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bioRxiv2018

ClusterMap: Compare analysis across multiple Single Cell RNA-Seq profiling

Single cell RNA-Seq facilitates the characterization of cell type heterogeneity and developmental processes. Further study of single cell profiles across different conditions enables the understanding of biological processes and underlying mechanisms at the sub-population level. However, developing proper methodology to compare multiple scRNA-Seq datasets remains challenging. We have developed ClusterMap, a systematic method and workflow to facilitate the comparison of scRNA profiles across distinct biological contexts. Using hierarchical clustering of the marker genes of each sub-group, ClusterMap matches the sub-types of cells across different samples and provides \"similarity\" as a metric to quantify the quality of the match. We introduce a purity tree cut method designed specifically for this matching problem. We use Circos plot and regrouping method to visualize the results concisely. Furthermore, we propose a new metric \"separability\" to summarize sub-population changes among all sample pairs. In three case studies, we demonstrate that ClusterMap has the ability to offer us further insight into the different molecular mechanisms of cellular sub-populations across different conditions. ClusterMap is implemented in R and available at https://github.com/xgaoo/ClusterMap.

bioinformatics↗

bioRxiv2017

Identification of Cell States Using Super-Enhancer RNA

A new class of regulatory elements called super-enhancers, comprised of multiple neighboring enhancers, have recently been reported to be the key transcriptional drivers of cellular, developmental, and disease states. Here, we propose to define super-enhancer RNA as highly expressed enhancer RNAs that are transcribed from a cluster of localized genomic regions. Using the cap analysis of gene expression sequencing data from FANTOM5, we systematically explored the enhancer and messenger RNA landscapes in hundreds of different cell types in response to various environments. Applying non-negative matrix factorization (NMF) to super-enhancer RNA profiles, we found that different cell types were well classified. In addition, through the NMF of individual time-course profiles from a single cell-type, super-enhancer RNAs were clustered into several states with progressive patterns. We further investigated the enriched biological functions of the proximal genes involved in each pattern, and found that they were associated with the corresponding developmental process. The proposed super-enhancer RNAs can act as a good alternative, without the complicated measurement of histone modifications, for identifying important regulatory elements of cell type specification and identifying dynamic cell states.

systems biology↗

bioRxiv2017

T1 white/gray contrast as a predictor of chronological age, and an index of cognitive performance

The maturational schedule of human brain development appears to be narrowly confined. The chronological age of an individual can be predicted from brain images with considerable accuracy, and deviation from the typical pattern of brain maturation has been related to cognitive performance. Methods using multi-modal data, or complex measures derived from voxels throughout the brain have shown the greatest accuracy, but are difficult to interpret in terms of the biology. Measures based on the cortical surface(s) have yielded less accurate predictions, suggesting that perhaps developmental changes related to cortical gray matter are not strongly related to chronological age, and that perhaps development is more strongly related to changes in subcortical regions or in deep white matter. We show that a simple metric based on the white/gray contrast at the inner border of the cortical gray-matter is a comparably good predictor of chronological age, and our usage of an elastic net penalized linear regression model reveals the brain regions which contribute most to age-prediction. We demonstrate this in two large datasets: the NIH Pediatric Data, with 832 scans of typically developing children, adolescents, and young adults; and the Pediatric Imaging, Neurocognition, and Genetics data, with 760 scans of individuals in a similar age-range. Moreover, we show that the residuals of age-prediction based on this white/gray contrast metric are more strongly related to IQ than are those from cortical thickness, suggesting that this metric is more sensitive to aspects of brain development that reflect cognitive performance.

neuroscience↗

bioRxiv2018

A fast and cost-effective microsampling protocol incorporating reduced animal usage for time-series transcriptomics in rodent malaria parasites

