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Genetics of human brain development

Nature Reviews Genetics volume 25, pages 26–45 (2024)Cite this article

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Abstract

Brain development in humans is achieved through precise spatiotemporal genetic control, the mechanisms of which remain largely elusive. Recently, integration of technological advances in human stem cell-based modelling with genome editing has emerged as a powerful platform to establish causative links between genotypes and phenotypes directly in the human system. Here, we review our current knowledge of complex genetic regulation of each key step of human brain development through the lens of evolutionary specialization and neurodevelopmental disorders and highlight the use of human stem cell-derived 2D cultures and 3D brain organoids to investigate human-enriched features and disease mechanisms. We also discuss opportunities and challenges of integrating new technologies to reveal the genetic architecture of human brain development and disorders.

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Fig. 1: Key processes of human brain development.
Fig. 2: Applications of human pluripotent stem cell-based systems for studying human brain development.
Fig. 3: Human-specific genetic modulation of brain development.
Fig. 4: Genetic basis of human brain development uncovered using hPS cell models by studying traits led by evolution, diseases and environmental exposure.
Fig. 5: Genetic basis of human brain development revealed by brain disorders.
Fig. 6: Current and future approaches for studying the genetics of human brain development.

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Acknowledgements

The authors thank members of the Song and Ming laboratories for discussion and thank K. M. Christian and Z. Zhang for comments. The authors apologize to colleagues whose relevant studies were not cited due to limited space. The research in the authors’ laboratories was supported by grants from the National Institutes of Health (R35NS097370 and RF1MH123979 to G-l.M., and R35NS116843 to H.S.), and from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G-l.M.).

Author information

Authors and Affiliations

  1. Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Yi Zhou, Hongjun Song & Guo-li Ming

  2. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Hongjun Song & Guo-li Ming

  3. Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Hongjun Song & Guo-li Ming

  4. The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Hongjun Song

  5. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Guo-li Ming

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  1. Yi Zhou
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The authors contributed equally to all aspects of the article.

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Correspondence to Guo-li Ming.

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Glossary

Gene editing

A type of genetic engineering technology in molecular biology by which a DNA sequence is inserted, deleted, modified or replaced in the genome of a living organism.

Genome-wide association studies

(GWAS). A research approach to identify genetic variants at the genome-wide level that are statistically associated with a risk for a disease or a particular trait.

Gyrified

Characterized by convolutions made of alternating gyri and sulci on the surface of cerebral cortex in certain species. Some disease conditions can alter gyrification, such as lissencephaly, where the cortical surface is smooth.

Human-accelerated regions

(HARs). Sets of segments of the human genome that are conserved throughout vertebrate evolution, but contain many substitutions in the human lineage.

Humanized animal models

Experimental animal models that have been xenografted with human cells and/or engineered to express human gene products, to obtain relevant insights in the in vivo context for understanding of human-specific physiology and pathologies.

Monogenic diseases

Genetic disorders that are caused by variation in a single gene.

Neural stem and progenitor cells

A collective term for neuroepithelial cells, radial glial cells, progenitor cells and other multipotent cells in the brain that give rise to various differentiated, postmitotic neuronal and glial cell types, often through intermediate progenitor cell stages.

Neurotypical

Description of individuals with intellectual and cognitive development typical of the larger population, as opposed to, for example, those impacted by neurodevelopmental or neuropsychiatric disorders (known as neuroatypical).

Organoids

Multicellular 3D structures — derived from primary tissue, embryonic stem cells or induced pluripotent stem cells — that self-organize in vitro and recapitulate developmental, anatomical and/or functional aspects of the primary tissue or organ counterpart.

Outer radial glia cells

(oRGCs). Radial glial neural stem cells that contain basal processes but lose their apical attachment to the ventricular surface and undergo distinct migratory and division behaviours; also known as basal radial glial cells.

Pleiotropy

The phenomenon that one gene or regulatory element affects multiple phenotypic traits (for example, biological processes, diseases).

Pluripotent stem cell

A cell that can be maintained in an undifferentiated state and can differentiate into most, if not all, cells of the body.

Polygenicity

A genetic disorder that is caused by the combined action of more than one gene.

Primary microcephaly

A brain disorder — known as ‘small head’ — characterized by significant reduction in head circumference at birth (more than three standard deviations below the mean for age and gender) usually coincident with intellectual disabilities.

Prime editing

A gene editing method by which new genetic information is written into a targeted DNA site in a precise ‘search-and-replace’ manner, involving a prime editing guide RNA capable of identifying the target site.

Single-cell multi-omic

Referring to high-throughput quantification of multiple types of biomolecules (for example, DNA, RNA, chromatin, protein and metabolites) from the same individual cell, aiming to achieve more biological insight than can be inferred by analysing each molecular layer from separate cells.

Xenografted

Refers to cells or tissue transplanted from a donor into a recipient of a different species.

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Zhou, Y., Song, H. & Ming, Gl. Genetics of human brain development. Nat Rev Genet 25, 26–45 (2024). https://doi.org/10.1038/s41576-023-00626-5

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