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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

FUMA: Functional mapping and annotation of genetic associations

A main challenge in genome-wide association studies (GWAS) is to prioritize genetic variants and identify potential causal mechanisms of human diseases. Although multiple bioinformatics resources are available for functional annotation and prioritization, a standard, integrative approach is lacking. We developed FUMA: a web-based platform to facilitate functional annotation of GWAS results, prioritization of genes and interactive visualization of annotated results by incorporating information from multiple state-of-the-art biological databases.

bioinformatics↗

bioRxiv2017

Representing Genetic Determinants in BacterialGWAS with Compacted De Bruijn Graphs

MotivationAntimicrobial resistance has become a major worldwide public health concern, calling for a better characterization of existing and novel resistance mechanisms. GWAS methods applied to bacterial genomes have shown encouraging results for new genetic marker discovery. Most existing approaches either look at SNPs obtained by sequence alignment or consider sets of kmers, whose presence in the genome is associated with the phenotype of interest. While the former approach can only be performed when genomes are similar enough for an alignment to make sense, the latter can lead to redundant descriptions and to results which are hard to interpret.\n\nResultsWe propose an alignment-free GWAS method detecting haplotypes of variable length associated to resistance, using compacted De Bruijn graphs. Our representation is flexible enough to deal with very plastic genomes subject to gene transfers while drastically reducing the number of features to explore compared to kmers, without loss of information. It accomodates polymorphisms in core genes, accessory genes and noncoding regions. Using our representation in a GWAS leads to the selection of a small number of entities which are easier to visualize and interpret than fixed-length kmers. We illustrate the benefit of our approach by describing known as well as potential novel determinants of antimicrobial resistance in P. aeruginosa, a pathogenic bacteria with a highly plastic genome.\n\nAvailability and implementationThe code and data used in the experiments will be made available upon acceptance of this manuscript.\n\nContactmagali.dancette@biomerieux.com

bioinformatics↗

bioRxiv2017

Genetic polymorphism of Cytochrome-P450-2C9 (CYP2C9) in Indian populations

Cytochrome-P450-2C9 (CYP2C9) metabolizes wide range of drugs and highly express in human liver. Various mutations of CYP2C9 (R144C, I359L etc.), associated with drug-response, are highly diverse. We aimed to investigate the genetic diversity of CYP2C9 in Indian-subcontinent, using 1278 subjects from 36 populations. High frequency of CYP2C9*3 (0-0.179) was observed, comparative to other populations, including Europeans. Subjects having CYP2C9*3/*3 requires lower dose of warfarin, comparative to CYP2C9*1/*3 or CYP2C9*1/*1. Since, Indians are practicing marriage among their caste system, we predicted and observed high frequency (0-0.05) of CYP2C9*3/*3. Out of 21 populations, living outside of Indian subcontinent, only Toscani and Southern Han-Chinese have 0.009 and 0.01 CYP2C9*3/*3, respectively, lower than Indians. We found a non-synonymous mutation (L362V), observed only in Indian-subcontinent, and have 0-0.056 allelic, 0-0.037 L/V and 00.037 V/V genotype frequency. We observed unfavorable interatomic interactions between hydroxylation sites of warfarin and reactive oxyferryl heme in mutant, comparative to wild-type CYP2C9, in molecular dynamic simulations; and predict lower kinetic activity.

evolutionary biology↗

bioRxiv2017

Genoppi: A web application for interactive integration of experimental proteomics results with genetic datasets

SummaryIntegrating protein-protein interaction experiments and genetic datasets can lead to new insight into the cellular processes implicated in diseases, but this integration is technically challenging. Here, we present Genoppi, a web application that integrates quantitative interaction proteomics data and results from genome-wide association studies or exome sequencing projects, to highlight biological relationships that might otherwise be difficult to discern. Written in R, Python and Bash script, Genoppi is a user-friendly framework easily deployed across Mac OS and Linux distributions.\n\nAvailabilityGenoppi is open source and available at https://github.com/lagelab/Genoppi\n\nContactaprilkim@broadinstitute.org and lage.kasper@mgh.harvard.edu

bioinformatics↗

bioRxiv2017

Geographically structured genetic variation in the Medicago lupulina-Ensifer mutualism

