Identification and characterisation of de novo germline structural variants in two commercial pig lines using trio-based whole genome sequencing.

BACKGROUND: De novo mutations arising in the germline are a source of genetic variation and their discovery broadens our understanding of genetic disorders and evolutionary patterns. Although the number of de novo single nucleotide variants (dnSNVs) has been studied in a number of species, relatively little is known about the occurrence of de novo structural variants (dnSVs). In this study, we investigated 37 deeply sequenced pig trios from two commercial lines to identify dnSVs present in the offspring. The identified dnSVs were characterised by identifying their parent of origin, their functional annotations and characterizing sequence homology at the breakpoints. RESULTS: We identified four swine germline dnSVs, all located in intronic regions of protein-coding genes. Our conservative, first estimate of the swine germline dnSV rate is 0.108 (95% CI 0.038-0.255) per generation (one dnSV per nine offspring), detected using short-read sequencing. Two detected dnSVs are clusters of mutations. Mutation cluster 1 contains a de novo duplication, a dnSNV and a de novo deletion. Mutation cluster 2 contains a de novo deletion and three de novo duplications, of which one is inverted. Mutation cluster 2 is 25 kb in size, whereas mutation cluster 1 (197 bp) and the other two individual dnSVs (64 and 573 bp) are smaller. Only mutation cluster 2 could be phased and is located on the paternal haplotype. Mutation cluster 2 originates from both micro-homology as well as non-homology mutation mechanisms, where mutation cluster 1 and the other two dnSVs are caused by mutation mechanisms lacking sequence homology. The 64 bp deletion and mutation cluster 1 were validated through PCR. Lastly, the 64 bp deletion and the 573 bp duplication were validated in sequenced offspring of probands with three generations of sequence data. CONCLUSIONS: Our estimate of 0.108 dnSVs per generation in the swine germline is conservative, due to our small sample size and restricted possibilities of dnSV detection from short-read sequencing. The current study highlights the complexity of dnSVs and shows the potential of breeding programs for pigs and livestock species in general, to provide a suitable population structure for identification and characterisation of dnSVs.

EEG theta and beta power spectra in adolescents with ADHD versus adolescents with ASD + ADHD.

Attention problems are common in youngsters with attention deficit hyperactivity disorder (ADHD) as well as in adolescents with combined autism spectrum disorder (ASD) and ADHD. However, it is unknown whether there is psychophysiological overlap and/or a difference in electroencephalogram (EEG) power spectra between ADHD and comorbid ASD and ADHD (ASD + ADHD), on and off stimulant medication. To explore potential differences and overlap, measures of theta and beta power in adolescents diagnosed with ADHD (n = 33) versus adolescents with combined ASD + ADHD (n = 20), categorized by stimulant medication use (57 % of the total sample), were compared. EEG measures were acquired in three conditions: (1) resting state, eyes closed (2) resting state, eyes open and (3) during an oddball task. In addition, performance on the d2 attention test was analyzed. Adolescents with ADHD displayed more absolute theta activity than adolescents with ASD + ADHD during the eyes open and task conditions, independent of stimulant medication use. In addition, only the adolescents with ADHD showed an association between diminished attention test performance and increased theta in the eyes open condition. Results of the current study suggest that although there is behavioral overlap between ADHD characteristics in adolescents with ADHD and adolescents with combined ASD + ADHD, the underlying psychophysiological mechanisms may be different. Adolescents with ASD + ADHD exhibited fewer of the EEG physiological signs usually associated with ADHD, although there was an overlap in attentional problems between the groups. This may indicate that treatments developed for ADHD work differently in some adolescents with ASD + ADHD and adolescents with ADHD only.

Bayesian QTL analyses using pedigreed families of an outcrossing species, with application to fruit firmness in apple.

