A copy of this work was available on the public web and has been preserved in the Wayback Machine. The capture dates from 2019; you can also visit the original URL.
The file type is
Here we report a thorough analysis of cross-predictions between coiled-coil and disordered protein segments using various prediction algorithms for both sequence classes. Coiled-coils are often predicted to be unstructured, consistent with their obligate multimeric nature, whereas reverse cross-predictions are rare due to the regularity of coiled-coil sequences. We propose the simultaneous use of the programs COILS and IUPRED to achieve acceptable prediction accuracy and minimize the extent ofdoi:10.1016/j.febslet.2010.03.026 pmid:20303956 fatcat:f5kowzqqpvdzbihsr2fgqjhdoe
more »... ross-predictions. The relevance of observed cross-predictions might be that disordered sequences can adopt coiled-coil conformation relatively easily during protein evolution.
Michel Espinoza-Fonseca 1,2 , Dániel Süveges 3 , Zoltán Gáspári 4 , Gábor Tóth 5 , László Nyitray 3 . 1 University of Minnesota, Minneapolis, MN, USA, 2 Instituto Politécnico Nacional, Mexico City, Mexico ... Hunter 2 , Sagarika Dev 1 , Daniel J. Shaw 3 , Godfrey S. Beddard 3 , Gavin D. ...doi:10.1016/j.bpj.2008.12.1616 fatcat:233czornbvevtcycpmnfib6u2q
The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we conduct high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals to fully assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance. We discover 132 independent sequence variant associations ( <7.45×10 ) across the allele frequency spectrum,doi:10.1101/854752 fatcat:h6qq65njuzghzicxoehfj23ti4
more »... 44 new -acting and 11 new acting loci, all of which replicate in an independent cohort (n=1,605, 18.4x WGS). We identify replicating evidence for rare-variant -acting protein quantitative trait loci for five genes, involving both coding and non-coding variation. We find causal links between protein biomarkers and cardiovascular, inflammatory and immune-related diseases. We construct and validate polygenic risk scores that explain up to 45% of protein level variation, and find significant correlation between genetically-predicted biomarker levels and cardiovascular disease risk in UK Biobank.
MotivationCopy number variants (CNVs) are large deletions or duplications at least 50 to 200 base pairs long. They play an important role in multiple disorders, but accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process.ResultsWe use a regression tree-based approach to call CNVs from whole-genome sequencing (WGS, > 18x) variant call-sets in 6,898 samples across four European cohorts, anddoi:10.1101/504209 fatcat:jwdrikaukzdb7fr4qtjj52olfe
more »... ibe a rich large variation landscape comprising 1,320 CNVs. 61.8% of detected events have been previously reported in the Database of Genomic Variants. 23% of high-quality deletions affect entire genes, and we recapitulate known events such as the GSTM1 and RHD gene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe the LD structure and copy number variation underlying the association between levels of the CCL3 protein and a complex structural variant (MAF = 0.15, p = 3.6×10-12) affecting CCL3L3, a paralog of the CCL3 gene. We also identify a cis- association between a low-frequency NOMO1 deletion and the protein product of this gene (MAF = 0.02, p = 2.2×10-7), for which no cis- or trans- single nucleotide variant-driven protein quantitative trait locus (pQTL) has been documented to date. This work demonstrates that existing population-wide WGS call-sets can be mined for CNVs with minimal computational overhead, delivering insight into a less well-studied, yet potentially impactful class of genetic variant.AvailabilityThe regression tree based approach, UN-CNVc, is available as an R and bash executable on GitHub at https://github.com/agilly/un-cnvc.Contacteleftheria.email@example.com; firstname.lastname@example.orgSupplementary InformationSupplementary information is appended.
Article: Casalone, E., Tachmazidou, I., Zengini, E. et al. (9 more authors) (2018) A novel variant in GLIS3 is associated with osteoarthritis.doi:10.1136/annrheumdis-2017-211848 pmid:29436472 pmcid:PMC5890630 fatcat:4ja4caqeafbvplnqucz36cv5eq
Motivation: Very low depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterisation of the genotype quality and association power for very low depth sequencing designs is still lacking. Results: We perform cohort-wide whole genome sequencing (WGS) at low depth in 1,239 individuals (990 at 1x depth and 249 at 4x depth) from an isolated population, and establish a robust pipelinedoi:10.1101/169789 fatcat:owq2rrd6h5fkvhqffg64xk3ixu
more »... calling and imputing very low depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (WES, 75x depth) and high-depth (22x) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1x WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1x further allowed the discovery of 140,844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design.
AbstractPodoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals. A previous genome-wide association study (GWAS) conducted in the Wolaita ethnic group from Ethiopia showed association between single nucleotide polymorphisms (SNPs) in the HLA class II region and podoconiosis. We aimed to conduct a second GWAS in a new sample (N = 1892) collected from the Wolaita and two other Ethiopian populations, thedoi:10.1038/s41598-021-81836-x pmid:33558538 pmcid:PMC7870958 fatcat:w6d346qbvzg6voq3i46imvakta
more »... and the Oromo, also affected by podoconiosis. Fourteen SNPs in the HLA class II region showed significant genome-wide association (P < 5.0 × 10−8) with podoconiosis. The lead SNP was rs9270911 (P = 5.51 × 10−10; OR 1.53; 95% CI 1.34–1.74), located near HLA-DRB1. Inclusion of data from the first GWAS (combined N = 2289) identified 47 SNPs in the class II HLA region that were significantly associated with podoconiosis (lead SNP also rs9270911 (P = 2.25 × 10−12). No new loci outside of the HLA class II region were identified in this more highly-powered second GWAS. Our findings confirm the HLA class II association with podoconiosis suggesting HLA-mediated abnormal induction and regulation of immune responses may have a direct role in its pathogenesis.
LC8 dynein light chain (DYNLL) is a highly conserved eukaryotic hub protein with dozens of binding partners and various functions beyond being a subunit of dynein and myosin Va motor proteins. Here, we compared the kinetic and thermodynamic parameters of binding of both mammalian isoforms, DYNLL1 and DYNLL2, to two putative consensus binding motifs (KXTQTX and XG(I/V)QVD) and report only subtle differences. Peptides containing either of the above motifs bind to DYNLL2 with micromolar affinity,doi:10.1074/jbc.m110.165894 pmid:20889982 pmcid:PMC2992297 fatcat:fjtqvy3rabgm7pr5zroqmo3u2a
more »... hereas a myosin Va peptide (lacking the conserved Gln) and the noncanonical Pak1 peptide bind with K d values of 9 and 40 M, respectively. Binding of the KXTQTX motif is enthalpy-driven, although that of all other peptides is both enthalpy-and entropy-driven. Moreover, the KXTQTX motif shows strikingly slower off-rate constant than the other motifs. As most DYNLL partners are homodimeric, we also assessed the binding of bivalent ligands to DYNLL2. Compared with monovalent ligands, a significant avidity effect was found as follows: K d values of 37 and 3.5 nM for a dimeric myosin Va fragment and a Leu zipper dimerized KXTQTX motif, respectively. Ligand binding kinetics of DYNLL can best be described by a conformational selection model consisting of a slow isomerization and a rapid binding step. We also studied the binding of the phosphomimetic S88E mutant of DYNLL2 to the dimeric myosin Va fragment, and we found a significantly lower apparent K d value (3 M). We conclude that the thermodynamic and kinetic fine-tuning of binding of various ligands to DYNLL could have physiological relevance in its interaction network.
Next-generation association studies can be empowered by sequence-based imputation and by studying founder populations. Here we report B9.5 million variants from whole-genome sequencing (WGS) of a Cretan-isolated population, and show enrichment of rare and low-frequency variants with predicted functional consequences. We use a WGS-based imputation approach utilizing 10,422 reference haplotypes to perform genome-wide association analyses and observe 17 genome-wide significant, independentdoi:10.1038/ncomms15606 pmid:28548082 pmcid:PMC5458552 fatcat:476sionlyjcnlero3lvklsiafa
more »... including replicating evidence for association at eight novel low-frequency variant signals. Two novel cardiometabolic associations are at lead variants unique to the founder population sequences: chr16:70790626 (high-density lipoprotein levels beta À 1.71 (SE 0.25), P ¼ 1.57 Â 10 À 11 , effect allele frequency (EAF) 0.006); and rs145556679 (triglycerides levels beta À 1.13 (SE 0.17), P ¼ 2.53 Â 10 À 11 , EAF 0.013). Our findings add empirical support to the contribution of low-frequency variants in complex traits, demonstrate the advantage of including population-specific sequences in imputation panels and exemplify the power gains afforded by population isolates.
