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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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

High-throughput, image-based screening of genetic variant libraries

Image-based, high-throughput, high-content screening of pooled libraries of genetic perturbations will greatly advance our understanding biological systems and facilitate many biotechnology applications. Here we introduce a high-throughput screening method that allows highly diverse genotypes and the corresponding phenotypes to be imaged in numerous individual cells. To facilitate genotyping by imaging, barcoded genetic variants are introduced into the cells, each cell carrying a single genetic variant connected to a unique, nucleic-acid barcode. To identify the genotype-phenotype correspondence, we perform live-cell imaging to determine the phenotype of each cell, and massively multiplexed FISH imaging to measure the barcode expressed in the same cell. We demonstrated the utility of this approach by screening for brighter and more photostable variants of the fluorescent protein YFAST. We imaged 20 million cells expressing ~60,000 YFAST mutants and identified novel YFAST variants that are substantially brighter and/or more photostable than the wild-type protein.

systems biology↗

bioRxiv2017

Genetic Identification Of Brain Cell Types Underlying Schizophrenia

With few exceptions, the marked advances in knowledge about the genetic basis for schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. The common variant genomic results consistently mapped to pyramidal cells, medium spiny neurons, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to distinct sets of genes specifically expressed in each of these cell types. Many of the diverse gene sets associated with schizophrenia (including antipsychotic targets) implicate the same brain cell types. Our results provide a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. While some of the genetic risk is associated with GABAergic interneurons, this risk largely does not overlap with that from projecting cells.

genomics↗

bioRxiv2017

Genetic variation in human drug-related genes

Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classical pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional-variants in in 806 drug-related genes, including 628 known drug targets. We find that most genetic variants in these genes are very rare (f < 0.1%) and thus likely not observed in clinical trials. Overall, however, four in five patients are likely to carry a functional-variant in a target for commonly prescribed drugs and many of these might alter drug efficacy. We further computed the likelihood of 1,236 FDA approved drugs to be affected by functional-variants in their targets and show that the patient-risk varies for many drugs with respect to geographic ancestry. A focused analysis of oncological drug targets indicates that the probability of a patient carrying germline variants in oncological drug targets is with 44% high enough to suggest that not only somatic alterations, but also germline variants carried over into the tumor genome should be included in therapeutic decision-making.

bioinformatics↗

bioRxiv2017

Drivers of genetic diversity in secondary metabolic gene clusters in a fungal population

Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed five general types of variation in SM gene clusters: non-functional gene polymorphisms, gene gain and loss polymorphisms, whole cluster gain and loss polymorphisms, allelic polymorphisms where different alleles corresponded to distinct, non-homologous clusters, and location polymorphisms in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid, as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms whose detection requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and non-homologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, genomic deletion and insertion events, as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.

genomics↗

bioRxiv2017

Uncovering genomic trajectories with heterogeneous genetic and environmental backgrounds across single-cells and populations

Pseudotime algorithms can be employed to extract latent temporal information from crosssectional data sets allowing dynamic biological processes to be studied in situations where the collection of genuine time series data is challenging or prohibitive. Computational techniques have arisen from areas such as single-cell omics and in cancer modelling where pseudotime can be used to learn about cellular differentiation or tumour progression. However, methods to date typically assume homogenous genetic and environmental backgrounds, which becomes particularly limiting as datasets grow in size and complexity. As a solution to this we describe a novel statistical framework that learns pseudotime trajectories in the presence of non-homogeneous genetic, phenotypic, or environmental backgrounds. We demonstrate that this enables us to identify interactions between such factors and the underlying genomic trajectory. By applying this model to both single-cell gene expression data and population level cancer studies we show that it uncovers known and novel interaction effects between genetic and enironmental factors and the expression of genes in pathways. We provide an R implementation of our method PhenoPath at https://github.com/kieranrcampbell/phenopath

bioinformatics↗

bioRxiv2017

Dissecting causal pathways using Mendelian randomization with summarized genetic data: application to age at menarche and risk of breast cancer

Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI) and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly-available data to better understand causal mechanisms.

epidemiology↗

bioRxiv2017

Revelation of the Genetic Basis for Convergent Innovative Anal Fin Pigmentation Patterns in Cichlid Fishes