KEY MESSAGE: Proof of concept of Bayesian integrated QTL analyses across pedigree-related families from breeding programs of an outbreeding species. Results include QTL confidence intervals, individuals' genotype probabilities and genomic breeding values. Bayesian QTL linkage mapping approaches offer the flexibility to study multiple full sib families with known pedigrees simultaneously. Such a joint analysis increases the probability of detecting these quantitative trait loci (QTL) and provide insight of the magnitude of QTL across different genetic backgrounds. Here, we present an improved Bayesian multi-QTL pedigree-based approach on an outcrossing species using progenies with different (complex) genetic relationships. Different modeling assumptions were studied in the QTL analyses, i.e., the a priori expected number of QTL varied and polygenic effects were considered. The inferences include number of QTL, additive QTL effect sizes and supporting credible intervals, posterior probabilities of QTL genotypes for all individuals in the dataset, and QTL-based as well as genome-wide breeding values. All these features have been implemented in the FlexQTL(™) software. We analyzed fruit firmness in a large apple dataset that comprised 1,347 individuals forming 27 full sib families and their known ancestral pedigrees, with genotypes for 87 SSR markers on 17 chromosomes. We report strong or positive evidence for 14 QTL for fruit firmness on eight chromosomes, validating our approach as several of these QTL were reported previously, though dispersed over a series of studies based on single mapping populations. Interpretation of linked QTL was possible via individuals' QTL genotypes. The correlation between the genomic breeding values and phenotypes was on average 90 %, but varied with the number of detected QTL in a family. The detailed posterior knowledge on QTL of potential parents is critical for the efficiency of marker-assisted breeding.

Multi-trait and multi-environment QTL analyses of yield and a set of physiological traits in pepper.

KEY MESSAGE: A mixed model framework was defined for QTL analysis of multiple traits across multiple environments for a RIL population in pepper. Detection power for QTLs increased considerably and detailed study of QTL by environment interactions and pleiotropy was facilitated. For many agronomic crops, yield is measured simultaneously with other traits across multiple environments. The study of yield can benefit from joint analysis with other traits and relations between yield and other traits can be exploited to develop indirect selection strategies. We compare the performance of three multi-response QTL approaches based on mixed models: a multi-trait approach (MT), a multi-environment approach (ME), and a multi-trait multi-environment approach (MTME). The data come from a multi-environment experiment in pepper, for which 15 traits were measured in four environments. The approaches were compared in terms of number of QTLs detected for each trait, the explained variance, and the accuracy of prediction for the final QTL model. For the four environments together, the superior MTME approach delivered a total of 47 regions containing putative QTLs. Many of these QTLs were pleiotropic and showed quantitative QTL by environment interaction. MTME was superior to ME and MT in the number of QTLs, the explained variance and accuracy of predictions. The large number of model parameters in the MTME approach was challenging and we propose several guidelines to help obtain a stable final QTL model. The results confirmed the feasibility and strengths of novel mixed model QTL methodology to study the architecture of complex traits.

Long-term effects of theta/beta neurofeedback on EEG power spectra in children with attention deficit hyperactivity disorder.

OBJECTIVE: Neurofeedback has been proposed as an effective alternative for pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD), with potentially long-term and delayed benefits. However, the specificity of such long-term behavioral improvements remains inconclusive and therefore additional research into the neurophysiological effects of neurofeedback is needed. We compared long-term effects of theta/beta neurofeedback (NFB) to methylphenidate (MPH) and physical activity (PA, semi-active control intervention) on electroencephalogram (EEG) power spectra. Based on the vigilance stabilization model, we hypothesized further reductions in theta and alpha power in the NFB compared to the control groups. METHOD: EEG power spectra (theta, alpha and beta) during resting and task conditions were recorded at pre-, post-intervention and 6-months follow-up in 67 children, aged 7-13 (NFB: n = 24, MPH: n = 23, or PA: n = 20). RESULTS: Analyses revealed no power spectra differences at follow-up between MPH and NFB (range p = .165-.905) and PA and NFB (range p = .172-.822). CONCLUSIONS: No evidence was found for the specificity of theta/beta NFB at follow-up. SIGNIFICANCE: This was the first study into long-term neurophysiological effects of theta/beta NFB. Future studies are encouraged to explore both specific and non-specific mechanisms of NFB. CLINICAL TRIALS REGISTRATION: Train Your Brain? Exercise and neurofeedback intervention for ADHD, https://clinicaltrials.gov/show/NCT01363544, Ref. No. NCT01363544.

Detection of quantitative trait loci in outbred populations with incomplete marker data.

