Case-control association testing by graphical modeling for the Genetic Analysis Workshop 17 mini-exome sequence data

We generalize recent work on graphical models for linkage disequilibrium to estimate the conditional independence structure between all variables for individuals in the Genetic Analysis Workshop 17 unrelated individuals data set. Using a stepwise approach for computational efficiency and an extension of our previously described methods, we estimate a model that describes the relationships between the disease trait, all quantitative variables, all covariates, ethnic origin, and the loci most strongly associated with these variables. We performed our analysis for the first 50 replicate data sets. We found that our approach was able to describe the relationships between the outcomes and covariates and that it could correctly detect associations of disease with several loci and with a reasonable false-positive detection rate

High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios

The 1000 Genomes Project (1kGP) is the largest fully open resource of whole-genome sequencing (WGS) data consented for public distribution without access or use restrictions. The final, phase 3 release of the 1kGP included 2,504 unrelated samples from 26 populations and was based primarily on low-coverage WGS. Here, we present a high-coverage 3,202-sample WGS 1kGP resource, which now includes 602 complete trios, sequenced to a depth of 30X using Illumina. We performed single-nucleotide variant (SNV) and short insertion and deletion (INDEL) discovery and generated a comprehensive set of structural variants (SVs) by integrating multiple analytic methods through a machine learning model. We show gains in sensitivity and precision of variant calls compared to phase 3, especially among rare SNVs as well as INDELs and SVs spanning frequency spectrum. We also generated an improved reference imputation panel, making variants discovered here accessible for association studies

Unilateral Handgrip Holds to Failure Result in Sex-Dependent Contralateral Facilitation

There can be differences in fatigue characteristics between men and women. In some cases, these differences may be manifested in unique strength responses in the fatigued and non-fatigued limbs following a unilateral fatiguing task. PURPOSE: This study examined changes in maximal voluntary isometric contraction (MVIC) force following dominant (Dm) and nondominant (NDm) unilateral, isometric handgrip holds to failure (HTF) for the exercised ipsilateral (IPS) and non-exercised contralateral (CT) limbs. Sex- and hand- (Dm vs NDm) dependent responses in HTF time, performance fatiguability (PF, %D in MVIC) for the exercised IPS limb, as well as changes in MVIC force for the CT limb following the HTF were examined. METHODS: Ten men and 10 women (Age = 22.2 yrs) performed an isometric, HTF at 50% MVIC for the Dm and NDm hand on separate days. Prior to, and immediately after the HTF, a MVIC was performed on the IPS and CT limbs, in a randomized order. A 2 (hand [Dm, NDm]) x 2 (limb [IPS, CON]) x 2 (time [pre-HTF, post-HTF]) x 2 (sex [men, women]) mixed-model ANOVA was used to examine the MVIC force (kg) and a 2 (hand [Dm, NDm]) x 2 (sex [men, women]) mixed-model ANOVA was used to examine time for the HTF. RESULTS: The Dm (130.3 ± 36.8s) HTF (collapsed across sex) was significantly longer (p = 0.002) than the NDm (112.1 ± 34.3s). The men (collapsed across hand) demonstrated IPS (%Δ= 22.9 ± 10.8%) PF and CT facilitation (%Δ= -6.1 ±6.9%) following the HTF, while the women demonstrated differences in PF between the Dm and NDm hands for the IPS (%Δ Dm = 28.0 ± 9.4%; NDm = 32.3% ± 10.1%; p = 0.027), but not the CT limb (%Δ Dm= -1.6 ± 5.7%; NDm = 1.7 ± 5.9%). CONCLUSIONS: Despite the greater fatigue resistance for the Dm compared to the NDm hand, there were no differences in PF for the IPS side for the men, but lesser IPS PF for Dm compared to NDm hand for the women. The cross-over facilitation of the CT limb for men, but not women, following a unilateral, isometric handgrip HTF may be related to post-activation potentiation