Determining whether convergent novelties share a common genetic basis is vital to understanding the extent to which evolution is predictable. The convergent evolution of innovative anal fin pigmentation patterns in cichlid fishes is an ideal model for studying this question. Here, we focused on two patterns: 1) egg-spots, circular pigmentation patterns with different numbers, sizes and positions; and 2) the blotch, irregular pattern with no variation among species. How these two novelties originate and evolve remains unclear. Based on a thorough comparative transcriptomic and genomic analysis, we observed a common genetic basis with high evolutionary rates and similar expression levels between egg-spots and the blotch. Furthermore, associations of common genes with transcription factors and signalling pathways in the core gene network, as well as the integration of advantageous genes were observed for egg-spots. We propose that the re-use of the common genetic basis indicates important conservative functions (e.g., toolkit genes) for the origin of these convergent novel phenotypes, whereas independently evolved associations of common genes with transcription factors and signalling pathways (intrinsic factor) can free the evolution of egg-spots, and together with the integration of advantageous genes (extrinsic factor) can provide a clue to link egg-spots as a key innovation to the adaptive radiation in cichlid fishes. This hypothesis will further illuminate the mechanism of the origin and evolution of novelties in a broad sense.

evolutionary biology↗

bioRxiv2017

High throughput amplicon sequencing to assess within- and between-host genetic diversity in plant viruses

Molecular epidemiology approaches at the landscape scale require to study the genetic diversity of viral populations from numerous hosts and to characterize mixed infections. In such a context, high-throughput amplicon sequencing (HTAS) techniques create interesting opportunities as they allow identifying distinct variants within a same host while simultaneously genotyping a high number of samples. Validating variants produced by HTAS may, however, remain difficult due to biases occurring at different steps of the data-generating process (e.g. environmental contaminations and sequencing error). Here, we focused on Endive necrotic mosaic virus (ENMV), a member of family Potyviridae, genus Potyvirus to develop an HTAS approach and to characterize the genetic diversity at the intra- and inter-host levels from 430 samples collected over an area of 1660 km2 located in south-eastern France. We demonstrated how it is possible, by incorporating various controls in the experimental design and by performing independent sample replicates, to estimate potential biases in HTAS results and to implement an automated and robust variant calling procedure.\n\nHighlightsO_LIHigh-throughput amplicon sequencing to assess plant virus genetic diversity\nC_LIO_LIEstimating bias in high throughput amplicon sequencing results\nC_LIO_LIAutomated variant calling procedure for robust high throughput amplicon sequencing\nC_LI

molecular biology↗

bioRxiv2017

Intra- and inter-chromosomal chromatin interactions mediate genetic effects on regulatory networks

Genome-wide studies on the genetic basis of gene expression and the structural properties of chromatin have considerably advanced our understanding of the function of the human genome. However, it remains unclear how structure relates to function and, in this work, we aim at bridging both by assembling a dataset that combines the activity of regulatory elements (e.g. enhancers and promoters), expression of genes and genetic variations of 317 individuals and across two cell types. We show that the regulatory activity is structured within 12,583 Cis Regulatory Domains (CRDs) that are cell type specific and highly reflective of the local (i.e. Topologically Associating Domains) and global (i.e. A/B nuclear compartments) nuclear organization of the chromatin. These CRDs essentially delimit the sets of active regulatory elements involved in the transcription of most genes, thereby capturing complex regulatory networks in which the effects of regulatory variants are propagated and combined to finally mediate expression Quantitative Trait Loci. Overall, our analysis reveals the complexity and specificity of cis and trans regulatory networks and their perturbation by genetic variation.

genomics↗

bioRxiv2017

Unexpected mixed-mode transmission and moderate genetic regulation of Symbiodinium communities in a brooding coral

Determining the extent to which Symbiodinium communities in corals are inherited versus environmentally-acquired is fundamental to understanding coral resilience and to predicting coral responses to stressors like warming oceans that disrupt this critical endosymbiosis. We examined the fidelity with which Symbiodinium communities in the brooding coral Seriatopora hystrix are vertically transmitted and the extent to which communities are genetically regulated, by genotyping 60 larvae and their parents (9 maternal and 45 paternal colonies) using high throughput sequencing of the ITS-2 locus. Unexpectedly, Symbiodinium communities associated with brooded larvae were distinct from those within parent colonies, including the presence of types not detected in adults. Bayesian heritability (h2) analysis revealed that 33% of variability in larval Symbiodinium communities was genetically controlled. Results highlight flexibility in the establishment of larval communities and overturn the paradigm that symbiont transmission is exclusively vertical in brooding corals. Instead, we show that Symbiodinium transmission in S. hystrix involves a mixed-mode strategy, similar to many terrestrial invertebrate symbioses. Also, variation in the abundances of common Symbiodinium types among adult communities suggests that microhabitat differences influence the structure of in hospite Symbiodinium communities. Partial genetic regulation coupled with flexibility in the environmentally-acquired component of larval Symbiodinium communities implies that corals with vertical transmission, like S. hystrix, may be more resilient to environmental change than previously thought.

microbiology↗

bioRxiv2017

Sex-biased gene expression resolves sexual conflict through the evolution of sex-specific genetic architecture

