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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Metabolome-scale genome-wide association studies reveal chemical diversity and genetic control of maize specialized metabolites

One Sentence SummaryHPLC-MS metabolite profiling of maize seedlings, in combination with genome-wide association studies, identifies numerous quantitative trait loci that influence the accumulation of foliar metabolites.\n\nAbstractCultivated maize (Zea mays) retains much of the genetic and metabolic diversity of its wild ancestors. Non-targeted HPLC-MS metabolomics using a diverse panel of 264 maize inbred lines identified a bimodal distribution in the prevalence of foliar metabolites. Although 15% of the detected mass features were present in >90% of the inbred lines, the majority were found in <50% of the samples. Whereas leaf bases and tips were differentiated primarily by flavonoid abundance, maize varieties (stiff-stalk, non-stiff-stalk, tropical, sweet corn, and popcorn) were differentiated predominantly by benzoxazinoid metabolites. Genome-wide association studies (GWAS), performed for 3,991 mass features from the leaf tips and leaf bases, showed that 90% have multiple significantly associated loci scattered across the genome. Several quantitative trait locus hotspots in the maize genome regulate the abundance of multiple, often metabolically related mass features. The utility of maize metabolite GWAS was demonstrated by confirming known benzoxazinoid biosynthesis genes, as well as by mapping isomeric variation in the accumulation of phenylpropanoid hydroxycitric acid esters to a single linkage block in a citrate synthase-like gene. Similar to gene expression databases, this metabolomic GWAS dataset constitutes an important public resource for linking maize metabolites with biosynthetic and regulatory genes.

genetics↗
bioRxiv2018

The Sicilian wolf: genetic identity of a recently extinct insular population

During historical times many local grey wolf (Canis lupus) populations underwent a substantial reduction of their sizes or became extinct. Among these, the wolf population once living in Sicily, the biggest island of the Mediterranean Sea, was completely eradicated by human persecution in the early decades of the XX century.\n\nIn order to understand the genetic identity of the Sicilian wolf, we applied ancient DNA techniques to analyse the mitochondrial DNA of six specimens actually stored in Italian museums.\n\nWe successfully amplified a diagnostic mtDNA fragment of the control region (CR) in four of the samples. Results showed that two samples shared the same haplotype, that differed by two substitutions from the currently most diffused Italian wolf haplotype (W14) and one substitution from the only other Italian haplotype (W16). The third sample showed a wolf-like haplotype never described before and the fourth a haplotype commonly found in dogs.\n\nFurthermore, all the wolf haplotypes detected in this study belonged to the mitochondrial haplogroup that includes haplotypes detected in all the known European Pleistocene wolves and in several modern southern European populations.\n\nUnfortunately, this endemic island population, bearing unique mtDNA variability, was definitively lost before it was possible to understand its taxonomic uniqueness and conservational value.

genetics↗
bioRxiv2018

Population based forward genetic screen of mutagenized zebrafish identifies loci associated with nicotine preference and human smoking behavior

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. Of 30 ENU mutagenized families screened, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations in the families, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants that predict cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.

genetics↗
bioRxiv2014

Rapidly characterizing the fast dynamics of RNA genetic circuitry with cell-free transcription-translation (TX-TL) systems

RNA regulators are emerging as powerful tools to engineer synthetic genetic networks or rewire existing ones. A potential strength of RNA networks is that they may be able to propagate signals on timescales that are set by the fast degradation rates of RNAs. However, a current bottleneck to verifying this potential is the slow design-build-test cycle of evaluating these networks in vivo. Here we adapt an Escherichia coli-based cell-free transcription-translation (TX-TL) system for rapidly prototyping RNA networks. We used this system to measure the response time of an RNA transcription cascade to be approximately five minutes per step of the cascade. We also show that this response time can be adjusted with temperature and regulator threshold response tuning. Finally we use TX-TL to prototype a new RNA network, an RNA single input module, and show that this network temporally stages the expression of two genes in vivo.

Synthetic Biology↗
bioRxiv2014

Dimorphic development in Streblospio benedicti: genetic analysis of morphological differences between larval types

The marine polychaete Streblospio benedicti exhibits two distinct larval types, making it a model for the study of developmental evolution. Females produce either large eggs or small ones, which develop into distinct lecithotrophic or planktotrophic larvae with concomitant morphological and life-history differences. Here, we investigate the inheritance of key morphological traits that distinguish the larval types. We use genetic crosses to establish the influence of maternal and zygotic differences on larval phenotypes. We find a large maternal effect on larval size and the number of larval chaetae, while the number and length of these chaetae are also strongly influenced by zygotic genotype. Interestingly, the distribution of larval phenotypes produced by these crosses suggests traits intermediate to the two parental types should not be uncommon. Yet, despite gene flow between the types in natural populations, such intermediates are rarely found in nature, suggesting that selection may be maintaining distinct larval modes.

