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Genome-wide association studies are used to identify common genetic variants that affect the structure of selected subcortical regions of the human brain; their identification provides insight into the causes of variability in brain development and may help to determine mechanisms of neuropsychiatric dysfunction. Genetic variants that alter brain development This genome-wide association study of 30,717 individuals identifies common genetic variants that affect the structure of selected subcortical regions of the brain known to be involved in functions associated with movement, learning, memory and motivation. The results provide insight into the causes of variability in human brain development and may help elucidate mechanisms of neuropsychiatric dysfunction. Of particular interest are six novel genetic loci influencing the volumes of the putamen, caudate nucleus and global head size. The highly complex structure of the human brain is strongly shaped by genetic influences 1 . Subcortical brain regions form circuits with cortical areas to coordinate movement 2 , learning, memory 3 and motivation 4 , and altered circuits can lead to abnormal behaviour and disease 2 . To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume 5 and intracranial volume 6 . These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10 −33 ; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

A high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis shows that although local regulatory interactions are frequent, long-range interactions are also very common; unexpectedly, most interactions appear unchanged between tissues and across development and are formed prior to gene expression, indicating that transcription initiates from preformed enhancer–promoter loops, which are associated with paused polymerase. Enhancer activity during embryogenesis Two papers in this issue of Nature examine the role of developmental enhancers in Drosophila melanogaster , an ideal model for the purpose, as it takes just 18 hours from egg laying to completion of embryogenesis and involves marked changes in transcription linked to changes in enhancer activity. Evgeny Kvon et al . systematically assayed the activity of more than 7,000 candidate enhancers. Nearly half of the tested genomic fragments are active in the embryo and display dynamic spatial patterns during development. Enhancer activity is matched to expression patterns of putative target genes and predictive cis -regulatory motifs are identified. Yad Ghavi-Helm et al . present a high-resolution map of enhancer three-dimensional contacts. They find that although there are many local regulatory interactions, long-range interactions are more common. Surprisingly, most interactions appear unchanged between tissues and across development. Thus, transcription initiates from preformed enhancer–promoter loops through release of paused polymerase. The study also implies that the general topology governing enhancer contacts is conserved from flies to humans. Developmental enhancers initiate transcription and are fundamental to our understanding of developmental networks, evolution and disease. Despite their importance, the properties governing enhancer–promoter interactions and their dynamics during embryogenesis remain unclear. At the β-globin locus, enhancer–promoter interactions appear dynamic and cell-type specific 1 , 2 , whereas at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed 3 , 4 . The extent to which preformed enhancer–promoter conformations exist at other, more typical, loci and how transcription is eventually triggered is unclear. Here we generated a high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis, covering two developmental stages and tissue contexts, at unprecedented resolution. Although local regulatory interactions are common, long-range interactions are highly prevalent within the compact Drosophila genome. Each enhancer contacts multiple enhancers, and promoters with similar expression, suggesting a role in their co-regulation. Notably, most interactions appear unchanged between tissue context and across development, arising before gene activation, and are frequently associated with paused RNA polymerase. Our results indicate that the general topology governing enhancer contacts is conserved from flies to humans and suggest that transcription initiates from preformed enhancer–promoter loops through release of paused polymerase.

Early enhancers revealed Identifying the genomic regulatory sequences, such as enhancers, that control early embryonic development remains a difficult challenge. Profiling of histone modifications and chromatin regulators in human embryonic stem cells now reveals unique signatures that are used to identify more than 2,000 putative enhancers. These enhancers are either active in the embryonic stem cells or are associated with early developmental genes. Identifying the genomic regulatory sequences, such as enhancers, that control early embryonic development remains a difficult challenge. Here, profiling of histone modifications and chromatin regulators in human embryonic stem cells (hESCs) reveals unique signatures that are used to identify over 2,000 putative enhancers. These enhancers are either active in the h ESCs or associated with early developmental genes. Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment 1 , 2 . However, identification of genomic sequences that control human embryonic development represents a formidable challenge 3 . Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term ‘poised enhancers’, are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.

