Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

Guardiola-Ripoll, Maria; Almodóvar-Payá, Carmen; Arias-Magnasco, Angelo; Latorre-Guardia, Mariona; Papiol, Sergi; Canales-Rodríguez, Erick J.; García-León, María Ángeles; Fuentes-Claramonte, Paola; Salavert, Josep; Tristany, Josep; Torres, Llanos; Rodríguez-Cano, Elena; Salvador, Raymond; Pomarol-Clotet, Edith; Fatjó-Vilas, Mar

doi:10.1038/s42003-023-05356-2

Cited by 3 publications

(3 citation statements)

References 106 publications

(133 reference statements)

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“…2023 ), the processing of sentences with unstated iterative meaning ( Lai et al. 2023 ), and the onset of schizophrenia ( Guardiola-Ripoll et al. 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Resting heart rate causally affects the brain cortical structure: Mendelian randomization study

Zhong,

Li,

Hong

et al. 2024

Cerebral Cortex

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Resting heart rate (RHR) has been linked to impaired cortical structure in observational studies. However, the extent to which this association is potentially causal has not been determined. Using genetic data, this study aimed to reveal the causal effect of RHR on brain cortical structure. A Two-Sample Mendelian randomization (MR) analysis was conducted. Sensitivity analyses, weighted median, MR Pleiotropy residual sum and outlier, and MR-Egger regression were conducted to evaluate heterogeneity and pleiotropy. A causal relationship between RHR and cortical structures was identified by MR analysis. On the global scale, elevated RHR was found to decrease global surface area (SA; P < 0.0125). On a regional scale, the elevated RHR significantly decreased the SA of pars triangularis without global weighted (P = 1.58 × 10−4) and the thickness (TH) of the paracentral with global weighted (P = 3.56 × 10−5), whereas it increased the TH of banks of the superior temporal sulcus in the presence of global weighted (P = 1.04 × 10−4). MR study provided evidence that RHR might be causally linked to brain cortical structure, which offers a different way to understand the heart–brain axis theory.

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“…2023 ), the processing of sentences with unstated iterative meaning ( Lai et al. 2023 ), and the onset of schizophrenia ( Guardiola-Ripoll et al. 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Resting heart rate causally affects the brain cortical structure: Mendelian randomization study

Zhong,

Li,

Hong

et al. 2024

Cerebral Cortex

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“…In particular, we show that surface area follows a continuous trajectory, contrary to what was shown in Bethlehem et al (2022). Surface area is a particularly critical feature in assessing neurodevelopmental normality, thus properly characterizing it is essential in the identification of healthy participants and biomarkers linked to neurodevelopmental disorders (Kline et al, 2020;Guardiola-Ripoll et al, 2023).…”

Section: Position With Respect To Previously Published Normative Curvesmentioning

confidence: 99%

Normative models combining fetal and postnatal MRI data to characterize neurodevelopmental trajectories during the transition from in- to ex-utero

Mihailov,

Pron,

Lefèvre

et al. 2024

Preprint

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The perinatal period involves transitioning from an intra- to an extrauterine environment, which requires a complex adaptation of the brain. This period is marked with dynamic and multifaceted cortical changes in both structure and function. Most studies to date have focused either on the fetal or postnatal period, independently. To the best of our knowledge, this is the first neurodevelopmental study targeting the cortical trajectory of typically developing perinatal subjects, combining MRIs from both fetal and postnatal participants. Prior to analysis, preprocessing and segmentation parameters were harmonized across all subjects in order to overcome methodological limitations that arise when studying such different populations. We conducted a normative modeling analysis on a sample of 607 subjects, age ranged 24 to 45 weeks post-conception, to observe changes that arise as participants traverse the birth barrier. We observed that the trajectories of global surface area and several volumetric features, including total gray matter, white matter, brainstem, cerebellum and hippocampi, follow distinct but continuous patterns during this transition. We further report three features presenting a discontinuity in their neurodevelopmental trajectories as participants traverse from a fetal to a postnatal environment: the extra-cerebrospinal fluid volume, the ventricular volume and global gyrification. The current study demonstrates the presence of unique neurodevelopmental patterns for several structural features during the perinatal period, and confirms that not all features are affected in the same way as they cross the birth barrier.

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“…Nearly 3,000 HARs have been identified, many of which are located nearby neurodevelopmental genes, and act as gene regulatory enhancers in neural cells 5,12,14,17–20 . Notably, mutations in HARs are associated with neurological diseases 21,22 . Use of transgenic mice and massively parallel reporter assays in vitro have shown HARs have tissue and species-specific enhancer activity regardless of the trans environment 5,13,14 .…”

mentioning

confidence: 99%

A human-specific enhancer fine-tunes radial glia potency and corticogenesis

Liu,

Mosti,

Zhao

et al. 2024

Preprint

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Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications. Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to human-specific cortical development is largely unknown. HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development. Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices containing more neurons. By measuring neural dynamics in vivo we show these anatomical features correlate with increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using live imaging, lineage analysis, and single-cell RNA sequencing. This reveals Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

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Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

Cited by 3 publications

References 106 publications

Resting heart rate causally affects the brain cortical structure: Mendelian randomization study

Resting heart rate causally affects the brain cortical structure: Mendelian randomization study

Normative models combining fetal and postnatal MRI data to characterize neurodevelopmental trajectories during the transition from in- to ex-utero

A human-specific enhancer fine-tunes radial glia potency and corticogenesis

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