Very low-depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterization of the genotype quality and association power for very low-depth sequencing designs is still lacking. We perform cohort-wide whole-genome sequencing (WGS) at low depth in 1239 individuals (990 at 1× depth and 249 at 4× depth) from an isolated population, and establish a robust pipeline for calling and imputingdoi:10.1093/bioinformatics/bty1032 pmid:30576415 pmcid:PMC6662288 fatcat:wjjhu24uazaodcxndwcekiafha
more »... very low-depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (75× depth) and high-depth (22×) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1× WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1× further allowed the discovery of 140 844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low-depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design. The HELIC genotype and WGS datasets have been deposited to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home): EGAD00010000518; EGAD00010000522; EGAD00010000610; EGAD00001001636, EGAD00001001637. The peakplotter software is available at https://github.com/wtsi-team144/peakplotter, the transformPhenotype app can be downloaded at https://github.com/wtsi-team144/transformPhenotype. Supplementary data are available at Bioinformatics online.
The N-terminal region of myosin's rod-like subfragment 2 (S2) joins the two heads of this dimeric molecule and is key to its function. Previously, a crystal structure of this predominantly coiled-coil region was determined for a short fragment (51 residues, plus leucine zipper) of the scallop striated muscle myosin isoform. Here, the N-terminal 10-14 residues were found to be disordered. We have now determined the structure of the same scallop peptide in three additional crystal environments.doi:10.1016/j.jmb.2007.11.071 pmid:18155233 pmcid:PMC2665131 fatcat:eazppoxqcjdm7epzsnjcd7rbcy
more »... each of two of these structures, improved order has now allowed visualization of the entire Nterminus in one chain of the dimeric peptide. We have also compared the melting temperatures of this scallop S2 peptide and analogous peptides from three other isoforms. Taken together, these studies, along with examination of sequences, point to a diminished stability of the N-terminal region of S2 in regulated myosins, compared to those myosins whose regulation is thin filament-linked. It seems plain that this isoform-specific instability promotes the off-state conformation of the heads in regulated myosins. We also discuss how myosin isoforms with varied thermal stabilities share the basic capacity to transmit force efficiently in order to produce contraction in their on states. F-actin of the thin filament. Each S1 head comprises a motor domain (MD), which has the binding sites for F-actin and a nucleotide, together with a light-chain-bearing "lever arm" (also called the regulatory domain (RD)) (see 3). Comparatively small movements among three of the relatively rigid subdomains of the MD (induced by the binding of nucleotide and/or actin) are amplified by its fourth subdomain (the "converter") and the adjoined lever arm by means of short flexible linkers between them 4 . The resulting force is transmitted through S2 to produce the sliding motion between the thick and thin filaments (see 5 for recent review). Contraction and other myosin-dependent functions are turned "on" and "off" by changes in Ca 2+ concentration, which lead to changes in the conformations of certain regulatory molecules. This switch involves either so-called "non-regulated" myosins, where the regulatory molecules are on the thin filament (as in vertebrate skeletal and cardiac muscles) (see 6 for recent review) and/or "regulated myosins" which themselves change conformation to control contraction (as in vertebrate smooth-muscle and non-muscle myosin II 7 as well as that in molluscan striated and smooth muscles 8 ) (see also 9 ).
Osteoarthritis is a common complex disease with huge public health burden. Here we perform a genome-wide association study for osteoarthritis using data across 16.5 million variants from the UK Biobank resource. Following replication and meta-analysis in up to 30,727 cases and 297,191 controls, we report 9 new osteoarthritis loci, in all of which the most likely causal variant is non-coding. For three loci, we detect association with biologically-relevant radiographic endophenotypes, and indoi:10.1101/174755 fatcat:hknfyclzcvcnbemjykyohsrl5q
more »... signals we identify genes that are differentially expressed in degraded compared to intact articular cartilage from osteoarthritis patients. We establish causal effects for higher body mass index, but not for triglyceride levels or type 2 diabetes liability, on osteoarthritis.
