Human nervous system development is an intricate and protracted process that requires precise spatiotemporal transcriptional regulation. We generated tissue-level and single-cell transcriptomic data ...from up to 16 brain regions covering prenatal and postnatal rhesus macaque development. Integrative analysis with complementary human data revealed that global intraspecies (ontogenetic) and interspecies (phylogenetic) regional transcriptomic differences exhibit concerted cup-shaped patterns, with a late fetal-to-infancy (perinatal) convergence. Prenatal neocortical transcriptomic patterns revealed transient topographic gradients, whereas postnatal patterns largely reflected functional hierarchy. Genes exhibiting heterotopic and heterochronic divergence included those transiently enriched in the prenatal prefrontal cortex or linked to autism spectrum disorder and schizophrenia. Our findings shed light on transcriptomic programs underlying the evolution of human brain development and the pathogenesis of neuropsychiatric disorders.
The transcriptome of every cell is orchestrated by the complex network of interaction between transcription factors (TFs) and their binding sites on DNA. Disruption of this network can result in many ...forms of organism malfunction but also can be the substrate of positive natural selection. However, understanding the specific determinants of each of these individual TF-DNA interactions is a challenging task as it requires integrating the multiple possible mechanisms by which a given TF ends up interacting with a specific genomic region. These mechanisms include DNA motif preferences, which can be determined by nucleotide sequence but also by DNA’s shape; post-translational modifications of the TF, such as phosphorylation; and dimerization partners and co-factors, which can mediate multiple forms of direct or indirect cooperative binding. Binding can also be affected by epigenetic modifications of putative target regions, including DNA methylation and nucleosome occupancy. In this review, we describe how all these mechanisms have a role and crosstalk in one specific family of TFs, the basic helix-loop-helix (bHLH), with a very conserved DNA binding domain and a similar DNA preferred motif, the E-box. Here, we compile and discuss a rich catalog of strategies used by bHLH to acquire TF-specific genome-wide landscapes of binding sites.
The human neonatal cerebellum is one-fourth of its adult size yet contains the blueprint required to integrate environmental cues with developing motor, cognitive and emotional skills into adulthood. ...Although mature cerebellar neuroanatomy is well studied, understanding of its developmental origins is limited. In this study, we systematically mapped the molecular, cellular and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics. We profiled functionally distinct regions and gene expression dynamics within cell types and across development. The resulting cell atlas demonstrates that the molecular organization of the cerebellar anlage recapitulates cytoarchitecturally distinct regions and developmentally transient cell types that are distinct from the mouse cerebellum. By mapping genes dominant for pediatric and adult neurological disorders onto our dataset, we identify relevant cell types underlying disease mechanisms. These data provide a resource for probing the cellular basis of human cerebellar development and disease.
The nervous system—in particular, the brain and its cognitive abilities—is among humans’ most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it ...differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations.
How does the human nervous system differ from those of closely related primates in terms of function, organization, and development?
Human herpesviruses 6-A and -B (HHV-6A, HHV-6B) are ubiquitous in human populations worldwide. These viruses have been associated with several diseases such as multiple sclerosis, Hodgkin's lymphoma ...or encephalitis. Despite of the need to understand the genetic diversity and geographic stratification of these viruses, the availability of complete viral sequences from different populations is still limited. Here, we present nine new inherited chromosomally integrated HHV-6 sequences from diverse geographical origin which were generated through target DNA enrichment on lymphoblastoid cell lines derived from healthy individuals. Integration with available HHV-6 sequences allowed the assessment of HHV-6A and -6B phylogeny, patterns of recombination and signatures of natural selection. Analysis of the intra-species variability showed differences between A and B diversity levels and revealed that the HHV-6B reference (Z29) is an uncommon sequence, suggesting the need for an alternative reference sequence. Signs of geographical variation are present and more defined in HHV-6A, while they appear partly masked by recombination in HHV-6B. Finally, we conducted a scan for signatures of selection in protein coding genes that yielded at least 6 genes (4 and 2 respectively for the A and B species) showing significant evidence for accelerated evolution, and 1 gene showing evidence of positive selection in HHV-6A.
