bluuebunny/crossref_metadata_2025 huggingface dataset:
PinaColada: peptide–inhibitor ant colony ad-hoc design algorithm
Authors: Zaidman Daniel , Wolfson Haim J.
Published: March 2016

Motivation: Design of protein–protein interaction (PPI) inhibitors is a major challenge in Structural Bioinformatics. Peptides, especially short ones (5–15 amino acid long), are natural candidates for inhibition of protein–protein complexes due to several attractive features such as high structural compatibility with the protein binding site (mimicking the surface of one of the proteins), small size and the ability to form strong hotspot binding connections with the protein surface. Efficient rational peptide design is still a major challenge in computer aided drug design, due to the huge space of possible sequences, which is exponential in the length of the peptide, and the high flexibility of peptide conformations.

Results: In this article we present PinaColada, a novel computational method for the design of peptide inhibitors for protein–protein interactions. We employ a version of the ant colony optimization heuristic, which is used to explore the exponential space (20n) of length n peptide sequences, in combination with our fast robotics motivated PepCrawler algorithm, which explores the conformational space for each candidate sequence. PinaColada is being run in parallel, on a DELL PowerEdge 2.8 GHZ computer with 20 cores and 256 GB memory, and takes up to 24 h to design a peptide of 5-15 amino acids length.

Availability and implementation: An online server available at: http://bioinfo3d.cs.tau.ac.il/PinaColada/.

Contact:  danielza@post.tau.ac.il; wolfson@tau.ac.il
ARGs-OAP: online analysis pipeline for antibiotic resistance genes detection from metagenomic data using an integrated structured ARG-database
Authors: Yang Ying , Jiang Xiaotao , Chai Benli , Ma Liping , Li Bing , Zhang Anni , Cole James R. , Tiedje James M. , Zhang Tong
Published: March 2016

Motivation: Environmental dissemination of antibiotic resistance genes (ARGs) has become an increasing concern for public health. Metagenomics approaches can effectively detect broad profiles of ARGs in environmental samples; however, the detection and subsequent classification of ARG-like sequences are time consuming and have been severe obstacles in employing metagenomic methods. We sought to accelerate quantification of ARGs in metagenomic data from environmental samples.

Results: A Structured ARG reference database (SARG) was constructed by integrating ARDB and CARD, the two most commonly used databases. SARG was curated to remove redundant sequences and optimized to facilitate query sequence identification by similarity. A database with a hierarchical structure (type-subtype-reference sequence) was then constructed to facilitate classification (assigning ARG-like sequence to type, subtype and reference sequence) of sequences identified through similarity search. Utilizing SARG and a previously proposed hybrid functional gene annotation pipeline, we developed an online pipeline called ARGs-OAP for fast annotation and classification of ARG-like sequences from metagenomic data. We also evaluated and proposed a set of criteria important for efficiently conducting metagenomic analysis of ARGs using ARGs-OAP.

Availability and Implementation: Perl script for ARGs-OAP can be downloaded from https://github.com/biofuture/Ublastx_stageone. ARGs-OAP can be accessed through http://smile.hku.hk/SARGs.

Contact:  zhangt@hku.hk or tiedjej@msu.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
D3M: detection of differential distributions of methylation levels
Authors: Matsui Yusuke , Mizuta Masahiro , Ito Satoshi , Miyano Satoru , Shimamura Teppei
Published: March 2016

Motivation: DNA methylation is an important epigenetic modification related to a variety of diseases including cancers. We focus on the methylation data from Illumina’s Infinium HumanMethylation450 BeadChip. One of the key issues of methylation analysis is to detect the differential methylation sites between case and control groups. Previous approaches describe data with simple summary statistics or kernel function, and then use statistical tests to determine the difference. However, a summary statistics-based approach cannot capture complicated underlying structure, and a kernel function-based approach lacks interpretability of results.

Results: We propose a novel method D3M, for detection of differential distribution of methylation, based on distribution-valued data. Our method can detect the differences in high-order moments, such as shapes of underlying distributions in methylation profiles, based on the Wasserstein metric. We test the significance of the difference between case and control groups and provide an interpretable summary of the results. The simulation results show that the proposed method achieves promising accuracy and shows favorable results compared with previous methods. Glioblastoma multiforme and lower grade glioma data from The Cancer Genome Atlas show that our method supports recent biological advances and suggests new insights.

Availability and Implementation: R implemented code is freely available from https://github.com/ymatts/D3M/.