The transcriptional regulation occurring in malaria parasites during the clinically important life stages within host erythrocytes can be studied in vivo with rodent malaria parasites propagated in mice. Time-series transcriptome profiling commonly involves the euthanasia of groups of mice at specific time points followed by the extraction of parasite RNA from whole blood samples. Current methodologies for parasite RNA extraction involve several steps and when multiple time points are profiled, these protocols are laborious, time consuming, and require the euthanisation of large cohorts of mice. We designed a simplified protocol for parasite RNA extraction from blood volumes as low as 20 microliters (microsamples), serially bled from mice via tail snips and directly lysed with TRIzol reagent. Gene expression data derived from microsampling using RNA-seq were closely matched to those derived from larger volumes of leucocyte-depleted and saponin-treated blood obtained from euthanized mice and also tightly correlated between biological replicates. Transcriptome profiling of microsamples taken at different time points during the intra-erythrocytic developmental cycle of the rodent malaria parasite Plasmodium vinckei revealed the transcriptional cascade commonly observed in malaria parasites. Microsampling is a quick, robust and cost-efficient approach to sample collection for in vivo time-series transcriptomic studies in rodent malaria parasites.

microbiology↗

bioRxiv2015

Selection for mitochondrial quality drives the evolution of sexes with a dedicated germline

The origin of the germline-soma distinction is a fundamental unsolved question. Plants and basal metazoans do not have a germline but generate gametes from somatic tissues (somatic gametogenesis), whereas most bilaterians sequester a germline. We develop an evolutionary model which shows that selection for mitochondrial quality drives germline evolution. In organisms with low mitochondrial mutation rates, segregation of mutations over multiple cell divisions generates variation, allowing selection to optimize gamete quality through somatic gametogenesis. Higher mutation rates promote early germline sequestration. Oogamy reduces mitochondrial segregation in early development, improving adult fitness by restricting variation between tissues, but also limiting variation between early-sequestered oocytes, undermining gamete quality. Oocyte variation is restored through proliferation and random culling (atresia) of precursor cells. We predict a novel pathway from basal metazoans lacking a germline to active bilaterians with early sequestration of large oocytes subject to atresia, allowing the emergence of complex developmental processes.

Evolutionary Biology↗

bioRxiv2018

Geometric morphometrics of nested symmetries: Hierarchical inter- and intra-individual variation in biological shapes

Symmetry is a pervasive feature of organismal shape and the focus of a large body of research in Biology. Here, we consider complex patterns of symmetry where a phenotype exhibits a hierarchically structured combination of symmetries. We extend the Procrustes ANOVA for the analysis of nested symmetries and the decomposition of the overall morphological variation into components of symmetry (among-individual variation) and asymmetry (directional and fluctuating asymmetry). We illustrate its use with the Aristotles lantern, the masticatory apparatus of regular sea urchins, a complex organ displaying bilateral symmetry nested within five-fold rotational symmetry. Our results highlight the importance of characterising the full symmetry of a structure with nested symmetries. Higher order rotational symmetry appears strongly constrained and developmentally stable compared to lower level bilateral symmetry. This contrast between higher and lower levels of asymmetry is discussed in relation to the spatial pattern of the lantern morphogenesis. This extended framework is applicable to any biological object exhibiting nested symmetries, regardless of their type (e.g., bilateral, rotational, translational). Such cases are extremely widespread in animals and plants, from arthropod segmentation to angiosperm inflorescence and corolla shape. The method therefore widens the research scope on developmental instability, canalization, developmental modularity and morphological integration.

evolutionary biology↗

bioRxiv2016

Dysregulation of Long Non-coding RNA (lncRNA) Genes and Predicted lncRNA-protein Interactions during Zika Virus Infection