Augmentation of marker genotypes for ungenotyped individuals is implemented in a Bayesian approach via the use of Markov chain Monte Carlo techniques. Marker data on relatives and phenotypes are combined to compute conditional posterior probabilities for marker genotypes of ungenotyped individuals. The presented procedure allows the analysis of complex pedigrees with ungenotyped individuals to detect segregating quantitative trait loci (QTL). Allelic effects at the QTL were assumed to follow a normal distribution with a covariance matrix based on known QTL position and identity by descent probabilities derived from flanking markers. The Bayesian approach estimates variance due to the single QTL, together with polygenic and residual variance. The method was empirically tested through analyzing simulated data from a complex granddaughter design. Ungenotyped dams were related to one or more sons or grandsires in the design. Heterozygosity of the marker loci and size of QTL were varied. Simulation results indicated a significant increase in power when ungenotyped dams were included in the analysis.

Cardiac reactivity and stimulant use in adolescents with autism spectrum disorders with comorbid ADHD versus ADHD.

A large number of youngsters with autism spectrum disorders (ASD) display comorbid attention deficit/hyperactivity disorder (ADHD) symptoms. However, previous studies are not conclusive whether psychophysiological correlates, like cardiac reactivity, are different for ASD with comorbid ADHD (ASD+) compared to ADHD. Therefore, the current study investigated (dis)similarities in cardiac reactivity and attention task performance. In a clinical sample, adolescents diagnosed with ASD+ (n = 20) versus ADHD (n = 36) and stimulant medication use (56 %) were compared during a baseline with eyes closed and task performance. Results for cardiac reactivity were similar for both diagnostic groups. Stimulant-medicated adolescents showed decreased adaptation of LF/HF ratio and faster reaction times than stimulant-free adolescents. The current study underlines the psychophysiological overlap of ADHD symptoms in adolescents with ASD+ and adolescents with ADHD.

Multiple QTL mapping in related plant populations via a pedigree-analysis approach.

QTL mapping experiments in plant breeding may involve multiple populations or pedigrees that are related through their ancestors. These known relationships have often been ignored for the sake of statistical analysis, despite their potential increase in power of mapping. We describe here a Bayesian method for QTL mapping in complex plant populations and reported the results from its application to a (previously analysed) potato data set. This Bayesian method was originally developed for human genetics data, and we have proved that it is useful for complex plant populations as well, based on a sensitivity analysis that was performed here. The method accommodates robustness to complex structures in pedigree data, full flexibility in the estimation of the number of QTL across multiple chromosomes, thereby accounting for uncertainties in the transmission of QTL and marker alleles due to incomplete marker information, and the simultaneous inclusion of non-genetic factors affecting the quantitative trait.

Scaling to account for heterogeneous variances in a Bayesian analysis of broiler quantitative trait loci.

A Bayesian method for QTL analysis that is capable of accounting for heterogeneity of variance between sexes, is introduced. The Bayesian method uses a parsimonious model that includes scaling parameters for polygenic and QTL allelic effects per sex. Furthermore, the method employs a reduced animal model to increase computational efficiency. Markov Chain Monte Carlo techniques were applied to obtain estimates of genetic parameters. In comparison with previous regression analyses, the Bayesian method 1) estimates dispersion parameters and polygenic effects, 2) uses individual observations instead of offspring averages, and 3) estimates fixed effect levels and covariates and heterogeneity of variance between sexes simultaneously with other parameters, taking uncertainties fully into account. Broiler data collected in a feed efficiency and a carcass experiment were used to illustrate QTL analysis based on the Bayesian method. The experiments were conducted in a population consisting of 10 full-sib families of a cross between two broiler lines. Microsatellite genotypes were determined on generation 1 and 2 animals and phenotypes were collected on third-generation offspring from mating members from different families. Chromosomal regions that seemed to contain a QTL in previous regression analyses and showed heterogeneity of variance were chosen. Traits analyzed in the feed efficiency experiment were BW at 48 d and growth, feed intake, and feed intake corrected for BW between 23 and 48 d. In the carcass experiment, carcass percentage was analyzed. The Bayesian method was successful in finding QTL in all regions previously detected.

Sensory integration in the rehabilitation of blind adults.

