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We have produced gene expression profiles of all 302 neurons of the C. elegans nervous system that match the single-cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses distinct codes of â¼23 neuropeptide genes and â¼36 neuropeptide receptors, delineating a complex and expansive "wireless" signaling network. To demonstrate the utility of this comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression and (2) reveal adhesion proteins with potential roles in process placement and synaptic specificity. Our expression data are available at https://cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity, and function throughout the C. elegans nervous system.
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Caenorhabditis elegans/metabolismo , Sistema Nervioso/metabolismo , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Colorantes Fluorescentes/metabolismo , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Larva/metabolismo , Neuronas/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Motivos de Nucleótidos/genética , RNA-Seq , Secuencias Reguladoras de Ácidos Nucleicos/genética , Transducción de Señal/genética , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
In a recent issue of Nature, Kanton et al. explore human brain evolution and development by profiling the single-cell transcriptomes and epigenomes of cerebral organoids derived from human, chimpanzee, and macaque stem cells. Their results reveal key molecular characteristics that differentiate humans and non-human primates at the earliest stages of brain development.
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Genómica , Organoides , Animales , Encéfalo , Humanos , Pan troglodytes , TranscriptomaRESUMEN
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.
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Evolución Biológica , Encéfalo/anatomía & histología , Encéfalo/fisiología , Sistema Nervioso/anatomía & histología , Sistema Nervioso/crecimiento & desarrollo , Animales , Encéfalo/citología , Regulación de la Expresión Génica , Lenguaje , Mutación , Proteínas del Tejido Nervioso/genética , Sistema Nervioso/citología , Fenómenos Fisiológicos del Sistema Nervioso , Primates/genética , Primates/fisiología , Especificidad de la EspecieRESUMEN
Primate genomics holds the key to understanding fundamental aspects of human evolution and disease. However, genetic diversity and functional genomics data sets are currently available for only a few of the more than 500 extant primate species. Concerted efforts are under way to characterize primate genomes, genetic polymorphism and divergence, and functional landscapes across the primate phylogeny. The resulting data sets will enable the connection of genotypes to phenotypes and provide new insight into aspects of the genetics of primate traits, including human diseases. In this Review, we describe the existing genome assemblies as well as genetic variation and functional genomic data sets. We highlight some of the challenges with sample acquisition. Finally, we explore how technological advances in single-cell functional genomics and induced pluripotent stem cell-derived organoids will facilitate our understanding of the molecular foundations of primate biology.
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Evolución Molecular , Genómica , Animales , Humanos , Genómica/métodos , Primates/genética , Genoma , Filogenia , Variación GenéticaRESUMEN
The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory1 and are thought to be altered in disorders such as autism2,3 and schizophrenia4,5. Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents6-9, the mechanisms that underlie the development of PFC-mediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function12-15, and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC-mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.
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Organogénesis , Corteza Prefrontal/embriología , Corteza Prefrontal/metabolismo , Tretinoina/metabolismo , Animales , Axones/metabolismo , Corteza Cerebral , Regulación hacia Abajo , Femenino , Humanos , Macaca mulatta , Masculino , Ratones , Pan troglodytes , Corteza Prefrontal/anatomía & histología , Corteza Prefrontal/citología , Receptores de Ácido Retinoico/deficiencia , Receptor gamma X Retinoide/deficiencia , Transducción de Señal , Sinapsis/metabolismo , Tálamo/anatomía & histología , Tálamo/citología , Tálamo/metabolismoRESUMEN
Herpesviruses are ubiquitous, genetically diverse DNA viruses, with long-term presence in humans associated with infrequent but significant pathology. Human leukocyte antigen (HLA) class I presents intracellularly derived peptide fragments from infected tissue cells to CD8+ T and natural killer cells, thereby directing antiviral immunity. Allotypes of highly polymorphic HLA class I are distinguished by their peptide binding repertoires. Because this HLA class I variation is a major determinant of herpesvirus disease, we examined if sequence diversity of virus proteins reflects evasion of HLA presentation. Using population genomic data from EpsteinBarr virus (EBV), human cytomegalovirus (HCMV), and VaricellaZoster virus, we tested whether diversity differed between the regions of herpesvirus proteins that can be recognized, or not, by HLA class I. Herpesviruses exhibit lytic and latent infection stages, with the latter better enabling immune evasion. Whereas HLA binding peptides of lytic proteins are conserved, we found that EBV and HCMV proteins expressed during latency have increased peptide sequence diversity. Similarly, latent, but not lytic, herpesvirus proteins have greater population structure in HLA binding than nonbinding peptides. Finally, we found patterns consistent with EBV adaption to the local HLA environment, with less efficient recognition of EBV isolates by high-frequency HLA class I allotypes. Here, the frequency of CD8+ T cell epitopes inversely correlated with the frequency of HLA class I recognition. Previous analyses have shown that pathogen-mediated natural selection maintains exceptional polymorphism in HLA residues that determine peptide recognition. Here, we show that HLA class I peptide recognition impacts diversity of globally widespread pathogens.