Mutualisms are interspecific interactions affecting the ecology and evolution of species. Patterns of geographic variation in interacting species may play an important role in understanding how variation is maintained in mutualisms, particularly in introduced ranges. One agriculturally and ecologically important mutualism is the partnership between legume plants and rhizobia. Through characterizing and comparing the population genomic structure of the legume Medicago lupulina and two rhizobial species (Ensifer medicae and E. meliloti), we explored the spatial scale of population differentiation between interacting partners in their introduced range in North America. We found high proportions of E. meliloti in southeastern populations and high proportions of E. medicae in northwestern populations. Medicago lupulina and the Ensifer genus showed similar patterns of spatial genetic structure (isolation by distance). However, we detected no evidence of isolation by distance or population structure within either species of bacteria. Genome-wide nucleotide diversity within each of the two Ensifer species was low, suggesting limited introduction of strains, founder events, or severe bottlenecks. Our results suggest that there is potential for geographically structured coevolution between M. lupulina and the Ensifer genus, but not between M. lupulina and either Ensifer species.

evolutionary biology↗

bioRxiv2017

CRISPulator: A Discrete Simulation Tool For Pooled Genetic Screens

The rapid adoption of CRISPR technology has enabled biomedical researchers to conduct CRISPR-based genetic screens in a pooled format. The quality of results from such screens is heavily dependent on optimal screen design, which also affects cost and scalability. We present CRISPulator, a computational tool that simulates the impact of screen parameters on the robustness of screen results, thereby enabling users to build intuition and insights that will inform their experimental strategy. We illustrate its power by deriving non-obvious rules for optimal screen design.

bioinformatics↗

bioRxiv2017

Population Genetics Based Phylogenetics Under Stabilizing Selection for an Optimal Amino Acid Sequence: A Nested Modeling Approach

We present a new phylogenetic approach SelAC (Selection on Amino acids and Codons), whose substitution rates are based on a nested model linking protein expression to population genetics. Unlike simpler codon models which assume a single substitution matrix for all sites, our model more realistically represents the evolution of protein coding DNA under the assumption of consistent, stabilizing selection using cost-benefit approach. This cost-benefit approach allows us generate a set of 20 optimal amino acid specific matrix families using just a handful of parameters and naturally links the strength of stabilizing selection to protein synthesis levels, which we can estimate. Using a yeast dataset of 100 orthologs for 6 taxa, we find SelAC fits the data much better than popular models by 104-105 AICc units. Our results indicate there is great potential for more accurate inference of phylogenetic trees and branch lengths from already existing data through the use of nested, mechanistic models. Additional parameters estimated by SelAC indicate that a large amount of non-phylogenetic, but biologically meaningful, information can be inferred from exisiting data. For example, SelAC prediction of gene specific protein synthesis rates correlates well with both empirical (r=0.33-0.48) and other theoretical predictions (r=0.45-0.64) for multiple yeast species. SelAC also provides estimates of the optimal amino acid at each site. Finally, because SelAC is a nested approach based on clearly stated biological assumptions, future modifications, such as including shifts in the optimal amino acid sequence within or across lineages, are possible.

evolutionary biology↗

bioRxiv2017

Fungus causing White-Nose Syndrome in bats accumulates genetic variability in North America and shows no sign of recombination

Emerging fungal diseases of wildlife are on the rise worldwide (3) and the best lens on the evolution of the fungal pathogens is population genomics. Our genome-wide analysis shows that the newly introduced North American population of Pseudogymnoascus destructans, the causal agent of White-Nose Syndrome (WNS) in bats, has expanded in size, has begun to accumulate variation through mutation, and presents no evidence as yet for genetic exchange and recombination among individuals.

evolutionary biology↗

bioRxiv2017

The Date Palm (Phoenix dactylifera L.) In Siwa Oasis (Egypt): How Ethnographic, Morphometric, And Genetic Analyses Together Explain The Local Agrobiodiversity

The agrobiodiversity of the Siwa oasis (in Egypt), located at the crossroads of ancient Trans-Saharan routes, is evaluated in this article focusing on the date palm (Phoenix dactylifera L.), the oasis \"ecosystem engineer\". This assessment confronts different ontologies: diversity as expressed and maintained by the folk categorization system of the Siwa inhabitants (through the results of an ethnographical analysis) and diversity described by genetic sciences and a morphometric tool based on the size and geometry of the seeds. This work is also an opportunity to evaluate this tool intended for archaeobotany. Beyond a simple instrumentalization of one discipline by another, this study offers a space of mutual enrichment: on the relative importance of the feral and cultivated date palms, the local relevance of the concept of \"cultivar\" and the confirmation of the existence of \"ethnovarieties\".

plant biology↗

bioRxiv2017

Developmental And Genetic Regulation Of The Human Cortex Transcriptome In Schizophrenia