Population demography and gene flow among African groups, as well as the putative archaic introgression of ancient hominins, have been poorly explored at the genome level.
Here, we examine 15 African ...populations covering all major continental linguistic groups, ecosystems, and lifestyles within Africa through analysis of whole-genome sequence data of 21 individuals sequenced at deep coverage. We observe a remarkable correlation among genetic diversity and geographic distance, with the hunter-gatherer groups being more genetically differentiated and having larger effective population sizes throughout most modern-human history. Admixture signals are found between neighbor populations from both hunter-gatherer and agriculturalists groups, whereas North African individuals are closely related to Eurasian populations. Regarding archaic gene flow, we test six complex demographic models that consider recent admixture as well as archaic introgression. We identify the fingerprint of an archaic introgression event in the sub-Saharan populations included in the models (~ 4.0% in Khoisan, ~ 4.3% in Mbuti Pygmies, and ~ 5.8% in Mandenka) from an early divergent and currently extinct ghost modern human lineage.
The present study represents an in-depth genomic analysis of a Pan African set of individuals, which emphasizes their complex relationships and demographic history at population level.
How the rich variety of neurons in the nervous system arises from neural stem cells is not well understood. Using single-cell RNA-sequencing and in vivo confirmation, we uncover previously ...unrecognized neural stem and progenitor cell diversity within the fetal mouse and human neocortex, including multiple types of radial glia and intermediate progenitors. We also observed that transcriptional priming underlies the diversification of a subset of ventricular radial glial cells in both species; genetic fate mapping confirms that the primed radial glial cells generate specific types of basal progenitors and neurons. The different precursor lineages therefore diversify streams of cell production in the developing murine and human neocortex. These data show that transcriptional priming is likely a conserved mechanism of mammalian neural precursor lineage specialization.
Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci ...may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci eQTLs) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
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•Whole-genome and RNA sequencing across human prefrontal cortex development•Gene-specific developmental trajectories characterize the late-fetal transition•Identification of constant, prenatal-predominant, and postnatal-predominant eQTLs•Integrated analysis implicates genes in loci associated with educational attainment
Werling et al. analyze gene expression across the span of human cerebral cortical development and profile the trajectories of individual genes, coordinated groups of genes, and their relationships to disorders. Integration of genetic variation identifies quantitative trait loci that implicate specific genes in loci associated with neuropsychiatric traits and disorders.
Composts are the products obtained after the aerobic degradation of different types of organic matter waste and can be used as substrates or substrate/soil amendments for plant cultivation. There is ...a small but increasing number of reports that suggest that foliar diseases may be reduced when using compost, rather than standard substrates, as growing medium. The purpose of this study was to examine the gene expression alteration produced by the compost to gain knowledge of the mechanisms involved in compost-induced systemic resistance. A compost from olive marc and olive tree leaves was able to induce resistance against Botrytis cinerea in Arabidopsis, unlike the standard substrate, perlite. Microarray analyses revealed that 178 genes were differently expressed, with a fold change cut-off of 1, of which 155 were up-regulated and 23 were down-regulated in compost-grown, as against perlite-grown plants. A functional enrichment study of up-regulated genes revealed that 38 Gene Ontology terms were significantly enriched. Response to stress, biotic stimulus, other organism, bacterium, fungus, chemical and abiotic stimulus, SA and ABA stimulus, oxidative stress, water, temperature and cold were significantly enriched, as were immune and defense responses, systemic acquired resistance, secondary metabolic process and oxireductase activity. Interestingly, PR1 expression, which was equally enhanced by growing the plants in compost and by B. cinerea inoculation, was further boosted in compost-grown pathogen-inoculated plants. Compost triggered a plant response that shares similarities with both systemic acquired resistance and ABA-dependent/independent abiotic stress responses.
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