Biology subjects

Fisher, S. E.

Publications and source records attributed to Fisher, S. E..

At least 19 recordsLinked to original sources

bioRxiv2026

Population-wide variation in connectopic organization of cerebral language hubs

The uniquely human capacity for language is supported by a distributed brain network with cerebral cortical hubs in the left inferior frontal gyrus (LIFG) and left superior temporal sulcus (LSTS). Individual differences in the graded spatial organization of function across these regions may provide sensitive phenotypes for behavioural and genetic association analyses, to better understand the biological underpinnings of language. In 41,437 UK Biobank participants we applied connectopic mapping to the LIFG and LSTS. This approach maps spatial changes across a region in terms of connectivity with the rest of the brain, based on resting state functional imaging. On average, we found that Brodmann Area (BA) 44, BA 45 and the posterior LSTS were strongly connected to the superior and inferior parietal lobe and the dorsal attention and frontoparietal networks, whereas BA 47 and the medial LSTS were strongly connected to superior frontal areas BA 8B and BA 9, and the default mode network more broadly. However, there was extensive population-wide variation in these graded connectopic patterns, which significantly mediated the effects of polygenic scores for reading ability and educational attainment on performance on a vocabulary task. Furthermore we identified 3 genomic loci displaying multivariate association patterns with these connectopic maps, one of which coincides with a long non-coding RNA, LINC01165, with potential relevance in human evolution. Overall, connectopic mapping produced fewer significant genetic association findings and lower heritability (range from 0.3 to 9.4%) than previous parcel-based approaches for mapping language network connectivity. These observations suggest higher genetic complexity and/or prominent roles for environmental or random developmental effects on these connectopic maps.

neuroscience↗

bioRxiv2025

Integrating brain structure and function for the neurobiology and genetics of language

Brain structure and function have largely been studied separately in relation to the neurobiology and genetics of language. Here we used linked independent component analysis to integrate language network functional connectivity with brain volumetric and white matter structure in 32,677 UK Biobank participants, followed by analysis of behavioural, neurobiological and genetic correlates of the derived multimodal structure-function imaging components. Stronger functional connectivity between brain language areas was associated with increased volume of parts of the cerebellum and motor cortex, together with smaller ventricles and sensory parietal and occipital areas. The brain structure-function language components mediated an association between vocabulary level and polygenic scores for reading ability. We report 18 genomic loci associated with brain structure-function language components. Single-nucleotide polymorphism (SNP)-based heritability estimates for these components were 23-30%, and there was significant enrichment of heritability in primate-conserved genomic loci and fetal brain human-gained enhancer elements. This study revealed that structural correlates of functional language network connectivity extend well beyond previously defined language areas of the brain, and highlights the value of multimodal brain phenotyping for human neurogenetic discovery.

neuroscience↗

bioRxiv2025

Structural and functional brain asymmetry in relation to heterogeneous causes of situs inversus totalis

Various aspects of brain organization differ between the left and right hemispheres. Clues to the developmental origins of these asymmetries may be gained through associations with situs inversus totalis (SIT), a rare condition in which visceral organs are reversed on the left-right axis. In the largest previous brain imaging analyses of SIT (38 cases, 38 controls from Belgium), typical functional asymmetries such as left-hemisphere language dominance were mostly unaltered, but various aspects of asymmetrical cerebral structure - petalia, bending, and posterior venous anatomy - were often reversed in this condition. SIT can be a monogenic trait that arises from rare genetic variants, usually affecting motile cilia which help to create the embryonic left-right body axis. However, most SIT cases do not have obvious genetic causes and may arise from environmental or random effects during embryogenesis. We sequenced the genomes of 23 SIT cases and 23 controls from the Belgian brain imaging dataset and pooled with prior data from 15 cases and 15 controls. We aimed to discover whether there are altered brain asymmetries in SIT cases with disruptive DNA variants in ciliary genes, or in other types of genes, as compared to genetically unsolved cases. In total, 19 cases had likely causal variants affecting ciliary function, while 19 cases remained genetically unsolved. Functional and structural brain asymmetries were not significantly different in genetically solved versus unsolved SIT cases. Therefore, functional brain asymmetries seem largely independent of known mechanisms of visceral situs formation, while structural brain torque is altered in SIT regardless of the presence or absence of overt genetic causes.