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Herpesviridae , Antígenos de Histocompatibilidad Clase I , Péptidos , Variación Genética , Herpesviridae/genética , Herpesviridae/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Péptidos/genéticaRESUMEN
The interaction between transcription factors (TFs) and DNA is the core process that determines the state of a cell's transcriptome [...].
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ADN , Factores de Transcripción , Sitios de Unión , Factores de Transcripción/metabolismo , Unión Proteica/genética , ADN/metabolismo , Variación Genética , Transcripción GenéticaRESUMEN
While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.
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Trastorno Autístico , Neuropéptidos , Animales , Trastorno Autístico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Corteza Cerebral/metabolismo , Humanos , Ratones , Neuronas/metabolismo , Neuropéptidos/metabolismo , Prosencéfalo/metabolismo , Factores de Transcripción/metabolismoRESUMEN
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.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , ADN/química , ADN/genética , ADN/metabolismo , Humanos , Unión Proteica , Activación TranscripcionalRESUMEN
Ancient genomic sequences have started to reveal the origin and the demographic impact of farmers from the Neolithic period spreading into Europe. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet. However, the limited data available from earlier hunter-gatherers preclude an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. Here we sequence an approximately 7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León, Spain, to retrieve a complete pre-agricultural European human genome. Analysis of this genome in the context of other ancient samples suggests the existence of a common ancient genomic signature across western and central Eurasia from the Upper Paleolithic to the Mesolithic. The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic times. Moreover, we provide evidence that a significant number of derived, putatively adaptive variants associated with pathogen resistance in modern Europeans were already present in this hunter-gatherer.
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Alelos , Fósiles , Inmunidad/genética , Pigmentación/genética , Población Blanca/genética , Agricultura/historia , Evolución Biológica , Cuevas , Color del Ojo/genética , Genoma Humano/genética , Genómica , Historia Antigua , Humanos , Intolerancia a la Lactosa/genética , Masculino , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Esqueleto , Pigmentación de la Piel/genética , España/etnologíaRESUMEN
Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.
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Variación Genética , Hominidae/genética , África , Animales , Animales Salvajes/genética , Animales de Zoológico/genética , Asia Sudoriental , Evolución Molecular , Flujo Génico/genética , Genética de Población , Genoma/genética , Gorilla gorilla/clasificación , Gorilla gorilla/genética , Hominidae/clasificación , Humanos , Endogamia , Pan paniscus/clasificación , Pan paniscus/genética , Pan troglodytes/clasificación , Pan troglodytes/genética , Filogenia , Polimorfismo de Nucleótido Simple/genética , Densidad de PoblaciónRESUMEN
PURPOSE: Although obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese-breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein-protein interaction (PPI) level between obese and non-obese patients. METHODS AND RESULTS: Gene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome. CONCLUSION: In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.