GWAS have identified 108 loci that confer risk for schizophrenia, but risk mechanisms for individual loci are largely unknown. Using developmental, genetic, and illness-based RNA sequencing expression analysis, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and post-natal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this eQTL database to show that 48.1% of risk variants for schizophrenia associated with nearby expression. Within patients and controls, we implemented a novel algorithm for RNA quality adjustment, and identified 237 genes significantly associated with diagnosis that replicated in an independent case-control dataset. These genes implicated synaptic processes and were strongly regulated in early development (p < 10-20). These data offer new targets for modeling schizophrenia risk in cellular systems.

neuroscience↗

bioRxiv2017

A Collection Of Genetically Engineered Populus Trees Reveals Wood Biomass Traits That Predict Glucose Yield From Enzymatic Hydrolysis

Wood represents a promising source of lignocellulosic biomass for the production of bio-based renewables, especially biofuels. However, woody feedstocks must be improved to become competitive against petroleum. We created a collection of Populus trees consisting of 40 genetically engineered lines to modify and to better understand wood biomass properties. A total of 65 traits were measured in these trees and in the corresponding wild-type clone, including growth parameters, wood anatomical and structural properties, cell wall composition and analytical saccharification. The relationships between saccharification of glucose and biomass traits were investigated using multivariate data analysis methods and mathematical modeling. To circumvent potential trade-offs between biomass production and saccharification potential, we also estimated the \"total-wood glucose yield\" (TWG) expected after pretreatment and 72h of enzymatic hydrolysis from whole trees. A mathematical model estimated TWG from a subset of 22 wood biomass traits with good predictivity (Q2 = 0.8), while saccharification of glucose could be predicted from seven biomass traits (Q2 = 0.49). Among the seven diagnostic traits for saccharification, four also affected biomass production, such as the ratio of S- to G-lignin which was beneficial for saccharification but detrimental for growth. The contents of various matrix polysaccharides appeared important for predicting both saccharification and TWG, including low abundance monosaccharides. In particular, fucose and mannose contents negatively correlated with TWG, apparently by negatively associating with biomass production. Both biomass production and saccharification, and hence TWG, negatively correlated with arabinose and rhamnose contents, suggesting that these low abundance monosaccharides represent markers/targets for improving feedstocks.

plant biology↗

bioRxiv2017

Spatial gene drives and pushed genetic waves

Gene drives have the potential to rapidly replace a harmful wild-type allele with a gene drive allele engineered to have desired functionalities. However, an accidental or premature release of a gene drive construct to the natural environment could damage an ecosystem irreversibly. Thus, it is important to understand the spatiotemporal consequences of the super-Mendelian population genetics prior to potential applications. Here, we employ a reaction-diffusion model for sexually reproducing diploid organisms to study how a locally introduced gene drive allele spreads to replace the wild-type allele, even though it posses a selective disadvantage s > 0. Using methods developed by N. Barton and collaborators, we show that socially responsible gene drives require 0.5 < s < 0.697, a rather narrow range. In this \"pushed wave\" regime, the spatial spreading of gene drives will be initiated only when the initial frequency distribution is above a threshold profile called \"critical propagule\", which acts as a safeguard against accidental release. We also study how the spatial spread of the pushed wave can be stopped by making gene drives uniquely vulnerable (\"sensitizing drive\") in a way that is harmless for a wild-type allele. Finally, we show that appropriately sensitized drives in two dimensions can be stopped even by imperfect barriers perforated by a series of gaps.

synthetic biology↗

bioRxiv2017

The Mu-Opioid Receptor Gene OPRM1 As A Genetic Marker For Placebo Analgesia

The aim of the present study was to examine if genetic factors associated with pain perception could predict the placebo analgesic response in healthy volunteers. 296 participants (182 women) were randomized to either a placebo group receiving placebo cream with information that the cream was an effective painkiller, or to a natural history group receiving no treatment. Pain was induced by contact heat stimuli. Genotyping for the mu-opioid receptor gene OPRM1, the serotonin transporter gene 5-HTT, and the dopamine-metabolizing gene COMT was performed. Individuals with the OPRM1 A/A genotype reported significantly higher placebo responses compared to individuals with the */G variant. No clear effect of the 5-HTT or COMT was observed. The OPRM1 A/A had a predictive accuracy of 92.5% in identification of placebo responders. Our data indicate that the OPRM1 rsl799971 A/A genotype can be used as a reliable identification marker for placebo analgesia.

physiology↗

bioRxiv2017

Salmonella enterica Serovar Typhimurium ST313 Responsible For Gastroenteritis In The UK Are Genetically Distinct From Isolates Causing Bloodstream Infections In Africa