Contact:  ymatsui@med.nagoya-u.ac.jp or shimamura@med.nagoya-u.ac.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
On genomic repeats and reproducibility
Authors: Firtina Can , Alkan Can
Published: March 2016

Results: Here, we present a comprehensive analysis on the reproducibility of computational characterization of genomic variants using high throughput sequencing data. We reanalyzed the same datasets twice, using the same tools with the same parameters, where we only altered the order of reads in the input (i.e. FASTQ file). Reshuffling caused the reads from repetitive regions being mapped to different locations in the second alignment, and we observed similar results when we only applied a scatter/gather approach for read mapping—without prior shuffling. Our results show that, some of the most common variation discovery algorithms do not handle the ambiguous read mappings accurately when random locations are selected. In addition, we also observed that even when the exact same alignment is used, the GATK HaplotypeCaller generates slightly different call sets, which we pinpoint to the variant filtration step. We conclude that, algorithms at each step of genomic variation discovery and characterization need to treat ambiguous mappings in a deterministic fashion to ensure full replication of results.

Availability and Implementation: Code, scripts and the generated VCF files are available at DOI:10.5281/zenodo.32611.

Contact:  calkan@cs.bilkent.edu.tr

Supplementary information:  Supplementary data are available at Bioinformatics online.
TreeDom: a graphical web tool for analysing domain architecture evolution
Authors: Haider Christian , Kavic Marina , Sonnhammer Erik L.L.
Published: March 2016

Summary: We present TreeDom, a web tool for graphically analysing the evolutionary history of domains in multi-domain proteins. Individual domains on the same protein chain may have distinct evolutionary histories, which is important to grasp in order to understand protein function. For instance, it may be important to know whether a domain was duplicated recently or long ago, to know the origin of inserted domains, or to know the pattern of domain loss within a protein family. TreeDom uses the Pfam database as the source of domain annotations, and displays these on a sequence tree. An advantage of TreeDom is that the user can limit the analysis to N sequences that are most similar to a query, or provide a list of sequence IDs to include. Using the Pfam alignment of the selected sequences, a tree is built and displayed together with the domain architecture of each sequence.

Availablility and implementation:  http://TreeDom.sbc.su.se

Contact:  Erik.Sonnhammer@scilifelab.se
FRODOCK 2.0: fast protein–protein docking server
Authors: Ramírez-Aportela Erney , López-Blanco José Ramón , Chacón Pablo
Published: March 2016

Summary: The prediction of protein–protein complexes from the structures of unbound components is a challenging and powerful strategy to decipher the mechanism of many essential biological processes. We present a user-friendly protein–protein docking server based on an improved version of FRODOCK that includes a complementary knowledge-based potential. The web interface provides a very effective tool to explore and select protein–protein models and interactively screen them against experimental distance constraints. The competitive success rates and efficiency achieved allow the retrieval of reliable potential protein–protein binding conformations that can be further refined with more computationally demanding strategies.

Availability and Implementation: The server is free and open to all users with no login requirement at http://frodock.chaconlab.org

Contact:  pablo@chaconlab.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
Fish and squid behaviour at the mouth of a drop-chain trawl: factors contributing to capture or escape
Authors: Bayse Shannon M. , Pol Michael V. , He Pingguo
Published: March 2016

Underwater video recordings in the mouth of a squid trawl were used to evaluate the effectiveness of a trawl configured with drop-chain groundgear to catch longfin inshore squid (Doryteuthis pealeii) and reduce bycatch of finfish in the Nantucket Sound squid fishery off Cape Cod, Massachusetts, USA. Entrance through the trawl mouth or escape underneath the fishing line and between drop chains was quantified for targeted squid, and two major bycatch species, summer flounder (Paralichthys dentatus) and skates (family Rajidae). Additionally, contact and impingement between animals and groundgear were also quantified. Fish and squid swimming behaviours, positions, orientations, and time in the trawl mouth were quantified and related to capture or escape at the trawl mouth. Squid entered the trawl singly and in schools, and no squid were observed escaping under the fishing line. Most squid entered the trawl in the upper portion of the trawl mouth; mantle orientated away from the trawl and swimming in the same direction, and were gradually overtaken, not actively attempting to escape. Summer flounder and skates were observed to remain on or near the seabed, orientated, and swimming in the same direction as the approaching trawl. The majority (60.5%) of summer flounder entered the trawl above the fishing line. Summer flounder that changed their orientation and turned 180° were significantly more likely to enter the trawl (p < 0.05). Most skates (89.7%) avoided trawl entrance and escaped under the fishing line. Neither squid nor summer flounder were observed to make contact or become impinged to the groundgear; however, 35.4% of skates had substantial contact with groundgear, with 12.3% becoming impinged. Video analysis results showed that the drop-chain trawl is effective at retaining targeted squid while allowing skates to escape. However, it is ineffective at avoiding the capture of summer flounder.
Pulse trawl fishing: characteristics of the electrical stimulation and the effect on behaviour and injuries of Atlantic cod (Gadus morhua)
Authors: de Haan D. , Fosseidengen J. E. , Fjelldal P. G. , Burggraaf D. , Rijnsdorp A. D.
Published: March 2016

