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1.
bioRxiv ; 2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37986891

RESUMO

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages.

2.
Science ; 382(6667): eade9516, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37824638

RESUMO

The cognitive abilities of humans are distinctive among primates, but their molecular and cellular substrates are poorly understood. We used comparative single-nucleus transcriptomics to analyze samples of the middle temporal gyrus (MTG) from adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets to understand human-specific features of the neocortex. Human, chimpanzee, and gorilla MTG showed highly similar cell-type composition and laminar organization as well as a large shift in proportions of deep-layer intratelencephalic-projecting neurons compared with macaque and marmoset MTG. Microglia, astrocytes, and oligodendrocytes had more-divergent expression across species compared with neurons or oligodendrocyte precursor cells, and neuronal expression diverged more rapidly on the human lineage. Only a few hundred genes showed human-specific patterning, suggesting that relatively few cellular and molecular changes distinctively define adult human cortical structure.


Assuntos
Cognição , Hominidae , Neocórtex , Lobo Temporal , Animais , Humanos , Perfilação da Expressão Gênica , Gorilla gorilla/genética , Hominidae/genética , Hominidae/fisiologia , Macaca mulatta/genética , Pan troglodytes/genética , Filogenia , Transcriptoma , Neocórtex/fisiologia , Especificidade da Espécie , Lobo Temporal/fisiologia
3.
Neuron ; 109(20): 3239-3251.e7, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34478631

RESUMO

Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Redes Reguladoras de Genes/genética , Animais , Evolução Biológica , Epigenômica , Evolução Molecular , Furões , Humanos , Macaca , Camundongos , Pan troglodytes
4.
Cell Host Microbe ; 26(2): 283-295.e8, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31415755

RESUMO

Despite substantial interest in the species diversity of the human microbiome and its role in disease, the scale of its genetic diversity, which is fundamental to deciphering human-microbe interactions, has not been quantified. Here, we conducted a cross-study meta-analysis of metagenomes from two human body niches, the mouth and gut, covering 3,655 samples from 13 studies. We found staggering genetic heterogeneity in the dataset, identifying a total of 45,666,334 non-redundant genes (23,961,508 oral and 22,254,436 gut) at the 95% identity level. Fifty percent of all genes were "singletons," or unique to a single metagenomic sample. Singletons were enriched for different functions (compared with non-singletons) and arose from sub-population-specific microbial strains. Overall, these results provide potential bases for the unexplained heterogeneity observed in microbiome-derived human phenotypes. One the basis of these data, we built a resource, which can be accessed at https://microbial-genes.bio.


Assuntos
Metagenoma/genética , Microbiota/genética , Microbiota/fisiologia , Bactérias/classificação , Bactérias/genética , Biodiversidade , Análise por Conglomerados , Impressões Digitais de DNA , Bases de Dados Factuais , Trato Gastrointestinal/microbiologia , Heterogeneidade Genética , Interações entre Hospedeiro e Microrganismos , Humanos , Metagenômica , Boca/microbiologia , Família Multigênica , Fenótipo
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