Many genes are subject to contradictory selection pressures in males and females, and balancing selection resulting from sexual conflict has the potential to substantially increase standing genetic diversity in populations and thereby act as an important force in adaptation. However, the underlying causes of sexual conflict, and the potential for resolution, remains hotly debated. Using transcriptome resequencing data from male and female guppies, we use a novel approach, combining patterns of genetic diversity and inter-sexual divergence in allele frequency, to distinguish the different scenarios that give rise to sexual conflict, and how this conflict may be resolved through regulatory evolution. We show that reproductive fitness is the main source of sexual conflict, and this is resolved via the evolution of male-biased expression. Furthermore, resolution of sexual conflict produces significant differences in genetic architecture between males and females, which in turn leads to specific alleles influencing sex-specific viability. Together, our findings suggest an important role for sexual conflict in shaping broad patterns of genome diversity, and show that regulatory evolution is a rapid and efficient route to the resolution of conflict.

evolutionary biology↗

bioRxiv2018

Response to Therapeutic Sleep Deprivation: A Naturalistic Study of Clinical and Genetic Factors and Post-Treatment Depressive Symptom Trajectory

Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the majority of depressed patients. Investigation of factors preceding and accompanying these effects may facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness course. Mood and tiredness during SD were also assessed via visual analogue scales (VAS). Depressed inpatients (n = 78) and healthy controls (n = 15) underwent ~36hrs of SD. Response to SD was defined as a score of [≤]2 on the Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using polygenic risk scores for major depressive disorder. 72% of patients responded to SD. Responders and nonresponders did not differ in baseline self/expert depression symptom ratings, but mood subjectively measured by VAS scale differed. Response was associated with lower age (p = 0.007) and later age at life-time disease onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy controls. Up to a month post-SD, depressive symptoms decreased in both patients groups, but more in responders, in whom effects were sustained. The present findings suggest that re-examining SD with a greater focus on biological mechanisms will lead to better understanding of mechanisms of depression.

epidemiology↗

bioRxiv2017

Inevitability of the emergence and persistence of genetic parasites caused by thermodynamic instability of parasite-free states

Genetic parasites, including viruses and mobile genetic elements, are ubiquitous among cellular life forms, and moreover, are the most abundant biological entities on earth that harbor the bulk of the genetic diversity. Here we examine simple thought experiments to demonstrate that both the emergence of parasites in simple replicator systems and their persistence in evolving life forms are inevitable because the putative parasite-free states are thermodynamically unstable.

evolutionary biology↗

bioRxiv2017

Determinants of genetic structure of the Sub-Saharan parasitic wasp Cotesia sesamiae

Parasitoid life style represents one of the most diversified life history strategies on earth. There are however very few studies on the variables associated with intraspecific diversity of parasitoid insects, especially regarding the relationship with spatial, biotic and abiotic ecological factors. Cotesia sesamiae is a Sub-Saharan stenophagous parasitic wasp that parasitizes several African stemborer species with variable developmental success. The different host-specialized populations are infected with different strains of Wolbachia, an endosymbiotic bacterium widespread in arthropods that is known for impacting life history traits notably reproduction, and consequently species distribution. In this study, first we analyzed the genetic structure of C. sesamiae across Sub-Saharan Africa, using 8 microsatellite markers, and 3 clustering software. We identified five major population clusters across Sub-Saharan Africa, which probably originated in East African Rift region and expanded throughout Africa in relation to host genus and abiotic factors such as climatic classifications. Using laboratory lines, we estimated the incompatibility between the different strains of Wolbachia infecting C. sesamiae. We observed an incompatibility between Wolbachia strains was asymmetric; expressed in one direction only. Based on these results, we assessed the relationships between direction of gene flow and Wolbachia infections in the genetic clusters. We found that Wolbachia-induced reproductive incompatibility was less influential than host specialization in the genetic structure. Both Wolbachia and host were more influential than geography and current climatic conditions. These results are discussed in the context of African biogeography, and co-evolution between Wolbachia, virus parasitoid and host, in the perspective of improving biological control efficiency through a better knowledge of the biodiversity of biological control agents.

evolutionary biology↗

bioRxiv2017

Ascertainment bias can create the illusion of genetic health disparities

BackgroundAccurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of GWAS, and extensive computer simulations to identify how genetic disease risks can be misestimated.\n\nResultsIn contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. Strikingly, ancestral risk alleles are found at 9.51% higher frequency in Africa and derived risk alleles are found at 5.40% lower frequency in Africa. By simulating GWAS with different study populations, we find that non-African cohorts yield disease associations that have biased allele frequencies and that African cohorts yield disease associations that are relatively free of bias. We also find empirical evidence that genotyping arrays and SNP ascertainment bias contribute to continental differences in risk allele frequencies. Because of these causes, polygenic risk scores can be grossly misestimated for individuals of African descent. Importantly, continental differences in risk allele frequencies are only moderately reduced if GWAS use whole genome sequences and hundreds of thousands of cases and controls. Finally, comparisons between uncorrected and corrected genetic risk scores reveal the benefits of considering whether risk alleles are ancestral or derived.\n\nConclusionsOur results imply that caution must be taken when extrapolating GWAS results from one population to predict disease risks in another population.

