Biology subjects

Boeckx, C.

Publications and source records attributed to Boeckx, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Contextualizing the polygenic basis of human brain shape

As the most recently evolved neuroanatomical trait of our species, our globular head shape ('globularity') constitutes a promising point of entry to probe possible associations between brain morphology and cognitive traits that may be distinctive of Homo sapiens. To shed additional light on the underlying biology of globularity and its cognitive consequences, we capitalize on data pairing genetic variation to brain shape differences from magnetic resonance imaging (MRI) scans of 34,595 adults of European ancestry, and embed genome-wide associations of globularity within genetic variation underpinning up to 75 brain-related traits. Through extensive hypergeometric tests, we observe significant associations between globularity and white matter traits at the gene level, but stronger associations with cerebellar volume, ventricular size, and the fornix at the genomic variant level. Combining conjunctional false discovery rate (FDR) with genetic correlations, we notice homogeneously concordant relations between globularity and the volume of the brain ventricles, and homogeneously discordant relations with glymphatic function. We also unravel more selective, spatially organized relations between globularity and cerebellar volume, white matter connectivity and sulcal width. Spatial permutation tests reveal that sulcal width associations are systematically distributed along a sensorimotor-association gradient of cortical organization. Additionally, correlations of brain- and lifespan-wise gene expression patterns linked to globularity and the brain ventricles highlight recurrent associations with the pentose phosphate metabolic pathway. Finally, deploying an open repository of genetic variant age estimations and an extensive catalog of single nucleotide changes distinguishing hominins, we uncover a coincidence between the establishment of globularity and the time of emergence of modifications in the cerebrospinal fluid proteome. Overall, we provide a finer-grained genetic architecture for globularity, with novel biological associations to traits across evolutionary and developmental timescales, leading us to draw implications for the early development of cognitive networks but also for liabilities to neurodegeneration late in life.

genetics↗

bioRxiv2026

Co-regulatory changes in Homo sapiens prefrontal cortex shape RNA-chromatin interactions

Noncoding RNAs (ncRNAs) regulate gene expression through RNA-chromatin interactions, yet their role in human brain evolution remains unclear. To map these interactions, we integrated FANTOM6 neurogenic data with a comprehensive atlas of regulatory regions active during early cortical development. This integration effort linked ncRNAs and transcription factors (TFs) to their genomic targets, revealing functional interactions captured by RNA-DNA contact mapping, yet largely missed by chromatin conformation data. Overlaying these interactions with nearly fixed variants in Homo sapiens relative to extinct hominins uncovered widespread rewiring of TF binding, affecting genes implicated in progenitor proliferation and neuronal differentiation. Gene regulatory network reconstruction identified TEAD2 and ONECUT2 as key regulators of intermediate progenitors and migrating neurons. Functional perturbation followed by Cut&Tag and ATAC-seq linked the two TFs to disease- and evolutionarily- relevant pathways. Together, these results show how ncRNA-TF cooperation and selective cis-regulatory rewiring contributed to sapiens-specific features of cortical development.

molecular biology↗

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↗

bioRxiv2025

CHD2 Dosage Ties Autolysosomal Pathway to Cortical Maturation in Disease and Evolution

The mechanisms linking evolutionary changes in gene regulation to brain development and neurodevelopmental disease susceptibility remain poorly understood. Here, we identify a human-specific variant in an enhancer region that reduces expression of the chromatin remodeler CHD2. We investigate the variant's functional consequences using genome editing, cross-primate induced pluripotent stem cell models, cortical organoids, single-cell transcriptomics, patient-derived cells, and neuronal network analyses. We demonstrate that CHD2 dosage bidirectionally regulates lysosomal function and autophagosome flux to set the tempo of neuronal maturation. Higher CHD2 expression, as found in ancestralized and non-human primate models, enhances lysosomal degradative capacity and accelerates dendritic and synaptic maturation. Conversely, CHD2 haploinsufficiency yields reciprocal defects and disrupts broader neurodevelopmental transcriptional programs. Restoring lysosomal function genetically or pharmacologically rescues neuronal maturation in CHD2-haploinsufficient neurons, establishing lysosomal dysfunction as a causal and therapeutically tractable mechanism. These findings reveal that CHD2 and lysosomal homeostasis constitute a critical molecular axis regulating the pace of cortical development across evolution and disease.

