Natural variation in Arabidopsis shoot branching plasticity in response to nitrate supply affects fitness.

The capacity of organisms to tune their development in response to environmental cues is pervasive in nature. This phenotypic plasticity is particularly striking in plants, enabled by their modular and continuous development. A good example is the activation of lateral shoot branches in Arabidopsis, which develop from axillary meristems at the base of leaves. The activity and elongation of lateral shoots depends on the integration of many signals both external (e.g. light, nutrient supply) and internal (e.g. the phytohormones auxin, strigolactone and cytokinin). Here, we characterise natural variation in plasticity of shoot branching in response to nitrate supply using two diverse panels of Arabidopsis lines. We find extensive variation in nitrate sensitivity across these lines, suggesting a genetic basis for variation in branching plasticity. High plasticity is associated with extreme branching phenotypes such that lines with the most branches on high nitrate have the fewest under nitrate deficient conditions. Conversely, low plasticity is associated with a constitutively moderate level of branching. Furthermore, variation in plasticity is associated with alternative life histories with the low plasticity lines flowering significantly earlier than high plasticity lines. In Arabidopsis, branching is highly correlated with fruit yield, and thus low plasticity lines produce more fruit than high plasticity lines under nitrate deficient conditions, whereas highly plastic lines produce more fruit under high nitrate conditions. Low and high plasticity, associated with early and late flowering respectively, can therefore be interpreted alternative escape vs mitigate strategies to low N environments. The genetic architecture of these traits appears to be highly complex, with only a small proportion of the estimated genetic variance detected in association mapping

A Multiparent Advanced Generation Inter-Cross to Fine-Map Quantitative Traits in Arabidopsis thaliana

Identifying natural allelic variation that underlies quantitative trait variation remains a fundamental problem in genetics. Most studies have employed either simple synthetic populations with restricted allelic variation or performed association mapping on a sample of naturally occurring haplotypes. Both of these approaches have some limitations, therefore alternative resources for the genetic dissection of complex traits continue to be sought. Here we describe one such alternative, the Multiparent Advanced Generation Inter-Cross (MAGIC). This approach is expected to improve the precision with which QTL can be mapped, improving the outlook for QTL cloning. Here, we present the first panel of MAGIC lines developed: a set of 527 recombinant inbred lines (RILs) descended from a heterogeneous stock of 19 intermated accessions of the plant Arabidopsis thaliana. These lines and the 19 founders were genotyped with 1,260 single nucleotide polymorphisms and phenotyped for development-related traits. Analytical methods were developed to fine-map quantitative trait loci (QTL) in the MAGIC lines by reconstructing the genome of each line as a mosaic of the founders. We show by simulation that QTL explaining 10% of the phenotypic variance will be detected in most situations with an average mapping error of about 300 kb, and that if the number of lines were doubled the mapping error would be under 200 kb. We also show how the power to detect a QTL and the mapping accuracy vary, depending on QTL location. We demonstrate the utility of this new mapping population by mapping several known QTL with high precision and by finding novel QTL for germination data and bolting time. Our results provide strong support for similar ongoing efforts to produce MAGIC lines in other organisms

Contributions of phonological and verbal working memory to language development in adolescents with fragile X syndrome

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Although language delays are frequently observed in FXS, neither the longitudinal course of language development nor its cognitive predictors are well understood. The present study investigated whether phonological and working memory skills are predictive of growth in vocabulary and syntax in individuals with FXS during adolescence. Forty-four individuals with FXS (mean age = 12.61 years) completed assessments of phonological memory (nonword repetition and forward digit recall), verbal working memory (backward digit recall), vocabulary, syntax, and nonverbal cognition. Vocabulary and syntax skills were reassessed at a 2-year follow-up. In a series of analyses that controlled for nonverbal cognitive ability and severity of autism symptoms, the relative contributions of phonological and working memory to language change over time were investigated. These relationships were examined separately for boys and girls. In boys with FXS, phonological memory significantly predicted gains in vocabulary and syntax skills. Further, verbal working memory was uniquely associated with vocabulary gains among boys. In girls with FXS, phonological and working memory skills showed no relationship with language change across the 2-year time period. Our findings indicate that, for adolescent boys with FXS, acquisition of vocabulary and syntax may be constrained by the ability to maintain and manipulate phonological representations online. Implications for the identification and treatment of language disorders in this population are discussed. The present study is the first to identify specific cognitive mechanisms contributing to language growth over time in individuals with FXS

An experimental study of executive function and social impairment in Cornelia de Lange syndrome

