EHMT2 suppresses the variation of transcriptional switches in the mouse embryo

EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–9.5 days of gestation. Using four-way comparisons between delayed and normal embryos we clarified what it takes to be normal and what it takes to develop. We identified differentially expressed genes, for example Hox genes that simply reflected the difference in developmental progression of wild type and the delayed mutant uterus-mate embryos. By comparing wild type and zygotic mutant embryos along the same developmental window we detected a role of EHMT2 in suppressing variation in the transcriptional switches. We identified transcription changes where precise switching during development occurred only in the normal but not in the mutant embryo. At the 6-somite stage, gastrulation-specific genes were not precisely switched off in the Ehmt2−/− zygotic mutant embryos, while genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on. The Ehmt2mat−/+ maternal mutant embryos displayed high transcriptional variation consistent with their variable survival. Variable derepression of transcripts occurred dominantly in the maternally inherited allele. Transcription was normal in the parental haploinsufficient wild type embryos despite their delay, consistent with their good prospects. Global profiling of transposable elements revealed EHMT2 targeted DNA methylation and suppression at LTR repeats, mostly ERVKs. In Ehmt2−/− embryos, transcription over very long distances initiated from such misregulated ‘driver’ ERVK repeats, encompassing a multitude of misexpressed ‘passenger’ repeats. In summary, EHMT2 reduced transcriptional variation of developmental switch genes and developmentally switching repeat elements at the six-somite stage embryos. These findings establish EHMT2 as a suppressor of transcriptional and developmental variation at the transition between gastrulation and organ specification.

The life cycle in late Paleozoic eryopid temnospondyls: developmental variation, plasticity and phylogeny

Eryopid temnospondyls were large apex predators in Carboniferous and Permian stream and lake habitats. The eryopid life cycle is exemplified by Onchiodon labyrinthicus from Niederhäslich (Saxony, Germany), which is represented by numerous size classes from small larvae to heavily ossified adults. Morphometric and principal component analyses provide new insights into ontogenetic changes in O. labyrinthicus, and comparison with adults of other eryopids documents phylogenetic patterns in the occupation of morphospace. Compared with small specimens of Sclerocephalus spp., immature O. labyrinthicus occupies a neighboring but much larger space, corresponding to a broader range of variation. Adults of Actinodon frossardi map with some juveniles of O. labyrinthicus, whereas other juveniles of the latter lie close to adults of O. thuringiensis, Glaukerpeton avinoffi and Osteophorus roemeri. Morphospace occupation of adult eryopids is partly consistent with cladistic tree topology, which gives the following branching pattern: Actinodon frossardi forms the basalmost eryopid, followed by Osteophorus roemeri, Glaukerpeton avinoffi and the genus Onchiodon (O. labyrinthicus + O. thuringiensis); then Clamorosaurus nocturnus; and finally the monophyletic genus Eryops. The presumably juvenile skull of Eryops anatinus falls well outside the domains of both adult eryopids and immature O. labyrinthicus, showing a unique combination of juvenile and adult features. Instead, Onchiodon langenhani and the Ruprechtice specimens referred to O. labyrinthicus map within the domain of immature O. labyrinthicus. Raised levels of variation in O. labyrinthicus coincide with evidence of a stressed habitat, in which limiting factors were fluctuating salinity, absence of fishes, enhanced competition and seasonal algal blooms. The documented broad variation was possibly caused by developmental plasticity responding to fluctuations in lake hydrology and nutrients in this small, short-lived water body.