Learning difficulties displayed by the blind adult prompted an investigation of a link with sensory integrative dysfunction. A review of the literature provided evidence that tactile and vestibular deficiencies were prevalent within this population. Through observational assessment, sensory integrative dysfunction was identified in a number of clients and individual sensory integrative treatment programs were initiated. In the three case studies presented, improvements were noted in mobility, activities of daily living, handwriting, and behaviour after six months of treatment. A discussion is provided on those deficit areas responding to sensory integrative treatment.

Bayesian reanalysis of a quantitative trait locus accounting for multiple environments by scaling in broilers.

A Bayesian method was developed to handle QTL analyses of multiple experimental data of outbred populations with heterogeneity of variance between sexes for all random effects. The method employed a scaled reduced animal model with random polygenic and QTL allelic effects. A parsimonious model specification was applied by choosing assumptions regarding the covariance structure to limit the number of parameters to estimate. Markov chain Monte Carlo algorithms were applied to obtain marginal posterior densities. Simulation demonstrated that joint analysis of multiple environments is more powerful than separate single trait analyses of each environment. Measurements on broiler BW obtained from 2 experiments concerning growth efficiency and carcass traits were used to illustrate the method. The population consisted of 10 full-sib families from a cross between 2 broiler lines. Microsatellite genotypes were determined on generations 1 and 2, and phenotypes were collected on groups of generation 3 animals. The model included a polygenic correlation, which had a posterior mean of 0.70 in the analyses. The reanalysis agreed on the presence of a QTL in marker bracket MCW0058-LEI0071 accounting for 34% of the genetic variation in males and 24% in females in the growth efficiency experiment. In the carcass experiment, this QTL accounted for 19% of the genetic variation in males and 6% in females.

Markov chain Monte Carlo for mapping a quantitative trait locus in outbred populations.

A Bayesian approach is presented for mapping a quantitative trait locus (QTL) using the 'Fernando and Grossman' multivariate Normal approximation to QTL inheritance. For this model, a Bayesian implementation that includes QTL position is problematic because standard Markov chain Monte Carlo (MCMC) algorithms do not mix, i.e. the QTL position gets stuck in one marker interval. This is because of the dependence of the covariance structure for the QTL effects on the adjacent markers and may be typical of the 'Fernando and Grossman' model. A relatively new MCMC technique, simulated tempering, allows mixing and so makes possible inferences about QTL position based on marginal posterior probabilities. The model was implemented for estimating variance ratios and QTL position using a continuous grid of allowed positions and was applied to simulated data of a standard granddaughter design. The results showed a smooth mixing of QTL position after implementation of the simulated tempering sampler. In this implementation, map distance between QTL and its flanking markers was artificially stretched to reduce the dependence of markers and covariance. The method generalizes easily to more complicated applications and can ultimately contribute to QTL mapping in complex, heterogeneous, human, animal or plant populations.

Whole genome scan to detect chromosomal regions affecting multiple traits in dairy cattle.

Chromosomal regions affecting multiple traits (multiple trait quantitative trait regions or MQR) in dairy cattle were detected using a method based on results from single trait analyses to detect quantitative trait loci (QTL). The covariance between contrasts for different traits in single trait regression analysis was computed. A chromosomal region was considered an MQR when the observed covariance between contrasts deviated from the expected covariance under the null hypothesis of no pleiotropy or close linkage. The expected covariance and the confidence interval for the expected covariance were determined by permutation of the data. Four categories of traits were analyzed: production (5 traits), udder conformation (6 traits), udder health (2 traits), and fertility (2 traits). The analysis of a granddaughter design involving 833 sons of 20 grandsires resulted in 59 MQR (alpha = 0.01, chromosomewise). Fifteen MQR were found on Bos taurus autosome (BTA) 14. Four or more MQR were found on BTA 6, 13, 19, 22, 23, and 25. Eight MQR involving udder conformation and udder health and 4 MQR involving production traits and udder health were found. Five MQR were identified for combinations of fertility and udder conformation traits, and another 5 MQR were identified for combinations of fertility and production traits. For 22 MQR, the difference between the correlation attributable to the MQR and the overall genetic correlation was >0.60. Although the false discovery rate was relatively high (0.52), it was considered important to present these results to assess potential consequences of using these MQR for marker-assisted selection.