neuroscience↗

bioRxiv2025

Perfect imperfections: seeking molecular and cellular asymmetries in the mouse brain

Although perfect symmetry is a mathematical ideal, many Bilateria exhibit left-right asymmetries of body, brain and behavior that are adaptive 1-3. In the human brain, various aspects of cognition are lateralized, including language 4 and handedness 5, which rely on left hemisphere dominance in most people. Brain hemispheric specialization can support parallel processing, neural efficiency, and action selection 3,6, while atypical structural or functional asymmetries are often found in neuropsychiatric disorders 7-10. Mice may be useful models for studying brain asymmetry because they show hemispheric differences of structure 11,12 and neurophysiology 13, but the extent to which molecular and cellular differences are involved remains unknown. We applied spatial transcriptomics with single molecule resolution to coronal sections from 31 adult mouse brains, to assess left-right differences of gene expression and cell types. Sections were chosen to capture the hippocampus and auditory cortex, as these two regions have shown the most prior evidence for functional asymmetry 13-15. In the hippocampus, Crhr1 (Corticotropin-Releasing Hormone Receptor 1) was more highly expressed in the pyramidal layers of CA1, CA3 and the dentate gyrus of the left hemisphere compared to the right. In the auditory cortex, three principal components capturing transcriptomic variation showed hemispheric differences, including prominent contributions from genes that have shown associations with human brain asymmetry. Overall cellular density and cell type proportions generally showed no significant hemispheric differences, with Car3 cortical excitatory neurons showing the most laterality. The transcriptional left-right differences that we found may relate to functional asymmetries for learning, memory and hearing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/675542v1_ufig1.gif" ALT="Figure 1"> View larger version (119K): org.highwire.dtl.DTLVardef@1530502org.highwire.dtl.DTLVardef@16dd244org.highwire.dtl.DTLVardef@107950corg.highwire.dtl.DTLVardef@ca52a3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMolecular and cellular basis of functional brain asymmetry is barely known C_LIO_LISpatial transcriptomics with cellular resolution applied to mouse brain coronal sections C_LIO_LIGenes implicated in human brain asymmetry showed hemispheric differences in mice C_LIO_LINo hemispheric differences of cell type abundances C_LI

neuroscience↗

bioRxiv2025

Genome-wide analysis of social behaviour in context: a meta-regression approach across social domains, reporters and developmental stages

Social behaviour is a heritable, context-dependent trait that changes across social settings and development, influencing wellbeing and mental health. We present the first genome-wide meta-regression study of social behaviour from infancy to early adulthood, leveraging 491,246 repeat measures of low prosocial behaviour and peer/social difficulties in European-ancestry cohorts (Neff=121,777, Nind=73,321). We modelled heterogeneity in genetic effects across social domains, informants, and ages (2-29 years), capturing social context through genomic influences. Six loci were identified, including variation within CADM2 (p=2.51x10-9). The SNP-based heritability was modest (2-7%), and the genetic architecture of social behaviour multidimensional. Polygenic scores demonstrated predictability and accuracy in independent European-ancestry cohorts and, partially, in African-ancestry cohorts (Nind=16,305). Genetic correlations with later-life and mental health outcomes showed context-dependent patterns. Modelling predicted onsets of associations with social behaviour revealed distinct profiles, as observed for autism, ADHD, depression and schizophrenia, highlighting novel opportunities to genetically proxy developmental trajectories.

genomics↗

bioRxiv2025

Disentangling multivariate relationships between cognition, language and social traits: structures of G, E, and rGE

