aneurysm leakage, aneurysm diameter, or duration of symptoms was found. The plasmacytic inflammation may be part of an immune response to atherosclerosis.

Aorta, Abdominal↗

PubMed2026

Long-read low-pass sequencing enhances variant detection in a peanut MAGIC population.

Accurate genotyping accelerates crop improvement, yet long-read sequencing remains underused in breeding due to cost. We present a scalable long-read low-pass (LRLP) sequencing framework for high-throughput variant discovery and trait mapping. Using PacBio HiFi reads in an allotetraploid peanut (Arachis hypogaea; AABB, 2n = 4x = 40) MAGIC population, we generated both LRLP and short-read low-pass (SRLP) data. At comparable depths, LRLP achieved substantially greater whole-genome and gene-space coverage than SRLP. Data were analyzed using both a single-reference genome and an 18-parent pangenome graph constructed with KhufuPan, a new tool for graph-based genotyping. Across analytical approaches, LRLP consistently identified more SNPs, indels (2-1,000 bp), and structural variants (>1 kb) than SRLP, improving genotype resolution and selection accuracy, particularly for large structural variants. By reducing cost barriers and increasing variant discovery in complex genomes, LRLP provides a practical path for deploying advanced genomics in under-resourced and orphan crops critical to global food security.

Arachis↗

PubMed1997

Differences in the phosphate oxygen requirements for self-cleavage by the extended and prototypical hammerhead forms.

The hammerhead self-cleaving motif occurs in a variety of RNAs that infect plants and consists of three non-conserved helices connected by a highly conserved central core. A variant hammerhead, called the extended hammerhead, is found in satellite 2 transcripts from a variety of caudate amphibians. The extended hammerhead has the same core as the prototypical hammerhead, but has unusually conserved sequence and structural elements in its peripheral helices. Here we present the results of a thiophosphate substitution interference analysis of the pro-Rp phosphate oxygen requirements in the two hammerhead forms. Five pro-Rp phosphate oxygens, all in the central core, were found to be important for self-cleavage by the prototypical hammerhead. A similar set of core positions were important for self-cleavage by the extended hammerhead, but five non-core positions were also found to be important. Thiosubstitution at one of these positions had the most severe effect on self-cleavage observed in this analysis. Mn2+ did not alleviate this negative effect, indicating that this position was not part of a divalent cation binding site. We propose that novel tertiary interactions in the extended hammerhead help form the same catalytic core structure as that used by the prototypical plant virus hammerhead.

Animals↗

PubMed1990

Alcohol and aldehyde dehydrogenase.

The enzymes mainly responsible for ethanol degradation in humans are liver alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH). Polymorphisms occur in both enzymes, with marked differences in the steady-state kinetic constants. The Km-values for ethanol of ADH isoenzymes relevant for alcohol degradation range from 49 microM to 36 microM, and the Vmax-values from 0.6 to 10 U/mg. Expression of an inactive form of the ALDH2 isoenzyme, the so-called Oriental variant, results in impaired acetaldehyde metabolizing capacity. The differences in ethanol and acetaldehyde metabolizing activities of allelic enzyme forms may be responsible in part for the large variation in the alcohol metabolism rate in humans. Interindividual differences in the isoenzyme pattern may contribute to the genetically determined predisposition for excessive alcohol intake.

Alcohol Dehydrogenase↗

PubMed2001

Wolbachia-mediated sperm modification is dependent on the host genotype in Drosophila.

Estimates of Wolbachia density in the eggs, testes and whole flies of drosophilid hosts have been unable to predict the lack of cytoplasmic incompatibility (CI) expression in so-called mod(-) variants. Consequently, the working hypothesis has been that CI expression, although related to Wolbachia density, is also governed by unknown factors that are influenced by both host and bacterial genomes. Here, we compare the behaviour of the mod(-) over-replicating Wolbachia popcorn strain in its native Drosophila melanogaster host to the same strain transinfected into a novel host, namely Drosophila simulans. We report that (i) the popcorn strain is a close relative of other D. melanogaster infections, (ii) the mod(-) status of popcorn in D. melanogaster appears to result from its inability to colonize sperm bundles, (iii) popcorn is present in the bundles in D. simulans and induces strong CI expression, which demonstrates that the bacterial strain does not lack the genetic machinery for inducing CI and that there is host-species-specific control over Wolbachia tissue tropism, and (iv) infection of sperm bundles by the mod(-) D. simulans wCof strain indicates that there are several independent routes by which a strain can be a CI non-expressor.

