RESUMEN
The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Macaca mulatta/genética , Transcriptoma , Envejecimiento/genética , Animales , Trastorno del Espectro Autista/genética , Encéfalo/citología , Encéfalo/embriología , Adhesión Celular , Secuencia Conservada , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Microcefalia/genética , Neocórtex/embriología , Neocórtex/crecimiento & desarrollo , Neocórtex/metabolismo , Trastornos del Neurodesarrollo/genética , Neurogénesis/genética , Factores de Riesgo , Esquizofrenia/genética , Análisis Espacio-Temporal , Especificidad de la Especie , Transcripción Genética/genéticaRESUMEN
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of â¼900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography-the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
Asunto(s)
Anatomía Artística , Atlas como Asunto , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Transcriptoma/genética , Adulto , Animales , Encéfalo/citología , Calbindinas , Bases de Datos Genéticas , Dopamina/metabolismo , Salud , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Hibridación in Situ , Internet , Macaca mulatta/anatomía & histología , Macaca mulatta/genética , Masculino , Ratones , Neocórtex/anatomía & histología , Neocórtex/citología , Neocórtex/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Densidad Postsináptica/genética , ARN Mensajero/análisis , ARN Mensajero/genética , Proteína G de Unión al Calcio S100/genética , Especificidad de la EspecieRESUMEN
As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer's disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.