What Is Social about Autism? The Role of Allostasis-Driven Learning

Scientific research on neuro-cognitive mechanisms of autism often focuses on circuits that support social functioning. However, autism is a heterogeneous developmental variation in multiple domains, including social communication, but also language, cognition, and sensory-motor control. This suggests that the underlying mechanisms of autism share a domain-general foundation that impacts all of these processes. In this Perspective Review, we propose that autism is not a social deficit that results from an atypical “social brain”. Instead, typical social development relies on learning. In social animals, infants depend on their caregivers for survival, which makes social information vitally salient. The infant must learn to socially interact in order to survive and develop, and the most prominent learning in early life is crafted by social interactions. Therefore, the most prominent outcome of a learning variation is atypical social development. To support the hypothesis that autism results from a variation in learning, we first review evidence from neuroscience and developmental science, demonstrating that typical social development depends on two domain-general processes that determine learning: (a) motivation, guided by allostatic regulation of the internal milieu; and (b) multi-modal associations, determined by the statistical regularities of the external milieu. These two processes are basic ingredients of typical development because they determine allostasis-driven learning of the social environment. We then review evidence showing that allostasis and learning are affected among individuals with autism, both neurally and behaviorally. We conclude by proposing a novel domain-general framework that emphasizes allostasis-driven learning as a key process underlying autism. Guided by allostasis, humans learn to become social, therefore, the atypical social profile seen in autism can reflect a domain-general variation in allostasis-driven learning. This domain-general view raises novel research questions in both basic and clinical research and points to targets for clinical intervention that can lower the age of diagnosis and improve the well-being of individuals with autism.

Developmental noise is an overlooked contributor to innate variation in psychological traits

Stochastic developmental variation is an additional important source of variance – beyond genes and environment – that should be included in considering how our innate psychological predispositions may interact with environment and experience, in a culture-dependent manner, to ultimately shape patterns of human behaviour.

Real age prediction from the transcriptome with RAPToR

Genome-wide gene expression profiling is a powerful tool for exploratory analyses, providing a high dimensional picture of the state of a biological system. However, uncontrolled variation among samples can obscure and confound the effect of variables of interest. Uncontrolled developmental variation is often a major source of unknown expression variation in developmental systems. Existing methods to sort samples from transcriptomes require many samples to infer developmental trajectories and only provide a relative pseudo-time.Here we present RAPToR (Real Age Prediction from Transcriptome staging on Reference), a simple computational method to estimate the absolute developmental age of even a single sample from its gene expression with up to minutes precision. We achieve this by staging samples on high-resolution reference developmental expression profiles we build from existing time series data. We implemented RAPToR for the most common animal model systems: nematode, fruit fly, zebrafish, and mouse, and demonstrate application for non-model organisms. We show how developmental variation discovered by RAPToR can be exploited to increase power to detect differential expression and to untangle the signal of perturbations of interest even when it is completely confounded with development. We anticipate our RAPToR post-profiling staging strategy will be especially useful in large scale single organism profiling because it eliminates the need for synchronization or for a tedious and potentially difficult step of accurate staging before profiling.

Experience-Driven Plasticity and the Emergence of Psychopathology: A Mechanistic Framework Integrating Development and the Environment into the Research Domain Criteria (RDoC) Model

Despite the clear importance of a developmental perspective for understanding the emergence of psychopathology across the life-course, such a perspective has yet to be integrated into the RDoC model. In this paper, we articulate a framework that incorporates developmentally-specific learning mechanisms that reflect experience-driven plasticity as additional units of analysis in the existing RDoC matrix. These include both experience-expectant learning mechanisms that occur during sensitive periods of development and experience-dependent learning mechanisms that may exhibit substantial variation across development. Incorporating these learning mechanisms allows for clear integration not only of development but also environmental experience into the RDoC model. We demonstrate how individual differences in environmental experiences—such as early-life adversity—can be leveraged to identify experience-driven plasticity patterns across development and apply this framework to consider how environmental experience shapes key biobehavioral processes that comprise the RDoC model. This framework provides a structure for understanding how affective, cognitive, social, and neurobiological processes are shaped by experience across development and ultimately contribute to the emergence of psychopathology. We demonstrate how incorporating an experience-driven plasticity framework is critical for understanding the development of many processes subsumed within the RDoC model, which will contribute to greater understanding of developmental variation in the etiology of psychopathology and can be leveraged to identify potential windows of heightened developmental plasticity when clinical interventions might be maximally efficacious.