Zika Virus (ZIKV) is a causative agent for poor pregnancy outcome and fetal developmental abnormalities, including microcephaly and eye defects. As a result, ZIKV is now a confirmed teratogen. Understanding host-pathogen interactions, specifically cellular perturbations caused by ZIKV, can provide novel therapeutic targets. In order to complete viral replication, viral pathogens control the host cellular machineries and regulate various factors, including long noncoding RNA (lncRNA) genes, at transcriptional levels. The role of lncRNA genes in the pathogenesis of ZIKV-mediated microcephaly and eye defects is currently unknown. To gain additional insights, we focused on profiling the differentially expressed lncRNA genes during ZIKV infection in mammalian cells. For this study, we employed a contemporary clinical Zika viral isolate, PRVABC59, of Asian genotype. We utilized an unbiased RNA sequencing approach to profile the lncRNA transcriptome in ZIKV infected Vero cells. We identified a total of 121 lncRNA genes that are differentially regulated at 48 hours post-infection. The majority of these genes are independently validated by reverse-transcription qPCR. A notable observation was that the lncRNAs, MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and NEAT1 (Nuclear Paraspeckle Assembly Transcript 1), are down-regulated upon Zika viral infection. MALAT1 and NEAT1 are known as nuclear localized RNAs that regulate gene expression and cell proliferation. Protein-lncRNA interaction maps revealed that MALAT1 and NEAT1 share common interacting partners and form a larger network comprising of 71 cellular factors. ZIKV-mediated dysregulation of these two regulatory lncRNAs can alter the expression of respective target genes and associated biological functions, an important one being cell division. In conclusion, this investigation is the first to provide insight into the biological connection of lncRNAs and ZIKV which can be further explored for developing antiviral therapy and understanding fetal developmental processes.

Microbiology↗

bioRxiv2018

Prenatal growth map of the mouse knee joint by mean of deformable registration technique

Joint morphogenesis is the process during which distinct and functional joint shapes emerge during pre- and post-natal joint development. In this study, a repeatable semi-automatic protocol capable of providing a 3D realistic developmental map of the prenatal mouse knee joint was designed by combining Optical Projection Tomography imaging (OPT) and a deformable registration algorithm (Sheffield Image Registration toolkit, ShIRT). Eleven left limbs of healthy murine embryos were scanned with OPT (voxel size: 14.63[1/4]m) at two different stages of development: Theiler stage (TS) 23 (approximately 14.5 embryonic days) and 24 (approximately 15.5 embryonic days). One TS23 limb was used to evaluate the precision of the displacement predictions for this specific case. The remaining limbs were then used to estimate Developmental Tibia and Femur Maps. Acceptable uncertainties of the displacement predictions were found for both epiphyses (between 0.7 and 1.4 m, along all directions and anatomical sites) for nodal spacing of 1 voxel. The protocol was found to be reproducible with maximum Modified Housdorff Distance differences equal to 1.9 m and 1.5 m for the tibial and femoral epiphyses respectively. The effect of the initial shape of the rudiment affected the developmental maps by 21.7 m and 21.9 m for the tibial and femoral epiphyses respectively, which correspond to 1.4 and 1.5 times the voxel size. To conclude, this study proposes a repeatable semi-automatic protocol capable of providing mean 3D realistic developmental map of a developing rudiment allowing researchers to study how growth and adaptation are directed by biological and mechanobiological factors.

bioengineering↗

bioRxiv2018

DevoWorm: data-theoretical synthesis of C. elegansdevelopment.

Biological development is often described as a dynamic, emergent process. This is evident across a variety of phenomena, from the temporal organization of cell types in the embryo to compounding trends that affect large-scale differentiation. To better understand this, we propose combining quantitative investigations of biological development with theory-building techniques. This provides an alternative to the gene-centric view of development: namely, the view that developmental genes and their expression determine the complexity of the developmental phenotype. Using the model system Caenorhabditis elegans, we examine time-dependent properties of the embryonic phenotype and utilize the unique life-history properties to demonstrate how these emergent properties can be linked together by data analysis and theory-building. We also focus on embryogenetic differentiation processes, and how terminally-differentiated cells contribute to structure and function of the adult phenotype. Examining embryogenetic dynamics from 200 to 400 minutes post-fertilization provides basic quantitative information on developmental tempo and process. To summarize, theory construction techniques are summarized and proposed as a way to rigorously interpret our data. Our proposed approach to a formal data representation that can provide critical links across life-history, anatomy and function.

systems biology↗

bioRxiv2018

Plasmodium falciparum mature schizont transcriptome variation among clinical isolates and laboratory-adapted clones

