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Smith, S.

Publications and source records attributed to Smith, S..

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The effects of training population design on genomic prediction accuracy in wheat

Genomic selection offers several routes for increasing genetic gain or efficiency of plant breeding programs. In various species of livestock there is empirical evidence of increased rates of genetic gain from the use of genomic selection to target different aspects of the breeders equation. Accurate predictions of genomic breeding value are central to this and the design of training sets is in turn central to achieving sufficient levels of accuracy. In summary, small numbers of close relatives and very large numbers of distant relatives are expected to enable accurate predictions.\n\nTo quantify the effect of some of the properties of training sets on the accuracy of genomic selection in crops we performed an extensive field-based winter wheat trial. In summary, this trial involved the construction of 44 F2:4 bi- and triparental populations, from which 2992 lines were grown on four field locations and yield was measured. For each line, genotype data were generated for 25,000 segregating single nucleotide polymorphism markers. The overall heritability of yield was estimated to 0.65, and estimates within individual families ranged between 0.10 and 0.85. Within cross genomic prediction accuracies of yield BLUEs were 0.125 - 0.127 using two different cross-validation approaches, and generally increased with training set size. Using related crosses in training and validation sets generally resulted in higher prediction accuracies than using unrelated crosses. The results of this study emphasize the importance of the training set design in relation to the genetic material to which the resulting prediction model is to be applied.

genetics

Micro computed tomography as an accessible imaging platform for exploring organism development and human disease modeling

Understanding how events at the molecular and cellular scales contribute to tissue form and function is key to uncovering mechanisms driving animal development, physiology and disease. Elucidating these mechanisms has been enhanced through the study of model organisms and the use of sophisticated genetic, biochemical and imaging tools. Here we present an optimized method for non-invasive imaging of Drosophila melanogaster at high resolution using micro computed tomography (-CT). Our method allows for rapid processing of intact animals at any developmental stage, provides precise quantitative assessment of tissue size and morphology, and permits analysis of inter-organ relationships. We then use the power of -CT imaging to model human diseases through the characterization of microcephaly in the fly. Our work demonstrates that -CT is a versatile and accessible tool that complements standard imaging techniques, capable of uncovering novel biological mechanisms that have remained undocumented due to limitations of current methods.

developmental biology

Muscle nonshivering thermogenesis in a feral mammal

While small mammals and neonates are able to maintain an optimal body temperature (Tb) independent of ambient conditions by producing heat via nonshivering thermogenesis (NST) in the brown adipose tissue (BAT), larger mammals and other mammals lacking BAT were long believed to rely primarily on shivering and behavioural adaptations. However, recently, a second mechanism of NST was found in skeletal muscle that could play an important role in thermoregulation of such species. Muscle NST is independent of muscle contractions and produces heat based on the activity of an ATPase pump in the sarcoplasmic reticulum (SERCA1a) and controlled by the protein sarcolipin. To evaluate whether muscle NST could indeed play an important role in thermoregulation in species lacking BAT, we investigated the thermogenic capacities of new-born wild boar piglets. During cold exposure over the first 5 days of life, total heat production was improved while shivering intensity decreased, indicating an increasing contribution of NST. Sampling skeletal muscle tissue for analyses of SERCA activity as well as gene expression of SERCA1a and sarcolipin, we found an age-related increase in all three variables as well as in Tb. Hence, the improved thermogenesis during the development of wild boars is not due to shivering but explained by the observed increase in SERCA activity. Our results suggest that muscle NST may be the primary mechanism of heat production during cold stress in large mammals lacking BAT, strengthening the hypothesis that muscle NST has likely played an important role in the evolution of endothermy.

physiology

Using GPUs to accelerate computational diffusion MRI: From microstructure estimation to tractography and connectomes

The great potential of computational diffusion MRI (dMRI) relies on indirect inference of tissue microstructure and brain connections, since modelling and tractography frameworks map diffusion measurements to neuroanatomical features. This mapping however can be computationally highly expensive, particularly given the trend of increasing dataset sizes and the complexity in biophysical modelling. Limitations on computing resources can restrict data exploration and methodology development. A step forward is to take advantage of the computational power offered by recent parallel computing architectures, especially Graphics Processing Units (GPUs). GPUs are massive parallel processors that offer trillions of floating point operations per second, and have made possible the solution of computationally-intensive scientific problems that were intractable before. However, they are not inherently suited for all problems. Here, we present two different frameworks for accelerating dMRI computations using GPUs that cover the most typical dMRI applications: a framework for performing biophysical modelling and microstructure estimation, and a second framework for performing tractography and long-range connectivity estimation. The former provides a front-end and automatically generates a GPU executable file from a user-specified biophysical model, allowing accelerated non-linear model fitting in both deterministic and stochastic ways (Bayesian inference). The latter performs probabilistic tractography, it can generate whole-brain connectomes and supports new functionality for imposing anatomical constraints, such as inherent consideration of surface meshes (GIFTI files) along with volumetric images. We validate the frameworks against well-established CPU-based implementations and we show that despite the very different challenges for parallelising these problems, GPU-based designs can offer accelerations of more than two orders of magnitude in both cases.