BackgroundCognitive, language, and social abilities are complex, heritable and intertwined traits shaping childrens development and later mental health. To better understand cross-trait interrelationships, we model here the structures of shared genomic and shared non-genomic/residual (i.e. broadly environmental) influences, and their correlation (rGE), investigating cognitive, language, and social behavioural/communication measures. MethodsData were obtained for unrelated children (8-13 years) from two population-based cohorts: the UK Avon Longitudinal Study of Parents and Children (ALSPAC, N[≤]6,543) and the US Adolescent Brain Cognitive DevelopmentSM (ABCD) Study (N[≤]4,412), and analyses were carried out implementing an extended data-driven genetic-relationship-matrix structural equation modelling (GRM-SEM) approach. ResultsIn ALSPAC, we identified two independent phenotypic domains, each captured by a structurally matching pair consisting of a genomic (A) and a non-genomic/residual (E) factor. The first domain reflected cognitive/language difficulties, with the largest genomic and residual factor loadings ({lambda}A and {lambda}E, respectively) for verbal IQ ({lambda}A=0.73(SE=0.05); {lambda}E=0.57(SE=0.07)). The second domain captured social difficulties, with the largest {lambda}A and {lambda}E for social communication measures ({lambda}A=0.39(SE=0.10); {lambda}E=0.82(SE=0.10)). We identified trait-specific rGE between pairs of A and E factors with different directions of effect (cognition/language rGE=0.89(SE=0.18), social rGE=-0.62(SE=0.17)). rGE patterns were linked to increased measurable A and E contributions for cognition/language difficulties, but decreased contributions for social problems. Analyses in ABCD confirmed the two domains for E and phenotypic structures, although genomic contributions were low. ConclusionsIn childhood, cognitive/language abilities versus social abilities are influenced by distinct genomic and/or environmental factors, potentially interlinked through trait-specific rGE, suggesting differences in developmental processes.

genomics↗

bioRxiv2025

Functional characterization of pathogenic SATB2 missense variants identifies distinct effects on chromatin binding and transcriptional activity

SATB2-associated syndrome is an autosomal dominant neurodevelopmental syndrome caused by genetic alterations in the transcription factor SATB2. The associated phenotype is variable, and genotype-phenotype correlation studies have not yet been able to explain differences in severity and symptoms across affected individuals. While haploinsufficiency is the most often described disease mechanism, with the majority of variants consisting of whole- or partial-gene deletions and protein truncating variants with predicted loss-of-function, approximately one-third of affected individuals carry a SATB2 missense variant with an unknown effect. In this study, we sought to functionally characterize these missense variants to uncover associated pathogenic mechanisms. We combined a set of human cell-based experiments to screen 31 etiological SATB2 missense variants for effects on nuclear localization, global chromatin binding, and transcriptional activity. Our data indicate partial loss-of-function effects for most of the studied missense variants, but identify at least eight variants with increased SATB2 function showing a combination (or subset) of features that include stronger co-localization with DNA, decreased nuclear protein mobility suggesting increased overall chromatin binding, and maintained or increased transcriptional activity. These results demonstrate that phenotypes associated with variants in SATB2 may have distinct underlying disease mechanisms, and the data could provide a resource for future studies investigating disease variability and potential therapies for this condition.

genetics↗

bioRxiv2025

Genetic underpinnings of chills from art and music

Art can evoke strong emotional responses in humans. Here, we examine genetic contributions to chills, a marker of such responses. We gather self-reports from a genotyped sample of thousands of partly related individuals from the Netherlands (N =15,606). Using genomic relationships based on common single-nucleotide polymorphism (SNP) data, we find that up to 29% of the variation in proneness to aesthetic (visual art and poetry) and music chills can be explained by familial relatedness effects, one-fourth of which is attributed to SNP variation. Furthermore, we reveal a moderate genetic correlation of .58 between aesthetic and music chills, pointing to shared genetic variation affecting susceptibility to strong emotional responses across different art forms. Finally, we find that a polygenic index (PGI) capturing openness to experiences, including propensities towards art (N = 234,880), is associated with susceptibilities both to aesthetic and music chills. Our results show that additive genetic variation, but also familial relatedness beyond shared common SNPs, contributes to proneness to chills from artistic, poetic, and musical expressions. These results open up a promising path towards studying the human attitude towards art, via both state-of-the-art genomics and intergenerational models of transmission. Author SummaryMany people experience chills when listening to music, reading poetry, or viewing art. Yet not everyone feels these reactions in the same way. These differences provide a window into how our brains and bodies respond to art, revealing individual variation in emotional experiences. To investigate what drives these differences, we analysed data from over 15,000 participants with available genetic information, examining whether DNA variation could help explain why some people are more prone to these intense responses. We estimated that roughly 30% of the variation in chills is linked to family-related factors, of which about one fourth was attributable to common DNA variants. Some genetic influences appear to be shared across music, poetry, and art, and are associated with individual openness to experience and general artistic interests, while others may be unique to each domain. These results suggest that genetics contributes to how strongly people respond to cultural experiences and pave the way for future studies on the genetics of sensitivity to art and music experiences.