Malaria parasite genes exhibit variation in both sequence and expression level. There is much information on sequence polymorphism, but less resolution on natural variation in transcriptomes of parasites at specific developmental stages. This is largely because it is challenging to obtain highly replicated sampling of transcriptomes to overcome potentially confounding technical and biological variation. We address the issue in the major human parasite Plasmodium falciparum by obtaining RNA-seq profiles of multiple independent replicate preparations of mature schizont-stage parasites from a panel of clinical isolates recently established in culture and from long-term laboratory-adapted clones. With a goal of robustly identifying variably expressed genes, we show that increasing the numbers of biological sample replicates greatly improves the discovery rate. Generally, six independent replicates of each parasite culture is recommendable as being significantly to lower numbers, although for highly expressed genes variable expression can be detected when fewer replicates are available. A broad comparison identifies genes differing in relative expression between cultured clinical isolates and laboratory-adapted clones. Genes more highly expressed in the laboratory-adapted clones include an AP2 transcription factor gene Pf3D7_0420300 and putative methyl transferase genes. The variable expression of several known merozoite invasion ligands is confirmed, and previously uncharacterised genes are shown to be differentially expressed among clinical isolates. New RT-qPCR assays validate the variation in transcript levels of these genes, and allow quantitation of expression to be extended to a wider panel of clinical isolate samples. These variably expressed genes are new candidates for investigation as potential determinants of alternative parasite developmental pathways or targets of immunity.\n\nAuthor summaryUnderstanding parasite diversity and adaptation may require characterisation of gene expression variation, and is vital if chemotherapeutic or vaccine development is to consider new candidate targets, but it is technically challenging to generate precise data on clinical isolates. Here, we analyse the transcriptomes of mature Plasmodium falciparum schizonts using RNA-sequencing, using large numbers of biological replicate samples to minimise the impact of inter-replicate variation on observed patterns of differential expression. This identifies genes that are differentially expressed in long term laboratory-adapted parasites and recently cultured clinical isolates, as well as among different clinical isolates. In additional samples of schizonts grown in the first cycle ex vivo prior to any erythrocyte invasion, expression levels of a selected panel of these genes vary among isolates, but mean levels are similar to those in the continuously cultured clinical isolates, indicating that the latter are useful for experimental studies requiring biological replication.

cell biology↗

bioRxiv2018

Bacterial contribution to genesis of the novel germ line determinant oskar

New cellular functions and developmental processes can evolve by modifying existing genes or creating novel genes. Novel genes can arise not only via duplication or mutation but also by acquiring foreign DNA, also called horizontal gene transfer (HGT). Here we show that HGT likely contributed to the creation of a novel gene indispensable for reproduction in some insects. Long considered a novel gene with unknown origin, oskar has evolved to fulfil a crucial role in insect germ cell formation. Our analysis of over 100 insect Oskar sequences suggests that Oskar arose de novo via fusion of eukaryotic and prokaryotic sequences. This work shows that highly unusual gene origin processes can give rise to novel genes that can facilitate evolution of novel developmental mechanisms. One Sentence SummaryOur research shows that gene origin processes often considered highly unusual, including HGT and de novo coding region evolution, can give rise to novel genes that can both participate in pre-existing gene regulatory networks, and also facilitate the evolution of novel developmental mechanisms.

evolutionary biology↗

bioRxiv2026

MIND the gap: methodological considerations and guidance for structural MRI similarity network analysis with MIND