neuroscience↗

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↗

bioRxiv2022

The genetic architecture of cerebellar lobules: Insights from the UK Biobank

In this work we take advantage of opportunities afforded by the UK Biobank, and complement recent studies examining the genetics of cerebellar volume from that vantage point. We examine the genetic underpinnings of the different cerebellar lob(ul)es, possible reflexes of their evolutionary history, and their genetic relation to psychiatric disorders, cognitive performance and the cortical language network as well as to subcortical regions. Overall, our results show that the cerebellum is a heritable structure, not only globally but also at the regional level. However, our analysis also reveals significant variability across different substructures, justifying the need for a more detailed analysis affording greater structural resolution. Aspects of the "neo-cerebellum", especially lobule VI/Crus I and, to a lesser extent, Crus II, stand out in our analysis.

neuroscience↗

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

Decreased synthesis and variable gene transcripts of oxytocin in a domesticated avian species

The Bengalese finch was domesticated more than 250 years ago from the wild white-rumped munia. Similar to other domesticated species, Bengalese finches show a reduced fear response and have lower corticosterone levels, compared to white-rumped munias. Bengalese finches and munias also have different song types. Since oxytocin (OT) has been found to be involved in stress coping and auditory processing, we tested whether the OT sequence and brain expression pattern and content differ in wild munias and domesticated Bengalese finches. We identified intra-strain variability in the untranslated regions of the OT sequence in Bengalese finches in comparison to the munia OT. Several of these changes fall in specific transcription factor binding sites, which show either a conserved or a relaxed evolutionary trend in the avian lineage, and in vertebrates in general. Although in situ hybridization in several hypothalamic nuclei did not reveal significant differences in the number of cells expressing OT between the two strains, real-time quantitative PCR showed significantly lower OT mRNA expression in the diencephalon of the Bengalese finches relative to munias. Our study thus points to a decreased OT synthesis in the domestic strain compared with the wild strain in birds. This is an opposite pattern from that found in some domesticated mammals, suggesting that different processes of OT function might have occurred in mammals and birds under domestication.

neuroscience↗

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↗

bioRxiv2020

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Adenylosuccinate Lyase (ADSL) functions in the de novo purine biosynthesis pathway. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal purine nucleotide levels but exhibit accumulation of the dephosphorylated ADSL substrates SAICAr and S-Ado. SAICAr was implicated in the neurotoxic effects of ADSLD, although its role remains unknown. We examined the effects of ADSL depletion in human cells and found increased DNA damage signaling, that was rescued by nucleosides, and impaired primary ciliogenesis, that was rescued by reducing SAICAr. By analyzing ADSL deficient chicken and zebrafish embryos we observed impaired neurogenesis and microcephaly, and neuroprogenitor attrition in zebrafish was rescued by reducing SAICAr. Zebrafish embryos also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and SAICAr accumulation contribute to neurodevelopmental pathology in ADSLD and defective ciliogenesis may influence the ADSLD phenotypic spectrum.

developmental biology↗

bioRxiv2020

An Agent-based model of the gradual emergence of modern linguistic complexity

A central question in the evolution of human language is whether it emerged as a result of one specific event or from a mosaic-like constellation of different phenomena and their interactions. Three potential processes have been identified by recent research as the potential primum mobile for the origins of modern linguistic complexity: Self-domestication, characterized by a reduction in reactive aggression and often associated with a gracilization of the face; changes in early brain development manifested by globularization of the skull; and demographic expansion of H. sapiens during the Middle Pleistocene. We developed an agent-based model to investigate how these three factors influence transmission of information within a population. Our model shows that there is an optimal degree of both hostility and mental capacity at which the amount of transmitted information is the largest. It also shows that linguistic communities formed within the population are strongest under circumstances where individuals have high levels of cognitive capacity available for information processing and there is at least a certain degree of hostility present. In contrast, we find no significant effects related to population size.