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Neoplasias de la Mama/genética , ADN-Topoisomerasas de Tipo II/genética , Quinasas Relacionadas con NIMA/genética , Obesidad/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Survivin/genética , Índice de Masa Corporal , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Etnicidad/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estadificación de Neoplasias , Obesidad/complicaciones , Obesidad/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Supervivencia sin Progresión , Mapas de Interacción de Proteínas/genética , Transcriptoma/genéticaRESUMEN
BACKGROUND: Whole genome re-sequencing data from dogs and wolves are now commonly used to study how natural and artificial selection have shaped the patterns of genetic diversity. Single nucleotide polymorphisms, microsatellites and variants in mitochondrial DNA have been interrogated for links to specific phenotypes or signals of domestication. However, copy number variation (CNV), despite its increasingly recognized importance as a contributor to phenotypic diversity, has not been extensively explored in canids. RESULTS: Here, we develop a new accurate probabilistic framework to create fine-scale genomic maps of segmental duplications (SDs), compare patterns of CNV across groups and investigate their role in the evolution of the domestic dog by using information from 34 canine genomes. Our analyses show that duplicated regions are enriched in genes and hence likely possess functional importance. We identify 86 loci with large CNV differences between dogs and wolves, enriched in genes responsible for sensory perception, immune response, metabolic processes, etc. In striking contrast to the observed loss of nucleotide diversity in domestic dogs following the population bottlenecks that occurred during domestication and breed creation, we find a similar proportion of CNV loci in dogs and wolves, suggesting that other dynamics are acting to particularly select for CNVs with potentially functional impacts. CONCLUSIONS: This work is the first comparison of genome wide CNV patterns in domestic and wild canids using whole-genome sequencing data and our findings contribute to study the impact of novel kinds of genetic changes on the evolution of the domestic dog.
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Variaciones en el Número de Copia de ADN , Perros/genética , Lobos/genética , Animales , Cruzamiento , Genómica , Duplicaciones Segmentarias en el Genoma , Análisis de Secuencia de ADNRESUMEN
Natural selection is crucial for the adaptation of populations to their environments. Here, we present the first global study of natural selection in the Hominidae (humans and great apes) based on genome-wide information from population samples representing all extant species (including most subspecies). Combining several neutrality tests we create a multi-species map of signatures of natural selection covering all major types of natural selection. We find that the estimated efficiency of both purifying and positive selection varies between species and is significantly correlated with their long-term effective population size. Thus, even the modest differences in population size among the closely related Hominidae lineages have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments. Most signatures of balancing and positive selection are species-specific, with signatures of balancing selection more often being shared among species. We also identify loci with evidence of positive selection across several lineages. Notably, we detect signatures of positive selection in several genes related to brain function, anatomy, diet and immune processes. Our results contribute to a better understanding of human evolution by putting the evidence of natural selection in humans within its larger evolutionary context. The global map of natural selection in our closest living relatives is available as an interactive browser at http://tinyurl.com/nf8qmzh.
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Hominidae/genética , Selección Genética , Alelos , Animales , Evolución Biológica , Bases de Datos de Ácidos Nucleicos , Evolución Molecular , Estudios de Asociación Genética , Variación Genética , Humanos/genética , Metagenómica/métodos , Polimorfismo Genético , Análisis de Secuencia de ADN/métodosRESUMEN
BACKGROUND: The rise of the primate lineage is accompanied by an outstanding emergence of microRNAs, small non-coding RNAs with a prominent role in gene regulation. In spite of their biological importance little is known about the way in which natural selection has influenced microRNAs in the human lineage. To study the recent evolutionary history of human microRNAs and to analyze the signatures of natural selection in genomic regions harbouring microRNAs we have investigated the nucleotide substitution rates of 1,872 human microRNAs in the human and chimpanzee lineages. RESULTS: We produced a depurated set of microRNA alignments of human, chimpanzee and orang-utan orthologs combining BLAT and liftOver and selected 1,214 microRNA precursors presenting optimal secondary structures. We classified microRNAs in categories depending on their genomic organization, duplication status and conservation along evolution. We compared substitution rates of the aligned microRNAs between human and chimpanzee using Tajima's Relative Rate Test taking orang-utan as out-group and found several microRNAs with particularly high substitution rates in either the human or chimpanzee branches. We fitted different models of natural selection on these orthologous microRNA alignments and compared them using a likelihood ratio test that uses ancestral repeats and microRNA flanking regions as neutral sequences. We found that although a large fraction of human microRNAs is highly conserved among the three species studied, significant differences in rates of molecular evolution exist among microRNA categories. Particularly, primate-specific microRNAs, which are enriched in isolated and single copy microRNAs, more than doubled substitution rates of those belonging to older, non primate-specific microRNA families. CONCLUSIONS: Our results corroborate the remarkable conservation of microRNAs, a proxy of their functional relevance, and indicate that a subset of human microRNAs undergo nucleotide substitutions at higher rates, which may be suggestive of the action of positive selection.
