Biology subjects

Moriano, J.

Publications and source records attributed to Moriano, J..

8 recordsLinked to original sources

bioRxiv2026

A multimodal interrogation of Broca's area in the pediatric and adult human brain

Language is a defining trait of our species, and disruptions in language acquisition can have profound consequences to the individuals affected. Uncovering the neurodevelopmental basis of this complex trait requires detailed molecular and cellular insights into the neocortical areas that support linguistic abilities. Here we performed joint gene expression and chromatin accessibility profiling at single-nucleus resolution (10x Genomics Single cell Multiome) and spatial transcriptomic profiling (Xenium high-plex in situ spatial transcriptomics) of Brocas area alongside adjacent motor cortical areas. We profiled individuals from different ancestries (European and African) and developmental stages (infancy, childhood, adolescence, and adulthood). We provide a high-resolution dissection of the cellular and molecular architecture of Brocas and motor cortical areas across early life stages and anchor the trajectories to the cellular states found in the adult human brain. We identify distinct area- and stage-specific cellular signatures, including a prominent role of glia populations and interneuron subtypes contributing to cytoarchitectonic specializations. Using longitudinal single cell spatial transcriptomic profiling, we orthogonally validate our consensus cell taxonomy and spatially resolve layer enrichment of neuronal and astrocyte subtypes that distinguish Brocas area and motor cortex. We also uncover cell type-specific molecular signatures that distinguish cell developmental trajectories in these cortical areas, including an early molecular code established by differential expression of cadherin genes that might contribute to area-specific intercellular communication. We also identify cell type-specific vulnerabilities to language- related neurodevelopmental and neuropsychiatric disorders, with selective susceptibility of particular somatostatin-positive interneuron subtypes to ASD/ADHD. Finally, evolutionary analysis of differentially accessible regions between Brocas area and motor cortex suggests that genetic mutations that might have contributed to the emergence of linguistic abilities accumulated over the course of million years following the divergence of human and chimpanzee lineages. Together, our study provides a comprehensive molecular, cellular and spatial definition of Brocas area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Benchmarking cerebellar organoids to model autism spectrum disorder and human brain evolution

While cortical organoids have been used to model different facets of neurodevelopmental conditions and human brain evolution, cerebellar organoids have not yet featured so prominently in the same context, despite increasing evidence of this brain regions importance for cognition and behavior. Here, we provide a longitudinal characterization of cerebellar organoids benchmarked against human fetal data and identify at very early stages of development a significant number of dynamically expressed genes relevant for neurodevelopmental conditions such as autism and attention deficit hyperactivity disorders. Then, we model an ASD mutation impacting CHD8, showing both granule cell and oligodendrocyte lineages prominently affected, resulting in altered network activity in more mature organoids. Lastly, using CRISPR/Cas9 editing, we also model an evolution-relevant mutation in a regulatory region of the CADPS2 gene. We investigate the effect of the derived allele exclusive to Homo sapiens, identifying a rerouting of the CADPS2-expression in rhombic lip cells, coupled with a different sensitivity to hypoxia which in turn lead to a differential timing of granule cell differentiation. HIGHLIGHTSO_LILongitudinal characterization of cerebellar organoids uncovers disorder related genes especially at early stages of development C_LIO_LIMutation in CHD8 alter rhombic lip and oligodendrocytes differentiation via WNT pathway C_LIO_LIRerouting of CADPS2 expression, delaying differentiation and migration, in recent human evolution C_LI IN BRIEFAprile and colleagues longitudinally profiled cerebellar organoids, benchmarking them against a fetal human atlas and identified a highly dynamic expression of genes related to cognitive and behavioral disorders especially at early stages of differentiation. Organoids were used to model the impact of a high-penetrance mutation associated with autism spectrum disorder and a high-frequency derived allele in Homo sapiens predicted to have played a role in recent brain evolution.

neuroscience↗

bioRxiv2025

Regulatory logic of human cortex evolution by combinatorial perturbations

Comparative genomic studies between contemporary and extinct hominins revealed key evolutionary modifications, but their number has hampered a system level investigation of their combined roles in scaffolding modern traits. Through multi-layered integration we selected 15 genes carrying nearly fixed sapiens-specific protein-coding mutations and developed a scalable design of combinatorial CRISPR-Cas9 bidirectional perturbations to uncover their regulatory hierarchy in cortical brain organoids. Interrogating the effects of overexpression and downregulation for all gene pairs in all possible combinations, we defined their impact on transcription and differentiation and reconstructed their regulatory architecture. We uncovered marked cell type-specific effects, including the promotion of alternative fates and the emergence of interneuron populations, alongside a core subnetwork comprising KIF15, NOVA1, RB1CC1 and SPAG5 acting as central regulator across cortical cell types.