genetics↗

bioRxiv2025

Spatial and single-nucleus transcriptomic profile of a chimpanzee frontal pole

Chimpanzees, our closest living relatives, share a vast amount of our genetic code, with the majority of differences found in non-coding regions of the genome. Functional and gene regulatory differences drive phenotypic divergence, including the distinctive brain anatomy of humans compared to chimpanzees and other apes. However, little is known about species differences in gene expression, and how they relate to the evolution of neuroanatomy and cognition. This is primarily due to the limited availability of great ape brain samples and challenges in comparative spatial transcriptomic studies. Here, we present the first spatial transcriptomic data from a chimpanzee brain based on post mortem tissue from an adult female, who was euthanised due to poor health. We focus on the frontal pole, a brain region that has undergone significant evolutionary changes in size and organisation since the last common ancestor of humans and chimpanzees, and is considered critical for cognitive evolution. We examined the gene expression profiles and cell-type composition of the frontal pole on the left hemisphere, including both neuronal and non-neuronal cell types across cortical layers and white matter. By integrating our spatial transcriptomic data with a publicly available single-nucleus transcriptomic dataset of the chimpanzee dorsolateral prefrontal cortex, we mapped the spatial distribution of 29 chimpanzee brain cell types. This study represents a first step towards characterisation of spatial gene regulatory differences between the brains of non-human great apes and humans. Significance statementRecent advances in spatial transcriptomics technologies provided important insights into the spatial organisation of gene expression and cell types in human and mouse brains, yet applications in non-model organisms remain limited. Here, we present the first-ever spatial transcriptomics dataset from a chimpanzee brain. We demonstrate i) the applicability of a widely used spatial transcriptomics technique to chimpanzee brain samples freshly frozen in isopentane, and ii) an end-to-end pipeline for generating good-quality spatial transcriptomics data from chimpanzee brains. Our work paves the way for future comparative spatial transcriptomics studies across human and non-human primate brains, and marks a step toward applying spatial omics methods to great ape brains.

evolutionary biology↗

bioRxiv2025

CHD3 regulates BMP signalling response during cranial neural crest cell specification

CHD3 is a component of the NuRD chromatin remodeling complex. Pathogenic CHD3 variants cause Snijders Blok-Campeau Syndrome, a neurodevelopmental disorder with variable features including developmental delays, intellectual disability, speech/language difficulties, and craniofacial anomalies. To unveil the role of CHD3 in craniofacial development, we differentiated CHD3-KO induced pluripotent stem cells into cranial neural crest cells (CNCCs). CHD3 expression is low in wild-type iPSCs and neuroectoderm, but upregulated during CNCC specification, where it opens the chromatin at BMP-responsive enhancers, to allow binding of DLX5 and other factors. CHD3 loss leads to repression of BMP target genes and an imbalance between BMP and Wnt signalling, ultimately resulting in aberrant mesodermal fate. Consequently, CNCC specification fails, replaced by early-mesoderm identity, which can be partially rescued by titrating Wnt levels. Our findings highlight a novel role for CHD3 as a pivotal regulator of BMP signalling, essential for proper neural crest specification and craniofacial development.

developmental biology↗

bioRxiv2024

Preschool musicality is associated with school-age communication abilities through genes related to rhythmicity