Animals↗

PubMed2025

vcfsim: flexible simulation of all-sites VCFs with missing data.

BACKGROUND |: VCFs are the most widely used data format for encoding genetic variation. By design, standard VCFs do not include data from sites where all individuals are homozygous for the reference allele ("invariant sites") and thus do not differentiate these from sites where data are completely missing. However, missing data are a key feature of biological datasets across all domains of genomics, and many recent studies have shown that missing data can introduce a variety of statistical biases in the estimation of key population genetic parameters. A solution to this limitation is to include invariant sites in a standard VCF, creating an "all-sites VCF", exposing missing and invariant sites explicitly. One hurdle to the wider adoption of all-sites VCFs is a reliable parameterized simulation framework for generating biologically realistic all-sites VCFs. RESULTS |: Here, we introduce an open-source command line tool, vcfsim, that interfaces with the popular coalescent simulation platform msprime and provides convenience functions for simulating all-sites VCFs with variable levels of ploidy and missing data. We show that the post-processed VCFs generated using vcfsim align precisely with population genetic expectations (i.e. are statistically identical to raw msprime output), accurately introduce missing data, and permit the simulation of data with varying ploidy levels, including the simulation of intraindividual ploidy variation (e.g. heterogametic sex chromosomes) and population structures. CONCLUSIONS |: Our results vcfsim is a useful and easy-to-use tool for the benchmarking of new software tools, performing population genetic inference, training of machine learning models, and the exploration of the effects of missing data in genomics data sets.

Benchmarking↗

PubMed1977

The deficiency of a lysosomal acid hydrolase in two clones derived from the human lymphoblastoid line F137 after mutagen treatment.

Two clones (out of a total of 181 clones tested) derived from the human lymphoblastoid (lymphoid) line F137 after mutagen treatment were found to be deficient in a lysosomal acid hydrolase. The clone N32 derived from EMS-treated F137 is deficient in N-acetyl hexosaminidase A and B but contains normal levels of N-acetyl hexosaminidase C and low levels of an enzyme resembling N-acetyl hexosaminidase S. Thus the enzyme deficiency in this clone appears to resemble the so-called Sandhoff variant of Tay-Sachs disease, a disease inherited as an autosomal recessive condition. The clone G3 derived from MNNG treated F137 is deficient in alpha-galactosidase A. This clone resembles the situation in X-linked Fabry's disease. Karyotype analysis of the clones failed to reveal any chromosome rearrangement or losses of chromosomal material that might have accounted for the mutations and it is suggested that a single point mutation might in each case account for the loss of enzyme activity. No storage of the natural substrates of the two enzymes could be demonstrated in the clones.

Cell Line↗

PubMed1996

Avoiding the pitfalls of EEG interpretation in childhood epilepsy.

The accurate interpretation of the electroencephalogram (EEG) of infants and children being evaluated for suspected epilepsy is based on the appreciation of normal and expected age-dependent characteristics, an awareness of the significance of both epileptiform and non-epileptiform activity, and the correlation of epileptiform abnormalities with clinical findings. Avoiding the pitfalls of pediatric EEG interpretation include the recognition of such normal EEG features in wakefulness as posterior slow waves of youth, mu rhythm, and lambda waves. In addition, the understanding of age-dependent characteristics of EEG state-changes is essential, such as: monorhythmic and paroxysmal hypnagogic hypersynchrony, special features of vertex transients and sleep spindles, positive occipital sharp transients, initial arousal responses and post-arousal hypersynchrony. The EEG response to activation procedures such as hyperventilation and photic stimulation may also be a source of confusion. Patterns of uncertain diagnostic significance also may be present in children, including 14- and 6-Hz bursts and rhythmic temporal theta bursts of drowsiness (the so-called psychomotor variant). Some nonepileptiform EEG abnormalities may also be misinterpreted as epileptiform. The determination of the clinical significance of spike foci and generalized abortive spike-and-wave may pose more of a problem as a potential pitfall than the identification by visual analysis of these interictal discharges. Another problem posed to the electroencephalographer is the determination of the EEG response to antiepileptic drug therapy including effect on spike foci, generalized spike-and-wave and electrical seizure activity, and effect on background activity. The recognition of the differences between the EEG of children and adults will provide the basis for more accurate interpretation and assist the electroencephalographer in avoiding the identification of normal, age-dependent features as epileptiform.

Adolescent↗

PubMed1994

Epidermoid carcinoma arising in Warthin's tumour: a case study.

