Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides

Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.Peer reviewe

Reply to : On powerful GWAS in admixed populations

Non peer reviewe

A novel lineage of the Capra genus discovered in the Taurus Mountains of Turkey using ancient genomics

Direkli Cave, located in the Taurus Mountains of southern Turkey, was occupied by Late Epipaleolithic hunters-gatherers for the seasonal hunting and processing of game including large numbers of wild goats. We report genomic data from new and published Capra specimens from Direkli Cave and, supplemented with historic genomes from multiple Capra species, find a novel lineage best represented by a ~14,000 year old 2.59 X genome sequenced from specimen Direkli4. This newly discovered Capra lineage is a sister clade to the Caucasian tur species (Capra cylindricornis and Capra caucasica), both now limited to the Caucasus region. We identify genomic regions introgressed in domestic goats with high affinity to Direkli4, and find that West Eurasian domestic goats in the past, but not those today, appear enriched for Direkli4-specific alleles at a genome-wide level. This forgotten 'Taurasian tur' likely survived Late Pleistocene climatic change in a Taurus Mountain refuge and its genomic fate is unknown

Pre-Impact Thermophysical Properties and the Yarkovsky Effect of NASA DART Target (65803) Didymos

The NASA DART (Double Asteroid Redirection Test) spacecraft impacted the secondary body of the binary asteroid (65803) Didymos on 2022 September 26and altered its orbit about the primary body. Before the DART impact, we performed visible and mid-infrared observations to constrain the pre-impact thermophysical properties of the Didymos system and to model its Yarkovsky effect. Analysis of the photometric phase curve derives a Bond albedo of 0.07 ± 0.01, and a thermophysical analysis of the mid-infrared observations derives a thermal inertia of 320 ± 70 J m-2 K-1 s-1/2 and a thermal roughness of 40° ± 3° RMS (root-mean-square) slope. These properties are compatible with the ranges derived for other S-type near-Earth asteroids. Model-to-measurement comparisons of the Yarkovsky orbital drift for Didymos derives a bulk density of 2750 ± 350 kg m-3, which agrees with other independent measures based on the binary mutual orbit. This bulk density indicates that Didymos is spinning at or near its critical spin-limit at which self-gravity balances equatorial centrifugal forces. Furthermore, comparisons with the post-impact infrared observations presented in Rivkin et al. (2023) indicate no change in the thermal inertia of the Didymos system following the DART impact. Finally, orbital temperature simulations indicate that sub-surface water ice is stable over geologic timescales in the polar regions if present. These findings will be investigated in more detail by the upcoming ESA Hera mission.<br/

Severe cholestatic jaundice after a single administration of ajmaline; a case report and review of the literature.

BACKGROUND: Ajmaline is a pharmaceutical agent now administered globally for a variety of indications, particularly investigation of suspected Brugada syndrome. There have been previous reports suggesting that repetitive use of this agent may cause severe liver injury, but little evidence exists demonstrating the same effect after only a single administration. CASE PRESENTATION: A 33-year-old man of Libyan origin with no significant past medical history underwent an ajmaline provocation test for investigation of suspected Brugada syndrome. Three weeks later, he presented with painless cholestatic jaundice which peaked in severity at eleven weeks after the test. Blood tests confirmed no evidence of autoimmune or viral liver disease, whilst imaging confirmed the absence of biliary tract obstruction. A liver biopsy demonstrated centrilobular cholestasis and focal rosetting of hepatocytes, consistent with a cholestatic drug reaction. Over the course of the next few months, he began to improve clinically and biochemically, with complete resolution by one year post-exposure. CONCLUSION: Whilst ajmaline-related hepatotoxicity was well-recognised in the era in which the drug was administered as a regular medication, clinicians should be aware that ajmaline may induce severe cholestatic jaundice even after a single dose administration

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

Comparison of Standard Ruler and Standard Candle constraints on Dark Energy Models

We compare the dark energy model constraints obtained by using recent standard ruler data (Baryon Acoustic Oscillations (BAO) at z=0.2 and z=0.35 and Cosmic Microwave Background (CMB) shift parameters R and l_a) with the corresponding constraints obtained by using recent Type Ia Supernovae (SnIa) standard candle data (ESSENCE+SNLS+HST from Davis et. al.). We find that, even though both classes of data are consistent with LCDM at the 2\sigma level, there is a systematic difference between the two classes of data. In particular, we find that for practically all values of the parameters (\Omega_0m,\Omega_b) in the 2\sigma range of the the 3-year WMAP data (WMAP3) best fit, LCDM is significantly more consistent with the SnIa data than with the CMB+BAO data. For example for (\Omega_0m,\Omega_b)=(0.24,0.042) corresponding to the best fit values of WMAP3, the dark energy equation of state parametrization w(z)=w_0 + w_1 (z/(1+z)) best fit is at a 0.5\sigma distance from LCDM (w_0=-1,w_1=0) using the SnIa data and 1.7\sigma away from LCDM using the CMB+BAO data. There is a similar trend in the earlier data (SNLS vs CMB+BAO at z=0.35). This trend is such that the standard ruler CMB+BAO data show a mild preference for crossing of the phantom divide line w=-1, while the recent SnIa data favor LCDM. Despite of this mild difference in trends, we find no statistically significant evidence for violation of the cosmic distance duality relation \eta \equiv d_L(z)/(d_A(z) (1+z)^2)=1. For example, using a prior of \Omega_0m=0.24, we find \eta=0.95 \pm 0.025 in the redshift range 0<z<2, which is consistent with distance duality at the 2\sigma level.Comment: References added. 9 pages, 7 figures. The Mathematica files with the numerical analysis of the paper can be found at http://leandros.physics.uoi.gr/rulcand/rulcand.ht

The mutational constraint spectrum quantified from variation in 141,456 humans

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes(1). Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.Peer reviewe

Hemispherical differences in the shape and topography of asteroid (101955) Bennu

We investigate the shape of near-Earth asteroid (101955) Bennu by constructing a high-resolution (20 cm) global digital terrain model from laser altimeter data. By modeling the northern and southern hemispheres separately, we find that longitudinal ridges previously identified in the north extend into the south but are obscured there by surface material. In the south, more numerous large boulders effectively retain surface materials and imply a higher average strength at depth to support them. The north has fewer large boulders and more evidence of boulder dynamics (toppling and downslope movement) and surface flow. These factors result in Bennu’s southern hemisphere being rounder and smoother, whereas its northern hemisphere has higher slopes and a less regular shape. We infer an originally asymmetric distribution of large boulders followed by a partial disruption, leading to wedge formation in Bennu’s history