Key Points A large fraction of genes in worms, flies and vertebrates express multiple mRNAs by alternative splicing. This produces extensive mRNA structural diversity that ultimately affects protein coding potential as well as mRNA cis -acting elements that are determinative for translation, mRNA stability and mRNA intracellular localization. Global analyses of alternative splicing regulation during periods of biological transition, such as during development, have revealed coordinated and conserved networks of alternative splicing. Several splicing regulatory networks controlled by individual RNA-binding proteins have been identified by combining recent advances in genome-wide analyses of alternative splicing with the identification of RNA binding sites in vivo . A high proportion of RNA-binding proteins that regulate alternative splicing are themselves regulated by alternative splicing and are subject to auto- and crossregulatory feedback. This type of regulation includes alternative splicing linked with nonsense-mediated decay (AS–NMD), which results in mRNA downregulation. Diverse physiological processes are regulated in a determinative fashion by alternative splicing patterns, including meiosis in budding yeast, neuronal arborization in the Drosophila melanogaster brain, and stem cell determination in vertebrates. The regulation of gene expression by alternative splicing is intricately linked with transcription, the epigenetic state of chromatin, and subsequent RNA processing events, such as 3′ end formation, mRNA export and mRNA translation efficiency. Recent transcriptomics studies have revealed extensive mRNA diversity generated by alternative splicing. An emerging theme is the existence of regulatory networks through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, involving robust and coordinated alternative splicing transitions. Genome-wide analyses of metazoan transcriptomes have revealed an unexpected level of mRNA diversity that is generated by alternative splicing. Recently, regulatory networks have been identified through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, which involve robust and coordinated alternative splicing transitions. The regulation of splicing in yeast, worms, flies and vertebrates affects a variety of biological processes. The functional classes of genes that are regulated by alternative splicing include both those with widespread homeostatic activities and those with cell-type-specific functions. Alternative splicing can drive determinative physiological change or can have a permissive role by providing mRNA variability that is used by other regulatory mechanisms.

\"Charles Darwin's On the Origin of Species appeared a little more than 150 years ago. Although Darwin had already been developing his theory for more than twenty years and others before him had advocated evolutionary views, the book was transformative and marked the beginning of the development of evolutionary biology. The story of the development of evolutionary theory over the last century and a half is fascinating and conceptually rich; it has involved repeated modification, clarification, experimentation and frustration. A Remarkable Journey: The Story of Evolution follows the theory of evolution along its captivating, often tortuous path--filled with intrigue and philosophical richness--from Darwin's original brilliant formulation to today's robust, vibrant and deeply explanatory principle. In many respects, the story of evolution documents the maturing of biological science; as the evolutionary biologist Theodosius Dobzhansky asserted in 1973, 'Nothing in biology makes sense except in the light of evolution.' A Remarkable Journey is a historical narrative of the discoveries, debates, experimentation and field work that became the evidential base on which the theory of evolution rests, of the systematic assembling of these into an elegant and powerful science, and of how it increasingly won over the biological and scientific communities. This considered and absorbing overview will provide all readers with an insight into the development of what most of us now take for granted as a basic--and beautiful--principle of life.\"--Dust jacket.

Stefan Mundlos, Darío Lupiáñez and colleagues investigate CNVs involving the regulatory landscape of IHH (Indian hedgehog), which cause craniosynostosis and synpolydactyly. Using genetic manipulation in mice, they show that Ihh is regulated by at least nine enhancers with individual tissue specificities and that duplications in this region can cause dose-dependent upregulation and also misexpression of Ihh . Copy number variations (CNVs) often include noncoding sequences and putative enhancers, but how these rearrangements induce disease is poorly understood. Here we investigate CNVs involving the regulatory landscape of IHH (encoding Indian hedgehog), which cause multiple, highly localized phenotypes including craniosynostosis and synpolydactyly 1 , 2 . We show through transgenic reporter and genome-editing studies in mice that Ihh is regulated by a constellation of at least nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. Consecutive deletions, resulting in growth defects of the skull and long bones, showed that these enhancers function in an additive manner. Duplications, in contrast, caused not only dose-dependent upregulation but also misexpression of Ihh , leading to abnormal phalanges, fusion of sutures and syndactyly. Thus, precise spatiotemporal control of developmental gene expression is achieved by complex multipartite enhancer ensembles. Alterations in the composition of such clusters can result in gene misexpression and disease.