In the North Sea flatfish fishery, electric pulse trawls have been introduced to replace the conventional mechanical method. Pulse trawls reduce the fuel consumption, reduce adverse impact on the ecosystem but cause injuries in gadoids. We describe the design and electrical properties of pulse trawls currently in use and study the behavioural response and injuries in cod exposed to electrical pulses under controlled conditions. Pulse trawls operate at an average power of 0.7 kW m−1 beam length and a duty cycle of ∼2%. The electric field is heterogeneous with highest field strength occurring close to the conductors. Cod were exposed to three different pulse types for a range of field strengths, frequencies, and duty cycles. Two size classes were tested representing cod that escape through the meshes (11–17 cm) and market-sized cod that are retained in the net (34–56 cm). Cod exposed to a field strength of ≥37 V m−1 responded by moderate-to-strong muscular contractions. Some of the large cod (n = 260) developed haemorrhages and fractures in the spine, and haemal and neural arches in the tail part of the body. The probability of injuries increased with field strength and decreased when frequency was increased from 100 to 180 Hz. None of the small cod (n = 132) were injured and all survived. The field strength at the lateral boundaries of the trawl was too low to inflict injuries in cod.
Spectral distortion of the CMB by the cumulative CO emission from galaxies throughout cosmic history
Authors: Mashian Natalie , Loeb Abraham , Sternberg Amiel
Published: March 2016

We show that the cumulative CO emission from galaxies throughout cosmic history distorts the spectrum of the cosmic microwave background at a level that is well above the detection limit of future instruments, such as the Primordial Inflation Explorer. The modelled CO signal has a prominent bump in the frequency interval 100–200 GHz, with a characteristic peak intensity of ∼2 × 10−23 W m−2 Hz−1 sr−1. Most of the CO foreground originates from modest redshifts, z ∼ 2–5, and needs to be efficiently removed for more subtle distortions from the earlier Universe to be detected.
Evaluation of Serum Creatinine Changes With Integrase Inhibitor Use in Human Immunodeficiency Virus-1 Infected Adults
Authors: Lindeman Tara A. , Duggan Joan M. , Sahloff Eric G.
Published: March 2016

This retrospective chart review evaluated changes in serum creatinine and creatinine clearance (CrCl) after initiation of an integrase inhibitor (INSTI)-based regimen as initial treatment in human immunodeficiency virus-infected adults. Serum creatinine and CrCl changes were similar to those seen in clinical trials for INSTIs. No renal-related serious adverse events or discontinuations occurred.
Acculturation Measurement
Authors: Doucerain Marina , Segalowitz Norman , Ryder Andrew G.
Published: March 2016

This article discusses the importance of clear and precise conceptualizations of acculturation as well as the need for consistencies in definition, operationalization, and measurement. More specifically, it argues for an expanded acculturation research toolkit that does not rely too heavily on self-report acculturation scales. The article begins with an overview of the state of affairs with respect to acculturation conceptualizations and methods, paying particular attention to the unidimensional, bidimensional, and multidimensional frameworks of psychological acculturation. It then considers ways in which commonly used definitions and methods of acculturation can be used more intelligently. It also describes alternative methods for researchers interested in moving beyond self-report rating scales, a tiered approach to acculturation research, and method-specific health considerations. Finally, it offers some recommendations aimed at helping the field of acculturation and health research move forward.
Childhood Personality and Temperament
Authors: De Pauw Sarah
Published: March 2016

This chapter discusses the blossoming research on childhood personality, addressing salient questions on its measurement, its foundational structure, and its convergence with child temperament. First, the discovery and contemporary measurement of FFM-antecedents in young age is reviewed, highlighting promises as well as pitfalls of the various approaches available today. Second, divergences between child and adult taxonomies are delineated, as accumulating research suggests that the structure of child personality is not identical to the established FFM-structure in adults. Finally, the issue of temperament-personality convergence is considered. Whereas influential narrative reviews proposed that temperament and personality appear to be “more alike than different,” empirical research suggests that a simple hierarchical mapping fails to capture the complexity of these relationships. We invite students of behavioral individuality in childhood and adolescence to take into account the salient differences between the various personality approaches, child and adult personality taxonomies, and child temperament and personality “vocabularies.”
Middle Palaeolithic Diets
Authors: Morin Eugène , Speth John D. , Lee-Thorp Julia
Published: March 2016