Developmental Biology↗
bioRxiv2014

Deciphering the genetic and transcriptional basis of cross-stress responses in Escherichia coli under complex evolutionary scenarios

A tantalizing question in microbial physiology is the inter-dependence and evolutionary potential of cellular stress response across multiple environmental dimensions. To address this question, we comprehensively characterized the cross-stress behavior of wild-type and evolved Escherichia coli populations in five abiotic stresses (n-butanol, osmotic, alkaline, acidic, and oxidative) by performing genome-scale genetic, transcriptional and growth profiling, thus identifying 18 cases of cross-stress protection and one case of cross-stress vulnerability. We identified 18 cases of cross-stress protection and one case of cross-stress vulnerability, along with core and stress-specific networks. We tested several hypotheses regarding the effect of the stress order, stress combinations, mutation reversal and varying environments to the evolution and final cellular fitness of the respective populations. Our results argue of a common systems-level core of the stress response with several crucial implicated pathways that include metal ion binding and glycolysis/gluconeogenesis that is further complemented by a stress-specific expression program.

Evolutionary Biology↗
bioRxiv2014

Genetic relateness of Haemophilus parasuis among reference strains and Chinese epidemic isolates

Haemophilus parasuis is the causative agent of Glassers disease and a commensal coloniser of the porcine upper respiratory tract. Multiple complex factors, including the early weaning of piglets and the management of high health status farms, make it a re-emerging agent, responsible for a recent increase in the prevalence and severity of disease in pigs in China. However, little genetic information is known about Chinese epidemic isolates. In this study, a phylogenetic method for genotyping the H. parasuis population with available Chinese epidemic isolates and reference strains from different origins is presented. Phylogenetic analysis confirmed that there are at least two different genotypes in H. parasuis population and a unique Chinese lineage with virulence results in the previous epidemics.

Microbiology↗
bioRxiv2015

The genetics of resistance to Morinda fruit toxin during the postembryonic stages in Drosophila sechellia

Many phytophagous insect species are ecologic specialists that have adapted to utilize a single host plant. Drosophila sechellia is a specialist that utilizes the ripe fruit of Morinda citrifolia, which is toxic to its sibling species, D. simulans. Here we apply multiplexed shotgun genotyping and QTL analysis to examine the genetic basis of resistance to M. citrifolia fruit toxin in interspecific hybrids. We find that at least four dominant and four recessive loci interact additively to confer resistance to the M. citrifolia fruit toxin. These QTL include a dominant locus of large effect on the third chromosome (QTL-IIIsima) that was not detected in previous analyses. The small-effect loci that we identify overlap with regions that were identified in selection experiments with D. simulans on octanoic acid and in QTL analyses of adult resistance to octanoic acid. Our high-resolution analysis sheds new light upon the complexity of M. citrifolia resistance, and suggests that partial resistance to lower levels of M. citrifolia toxin could be passed through introgression from D. sechellia to D. simulans in nature. The identification of a locus of major effect, QTL-IIIsima, is an important step towards identifying the molecular basis of host plant specialization by D. sechellia.

Evolutionary Biology↗
bioRxiv2015

Large-scale assessment of olfactory preferences and learning in Drosophila melanogaster: behavioral and genetic measures

In the Evolve and Resequence method (E&R), experimental evolution and genomics are combined to investigate evolutionary dynamics and the genotype-phenotype link. This approach requires many replicates with large population sizes, which imposes severe restrictions on the analysis of behavioral phenotypes. Aiming to use E&R for investigating the evolution of behavior in Drosophila, we have developed a simple and effective method to assess spontaneous olfactory preferences and learning in large samples of fruit flies using a T-maze. We tested this procedure on (a) a large wild-caught population and (b) 11 isofemale lines of Drosophila melanogaster. Compared to previous methods, this procedure reduces the environmental noise and allows for the analysis of large population samples. Consistent with previous results, we show that flies have a spontaneous preference for orange vs. apple odor. With our procedure wild-derived flies exhibit olfactory learning in the absence of previous laboratory selection. Furthermore, we find genetic differences in the olfactory learning with relatively high heritability. We propose this large-scale method as an effective tool for E&R and genome-wide association studies on olfactory preferences and learning.