animal behavior and cognition↗

bioRxiv2019

Derived Homo sapiens cis-eQTL regulation: implications for brain evolution

The availability of high-coverage genomes of our extinct relatives, the Neanderthals and Denisovans, and the emergence of large, tissue-specific databases of modern human genetic variation, offer the possibility of probing the evolutionary trajectory of heterogenous structures of great interest, such as the brain. Using the GTEx cis-eQTL dataset and an extended catalog of Homo sapiens-specific alleles relative to Neanderthals and Denisovans, we generated a dataset of nearly fixed, Homo sapiens-derived alleles that affect the regulation of gene expression across 15 brain (and brain related) structures. The list of variants obtained reveals enrichments in regions of the modern human genome showing putative signals of positive selection relative to archaic humans, and bring out the highly derived status of the cerebellum. Additionally, we complement previous literature on the expression effects of ancestral alleles in the Homo sapiens brain by pointing at a downregulation bias caused by linkage disequilibrium.

genetics↗

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↗

bioRxiv2019

7q11.23 Syndromes Reveal BAZ1B as a Master Regulator of the Modern Human Face and Validate the Self-Domestication Hypothesis

Symmetrical 7q11.23 dosage alterations cause craniofacial and cognitive/behavioral phenotypes that provide a privileged entry point into the evolution of the modern human face and (pro-) sociality. We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 Copy Number Variants (CNVs). Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in neural crest (NC)-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we uncover a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face.\n\nOne Sentence SummaryBAZ1B dosage shapes the modern human face.

evolutionary biology↗

bioRxiv2019

Evolutionary Dynamics Do Not Motivate a Single-Mutant Theory of Human Language

AbstractOne of the most controversial hypotheses in cognitive science is the Chomskyan evolutionary conjecture that language arose instantaneously in our species as the result of a single staggeringly fortuitous mutation. Here we analyze the evolutionary dynamics implied by this hypothesis, which has never been formalized. The theory supposes the emergence and fixation of a single mutant (capable of the syntactic operation Merge) during a narrow historical window as a result of frequency-independent selection under a huge fitness advantage in a population of an effective size that is standardly assumed to have been no larger than ~15 000 early humans. We examine this proposal by combining diffusion analysis and extreme value theory to derive a probabilistic formulation of its dynamics. Perhaps counter-intuitively, a macro-mutation is much more unlikely a priori than multiple mutations with smaller fitness effects, yet both hypotheses predict fixation with high conditional probability. The consequences of this asymmetry have not been accounted for previously. Our results diffuse any suggestion that evolutionary reasoning provides an independent rationale for the controversial single-mutant theory of language.\n\nSignificance statementIn recent years, Chomsky and colleagues have sought support for their minimalist theory of the language faculty from evolutionary considerations. They have argued for a spontaneous emergence of a mutation conferring an advantage for thought independent of communication. Here for the first time a formalization of this view is offered, and contrasted with a more gradual evolutionary scenario. The outcome of our analysis argues against the Chomskyan view.

evolutionary biology↗

bioRxiv2018

Oxytocin and Vasopressin Receptor variants as a window onto the evolution of human prosociality

Modern human lifestyle strongly depends on complex social traits like empathy, tolerance and cooperation. These diverse facets of social cognition have been associated with variation in the oxytocin receptor (OTR) and its sister genes, the vasotocin/vasopressin receptors (VTR1A/AVPR1A and AVPR1B/VTR1B). Here, we compared the full genomic sequences of these receptors between modern humans, archaic humans, and 12 non-human primate species, and identified sites that show heterozygous variation in modern humans and archaic humans distinct from variation in other primates, and that have associated literature. We performed variant clustering, pathogenicity prediction, regulation, linkage disequilibrium frequency and selection analyses on data in different modern-human populations. We found five sites with modern human specific variation, where the modern human allele is the major allele in the global population (OTR: rs1042778, rs237885, rs6770632; VTR1A: rs10877969; VTR1B: rs33985287). Among them, the OTR-rs6770632 was predicted to be the most functional. We found two sites where alleles (OTR: rs59190448 and rs237888)1 present only in modern humans and archaic humans are under positive selection in modern humans, with rs237888 predicted to be a highly functional site. We identified three sites of convergent evolution between modern humans and bonobos (OTR: rs2228485 and rs237897; VTR1A: rs1042615), with OTR-rs2228485 ranking very highly in terms of functionality and being under balancing selection in modern humans. Our findings shed light on evolutionary questions of modern human and hominid prosociality, as well as on similarities in the social behavior between modern humans and bonobos.

genetics↗