Somatic Dnmt3a inactivation leads to slow, canonical DNA methylation loss in murine hematopoietic cells

Mutations in the gene encoding DNA methyltransferase 3A

Persistent molecular disease in adult patients with AML evaluated with whole-exome and targeted error-corrected DNA sequencing

PURPOSE: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML. MATERIALS AND METHODS: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq). RESULTS: WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (\u3e2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in CONCLUSION: PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML

Mapping and characterization of structural variation in 17,795 human genomes

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles. A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline(1)to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.Peer reviewe

A draft human pangenome reference

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individual

Singlet-triplet energy gaps modulation of Diindeno [1,2-b: 1’2’-g] anthracene molecular family

Nowadays there is a large interest in organic materials based on diradical polycyclic aromatic hydrocarbons (PAHs) due to their unique properties, such as narrow frontier-orbital energy gaps, strong absorption in the visible spectrum, etc. However, the inherent diradical nature make these compounds with limited chemical stability giving rise to rapid decomposition under ambient conditions thus reducing their practical use. In recent years PAH diradicals that exhibit remarkable stability have been prepared thanks to the description of efficient synthetic routes to access them. One of these remarkable cases is the diindeno [1,2-b: 1’2’-g] anthracene, named as DIAn. DIAn is constituted by antiaromatic segments together with a central pro-aromatic structure. One of the important observable properties of diradicals is the singlet-triplet energy gap, ∆EST, which is intimately connected with the diradical character. The possibility of access to the molecular structure of diradicals is very valuable since properties such as the bond-order or the bond-length alternation of the mentioned moieties reveal the diradical content. Electronic and vibrational spectroscopies are alternative sources of structural information that often compensate the absence of solid-state structures. In this communication, we expand the studies of DIAn by introducing another aspect of the modulation of the ∆EST which concerns with: i) the extension of the terminal benzenes with another fused benzene (i.e., forming terminal napthalenes) and ii) with the isomerization resulting from the fusion topology of these terminal benzenes. We will present a UV-Vis-NIR and Raman spectroscopic study of the new compounds. The variation of the spectra within molecular family will be discussed in connection with the variation of ∆EST and with the diradical character of the new molecules.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Orbital Nature of Carboionic Monoradicals Made from Diradicals

The electronic, optical, and solid state properties of a series of monoradicals, anions and cations obtained from starting neutral diradicals have been studied. Diradicals based on s-indacene and indenoacenes, with benzothiophenes fused and in different orientations, feature a varying degree of diradical character in the neutral state, which is here related with the properties of the radical redox forms. The analysis of their optical features in the polymethine monoradicals has been carried out in the framework of the molecular orbital and valence bond theories. Electronic UVVis-NIR absorption, X-ray solid-state diffraction and quantum chemical calculations have been carried out. Studies of the different positive-/negative-charged species, both residing in the same skeletal π-conjugated backbone, are rare for organic molecules. The key factor for the dual stabilization is the presence of the starting diradical character that enables to indistinctively accommodate a pseudo-hole and a pseudoelectron defect with certainly small reorganization energies for ambipolar charge transport.The authors thank the Spanish Ministry of Science and Innovation (projects MINECO/FEDER PGC2018-098533-B-100 and PID2021-127127NB-I00) and the Junta de Andalucía, Spain (UMA18FEDERJA057 and Proyecto de Excelencia PROYEXCEL- 00328). We also thank the Research Central Services (SCAI) of the University of Málaga and the US National Science Foundation (CHE-1954389 to M.M.H., CHE-2003411 to M.A. P.). F.N and Y.D. acknowledge support from “Valutazione della Ricerca di Ateneo” (VRA)-University of Bologna. Y.D. acknowledges Ministero dell’Università e della Ricerca (MUR) for her Ph.D. fellowship. Funding for open access charge: Universidad de Málaga / CBU

Exome sequencing of Finnish isolates enhances rare-variant association power.

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power