The ST313 sequence type of Salmonella enterica serovar Typhimurium causes invasive non-typhoidal salmonellosis amongst immunocompromised people in sub-Saharan Africa (sSA). Previously, two distinct phylogenetic lineages of ST313 have been described which have rarely been found outside sSA. Following the introduction of routine whole genome sequencing of Salmonella enterica by Public Health England in 2014, we have discovered that 2.7% (79/2888) of S. Typhimurium from patients in England and Wales are ST313. Of these isolates, 59/72 originated from stool and 13/72 were from extra-intestinal sites. The isolation of ST313 from extra-intestinal sites was significantly associated with travel to Africa (OR 12 [95% CI: 3,53]). Phylogenetic analysis revealed previously unsampled diversity of ST313, and distinguished UK-linked isolates causing gastroenteritis from African-associated isolates causing invasive disease. Bayesian evolutionary investigation suggested that the two African lineages diverged from their most recent common ancestors independently, circa 1796 and 1903. The majority of genome degradation of African ST313 lineage 2 is conserved in the UK ST313 lineages and only 10/44 pseudogenes were lineage 2-specific. The African lineages carried a characteristic prophage and antibiotic resistance gene repertoire, suggesting a strong selection pressure for these horizontally-acquired genetic elements in the sSA setting. We identified an ST313 isolate associated with travel to Kenya that carried a chromosomally-located blaCTX-M-15, demonstrating the continual evolution of this sequence type in Africa in response to selection pressure exerted by antibiotic usage.\n\nThe S. Typhimurium ST313 sequence type has been primarily associated with invasive disease in Africa. Here, we highlight the power of routine whole-genome-sequencing by public health agencies to make epidemiologically-significant deductions that would be missed by conventional microbiological methods. The discovery of ST313 isolates responsible for gastroenteritis in the UK reveals new diversity in this important sequence type. We speculate that the niche specialization of sub-Saharan African ST313 lineages is driven in part by the acquisition of accessory genome elements.

microbiology↗

bioRxiv2017

The Genetic Intractability Of Symbiodinium microadriaticum To Standard Algal Transformation Methods

Modern transformation and genome editing techniques have shown great success across a broad variety of organisms. However, no study of successfully applied genome editing has been reported in a dinoflagellate despite the first genetic transformation of Symbiodinium being published about 20 years ago. Using an array of different available transformation techniques, we attempted to transform Symbiodinium microadriaticum (CCMP2467), a dinoflagellate symbiont of reef-building corals, with the view to performing subsequent CRISPR-Cas9 mediated genome editing. Plasmid vectors designed for nuclear transformation containing the chloramphenicol resistance gene under the control of the CaMV p35S promoter as well as several putative endogenous promoters were used to test a variety of transformation techniques including biolistics, electroporation and silicon carbide whiskers. Chloroplast-targeted transformation were attempted using an engineered Symbiodinium chloroplast minicircle encoding a modified PsbA protein that confers atrazine resistance. We report that we have been unable to confer chloramphenicol or atrazine resistance to Symbiodinium microadriaticum strain CCMP2467.

molecular biology↗

bioRxiv2017

Insuperable Problems Of The Genetic Code Initially Emerging In An RNA World

Differential equations for error-prone information transfer (template replication, transcription or translation) are developed in order to consider, within the theory of autocatalysis, the advent of coded protein synthesis. Variations of these equations furnish a basis for comparing the plausibility of contrasting scenarios for the emergence of tRNA aminoacylation, ultimately by enzymes, and the relationship of this process with the origin of the universal system of molecular biological information processing embodied in the Central Dogma. The hypothetical RNA World does not furnish an adequate basis for explaining how this system came into being, but principles of self-organisation that transcend Darwinian natural selection furnish an unexpectedly robust basis for a rapid, concerted transition to genetic coding from a peptide*RNA world.

evolutionary biology↗

bioRxiv2017

RANKL Signaling Sustains Primary Tumor Growth In Genetically Engineered Mouse Models Of Lung Adenocarcinoma

HypothesisNon-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-{kappa}B (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy.\n\nMethodsRANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial.\n\nResultsIn human lung adenocarcinoma datasets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and LKB1 mutations. In KrasLSL-G12D/WT, KrasLSL-G12D/WT; Lkb1Flox/Flox and KrasLSL-G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK-Fc with cisplatin revealed increased efficacy compared to single agents.\n\nConclusionsRANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma, and suggest that patients with KRAS mutant lung tumors will benefit from such treatments.

cancer biology↗

bioRxiv2017

Genetically Engineered Orange Petunias On The Market

Genetic engineering of petunia was shown to lead to novel flower color some twenty years ago. Here we show that petunia lines with orange flowers, generated for scientific purposes, apparently found their way to petunia breeding programmes, intentionally or unintentionally. Today they are widely available, but have not been registered for commerce.

plant biology↗