Animal Behavior and Cognition↗
bioRxiv2015

Coalescent times and patterns of genetic diversity in species with facultative sex: effects of gene conversion, population structure and heterogeneity

Many diploid organisms undergo facultative sexual reproduction. However, little is currently known concerning the distribution of neutral genetic variation amongst facultative sexuals except in very simple cases. Under-standing this distribution is important when making inferences about rates of sexual reproduction, effective population size and demographic history. Here, we extend coalescent theory in diploids with facultative sex to consider gene conversion, selfing, population subdivision, and temporal and spatial heterogeneity in rates of sex. In addition to analytical results for two-sample coalescent times, we outline a coalescent algorithm that accommodates the complexities arising from partial sex; this algorithm can be used to generate multi-sample coalescent distributions. A key result is that when sex is rare, gene conversion becomes a significant force in reducing diversity within individuals, which can remove genomic signatures of infrequent sex (the Meselson Effect) or entirely reverse the predictions. Our models offer improved methods for assessing the null model (I.e. neutrality) of patterns of molecular variation in facultative sexuals.

Evolutionary Biology↗
bioRxiv2015

The effects of time-varying temperature on delays in genetic networks

Delays in gene networks result from the sequential nature of protein assembly. However, it is unclear how models of gene networks that use delays should be modified when considering time-dependent changes in temperature. This is important, as delay is often used in models of genetic oscillators that can be entrained by periodic fluctuations in temperature. Here, we analytically derive the time dependence of delay distributions in response to time-varying temperature changes. We find that the resulting time-varying delay is nonlinearly dependent on parameters of the time-varying temperature such as amplitude and frequency, therefore, applying an Arrhenius scaling may result in erroneous conclusions. We use these results to examine a model of a synthetic gene oscillator with temperature compensation. We show that temperature entrainment follows from the same mechanism that results in temperature compensation. Under a common Arrhenius scaling alone, the frequency of the oscillator is sensitive to changes in the mean temperature but robust to changes in the frequency of a periodically time-varying temperature. When a mechanism for temperature compensation is included in the model, however, we show that the oscillator is entrained by periodically varying temperature even when maintaining insensitivity to the mean temperature.

Systems Biology↗
bioRxiv2015

Estimating information flow through a memory system: the utility of meta-analytic methods for genetics

Critics of significance testing claim that this statistical framework promotes discrepancies by using arbitrary thresholds () to impose reject/accept dichotomies on continuous data, which is not reflective of the biological reality of quantitative phenotypes. Here we explore this idea and evaluate an alternative approach, demonstrating the potential for meta-analysis and related estimation methods to resolve discordance generated by the use of traditional significance tests. We selected a set of behavioral studies proposing differing models of the physiological basis of Drosophila olfactory memory and used systematic review and meta-analysis approaches to define the true role of lobular specialization within the brain. The mainstream view is that each of the three lobes of the Drosophila mushroom body play specialized roles in short-term aversive olfactory memory [1-5], but a number of studies have made divergent conclusions based on their discordant experimental findings [6-8]. Multivariate meta-regression models revealed that short-term memory lobular specialization is not in fact supported by the data, and identified the cellular extent of a transgenic driver as the major predictor of its effect on short-term memory. Our findings demonstrate that meta-analysis, meta-regression, hierarchical models and estimation methods in general can be successfully harnessed to identify knowledge gaps, synthesize divergent results, accommodate heterogeneous experimental design and quantify genetic mechanisms.

Neuroscience↗
bioRxiv2015

Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls

Identifying whether potential causal variants for related diseases are shared can increase understanding of the shared etiology between diseases. Colocalization methods are designed to disentangle shared and distinct causal variants in regions where two diseases show association, but existing methods are limited by assuming independent datasets. We extended existing methods to allow for the shared control design common in GWAS and applied them to four autoimmune diseases: type 1 diabetes (T1D); rheumatoid arthritis; celiac disease (CEL) and multiple sclerosis (MS). Ninety regions associated with at least one disease. In 22 regions (24%), we identify association to precisely one of our four diseases and can find no published association of any other disease to the same region; some of these may reflect effects mediated by the target of immune attack. Thirty-three regions (37%) were associated with two or more, but in 14 of these there was evidence that causal variants differed between diseases. By leveraging information across datasets, we identified novel disease associations to 12 regions previously associated with one or more of the other three autoimmune disorders. For instance, we link the CEL-associated FASLG region to T1D and identify a single SNP, rs78037977, as a likely causal variant. We also highlight several particularly complex association patterns, including the CD28-CTLA4-ICOS region, in which it appears that three distinct causal variants associate with three diseases in three different patterns. Our results underscore the complexity in genetic variation underlying related but distinct autoimmune diseases and help to approach its dissection.