Structural similarity networks quantify the similarity of structural properties across cortical regions, providing a macroscopic window onto the organisation of cortical architecture. Morphometric inverse divergence (MIND) is a multivariate metric of similarity between cortical areas, based on the Kullback-Leibler (KL) divergence between areal distributions of multiple MRI features or morphometric variables locally measured at voxel or vertex resolution. MIND has demonstrated technical robustness and biological validity and is increasingly widely used as a measure of cortico-cortical similarity in clinical and developmental network neuroscience. Here we provide in-depth methodological background on KL divergence and MIND, highlighting possible sources of bias, critical user decision points in the design of a MIND processing pipeline, and recommendations for technical risk mitigation in using MIND as a metric of cortical similarity. We use simulated data and observational MRI datasets from adults (UK Biobank, N = 500 T1-weighted and diffusion scans) and neonates (Developing Human Connectome Project, N = 752 T2-weighted scans), to show how the estimator of KL divergence implemented in MIND is potentially influenced or biased by five properties of input MRI feature maps: (i) their smoothness; (ii) the proportion of identical values; (iii) analysis in native or common space and the choice of vertex mesh resolution; (iv) parcellation choice; and (v) covariance between input features. We offer principled and practical guidance for investigators wanting to specify and implement the MIND processing pipeline that is best suited to the constraints and opportunities of the MRI data available to them. These recommendations outline which pipeline steps should be used sparingly, such as vertex map smoothing; which should be used with informed caution, such as parcellation choice or vertex mesh resampling; and which could be newly implemented for more robust estimation of MIND, such as the use of principal component analysis to preprocess multivariate MRI features. To support further development of structural MRI similarity network analysis, and wider adoption of robust MIND methods, we also publish the code used to generate the results in this paper as an open resource.

neuroscience↗

bioRxiv2017

Dramatic evolution of body length due to post-embryonic changes in cell size in a newly discovered close relative of C. elegans

Understanding morphological diversity--and morphological constrainto--has been a central question in evolutionary biology since its inception. Nematodes of the genus Caenorhabditis, which contains the well-studied model system C. elegans, display remarkable morphological consistency in the face of extensive genetic divergence. Here, we provide a description of the broad developmental patterns of a recently discovered species, C. sp. 34, which was isolated from fresh figs in Okinawa and which is among the closest known relatives of C. elegans. C. sp. 34 displays an extremely large body size and can grow to be nearly twice as long as C. elegans and all other known members of the genus. Observations of the timing of developmental milestones reveal that C. sp. 34 develops about twice as slowly as C. elegans. Measurements of embryo and larval size show that the size difference between C. sp. 34 and C. elegans is largely due to post-embryonic events, particularly during the transition from larval to adult stages. This difference in size is not attributable to differences in germ line chromosome number or the number of somatic cells. The overall difference in body size is therefore largely attributable to changes in cell size via increased cytoplasmic volume. Because of its close relationship to C. elegans, the distinctness of C. sp. 34 provides an ideal system for the detailed analysis of evolutionary diversification. The context of over forty years of C. elegans developmental genetics also reveals clues into how natural selection and developmental constraint act jointly to promote patterns of morphological stasis and divergence in this group.

evolutionary biology↗

bioRxiv2017

Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories

Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole-genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate.\n\nHere, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data -runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)- are analyzed in relation to cognitive abilities (n=4183) and brain structure (n=516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort.\n\nThe findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition~ROH and cognition~PGRS associations obtained in this cohort may respectively evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient.\n\nNeuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia.

neuroscience↗

bioRxiv2015

An evolutionary hourglass of herbivore-induced transcriptomic responses in Nicotiana attenuata

Herbivore induced defences are robust, evolve rapidly and activated in plants when specific elicitors, frequently found in the herbivores oral secretions (OS) are introduced into wounds during attack. How these complex induced defences evolve remains unclear. Here, we show that herbivore-induced transcriptomic responses in a wild tobacco, Nicotiana attenuata, display an evolutionary hourglass: the pattern that characterises the transcriptomic evolution of embryogenesis in animals, plants, and fungi. While relatively young and rapidly evolving genes involved in signal perception and processing to regulate defence metabolite biosynthesis are recruited both early (1 h) and late (9-21 h) in the defence elicitation process, a group of highly conserved and older genes involved in transcriptomic regulation are activated in the middle stage (5 h). The appearance of the evolutionary hourglass architecture in both developmental and defence elicitation processes may reflect the importance of robustness and evolvability in the signalling of these important biological processes.