LC8 dynein light chain (DYNLL) is a eukaryotic hub protein that is thought to function as a dimerization engine. Its interacting partners are involved in a wide range of cellular functions. In its dozens of hitherto identified binding partners DYNLL binds to a linear peptide segment. The known segments define a loosely characterized binding motif: The motifs are localized in disordered segments of the DYNLL-binding proteins and are often flanked by coiled coil or other potential dimerizationdoi:10.1371/journal.pone.0018818 pmid:21533121 pmcid:PMC3078936 fatcat:w37mnljkefgw5kosp267bzqekm
more »... ains. Based on a directed evolution approach, here we provide the first quantitative characterization of the binding preference of the DYNLL binding site. We displayed on M13 phage a naïve peptide library with seven fully randomized positions around a fixed, naturally conserved glutamine. The peptides were presented in a bivalent manner fused to a leucine zipper mimicking the natural dimer to dimer binding stoichiometry of DYNLL-partner complexes. The phage-selected consensus sequence V -5 S -4 R -3 G -2 T -1 Q 0 T 1 E 2 resembles the natural one, but is extended by an additional N-terminal valine, which increases the affinity of the monomeric peptide twentyfold. Leu-zipper dimerization increases the affinity into the subnanomolar range. By comparing crystal structures of an SRGTQTE-DYNLL and a dimeric VSRGTQTE-DYNLL complex we find that the affinity enhancing valine is accommodated in a binding pocket on DYNLL. Based on the in vitro evolved sequence pattern we predict a large number of novel DYNLL binding partners in the human proteome. Among these EML3, a microtubule-binding protein involved in mitosis contains an exact match of the phage-evolved consensus and binds to DYNLL with nanomolar affinity. These results significantly widen the scope of the human interactome around DYNLL and will certainly shed more light on the biological functions and organizing role of DYNLL in the human and other eukaryotic interactomes.
The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1,457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens overlapping with, and mostly independent of established common variant signals (ADIPOQ and adiponectin, P=4.2x10 -8 ; APOC3 and triglyceride levels,doi:10.1101/283481 fatcat:oidmcfnpfzgilgr6qpahx6vqni
more »... P=1.58x10 -26 ; GGT1 and gamma-glutamyltransferase, P=2.3x10 -6 ; UGT1A9 and bilirubin, P=1.9x10 -8 ), and identify replicating evidence for a burden associated with triglyceride levels in FAM189A (P=2.26x10 -8 ), indicating a role for this gene in lipid metabolism.
Abstract. Tritium (3H) as a constituent of the water molecule is an important natural tracer in hydrological sciences. The anthropogenic tritium introduced into the atmosphere unintentionally became an excellent tracer of processes on a time scale of up to 100 years. A prerequisite for tritium applications is to know the distribution of tritium activity in precipitation. Here we present a database of isoscapes derived from 41 stations for amount-weighted annual mean tritium activity indoi:10.5194/essd-12-2061-2020 fatcat:ygbofxnd4vctjbgevij53exovu
more »... tion for the period 1976 to 2017 on spatially continuous interpolated 1 km×1 km grids for the Adriatic–Pannonian region (called the AP3H_v1 database), with a special focus on post-2010 years, which are not represented by existing global models. Five stations were used for out-of-sample evaluation of the model performance, independently confirming its capability of reproducing the spatiotemporal tritium variability in the region. The AP3H database is capable of providing reliable spatiotemporal input for hydrogeological application at any place within Slovenia, Hungary, and their surroundings. Results also show a decrease in the average spatial representativity of the stations regarding tritium activity in precipitation from ∼440 km in 1970s, when bomb tritium still prevailed in precipitation, to ∼235 km in the 2010s. The post-2010 isoscapes can serve as benchmarks for background tritium activity for the region, helping to determine potential future local increases in technogenic tritium from these backgrounds. The gridded tritium isoscape is available in NetCDF-4 at https://doi.org/10.1594/PANGAEA.896938 (Kern et al., 2019).
« Previous Showing results 1 — 15 out of 153 results