This chapter examines the evidence for diet amongst Middle Palaeolithic foragers in Europe and south-west Asia from c. 300,000 to 40,000 years ago, concentrating on faunal and isotopic approaches. Published faunal evidence shows that Middle Palaeolithic hominins in both regions hunted a relatively narrow range of medium- to large-sized ungulates, with occasional exploitation of megaherbivores more evident in open sites than in caves and rockshelters. Broader diets have been documented in southern Europe, although regular consumption of fast, small-sized taxa emerged only later during the Upper Palaeolithic. Stable light isotope data, often interpreted as indicating that European Neanderthals were top-level predators preferring either megaherbivores, or bovids and horses, only partly accords with the faunal evidence. Taphonomic considerations suggest that energy procurement, especially as fat, and the effects of transport constraints have so far not been sufficiently considered when assessing the dietary composition of Middle Palaeolithic hominins.
Coptic
Authors: Orlandi Tito
Published: March 2016

Coptic literature was born together with the Coptic language in Roman Egypt, around the third century, inside the Christian Church. It developed following the exigencies of the Church, together with a parallel literature in Greek: after biblical translations, and Gnosticizing (and Manichaean) treatises, homilies, canons, historical, and monastic texts were produced. After the Chalcedonian crisis, Coptic texts acquired a new autonomy, replacing Greek texts and supporting the life of the anti-Chalcedonian Church.
Shocking Behavior: Random Wealth in Antebellum Georgia and Human Capital Across Generations
*
Authors: Bleakley Hoyt , Ferrie Joseph
Published: March 2016

Does the lack of wealth constrain parents’ investments in the human capital of their descendants? We conduct a nearly 50-year follow-up of an episode in which such constraints would have been plausibly relaxed by a random allocation of substantial wealth to families. We track descendants of participants in Georgia’s Cherokee Land Lottery of 1832, in which nearly every adult white male in the state took part. Winners received close to the median level of wealth—a large financial windfall orthogonal to participants’ underlying characteristics that might have also affected their children’s human capital. Although winners had slightly more children than did nonwinners, they did not send them to school more. Sons of winners have no better adult outcomes (wealth, income, literacy) than the sons of nonwinners, and winners’ grandchildren do not have higher literacy or school attendance than nonwinners’ grandchildren. We can reject effects implied by the cross-sectional gradient of child outcomes by paternal wealth. This suggests only a limited role for family financial resources in the formation of human capital in the next generations in this environment and a potentially more important role for other factors that persist through family lines.
Innovation, Competition, and Investment Timing
Authors: Koskinen Yrjö , Maeland Joril
Published: March 2016

In our model multiple innovators compete against each other by submitting investment proposals to an investor. The investor chooses the least expensive proposal and the timing of the investment. Innovators privately learn the cost of investing. The investor has to compensate the innovators for their reservation wages, but competition makes screening easier and helps to erode innovators’ informational rents. Consequently, competition leads to faster innovation, because the investor has less need to delay expensive investments. With an endogenous number of innovators investment timing becomes first best.

Received June 5, 2013; accepted February 26, 2016 by Editor Paolo Fulghieri.
Neural Pattern Change During Encoding of a Narrative Predicts Retrospective Duration Estimates
Authors: Lositsky Olga , Chen Janice , Toker Daniel , Honey Christopher J. , Poppenk Jordan L. , Hasson Uri , Norman Kenneth A.
Published: March 2016

What mechanisms support our ability to estimate durations on the order of minutes? Behavioral studies in humans have shown that changes in contextual features lead to overestimation of past durations. Based on evidence that the medial temporal lobes and prefrontal cortex represent contextual features, we related the degree of fMRI pattern change in these regions with people’s subsequent duration estimates. After listening to a radio story in the scanner, participants were asked how much time had elapsed between pairs of clips from the story. Our ROI analysis found that the neural pattern distance between two clips at encoding was correlated with duration estimates in the right entorhinal cortex and right pars orbitalis. Moreover, a whole-brain searchlight analysis revealed a cluster spanning the right anterior temporal lobe. Our findings provide convergent support for the hypothesis that retrospective time judgments are driven by “drift” in contextual representations supported by these regions.
Beyond clines: lineages and haplotype blocks in hybrid zones
Authors: Sedghifar Alisa , Brandvain Yaniv , Ralph Peter
Published: March 2016

Hybrid zones formed between recently diverged populations offer an opportunity to study the mechanisms underlying reproductive isolation and the process of speciation. Here, we use a combination of analytical theory and explicit forward simulations to describe how selection against hybrid genotypes impacts patterns of introgression across genomic and geographic space. By describing how lineages move across the hybrid zone, in a model without coalescence, we add to modern understanding of how clines form and how parental haplotypes are broken up during introgression. Working with lineages makes it easy to see that clines form in about 1/sgenerations, where s is the strength of selection against hybrids, and linked clines persist over a genomic scale of 1/T, whereTis the age, in generations, of the hybrid zone. Locally disadvantageous alleles tend to exist as small families, whose lineages trace back to the side from which they originated at speeddispersal distances per generation. The lengths of continuous tracts of ancestry provide an additional source of information: blocks of ancestry surrounding incompatibilities can be substantially longer than the genome-wide average block length at the same spatial location, an observation that might be used to identify candidate targets of selection.
Whole-genome characterization in pedigreed non-human primates using Genotyping-By-Sequencing and imputation
Authors: Bimber Ben N , Raboin Michael J , Letaw John , Nevonen Kimberly , Spindel Jennifer E , McCouch Susan R , Cervera-Juanes Rita , Spindel Eliot , Carbone Lucia , Ferguson Betsy , Vinson Amanda
Published: March 2016