We present a case of epidermoid carcinoma arising in Warthin's tumour of parotid gland in an 80-year-old woman. Light microscopy revealed small foci typical of benign Warthin's tumour with transition to epidermoid carcinoma. Immunohistochemical and ultrastructural observations confirmed the epidermoid features of the malignant cells. The differential diagnosis of a metastasis from an epidermoid carcinoma to the stroma of Warthin's tumour and also of the so-called metaplastic variant of Warthin's tumour is discussed.

Adenolymphoma↗

PubMed2001

Quantitative analysis of estrogen receptor proteins in rat mammary gland.

Estrogen receptor alpha and beta proteins (ERalpha and ERbeta) at various stages of development of the rat mammary gland were quantified by Western blotting. ERalpha and ERbeta recombinant proteins were used as standards, and their molar concentrations were measured by ligand binding assays. In 3-week-old pregnant, lactating, and postlactating rats the ERalpha content ranged from 0.30-1.55 fmol/microg total protein (mean values). The ERbeta content of the same samples ranged between 1.06-7.50 fmol/microg total protein. At every developmental stage, the ERbeta content of the mammary gland was higher than that of ERalpha. When receptor levels were normalized against beta-actin, it was evident that ER expression changed during development, with maximum expression of both receptors during the lactation period. With an antibody raised against the 18-amino acid insert of the ERbeta variant, originally called ERbeta2 but named ERbetains in this paper, Western blots revealed that ERbetains protein was up-regulated during the lactation period. RT-PCR showed that the levels of messenger RNA of ERbetains paralleled those of the protein. Double immunohistochemical staining with anti-ERalpha and anti-ERbetains antibodies revealed that ERbetains protein colocalized with ERalpha in 70-80% of the ERalpha-expressing epithelial cells during lactation and with 30% of these cells during pregnancy. These observations indicate that expression of ERbetains is regulated not only quantitatively, but also with regard to its cellular distribution. As ERbetains acts as the dominant repressor of ERalpha, we suggest that its coexpression with ERalpha quenches ERalpha function and may be one of the factors that contribute to the previously described insensitivity of the mammary gland to estrogens during lactation.

Actins↗

PubMed1999

Coexpression of alternatively spliced estrogen and progesterone receptor transcripts in human breast cancer.

Primary transcripts of the human estrogen receptor (ER) and progesterone receptor (PR) are subject to a number of alternative splicing events resulting in a range of variant messenger ribonucleic acid species in receptor-positive tissues. Despite in vitro demonstrations of a possible role for some of these variants in hormonal sensitivity, the clinical significance of this process is uncertain. In this study the coexpression of variant ER and PR transcripts has been documented by RT-PCR and Southern blot analysis in a series of receptor-positive breast tumors. In 35 ER-positive tumors, a common profile of variant ER transcripts was present, with all tumors containing the delta2ER and delta7ER, 94% containing the delta4ER, and 83% containing the delta5ER. In 25 of these cases, which were also PR positive, the most highly expressed PR variants, the delta4PR, delta6PR, and delta(4/2)PR, a transcript from which a 126-bp portion of PR exon 4 was deleted, were detected in over 90% of the cases. The alternatively spliced ER variants were expressed at higher relative levels than the PR species, which had mean levels of expression less than 10% that of wild-type PR. The most abundant species was the delta7ER, which was present at levels ranging from 29-83% of the wild type. There was no relationship between the level of delta7ER in individual tumors and the pattern of expression of the estrogen-responsive proteins PR and pS2. The common profile of alternatively spliced ER and PR transcripts in breast tumors means that this feature cannot be used as a discriminator of hormone responsiveness or other clinical end points. Further, the low level of expression of the majority of variant species calls into question their potential for impacting significantly on receptor function.

Adult↗

PubMed1994

Hierarchical regression for epidemiologic analyses of multiple exposures.

Many epidemiologic investigations are designed to study the effects of multiple exposures. Most of these studies are analyzed either by fitting a risk-regression model with all exposures forced in the model, or by using a preliminary-testing algorithm, such as stepwise regression, to produce a smaller model. Research indicates that hierarchical modeling methods can outperform these conventional approaches. These methods are reviewed and compared to two hierarchical methods, empirical-Bayes regression and a variant here called "semi-Bayes" regression, to full-model maximum likelihood and to model reduction by preliminary testing. The performance of the methods in a problem of predicting neonatal-mortality rates are compared. Based on the literature to date, it is suggested that hierarchical methods should become part of the standard approaches to multiple-exposure studies.

Algorithms↗