Background Extreme shyness and social anxiety is reported to be characteristic of adolescents and adults with Cornelia de Lange syndrome (CdLS); however, the nature of these characteristics is not well documented. In this study, we develop and apply an experimental assessment of social anxiety in a group of adolescents and adults with CdLS to determine the nature of the social difficulties and whether they are related to impairments in executive functioning. Methods A familiar and unfamiliar examiner separately engaged in socially demanding tasks comprising three experimental conditions with a group of individuals with CdLS (n = 25; % male = 44; mean age = 22.16; SD = 8.81) and a comparable group of individuals with Down syndrome (DS; n = 20; % male = 35; mean age = 24.35; SD = 5.97). Behaviours indicative of social anxiety were coded. The Behavior Rating Inventory of Executive Function-Preschool version, an informant measure of executive function, was completed by participants’ caregivers. Results Significantly less verbalisation was observed in the CdLS group than the DS group in conditions requiring the initiation of speech. In the CdLS group, impairments in verbalisation were not associated with a greater degree of intellectual disability but were significantly correlated with impairments in both planning and working memory. This association was not evident in the DS group. Conclusions Adolescents and adults with CdLS have a specific difficulty with the initiation of speech when social demands are placed upon them. This impairment in verbalisation may be underpinned by specific cognitive deficits, although further research is needed to investigate this fully

Simple mindreading abilities predict complex theory of mind: developmental delay in autism spectrum disorders

Theory of Mind (ToM) is impaired in individuals with Autism Spectrum Disorders (ASD). The aims of this study were to: i) examine the developmental trajectories of ToM abilities in two different mentalizing tasks in children with ASD compared to TD children; and ii) to assess if a ToM simple test known as Eyes-test could predict performance on the more advanced ToM task, i.e. Comic Strip test. Based on a sample of 37 children with ASD and 55 TD children, our results revealed slower development at varying rates in all ToM measures in children with ASD, with delayed onset compared to TD children. These results could stimulate new treatments for social abilities, which would lessen the social deficit in ASD

High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model

Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon\u27s (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits

Limiting damage during infection:lessons from infection tolerance for novel therapeutics

The distinction between pathogen elimination and damage limitation during infection is beginning to change perspectives on infectious disease control, and has recently led to the development of novel therapies that focus on reducing the illness caused by pathogens ("damage limitation") rather than reducing pathogen burdens directly ("pathogen elimination"). While beneficial at the individual host level, the population consequences of these interventions remain unclear. To address this issue, we present a simple conceptual framework for damage limitation during infection that distinguishes between therapies that are either host-centric (pro-tolerance) or pathogen-centric (anti-virulence). We then draw on recent developments from the evolutionary ecology of disease tolerance to highlight some potential epidemiological and evolutionary responses of pathogens to medical interventions that target the symptoms of infection. Just as pathogens are known to evolve in response to antimicrobial and vaccination therapies, we caution that claims of "evolution-proof" anti-virulence interventions may be premature, and further, that in infections where virulence and transmission are linked, reducing illness without reducing pathogen burden could have non-trivial epidemiological and evolutionary consequences that require careful examination

Neural processing of natural sounds

Natural sounds include animal vocalizations, environmental sounds such as wind, water and fire noises and non-vocal sounds made by animals and humans for communication. These natural sounds have characteristic statistical properties that make them perceptually salient and that drive auditory neurons in optimal regimes for information transmission.Recent advances in statistics and computer sciences have allowed neuro-physiologists to extract the stimulus-response function of complex auditory neurons from responses to natural sounds. These studies have shown a hierarchical processing that leads to the neural detection of progressively more complex natural sound features and have demonstrated the importance of the acoustical and behavioral contexts for the neural responses.High-level auditory neurons have shown to be exquisitely selective for conspecific calls. This fine selectivity could play an important role for species recognition, for vocal learning in songbirds and, in the case of the bats, for the processing of the sounds used in echolocation. Research that investigates how communication sounds are categorized into behaviorally meaningful groups (e.g. call types in animals, words in human speech) remains in its infancy.Animals and humans also excel at separating communication sounds from each other and from background noise. Neurons that detect communication calls in noise have been found but the neural computations involved in sound source separation and natural auditory scene analysis remain overall poorly understood. Thus, future auditory research will have to focus not only on how natural sounds are processed by the auditory system but also on the computations that allow for this processing to occur in natural listening situations.The complexity of the computations needed in the natural hearing task might require a high-dimensional representation provided by ensemble of neurons and the use of natural sounds might be the best solution for understanding the ensemble neural code

Mechanism of Mechanism of Formation of 1-Methylcyclobutanol from (β-Methylallyl)carbinylamine with Nitrous Acid

Evidence has been presented for formation of a common intermediate(s) in the carbonium ion interconversion reactions of (1-methylcyclopropyl)carbinyl, (P-methylallyl)carbinyl, and 1-methylcyclobutyl derivatives