genomics↗

bioRxiv2017

Decoupled Maternal and Zygotic Genetic Effects Shape the Evolution of Development

Many animals develop indirectly via a larval stage that is morphologically and ecologically distinct from its adult form. Hundreds of lineages across animal phylogeny have secondarily lost larval forms, instead producing offspring that directly develop into adult form without a distinct larval ecological niche1-7. Indirect development in the sea is typically planktotrophic: females produce large numbers of small offspring that require exogenous planktonic food to develop before metamorphosing into benthic juveniles. Direct development is typically lecithotrophic: females produce a smaller number of larger eggs, each developing into a juvenile without the need for larval feeding, provisioned by yolk. Evolutionary theory suggests that these alternative developmental strategies represent stable alternative fitness peaks, while intermediate states are disfavored4,8-11. Transitions from planktotrophy to lecithotrophy thus require crossing a fitness valley and represent radical and coordinated transformations of life-history, fecundity, ecology, dispersal, and development7,12-16. Here we dissect this transition in Streblospio benedicti, the sole genetically tractable species that harbors both states as heritable variation17-19. We identify large-effect loci that act maternally to influence larval size and independent, unlinked large-effect loci that act zygotically to affect discrete aspects of larval morphology. Because lecithotrophs and planktotrophs differ in both size and morphology, the genetic basis of larval form exhibits strong maternal-by-zygotic epistasis for fitness20. The fitness of zygotic alleles depends on their maternal background, creating a positive frequency-dependence that may homogenize local populations. Developmental and population genetics interact to shape larval evolution.

evolutionary biology↗

bioRxiv2017

Partial selfing eliminates inbreeding depression while maintaining genetic diversity

Classical theory on the origin and evolution of selfing and outcrossing relies on the role of inbreeding depression created by unlinked partially-deleterious recessive alleles to predict that individuals from natural populations predominantly self or outcross. Comparative data indicates, however, that maintenance of partial selfing and outcrossing at intermediate frequencies is common in nature. In part to explain the presence of mixed reproductive modes within populations, several hypotheses regarding the evolution of inbreeding depression have been put forward based on the complex interaction of linkage and identity disequilibrium among fitness loci, together with Hill-Robertson effects. We here ask what is the genetic basis of inbreeding depression so that populations with intermediate selfing rates can eliminate it while maintain potentially adaptive genetic diversity. For this, we use experimental evolution in the nematode C. elegans under partial selfing and compare it to the experimental evolution of populations evolved under exclusive selfing and predominant outcrossing. We find that the ancestral risk of extinction upon enforced inbreeding by selfing is maintained when populations evolve under predominant outcrossing, but reduced when populations evolve under partial or exclusive selfing. Analysis of genome-wide single-nucleotide polymorphism (SNP) during experimental evolution and after enforced inbreeding suggests that, under partial selfing, populations were purged of unlinked deleterious recessive alleles that segregate in the ancestral population, which in turn allowed the expression of unlinked overdominant fitness loci. Taken together, these observations indicate that populations evolving under partial selfing gain the short-term benefits of selfing, in purging deleterious recessive alleles, but also the long-term benefits of outcrossing, in maintaining genetic diversity that may important for future adaptation.

evolutionary biology↗

bioRxiv2017

Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes

Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes for cancer patients, with almost half of patients expected to ultimately develop congestive heart failure given high drug doses. However, the genetic basis of sensitivity to anthracyclines such as doxorubicin remains unclear. To begin addressing this, we created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24h exposure to varying levels of doxorubicin. The transcriptomic response to doxorubicin is substantial, with the majority of genes being differentially expressed across treatments of different concentrations and over 6000 genes showing evidence of differential splicing. Overall, our observations indicate that splicing fidelity decreases in the presence of doxorubicin. We detect 376 response-expression QTLs and 42 response-splicing QTLs, i.e. genetic variants that modulate the individual transcriptomic response to doxorubicin in terms of expression and splicing changes respectively. We show that inter-individual variation in transcriptional response is predictive of cell damage measured in vitro using a cardiac troponin assay, which in turn is shown to be associated with in vivo ACT risk. Finally, the molecular QTLs we detected are enriched in lower ACT GWAS p-values, further supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

genomics↗