Evolutionary Biology↗

bioRxiv2017

Selection On Morphological Traits And Fluctuating Asymmetry By A Fungal Parasite In The Yellow Dung Fly

A Preprint reviewed and recommended by Peer Community Evolutionary Biology: http://dx.doi.org/10.24072/pci.evolbiol.100027\n\nEvidence for selective disadvantages of large body size remains scarce in general. Previous phenomenological studies of the yellow dung fly Scathophaga stercoraria have demonstrated strong positive sexual and fecundity selection on male and female size. Nevertheless, the body size of flies from a Swiss study population has declined by almost 10% from 1993 to 2009. Given substantial heritability of body size, this negative evolutionary response of an evidently positively selected trait suggests important selective factors being missed (e.g. size-selective predation or parasitism). A periodic epidemic outbreak of the fungus Entomophthora scatophagae allowedassessment of selection exerted by this parasite fatal to adult flies. Fungal infection varied over the season from ca. 50% in the cooler and more humid spring and autumn to almost 0% in summer. The probability of dying from fungal infection increased with adult body size. All infected females died before laying eggs, so there was no fungus impact on female fecundity beyond its impact on mortality. Large males showed the typical mating advantage in the field, but this pattern of positive sexual selection was nullified by fungal infection. Mean fluctuating asymmetry of paired appendages (legs, wings) did not affect the viability, fecundity or mating success of yellow dung flies in the field. This study demonstrates rare parasite-mediated disadvantages of large adult body size in the field. Reduced ability to combat parasites such as Entomophthora may be an immunity cost of large size in dung flies, although the hypothesized trade-off between fluctuating asymmetry, a presumed indicator of developmental instability and environmental stress, and immunocompetence was not found here.

evolutionary biology↗

bioRxiv2017

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

Some of the fastest evolving regions of the human genome are conserved non-coding elements with many human-specific DNA substitutions. These Human Accelerated Regions (HARs) are enriched nearby regulatory genes, and several HARs function as developmental enhancers. To investigate if this evolutionary signature is unique to humans, we quantified evidence of accelerated substitutions in conserved genomic elements across multiple lineages and applied this approach simultaneously to the genomes of five apes: human, chimpanzee, gorilla, orangutan, and gibbon. We find roughly similar numbers and genomic distributions of lineage-specific accelerated regions (linARs) in all five apes. In particular, apes share an enrichment of linARs in regulatory DNA nearby genes involved in development, especially transcription factors and other regulators. Many developmental loci harbor clusters of nonoverlapping linARs from multiple apes, suggesting that accelerated evolution in each species affected distinct regulatory elements that control a shared set of developmental pathways. Our statistical tests distinguish between GC-biased and unbiased accelerated substitution rates, allowing us to quantify the roles of different evolutionary forces in creating linARs. We find evidence of GC-biased gene conversion in each ape, but unbiased acceleration consistent with positive selection or loss of constraint is more common in all five lineages. It therefore appears that similar evolutionary processes created independent accelerated regions in the genomes of different apes, and that these lineage-specific changes to conserved non-coding sequences may have differentially altered expression of a core set of developmental genes across ape evolution.

evolutionary biology↗

bioRxiv2017

Frequent Non-random Shifts in the Temporal Sequence of Developmental Landmark Events during Fish Evolutionary Diversification

Morphological transformations can be generated by evolutionary changes in the sequence of developmental events. In this study, we examined the evolutionary dynamics of the developmental sequence on a macroevolutionary scale using the teleost. Using the information from previous reports describing the development of 31 species, we extracted the developmental sequences of 19 landmark events involving the formation of phylogenetically conserved body parts; we then inferred ancestral developmental sequences by two different parsimony-based methods--event-pairing (Jeffery, Bininda-Emonds, Coates & Richardson, 2002a) and continuous analysis (Germain & Laurin, 2009). The phylogenetic comparisons of these sequences revealed event-dependent heterogeneity in the frequency of sequence changes. Most of the sequence changes occurred as exchanges of temporally neighboring events. The phylogenetic analyses suggested that the ancestral species had experienced frequent changes in developmental sequences. Although the analyses showed that these heterochronic changes accumulated along phylogenic time, the precise distribution of the changes over the teleost phylogeny remains unclear due to technical limitations. Finally, this first comprehensive analysis of teleost developmental sequences will provide solid ground on which to elucidate the significance of developmental timing in animal morphological diversification.

evolutionary biology↗