Early-life musical engagement is an understudied but developmentally important and heritable precursor of later (social) communication and language abilities. This study aims to uncover the aetiological mechanisms linking musical to communication abilities. We derived polygenic scores (PGS) for self-reported beat synchronisation abilities (PGSrhythmicity) in children (N[≤]6,737) from the Avon Longitudinal Study of Parents and Children and tested their association with preschool musical (0.5-5 years) and school-age (social) communication and cognition-related abilities (9-12 years). We further assessed whether relationships between preschool musicality and school-age communication are shared through PGSrhythmicity, using structural equation modelling techniques. PGSrhythmicity were associated with preschool musicality (Nagelkerke-R2=0.70-0.79%), and school-age communication and cognition-related abilities (R2=0.08-0.41%), but not social communication. We identified links between preschool musicality and school-age speech-and syntax-related communication abilities as captured by known genetic influences underlying rhythmicity (shared effect {beta}=0.0065(SE=0.0021), p=0.0016), above and beyond general cognition, strengthening support for early music intervention programmes.

genetics↗

bioRxiv2024

No phenotypic consequences of archaic hominin alleles in present-day humans

Advances in paleo-genetics allowed the identification of protein-coding changes arising on the lineage leading to Homo sapiens, by comparing genomes of present-day and archaic hominins. Experimental validation of the potential impact of such changes has so far been restricted to functional assays and model organisms. Large-scale biobanking now makes it possible to identify present-day carriers of archaic alleles and to directly assess phenotypic consequences in living adults. We queried exomes of half a million people in the UK Biobank at 37 genomic positions with supposedly fixed human-specific protein-coding changes. This yielded 103 carriers at 17 positions, with variable allele counts across ancestries. Contrasting carriers and non-carriers of an exemplary archaic allele in SSH2, we observed no deviation from the norm in a range of health, psychological, and cognitive traits. We also identified 62 archaic-allele carriers for a TKTL1 missense change, previously shown to have large effects on cortical neurogenesis in brain organoids and animal models. Carriers did not show differences in relevant anatomical brain measures, and a substantial proportion had college/university degrees. This work offers an empirical demonstration of how large-scale biobank investigations of living adults can transform our understanding of human evolution. The findings challenge the notion of fixed human-specific genomic changes, highlight that individual interrogation of relevant sites is unlikely to yield major insights into the emergence of complex human traits, and emphasise the importance of including diverse ancestries when investigating origins of our species.

genetics↗

bioRxiv2024

The chromatin remodeler CHD3 is highly expressed in mature neurons and regulates genes involved in synaptic development and function

Changes in the dynamics of chromatin state that control spatiotemporal gene expression patterns are crucial during brain development. CHD3 is a chromatin remodeler that is highly expressed during neurogenesis and that functions as a core member of the NuRD complex, a large multiprotein complex mediating chromatin state. Genetic disruptions in CHD3 have been implicated in a neurodevelopmental disorder characterized by intellectual disability, macrocephaly and severe speech deficits. To study the roles of CHD3 during early human brain development, we generated induced pluripotent stem cells with heterozygous and homozygous loss-of-function mutations, differentiated them into unguided neural organoids and cortical neurons, and analyzed these by immunohistochemistry, bulk RNA-, single-cell RNA-, and ChIP-sequencing. Loss of CHD3 expression had no detectable effects on early neuroepithelium formation and organoid growth, nor did it significantly affect cell type composition or neuronal differentiation speed. Instead, upon loss of CHD3, we observed dysregulation of genes related to axon guidance and synapse development across all datasets, identifying a novel role for the protein as a regulator that facilitates neurogenesis, in particular neuronal maturation. Our results based on genetically engineered knockout organoids pave the way for future studies modeling the neurobiological pathways affected in CHD3-related disorder.