Genomics↗
bioRxiv2015

The Nature, Extent, and Consequences of Genetic Variation in the opa Repeats of Notch in Drosophila

Polyglutamine (pQ) tracts are abundant in many proteins co-interacting on DNA. The lengths of these pQ tracts can modulate their interaction strengths. However, pQ tracts > 40 residues are pathologically prone to amyloidogenic self-assembly. Here, we assess the extent and consequences of variation in the pQ-encoding opa repeats of Notch (N) in Drosophila melanogaster. We use Sanger sequencing to genotype opa sequences (50-CAX repeats), which have resisted assembly using short sequence reads. While the majority of N sequences pertain to reference opa31 (Q13HQ17) and opa32 (Q13HQ18) allelic classes, several rare alleles encode tracts > 32 residues: opa33a (Q14HQ18), opa33b (Q15HQ17), opa34 (Q16HQ17), opa35a1/opa35a2 (Q13HQ21), opa36 (Q13HQ22), and opa37 (Q13HQ23). Only one rare allele encodes a tract < 31 residues: opa23 (Q13-Q10). This opa23 allele shortens the pQ tract while simultaneously eliminating the interrupting histidine. Homozygotes for the short and long opa alleles have defects in sensory bristle organ specification, abdominal patterning, and embryonic survival. Inbred stocks with wild-type opa31 alleles become more viable when outbred, while an inbred stock with the longer opa35 becomes less viable after outcrossing to different backgrounds. In contrast, an inbred stock with the short opa23 allele is semi-viable in both inbred and outbred genetic backgrounds. This opa23 Notch allele also produces notched wings when recombined out of the X chromosome. Importantly, wa-linked X balancers carry the N allele opa33b and suppress AS-C insufficiency caused by the sc8 inversion. Our results demonstrate potent pQ variation and epistatic sensitivity for the N locus, and the need for long read genotyping of key repeat variables underlying gene regulatory networks.

Evolutionary Biology↗
bioRxiv2015

Genome variation and meiotic recombination in Plasmodium falciparum: insights from deep sequencing of genetic crosses

The malaria parasite Plasmodium falciparum has a great capacity for evolutionary adaptation to evade host immunity and develop drug resistance. Current understanding of parasite evolution is impeded by the fact that a large fraction of the genome is either highly repetitive or highly variable, and thus difficult to analyse using short read technologies. Here we describe a resource of deep sequencing data on parents and progeny from genetic crosses, which has enabled us to perform the first genome-wide, integrated analysis of SNP, INDEL and complex polymorphisms, using Mendelian error rates as an indicator of genotypic accuracy. These data reveal that INDELs are exceptionally abundant, being more common than SNPs and thus the dominant mode of polymorphism within the core genome. We use the high density of SNP and INDEL markers to analyse patterns of meiotic recombination, confirming a high rate of crossover events, and providing the first estimates for the rate of non-crossover events and the length of conversion tracts. We observe several instances of recombination that modify copy number variants associated with drug resistance, demonstrating a mechanism whereby fitness costs associated with resistance mutations could be compensated and greater phenotypic plasticity could be acquired. We describe a novel web application that allows these data to be explored in detail.

Genomics↗
bioRxiv2015

Allele-specific expression reveals interactions between genetic variation and environment

Introduction Introduction Main text Methods References The impact of environment on human health is dramatic, with major risk factors including substance use1, diet2 and exercise3. However, identifying interactions between the environment and an individuals genetic background (GxE) has been hampered by statistical and computational challenges4,5. By combining RNA sequencing of whole blood and extensive environmental annotations collected from 922 individuals6, we have evaluated GxE interactions at a cellular level. We have developed EAGLE, a hierarchical Bayesian model for identifying GxE interactions based on association between environment and allele-specific expression (ASE). EAGLE inc ...

Genomics↗
bioRxiv2015

Genetic structure of the stingless bee Tetragonisca angustula

The stingless bee Tetragonisca angustula Latreille 1811 is distributed from Mexico to Argentina and is one of the most widespread bee species in the Neotropics. However, this wide distribution contrasts with the short distance traveled by females to build new nests. Here we evaluate the genetic structure of several populations of T. angustula using mitochondrial DNA and microsatellites. These markers can help us to detect differences in the migratory behavior of males and females. Our results show that the populations are highly differentiated suggesting that both females and males have low dispersal distance. Therefore, its continental distribution probably consists of several cryptic species.

Evolutionary Biology↗