High degree of non-genetic phenotypic variation in the vascular system of crayfish: a discussion of possible causes and implications

In this study, the hemolymph vascular system (HVS) in two cambarid crayfishes, i.e. the Marbled Crayfish, Procambarus virginalis Lyko, 2017 and the Spiny Cheek Crayfish, Faxonius limosus (Rafinesque, 1817), is investigated in regard of areas of non-genetic phenotypic variation. Despite their genetic identity, specimens of P. virginalis show variability in certain features of the HVS. Thus, we describe varying branching patterns, sporadic anastomoses, and different symmetry states in the vascular system of the marbled crayfish. We visualize our findings by application of classical and modern morphological methods, e.g. injection of casting resin, micro-computed tomography and scanning electron microscopy. By comparing our findings for P. virginalis to the vasculature in sexually reproducing crayfishes, i.e. F. limosus and Astacus astacus, we discuss phenotypic variation of the HVS in arthropods in general. We conclude that constant features of the HVS are hereditary, whereas varying states identified by study of the clonal P. virginalis must be caused by non-genetic factors and, that congruent variations in sexually reproducing F. limosus and A. astacus are likely also non-genetic phenotypic variations. Both common causal factors for non-genetic phenotypic variation, i.e., phenotypic plasticity and stochastic developmental variation are discussed along our findings regarding the vascular systems. Further aspects, such as the significance of non-genetic phenotypic variation for phylogenetic interpretations are discussed.

Developmental variation in testosterone:cortisol ratio alters cortical- and amygdala-based cognitive processes

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal–amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4–22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) covariance of the amygdala with CTh in visual and somatosensory areas. These brain parameters were in turn associated with lower verbal/executive function and higher spatial working memory. In sum, individual TC profiles may confer a particular brain phenotype and set of cognitive strengths and vulnerabilities, prior to adulthood.

The Structure of Developmental Variation in Early Childhood

Do children’s abilities develop in tandem or on their own separate timetables? Piaget proposed that development proceeded globally through stages; more recent theories view development as more modular with different abilities developing independently and on different time-scales. The developmental differentiation hypothesis suggests that the structure of a child’s development is unitary early in infancy but becomes more complex with age. Despite an abundance of theoretical interest in this question, there is little empirical work on the macrostructure of developmental changes in early childhood. We investigate this structure using two large datasets of parent-reported developmental milestones. Applying item response theory models, we find that variation in development across infancy and early childhood is multidimensional. Consistent with the differentiation hypothesis, differences among older children are better described by higher-dimensional models. In addition, in longitudinal data, we find that, within-person changes in underlying abilities are highly coupled early in life but their coupling decreases by age 12 months. Our work provides a model-based method for linking holistic descriptions of early development to basic theoretical questions about the nature of change in childhood.

Nature, Nurture, and Noise: Developmental Instability, Fluctuating Asymmetry, and the Causes of Phenotypic Variation

Phenotypic variation arises from genetic and environmental variation, as well as random aspects of development. The genetic (nature) and environmental (nurture) components of this variation have been appreciated since at least 1900. The random developmental component (noise) has taken longer for quantitative geneticists to appreciate. Here, I sketch the historical development of the concepts of random developmental noise and developmental instability, and its quantification via fluctuating asymmetry. The unsung pioneers in this story are Hugo DeVries (fluctuating variation, 1909), C. H. Danforth (random variation between monozygotic twins, 1919), and Sewall Wright (random developmental variation in piebald guinea pigs, 1920). The first pioneering study of fluctuating asymmetry, by Sumner and Huestis in 1921, is seldom mentioned, possibly because it failed to connect the observed random asymmetry with random developmental variation. This early work was then synthesized by Boris Astaurov in 1930 and Wilhelm Ludwig in 1932, and then popularized by Drosophila geneticists beginning with Kenneth Mather in 1953. Population phenogeneticists are still trying to understand the origins and behavior of random developmental variation. Some of the developmental noise represents true stochastic behavior of molecules and cells, while some represents deterministic chaos, nonlinear feedback, and symmetry breaking.