Background

Rhesus macaques are widely used in biomedical research, but the application of genomic information in this species to better understand human disease is still undeveloped. Whole-genome sequence (WGS) data in pedigreed macaque colonies could provide substantial experimental power, but the collection of WGS data in large cohorts remains a formidable expense. Here, we describe a cost-effective approach that selects the most informative macaques in a pedigree for whole-genome sequencing, and imputes these dense marker data into all remaining individuals having sparse marker data, obtained using Genotyping-By-Sequencing (GBS).

Results

We developed GBS for the macaque genome using a single digest withPstI, followed by sequencing to 30X coverage. From GBS sequence data collected on all individuals in a 16-member pedigree, we characterized an optimal 22,455 sparse markers spaced ~125 kb apart. To characterize dense markers for imputation, we performed WGS at 30X coverage on 9 of the 16 individuals, yielding ~10.2 million high-confidence variants. Using the approach of “Genotype Imputation Given Inheritance” (GIGI), we imputed alleles at an optimized dense set of 4,920 variants on chromosome 19, using 490 sparse markers from GBS. We assessed changes in accuracy of imputed alleles, 1) across 3 different strategies for selecting individuals for WGS, i.e., a) using “GIGI-Pick” to select informative individuals, b) sequencing the most recent generation, or c) sequencing founders only; and 2) when using from 1-9 WGS individuals for imputation. We found that accuracy of imputed alleles was highest using the GIGI-Pick selection strategy (median 92%), and improved very little when using >4 individuals with WGS for imputation. We used this ratio of 4 WGS to 12 GBS individuals to impute an expanded set of ~14.4 million variants across all 20 macaque autosomes, achieving ~85-88% accuracy per chromosome.

Conclusions

We conclude that an optimal tradeoff exists at the ratio of 1 individual selected for WGS using the GIGI-Pick algorithm, per 3-5 relatives selected for GBS, a cost savings of ~67-83% over WGS of all individuals. This approach makes feasible the collection of accurate, dense genome-wide sequence data in large pedigreed macaque cohorts without the need for expensive WGS data on all individuals.
From genomes to phenotypes: Traitar, the microbial trait analyzer
Authors: Weimann Aaron , Mooren Kyra , Frank Jeremy , Pope Phillip B. , Bremges Andreas , McHardy Alice C.
Published: March 2016

The number of sequenced genomes is growing exponentially, profoundly shifting the bottleneck from data generation to genome interpretation. Traits are often used to characterize and distinguish bacteria, and are likely a driving factor in microbial community composition, yet little is known about the traits of most microbes. We describe Traitar, the microbial trait analyzer, which is a fully automated software package for deriving phenotypes from the genome sequence. Traitar provides phenotype classifiers to predict 67 traits related to the use of various substrates as carbon and energy sources, oxygen requirement, morphology, antibiotic susceptibility, proteolysis and enzymatic activities. Furthermore, it suggests protein families associated with the presence of particular phenotypes. Our method uses L1-regularized L2-loss support vector machines for phenotype assignments based on phyletic patterns of protein families and their evolutionary histories across a diverse set of microbial species. We demonstrate reliable phenotype assignment for Traitar to bacterial genomes from 572 species of 8 phyla, also based on incomplete single-cell genomes and simulated draft genomes. We also showcase its application in metagenomics by verifying and complementing a manual metabolic reconstruction of two novel Clostridiales species based on draft genomes recovered from commercial biogas reactors. Traitar is available athttps://github.com/hzi-bifo/traitar.
Demographic stochasticity and resource autocorrelation control biological invasions in heterogeneous landscapes
Authors: Giometto Andrea , Altermatt Florian , Rinaldo Andrea
Published: March 2016