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MicroARNs/genética , Pan troglodytes/genética , Pongo/genética , Análisis de Secuencia de ARN/métodos , Sustitución de Aminoácidos , Animales , Evolución Molecular , Genoma Humano , Humanos , Funciones de Verosimilitud , MicroARNs/química , Modelos Genéticos , Tasa de Mutación , Selección GenéticaRESUMEN
The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explored the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identified risk genes expressed in brain organizers and sequential gene regulatory networks across corticogenesis revealing disease-specific critical phases, when NSCs are more vulnerable to gene dysfunctions, and converging signaling across multiple diseases. Moreover, we simulated the impact of risk transcription factor (TF) depletions on different neural cell types spanning the developing human neocortex and observed a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of newly generated autism-affected patient-derived NSCs in vitro revealed recurrent alterations of TFs orchestrating brain patterning and NSC lineage commitment. This work opens new perspectives to explore human brain dysfunctions at the early phases of development.
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Vast quantities of multi-omic data have been produced to characterize the development and diversity of cell types in the cerebral cortex of humans and other mammals. To more fully harness the collective discovery potential of these data, we have assembled gene-level transcriptomic data from 188 published studies of neocortical development, including the transcriptomes of ~30 million single-cells, extensive spatial transcriptomic experiments and RNA sequencing of sorted cells and bulk tissues: nemoanalytics.org/landing/neocortex. Applying joint matrix decomposition (SJD) to mouse, macaque and human data in this collection, we defined transcriptome dynamics that are conserved across mammalian neurogenesis and which elucidate the evolution of outer, or basal, radial glial cells. Decomposition of adult human neocortical data identified layer-specific signatures in mature neurons and, in combination with transfer learning methods in NeMO Analytics, enabled the charting of their early developmental emergence and protracted maturation across years of postnatal life. Interrogation of data from cerebral organoids demonstrated that while broad molecular elements of in vivo development are recapitulated in vitro, many layer-specific transcriptomic programs in neuronal maturation are absent. We invite computational biologists and cell biologists without coding expertise to use NeMO Analytics in their research and to fuel it with emerging data (carlocolantuoni.org).
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Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of hyperphosphorylated tau in neurons and glia. Primary tauopathies are not uncommon in humans but exceptional in other species. We evaluate the clinical, neuropathological, and genetic alterations related to tau pathology in 16 cats aged from 1 to 21 years with different clinical backgrounds. Interestingly, a 10-year-old female cat presented a six-year progressive history of mental status and gait abnormalities. The imaging study revealed generalized cortical atrophy. Due to the poor prognosis, the cat was euthanatized at the age of ten. Neuropathological lesions were characterized by massive neuronal loss with marked spongiosis and associated moderate reactive gliosis in the parietal cortex, being less severe in other areas of the cerebral cortex, and the loss of Purkinje cells of the cerebellum. Immunohistochemical methods revealed a 4R-tauopathy with granular pre-tangles in neurons and coiled bodies in oligodendrocytes. Deposits were recognized with several phospho-site antibodies (4Rtau, tau5, AT8, PFH, tau-P Thr181, tau-P-Ser 262, tau-P Ser 422) and associated with increased granular expression of active tau kinases (p38-P Thr180/Tyr182 and SAPK/JNK-P Thr138/Thr185). The genetic study revealed well-preserved coding regions of MAPT. No similar alterations related to tau pathology were found in the other 15 cats processed in parallel. To our knowledge, this is the first case reporting a primary 4R-tauopathy with severe cerebral and Purkinje cell degeneration in an adult cat with neurological signs starting at a young age.
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Comparative "omics" studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. Here, we performed multi-regional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry, then integrated these data with complementary glycotranscriptomic data. We found that in primates the brain N-glycome has evolved more rapidly than the underlying transcriptomic framework, providing a mechanism for generating additional diversity. We show that brain N-glycome evolution in hominids has been characterized by an increase in complexity and α(2-6)-linked N-acetylneuraminic acid along with human-specific cell-type expression of key glycogenes. Finally, by comparing the prenatal and adult human brain N-glycome, we identify region-specific neurodevelopmental pathways that lead to distinct spatial N-glycosylation profiles in the mature brain. One-Sentence Summary: Evolution of the human brain N-glycome has been marked by an increase in complexity and a shift in sialic acid linkage.