systems biology↗

bioRxiv2023

A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution

The definition of molecular and cellular mechanisms contributing to evolutionary divergences in brain ontogenetic trajectories is essential to formulate hypotheses about the emergence of our species. Yet the functional dissection of evolutionary modifications derived in the Homo sapiens lineage at an appropriate level of granularity remains particularly challenging. Capitalizing on recent single-cell sequencing efforts that have massively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework in which we perform (i) trajectory inference and gene regulatory network reconstruction, (ii) (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and (iii) paleogenomic analysis for a higher-resolution mapping of the regulatory landscape where our species acquired derived mutations in comparison to our closest relatives. We provide evidence for cell type-specific activation and regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a zinc-finger transcription factor, KLF6, as a key regulator of a cholesterol metabolic program specifically in outer radial glia. Our strategy allows us to further probe whether the (semi)discrete gene expression programs identified have been under selective pressures in our species lineage. A cartography of the regulatory landscape impacted by Homo sapiens-derived transcription factor binding site disruptions reveals signals of selection clustering around regulatory regions associated with GLI3, a well-known regulator of the radial glial cell cycle. As a whole, our study contributes to the evidence of significant changes impacting metabolic pathways in recent human brain evolution.

evolutionary biology↗

bioRxiv2021

Human-derived alleles in SOST and RUNX2 3'UTRs cause differential regulation in a bone cell-line model

The inquiry into the phenotypic features that set apart human species, such as a light, gracile skeleton and a rounded skull characteristic of Homo sapiens, can now benefit from the examination of ancient genomes. These have added a new layer of analysis allowing the identification of genetic differences between species like ours and our closest extinct relatives. Most of these genetic differences are non-coding changes with unknown functional consequences, and dissecting their putative regulatory effect remains challenging. Here we focus on the three prime untranslated regions (3UTR), known to play a critical role in messenger RNA regulation and a plausible locus for divergent regulation between Homo species. We report a set of genes with derived 3UTR changes in either the Homo sapiens or the Neanderthal/Denisovan lineages and experimentally evaluate the impact of 3UTR variants in four genes: E2F6, GLI3, RUNX2 and SOST. We performed a luciferase reporter assay in a bone cell-line model and found a statistically significant difference for the 3UTR variants of SOST (Homo sapiens-derived) and RUNX2 (Neanderthal/Denisovan-derived). The differential expression caused by these variants in our experimental model points to species differences in bone mineral density. Thus, this study adds insights into the functional effects of regulatory variants that emerged in recent human evolution.

evolutionary biology↗

bioRxiv2021

A distinct expression profile in the cerebellum and striatum for genes under selection within introgression deserts

Analyses of ancient DNA from extinct hominins have provided unique insights into the complex evolutionary history of Homo sapiens, intricately related to that of the Neanderthals and the Denisovans as revealed by several instances of admixture events. These analyses have also allowed the identification of introgression deserts: genomic regions in our species that are depleted of archaic haplotypes. The presence of genes like FOXP2 in these deserts has been taken to be suggestive of brain-related functional differences between Homo species. Here, we seek a deeper characterization of these regions, taking into account signals of positive selection in our lineage. Analyzing publicly available transcriptomic data from the human brain at different developmental stages, we found that structures outside the cerebral neocortex, in particular the cerebellum, the striatum and the mediodorsal nucleus of the thalamus show the most divergent transcriptomic profiles when considering genes within large introgression deserts and under positive selection.

evolutionary biology↗

bioRxiv2021

Fine-grained temporal mapping of derived high-frequency variants supports the mosaic nature of the evolution of Homo sapiens

As our knowledge about the history of the Homo sapiens lineage becomes increasingly complex, large-scale estimations of the time of emergence of derived variants become essential to be able to offer more precise answers to time-sensitive hypotheses concerning human evolution. Using an open repository of genetic variant age estimations recently made available, we offer here a temporal evaluation of various evolutionarily relevant datasets, such as Homo sapiens-specific variants, high-frequency variants found in genetic windows under positive selection, introgressed variants from extinct human species, as well as putative regulatory variants in various brain regions. We find a recurrent bimodal distribution of high-frequency variants, but also evidence for specific enrichments of gene categories in various time windows, which brings into prominence the 300-500k time slice. We also find evidence for very early mutations impacting the facial phenotype, and much more recent molecular events linked to specific brain regions such as the cerebellum or the precuneus. Additionally, we present a case study of an evolutionarily relevant gene, BAZ1B, and its targets, to emphasize the importance of applying temporal data to specific evolutionary questions. Overall, we present a unique resource that informs and complements our previous knowledge of Homo sapiens evolution using publicly available data, and reinforce the case for the mosaic, temporally very extended nature of the evolutionary trajectory of our species.

evolutionary biology↗

bioRxiv2019

Modern human-specific changes in regulatory regions implicated in cortical development

Recent paleogenomic studies have highlighted a very small set of proteins carrying modern human-specific missense changes in comparison to our closest extinct relatives. Despite being frequently alluded to as highly relevant, species-specific differences in regulatory regions remain understudied. Here, we integrate data from paleogenomics, chromatin modification and physical interaction, and single-cell gene expression of neural progenitor cells to report a set of genes whose enhancers and/or promoters harbor modern human single nucleotide changes that appeared after the split from the Neanderthal/Denisovan lineage. These regulatory regions exert their functions at early stages of cortical development and control a set of genes among which those related to chromatin regulation stand out. This functional category has not yet figured prominently in modern human evolution studies. Specifically, we find an enrichment for the SETD1A histone methyltransferase complex, known to regulate WNT-signaling for the generation and proliferation of intermediate progenitor cells.

evolutionary biology↗