neuroscience

NOTCH-mediated non-cell autonomous regulation of chromatinstructure during senescence

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. In addition to autocrine and paracrine signalling mediated by factors of the senescence-associated secretory phenotype, we have recently identified that NOTCH1 can drive lateral induction of a unique form of senescence in adjacent cells through specific induction of the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure both autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells in culture exhibit a massive increase in nucleosome-free regions (NRFs). NOTCH signalling suppresses both SAHF and NFR formation in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, also drive similar chromatin architectural changes in adjacent cells through cell-cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in a range of human cancers. Thus, HMGA1 is involved not only in SAHFs, but also RIS-specific NFR formation. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.

cell biology

Model reduction permits Turing instability analysis of arbitrary reaction-diffusion models

Synthesising a genetic network which generates stable Turing patterns is one of the great challenges of synthetic biology, but a significant obstacle is the disconnect between the mathematical theory and the biological reality. Current mathematical understanding of patterning is typically restricted to systems of 2 or 3 chemical species, for which equations are tractable, but plausible genetic networks typically consist of dozens of interacting species. In this article, we suggest a method for reducing large biochemical systems to systems with 2 or 3 species which can then be studied analytically. We provide conditions to guarantee that the full system forms patterns if the reduced system does, and vice-versa. We confirm our technique with 3 examples: the Brusselator, an example proposed by Turing, and a biochemically plausible patterning system consisting of 17 species. These examples show that our method significantly simplifies the study of pattern formation in large systems.

synthetic biology

The genetic basis of human brain structure and function: 1,262 genome-wide associations found from 3,144 GWAS of multimodal brain imaging phenotypes from 9,707 UK Biobank participants

The genetic basis of brain structure and function is largely unknown. We carried out genome-wide association studies of 3,144 distinct functional and structural brain imaging derived phenotypes in UK Biobank (discovery dataset 8,428 subjects). We show that many of these phenotypes are heritable. We identify 148 clusters of SNP-imaging associations with lead SNPs that replicate at p<0.05, when we would expect 21 to replicate by chance. Notable significant and interpretable associations include: iron transport and storage genes, related to changes in T2* in subcortical regions; extracellular matrix and the epidermal growth factor genes, associated with white matter micro-structure and lesion volume; genes regulating mid-line axon guidance development associated with pontine crossing tract organisation; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide new insight into the genetic architecture of the brain with relevance to complex neurological and psychiatric disorders, as well as brain development and aging. The full set of results is available on the interactive Oxford Brain Imaging Genetics (BIG) web browser.

genetics

Membrane bending begins at any stage of clathrin-coat assembly and defines endocytic dynamics

Summary ParagraphClathrin-mediated endocytosis internalizes membrane from the cell surface by reshaping flat regions of membrane into spherical vesicles(1, 2). The relationship between membrane bending and clathrin coatomer assembly has been inferred from electron microscopy and structural biology, without directly visualization of membrane bending dynamics (3-6). This has resulted in two distinct and opposing models for how clathrin bends membrane (7-10). Here, polarized Total Internal Reflection Fluorescence microscopy was improved and combined with electron microscopy, atomic force microscopy, and super-resolution imaging to measure membrane bending during endogenous clathrin and dynamin assembly in living cells. Surprisingly, and not predicted by either model, the timing of membrane bending was variable relative to clathrin assembly. Approximately half of the time, membrane bending occurs at the start of clathrin assembly, in the other half, the onset of membrane bending lags clathrin arrival, and occasionally completely assembled flat clathrin transitions into a pit. Importantly, once the membrane bends, the process proceeds to scission with similar timing. We conclude that the pathway of coatomer formation is versatile and can bend the membrane during or after the assembly of the clathrin lattice. These results highlight the heterogeneity in this fundamental biological process, and provide a more complete nanoscale view of membrane bending dynamics during endocytosis.

cell biology

Improved Transcriptome Sampling Pinpoints 26 Paleopolyploidy Events In Caryophyllales, Including Two Paleo-Allopolyploidy Events