Classical models of biological invasions assess species spread in homogeneous landscapes by assuming constant growth rates and random local movement. Mounting evidence suggests, however, that demographic stochasticity, environmental heterogeneity and non-random movement of individuals affect considerably the spread dynamics. Here, we show that the dynamics of biological invasions are controlled by the spatial heterogeneity of the resource distribution. We show theoretically that increasing the landscape resource autocorrelation length causes a reduction in the average speed of species spread. Demographic stochasticity plays a key role in the slowdown, which is streghtened when individuals can actively move towards resources. The reduction in the front propagation speed is verified in laboratory microcosm experiments with the flagellated protistEuglena gracilisby comparing spread in habitats characterized by different resource heterogeneity. Our theoretical and experimental findings highlight the need to account for the intrinsic stochasticity of population dynamics to describe spread in spatially extended landscapes, which are inevitably characterized by heterogeneous spatial distributions of resources controlling vital rates. Our work identifies the resource autocorrelation length as a key modulator and a simple measure of landscape susceptibility to biological invasions, with implications for predicting the characters of biological invasions within naturally heterogeneous environmental corridors.
Structural basis for acyl group discrimination by human Gcn5L2
Authors: Ringel Alison E. , Wolberger Cynthia
Published: March 2016

Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modificationsin vivo, we examined the acyl chain specificity of the acetyltransferase, human Gcn5 (Gcn5L2). Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 gets progressively weaker with increasing acyl chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, we determined structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor for Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group.
Can secondary contact following range expansion be distinguished from barriers to gene flow?
Authors: Bertl Johanna , Ringbauer Harald , Blum Michael G. B.
Published: March 2016

Secondary contact is the reestablishment of gene flow between sister populations that have diverged. For instance, at the end of the Quaternary glaciations in Europe, secondary contact occurred during the northward expansion of the populations which had found refugia in the southern peninsulas. With the advent of multi-locus markers, secondary contact can be investigated using various molecular signatures including gradients of allele frequency, admixture clines, and local increase of genetic differentiation. We use coalescent simulations to investigate if molecular data provide enough information to distinguish between secondary contact following range expansion and an alternative evolutionary scenario consisting of a barrier to gene flow in an isolation-by-distance model. We find that an excess of Linkage Disequilibrium and of genetic diversity at the suture zone is a unique signature of secondary contact. We also find that the directionality index Ψ, which was proposed to study range expansion, is informative to distinguish between the two hypotheses. However, although evidence for secondary contact is usually conveyed by statistics related to admixture coefficients, we find that they can be confounded by isolation-by-distance. We recommend to account for the spatial repartition of individuals when investigating secondary contact in order to better reflect the complex spatio-temporal evolution of populations and species.
Genome-wide association between transcription factor expression and chromatin accessibility reveals chromatin state regulators
Authors: Lamparter David , Marbach Daniel , Rueedi Rico , Bergmann Sven , Kutalik Zoltán
Published: March 2016

To better understand genome regulation, it is important to uncover the role of transcription factors in the process of chromatin structure establishment and maintenance. Here we present a data-driven approach to systematically characterize transcription factors that are relevant for this process. Our method uses a linear mixed modeling approach to combine data sets of transcription factor binding motif enrichments in open chromatin and gene expression across the same set of cell lines. Applying this approach to the ENCODE data set we confirm already known and imply numerous novel transcription factors in playing a role in the establishment or maintenance of open chromatin.
Strength of functional signature correlates with effect size in autism
Authors: Ballouz Sara , Gillis Jesse
Published: March 2016

Background

Disagreements over genetic signatures associated with disease have been particularly prominent in the field of psychiatric genetics, creating a sharp divide between disease burdens attributed to common and rare variation, with study designs independently targeting each. Meta-analysis within each of these study designs is routine, whether using raw data or summary statistics, but combining results across study designs is atypical. However, tests of functional convergence are used across all study designs, where candidate gene sets are assessed for overlaps with previously known properties. This suggests one possible avenue for combining not study data, but the functional conclusions that they reach.

Method

In this work, we test for functional convergence in autism spectrum disorder (ASD) across different study types, and specifically whether the degree to which a gene is implicated in autism is correlated with the degree to which it drives functional convergence. Because different study designs are distinguishable by their differences in effect size, this also provides a unified means of incorporating the impact of study design into the analysis of convergence.

Results

We detected remarkably significant positive trends in aggregate (p < 2.2e-16) with 14 individually significant properties (FDR<0.01), many in areas researchers have targeted based on different reasoning, such as the fragile X mental retardation protein(FMRP)interactor enrichment (FDR 0.003). We are also able to detect novel technical effects and we see that network enrichment from protein-protein interaction data is heavily confounded with study design, arising readily in control data.