Conceptual priming in a generative problem-solving task.

Three experiments explored how participants solved a very open-ended generative problem-solving task. Previous research has shown that when participants are shown examples, novel creations will tend to conform to features shared across those examples (Smith, Ward, & Schumacher, 1993). We made the shared features of the examples conceptually related to one another. We found that when the features were related to the concept of hostility, participants' creations contained hostile features that were not part of any of the examples. These results suggest that participants will design novel entities to be consistent with emergent properties of examples shown to them. We also found that a mild hostility prime from unscrambling sentences had a similar conceptual effect. Together, the two effects suggest that conceptual priming of generative cognitive tasks will influence the cognitive aspects of the creative process.

Restricted maximum likelihood analysis of linkage between genetic markers and quantitative trait loci for a granddaughter design.

A REML for the estimation of location and variance of a single quantitative trait locus, together with polygenic and residual variance, is described for the analysis of a granddaughter design. The method is based on a mixed linear model that includes the allelic effects of the quantitative trait locus, which are assumed to be normally distributed. Information from four marker loci situated on a single chromosome was available to derive the covariances at the linked quantitative trait locus. A derivative-free algorithm is described that makes use of the specific structure of the granddaughter design. The procedure has been applied to simulated data for a granddaughter design with 50 grandsire families of 40 sires each. Error variance was 60, and total additive genetic variance equaled 40; the quantitative trait locus explained either 10 or 25% of the latter variance. The size of the marker bracket containing the quantitative trait locus was either 10 or 30 cM. The power of detecting the quantitative trait locus ranged from 19 to 99%. Estimates of total genetic variance and variance explained by the quantitative trait locus were found to be empirically unbiased. A small bias was found in location estimates, especially when markers were not fully informative. The accuracy of parameter estimates was greatly improved by the use of information from individual daughters.

A transmission/disequilibrium test approach to screen for quantitative trait loci in two selected lines of large white pigs.

Pedigree and marker data from a multiple-generation pig selection experiment have been analysed to screen for loci affecting quantitative traits (QTL). Pigs from a base population were selected either for low backfat thickness at fixed live weight (L-line) or high live weight at fixed age (F-line). Selection was based on single-trait own performance and DNA was available on selected individuals only. Genotypes for three marker loci with known positions on chromosome 4 were available. The transmission/disequilibrium test (TDT) was originally described in human genetics to test for linkage between a genetic marker and a disease-susceptibility locus, in the presence of association. Here, we adapt the TDT to test for linkage between a marker and QTL favoured by selection, and for linkage disequilibrium between them in the base population. The a priori unknown distribution of the test statistic under the null hypothesis, no linkage, was obtained via Monte Carlo simulation. Significant TDT statistics were found for markers AFABP and SW818 in the F-line, indicating the presence of a closely linked QTL affecting growth performance. In the L-line, none of the markers studied showed significance. This study emphasizes the potential of the TDT as a quick and simple approach to screen for QTL in situations where marker genotypes are available on selected individuals. The results suggest that previously identified QTL in crosses of genetically diverse breeds may also segregate in commercial selection lines.

The credibility of a source influences the rate of unconscious plagiarism.

Three experiments were conducted to investigate the relationship between the credibility of information and later unconscious plagiarism of that information. In each experiment, ideas concerning ways to reduce traffic accidents were presented from a more credible source (traffic planners) and a less credible source (college freshmen). After a distractor task, participants were asked to generate novel ways to reduce traffic accidents. In Experiments 1 and 2, unconscious plagiarism of ideas presented from the more credible source was greater than from the less credible source. In neither experiment was explicit memory for ideas from each source different in tests of source monitoring or free recall. However, the difference in unconscious plagiarism was eliminated in Experiment 3 by having participants generate the implications of ideas at study. The results are discussed in terms of the explicit factors that affect the incidence of unconscious plagiarism.

Hypertensive encephalopathy in a patient with neonatal thyrotoxicosis.

UNLABELLED: Neonatal hyperthyroidism may give rise to serious cardiovascular complications. A girl with severe thyrotoxicosis in whom hypertensive encephalopathy developed is described. CONCLUSION: Neonatal thyrotoxicosis can give rise to hypertension and may lead to hypertensive encephalopathy.