O_LIStudies of the macroevolutionary legacy of paleopolyploidy are limited by an incomplete sampling of these events across the tree of life. To better locate and understand these events, we need comprehensive taxonomic sampling as well as homology inference methods that accurately reconstruct the frequency and location of gene duplications.\nC_LIO_LIWe assembled a dataset of transcriptomes and genomes from 169 species in Caryophyllales, of which 43 were newly generated for this study, representing one of the densest sampled genomic-scale datasets yet available. We carried out phylogenomic analyses using a modified phylome strategy to reconstruct the species tree. We mapped phylogenetic distribution of paleopolyploidy events by both tree-based and distance-based methods, and explicitly tested scenarios for paleo-allopolyploidy.\nC_LIO_LIWe identified twenty-six paleopolyploidy events distributed throughout Caryophyllales, and using novel techniques inferred two to be paleo-allopolyploidy.\nC_LIO_LIThrough dense phylogenomic sampling, we show the propensity of paleo-polyploidy in the clade Caryophyllales. We also provide the first method for utilizing transcriptome data to detect paleo-allopolyploidy, which is important as it may have different macro-evolutionary implications compared to paleo-autopolyploidy.\nC_LI

evolutionary biology

Disparity, Diversity, And Duplications In The Caryophyllales

O_LIThe role whole genome duplication (WGD) plays in the history of lineages is actively debated. WGDs have been associated with advantages including superior colonization, various adaptations, and increased effective population size. However, the lack of a comprehensive mapping of WGDs within a major plant clade has led to uncertainty regarding the potential association of WGDs and higher diversification rates.\nC_LIO_LIUsing seven chloroplast and nuclear ribosomal genes, we constructed a phylogeny of 5,036 species of Caryophyllales, representing nearly half of the extant species. We phylogenetically mapped putative WGDs as identified from analyses on transcriptomic and genomic data and analyzed these in conjunction with shifts in climatic niche and lineage diversification rate.\nC_LIO_LIThirteen putative WGDs and twenty-seven diversification shifts could be mapped onto the phylogeny. Of these, four WGDs were concurrent with diversification shifts, with other diversification shifts occurring at more recent nodes than WGDs. Five WGDs were associated with shifts to colder climatic niches.\nC_LIO_LIWhile we find that many diversification shifts occur after WGDs it is difficult to consider diversification and duplication to be tightly correlated. Our findings suggest that duplications may often occur along with shifts in either diversification rate, climatic niche, or rate of evolution.\nC_LI

evolutionary biology

The development of scientific consensus: analyzing conflict and concordance among Avian phylogenies

Recent developments in phylogenetic methods and data acquisition have allowed for the construction of large and comprehensive phylogenetic relationships. Published phylogenies represent an enormous resource that not only facilitate the resolution of questions related to comparative biology, but also provide a resource on which to gauge the development of consensus across the tree of life. From the Open Tree of Life, we gathered 290 avian phylogenies representing all major groups that have been published over the last few decades and analyzed how concordance and conflict develop among these trees through time. Nine large scale backbone trees (including a new synthetic tree from this study) were used for the consensus assessment. We found that conflicts were over-represented both along the backbone (higher-level neoavian relationships) and within the oscine Passeriformes. Importantly, although we have made major strides in our knowledge of major clades, recent published comprehensive trees, as well as trees of individual clades, continue to contribute significantly to the resolution of clades in the avian phylogeny. These findings are somewhat unexpected, given that birds constitute a relatively well-studied and small clade of the tree of life (i.e., Aves). Therefore, our analysis highlights that much work is still needed before we can confidently resolve the less well studied areas of the tree of life.

evolutionary biology

So many genes, so little time: comments on divergence-time estimation in the genomic era

Phylogenomic datasets have been successfully used to address questions involving evolutionary relationships, patterns of genome structure, signatures of selection, and gene and genome duplications. However, despite the recent explosion in genomic and transcriptomic data, the utility of these data sources for efficient divergence-time inference remains unexamined. Phylogenomic datasets pose two distinct problems for divergence-time estimation: (i) the volume of data makes inference of the entire dataset intractable, and (ii) the extent of underlying topological and rate heterogeneity across genes makes model mis-specification a real concern. \"Gene shopping\", wherein a phylogenomic dataset is winnowed to a set of genes with desirable properties, represents an alternative approach that holds promise in alleviating these issues. We implemented an approach for phylogenomic datasets (available in SortaDate) that filters genes by three criteria: (i) clock-likeness, (ii) reasonable tree length (i.e., discernible information content), and (iii) least topological conflict with a focal species tree (presumed to have already been inferred). Such a winnowing procedure ensures that errors associated with model (both clock and topology) mis-specification are minimized, therefore reducing error in divergence-time estimation. We demonstrated the efficacy of this approach through simulation and applied it to published animal (Aves, Diplopoda, and Hymenoptera) and plant (carnivorous Caryophyllales, broad Caryophyllales, and Vitales) phylogenomic datasets. By quantifying rate heterogeneity across both genes and lineages we found that every empirical dataset examined included genes with clock-like, or nearly clock-like, behavior. Moreover, many datasets had genes that were clock-like, exhibited reasonable evolutionary rates, and were mostly compatible with the species tree. We identified overlap in age estimates when analyzing these filtered genes under strict clock and uncorrelated lognormal (UCLN) models. However, this overlap was often due to imprecise estimates from the UCLN model. We find that \"gene shopping\" can be an efficient approach to divergence-time inference for phylogenomic datasets that may otherwise be characterized by extensive gene tree heterogeneity.

evolutionary biology