Conclusions

We see a convergent functional signal for a subset of known and novel functions in ASD from all sources of genetic variation. Meta-analytic approaches explicitly accounting for different study designs can be adapted to other diseases to discover novel functional associations and increase statistical power.
Computational Pan-Genomics: Status, Promises and Challenges
Authors:   The Computational Pan-Genomics Consortium, Marschall Tobias , Marz Manja , Abeel Thomas , Dijkstra Louis , Dutilh Bas E. , Ghaffaari Ali , Kersey Paul , Kloosterman Wigard P. , Mäkinen Veli , Novak Adam M. , Paten Benedict , Porubsky David , Rivals Eric , Alkan Can , Baaijens Jasmijn , De Bakker Paul I. W. , Boeva Valentina , Bonnal Raoul J. P. , Chiaromonte Francesca , Chikhi Rayan , Ciccarelli Francesca D. , Cijvat Robin , Datema Erwin , Van Duijn Cornelia M. , Eichler Evan E. , Ernst Corinna , Eskin Eleazar , Garrison Erik , El-Kebir Mohammed , Klau Gunnar W. , Korbel Jan O. , Lameijer Eric-Wubbo , Langmead Benjamin , Martin Marcel , Medvedev Paul , Mu John C. , Neerincx Pieter , Ouwens Klaasjan , Peterlongo Pierre , Pisanti Nadia , Rahmann Sven , Raphael Ben , Reinert Knut , de Ridder Dick , de Ridder Jeroen , Schlesner Matthias , Schulz-Trieglaff Ole , Sanders Ashley D. , Sheikhizadeh Siavash , Shneider Carl , Smit Sandra , Valenzuela Daniel , Wang Jiayin , Wessels Lodewyk , Zhang Ying , Guryev Victor , Vandin Fabio , Ye Kai , Schönhuth Alexander
Published: March 2016

Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case ofHomo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic datasets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension ofcomputational pan-genomics, a new sub-area of research in computational biology. In this paper, we generalize existing definitions and understand apan-genomeas any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies, and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.
PCR-free library preparation greatly reduces stutter noise at short tandem repeats
Authors: Gymrek Melissa
Published: March 2016

Over the past several decades, the forensic and population genetic communities have increasingly leveraged short tandem repeats (STRs) for a variety of applications. The advent of next-generation sequencing technologies and STR-specific bioninformatic tools has enabled the profiling of hundreds of thousands of STRs across the genome. Nonetheless, these genotypes remain error-prone, hindering their utility in downstream analyses. One of the primary drivers of STR genotyping errors are “stutter” artifacts arising during the PCR amplification step of library preparation that add or delete copies of the repeat unit in observed sequencing reads. Recently, Illumina developed the TruSeq PCR-free library preparation protocol which eliminates the PCR step and theoretically should reduce stutter error. Here, I compare two high coverage whole genome sequencing datasets prepared with and without the PCR-free protocol. I find that this protocol reduces the percent of reads due to stutter by more than four-fold and results in higher confidence STR genotypes. Notably, stutter at homopolymers was decreased by more than 6fold, making these previously inaccessible loci amenable to STR calling. This technological improvement shows good promise for significantly increasing the feasibility of obtaining high quality STR genotypes from next-generation sequencing technologies.
Most Compositae (Asteraceae) are descendants of a paleohexaploid and all share a paleotetraploid ancestor with the Calyceraceae
Authors: Barker Michael S. , Li Zheng , Kidder Thomas I. , Reardon Chris R. , Lai Zhao , Oliveira Luiz O. , Scascitelli Moira , Rieseberg Loren H.
Published: March 2016

Premise of the study

Like many other flowering plants, members of the Compositae (Asteraceae) have a polyploid ancestry. Previous analyses found evidence for an ancient duplication or possibly triplication in the early evolutionary history of the family. We sought to better place this paleopolyploidy in the phylogeny and assess its nature.

Methods

We sequenced new transcriptomes forBarnadesia, the lineage sister to all other Compositae, and four representatives of closely related families. Using a recently developed algorithm, MAPS, we analyzed nuclear gene family phylogenies for evidence of paleopolyploidy.

Key results

We found that the previously recognized Compositae paleopolyploidy is also in the ancestry of the Calyceraceae. Our phylogenomic analyses uncovered evidence for a successive second round of genome duplication among all sampled Compositae exceptBarnadesia.

Conclusions

Our analyses of new samples with new tools provide a revised view of paleopolyploidy in the Compositae. Together with results from a high densityLactucalinkage map, our results suggest that the Compositae and Calyceraceae have a common paleotetraploid ancestor and most Compositae are descendants of a paleohexaploid. Although paleohexaploids have been previously identified, this is the first example where the paleotetraploid and paleohexaploid lineages have survived over tens of millions of years. The complex polyploidy in the ancestry of the Compositae and Calyceraceae represents a unique opportunity to study the long-term evolutionary fates and consequences of different ploidal levels.
Most microRNAs in the single-cell alga Chlamydomonas reinhardtii are produced by Dicer-like 3-mediated cleavage of introns and untranslated regions of coding RNAs
Authors: Valli Adrian A. , Santos Bruno A.C.M. , Hnatova Silvia , Bassett Andrew R. , Molnar Attila , Chung Betty Y. , Baulcombe David C.
Published: March 2016