neuroscience↗

bioRxiv2024

Distinct genetic pathways to music enjoyment

Humans engage with music for various reasons that range from emotional regulation and relaxation to social bonding. While there are large inter-individual differences in how much humans enjoy music, little is known about the origins of those differences. Here, we disentangled the genetic factors underlying such variation. We collected behavioural data on several facets of music reward sensitivity, music perceptual ability, and general reward sensitivity from a large sample of Swedish twins (N = 9,169). We found that genetic factors substantially explain variance in music reward sensitivity above and beyond genetic influences shared with music perception and general reward sensitivity. Furthermore, multivariate analyses showed that genetic influences on the different facets of music reward sensitivity are partly distinct, uncovering distinct pathways to music enjoyment and different patterns of genetic associations with objectively assessed music perceptual abilities. These results paint a complex picture in which partially distinct sources of genetic variation contribute to different aspects of musical enjoyment and open up new possibilities for using inter-individual differences to gain insights into the biology of a key aspect of human behaviour.

genetics↗

bioRxiv2024

Imaging genomics reveals genetic architecture of the globular human braincase

Compared with our fossil ancestors and Neandertal kin, modern humans have evolved a distinctive skull shape, with a rounder braincase and more delicate face. Competing explanations for this rounder skull have either linked it to changes in brain organisation, or seen it as a by-product of gracilization (evolution of thinner and lighter skeletal anatomy). Here, we combined palaeoanthropological data from hominin fossils and imaging genomics data from living humans to gain insight into evolutionary and developmental mechanisms shaping this uniquely modern human phenotype. We analysed endocranial globularity from magnetic resonance imaging (MRI) brain scans and genetic data of more than 33,000 adults. We discovered 28 genomic loci significantly associated with endocranial globularity. There was genetic overlap with the brains ventricular system, white matter microstructure, and sulcal morphology, and with multivariate genetic analyses of reading/language skills, but not with general cognition. The associated genes exhibited enriched expression in the brain during prenatal development and early childhood. The connection to the ventricular system hints at a role for cerebrospinal fluid pressure in shaping the endocranium during development. Genes linked to endocranial globularity also showed enhanced expression in the cardiovascular and female reproductive systems. This finding suggests co-evolutionary pathways whereby changes impacting factors such as energy needs, pregnancy, or fertility concurrently shape the brain and its structure.

genetics↗

bioRxiv2024

The neocortical infrastructure for language involves region-specific patterns of laminar gene expression

The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here we generated a new gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with inter-individual variation in structural connectivity between left-hemisphere frontal and temporal language cortex, and with predisposition to dyslexia. The axon guidance genes SLIT1 and SLIT2 were consistently implicated. These findings identify region-specific patterns of laminar gene expression as a feature of the brains language network.

genetics↗

bioRxiv2023

Imaging genetics of language network functional connectivity reveals links with language-related abilities, dyslexia and handedness

Language is supported by a distributed network of brain regions with a particular contribution from the left hemisphere. A multi-level understanding of this network requires studying its genetic architecture. We used resting-state imaging data from 29,681 participants (UK Biobank) to measure connectivity between 18 left-hemisphere regions involved in multimodal sentence-level processing, as well as their right-hemisphere homotopes, and interhemispheric connections. Multivariate genome-wide association analysis of this total network, based on genetic variants with population frequencies > 1%, identified 14 genomic loci, of which three were also associated with asymmetry of intrahemispheric connectivity. Polygenic dispositions to lower language-related abilities, dyslexia and left-handedness were associated with generally reduced leftward asymmetry of functional connectivity. Exome-wide association analysis based on rare, protein-altering variants (frequencies[≤] 1%) suggested 7 additional genes. These findings shed new light on genetic contributions to language network organization and related behavioural traits.

genomics↗

bioRxiv2023

The shared genetic architecture and evolution of human language and musical rhythm

Rhythm and language-related traits are phenotypically correlated, but their genetic overlap is largely unknown. Here, we leveraged two large-scale genome-wide association studies performed to shed light on the shared genetics of rhythm (N=606,825) and dyslexia (N=1,138,870). Our results reveal an intricate shared genetic and neurobiological architecture, and lay groundwork for resolving longstanding debates about the potential co-evolution of human language and musical traits.

genomics↗