We describe here a forward genetic screen to investigate the biogenesis, mode of action, and biological function of miRNA-mediated RNA silencing in the model algal species, Chlamydomonas reinhardtii. Among the mutants from this screen, there were three at Dicer-like 3 that failed to produce both miRNAs and siRNAs and others affecting diverse post-biogenesis stages of miRNA-mediated silencing. The DCL3-dependent siRNAs fell into several classes including transposon- and repeat-derived siRNAs as in higher plants. The DCL3-dependent miRNAs differ from those of higher plants, however, in that many of them are derived from mRNAs or from the introns of pre-mRNAs. Transcriptome analysis of the wild-type and dcl3 mutant strains revealed a further difference from higher plants in that the sRNAs are rarely negative switches of mRNA accumulation. The few transcripts that were more abundant in dcl3 mutant strains than in wild-type cells were not due to sRNA-targeted RNA degradation but to direct DCL3 cleavage of miRNA and siRNA precursor structures embedded in the untranslated (and translated) regions of the mRNAs. Our analysis reveals that the miRNA-mediated RNA silencing in C. reinhardtii differs from that of higher plants and informs about the evolution and function of this pathway in eukaryotes.
Biochemical effects of the flavanol‐rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species
Authors: Hagiwara Kazuya , Okura Masae , Sumikawa Yasuyuki , Hida Tokimasa , Kuno Atsushi , Horio Yoshiyuki , Yamashita Toshiharu
Published: March 2016

An ingredient of fruit polyphenol, resveratrol, is known to have an inhibitory effect on melanogenesis. In order to examine the functional differences between resveratrol and other fruit polyphenols, we compared biochemical effects of a resveratrol‐free polyphenol, flavanol‐rich lychee fruit extract (FRLFE), with other phenolic compounds including resveratrol.FRLFEas well as hydroquinone and resveratrol suppressed growth of B16F1 melanoma cells more significantly than rhododendrol or arbutin. Resveratrol suppressed mushroom tyrosinase at the lowest concentration (23.0 μmol/L) among the compounds tested.FRLFEand hydroquinone suppressed tyrosinase at almost the same concentration (half maximal inhibitory concentration [IC50], 83.5 and 94.6 μmol/L, respectively), which was higher than rhododendrol, ascorbic acid and arbutin (IC50, 245, 345 and 421 μmol/L, respectively). Western blot analysis revealed that although resveratrol decreased expressions of tyrosinase and tyrosinase‐related protein 1,FRLFEdid not affect their expressions. BothFRLFEand resveratrol suppressed antimycin A‐mediated reactive oxygen species (ROS) production in melanocytic cells. Resveratrol‐mediatedROSsuppression was inhibited by nicotinamide, aSIRT1 inhibitor. However,FRLFE‐mediated suppression was not affected by nicotinamide. Moreover,FRLFEdirectly decreased superoxidein vitro, as detected by superoxide dismutase‐like scavenging activity assay. These results suggest thatFRLFEcan protect melanocytes from cytotoxicity caused by an excess amount of melanin andROSin a different manner from resveratrol.
Negative relationships between population density and metabolic rates are not general
Authors: Yashchenko Varvara , Fossen Erlend Ignacio , Kielland Øystein Nordeide , Einum Sigurd
Published: March 2016

Population density has recently been suggested to be an important factor influencing metabolic rates and to represent an important ‘third axis’ explaining variation beyond that explained by body mass and temperature. In situations where population density influences food consumption, the immediate effect on metabolism acting through specific dynamic action (SDA), and downregulation due to fasting over longer periods, is well understood. However, according to a recent review, previous studies suggest a more general effect of population density per se, even in the absence of such effects. It has been hypothesized that this results from animals performing anticipatory responses (i.e. reduced activity) to expected declines in food availability.

Here, we test the generality of this finding by measuring density effects on metabolic rates in 10 clones from two different species of the zooplankton Daphnia (Daphnia pulex Leydig and D. magna Straus). Using fluorescence‐based respirometry, we obtain high‐precision measures of metabolism.

We also identify additional studies on this topic that were not included in the previous review, compare the results and evaluate the potential for measurement bias in all previous studies.

We demonstrate significant variation in mass‐specific metabolism among clones within both species. However, we find no evidence for a negative relationship between population density and mass‐specific metabolism. The previously reported pattern also disappeared when we extended the set of studies analysed.

We discuss potential reasons for the discrepancy among studies, including two main sources of potential bias (microbial respiration and declining oxygen consumption due to reduced oxygen availability). Only one of the previous studies gives sufficient information to conclude the absence of such biases, and consistent with our results, no effect of density on metabolism was found. We conclude that population density per se does not have a general effect on mass‐specific metabolic rate.