Genetic architecture of human brain evolution

Fair, Tyler; Pollen, Alex A.

doi:10.1016/j.conb.2023.102710

Cited by 11 publications

(5 citation statements)

References 89 publications

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“…Among primates, the human neocortex exhibits the biggest volume and largest number of neurons 2 , 3 , which is considered to be a basis of human cognitive abilities 1 , 4 . Recent studies have implicated a number of human-specific and hominid-specific genes and mutations in the evolution of human brain size and brain morphology 5 – 12 .…”

Section: Introductionmentioning

confidence: 99%

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development

Xing,

Gkini,

Nieminen

et al. 2024

Nat Commun

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Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B’s ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.

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Section: Introductionmentioning

confidence: 99%

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development

Xing,

Gkini,

Nieminen

et al. 2024

Nat Commun

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show abstract

“…The evolutionary expansion and elaboration of the human cerebral cortex is in part the product of modifications to neural stem cell (NSC) fate specification, migration, proliferation, and the timing of neural differentiation in development [1][2][3] . Genetic changes that altered developmental enhancer activity have been hypothesized to drive many of these traits [4][5][6][7] . Human Accelerated Regions (HARs) are genomic regions that are highly constrained across multiple species, but which show a significant excess of human-specific substitutions (Fig.…”

Section: Introductionmentioning

confidence: 99%

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

Noble,

Ji,

Yim

et al. 2024

Preprint

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The evolution of the human cerebral cortex involved modifications in the composition and proliferative potential of the neural stem cell (NSC) niche during brain development. Human Accelerated Regions (HARs) exhibit a significant excess of human-specific sequence changes and have been implicated in human brain evolution. Multiple studies support that HARs include neurodevelopmental enhancers with novel activities in humans, but their biological functions in NSCs have not been empirically assessed at scale. Here we conducted a direct-capture Perturb-seq screen repressing 180 neurodevelopmentally active HARs in human iPSC-derived NSCs with single-cell transcriptional readout. After profiling >188,000 NSCs, we identified a set of HAR perturbations with convergent transcriptional effects on gene networks involved in NSC apicobasal polarity, a cellular process whose precise regulation is critical to the developmental emergence of basal radial glia (bRG), a progenitor population that is expanded in humans. Across multiple HAR perturbations, we found convergent dysregulation of specific apicobasal polarity and adherens junction regulators, includingPARD3, ABI2, SETD2, andPCM1. We found that the repression of one candidate from the screen, HAR181, as well as its target geneCADM1, disrupted apical PARD3 localization and NSC rosette formation. Our findings reveal interconnected roles for HARs in NSC biology and cortical development and link specific HARs to processes implicated in human cortical expansion.

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“… 2 , 3 , 4 , 5 These changes are linked to the evolution of mechanisms underlying cortical development, which have started to be unraveled by convergent results of genomics, genetics, and developmental neurobiology. 4 , 5 , 6 , 7 …”

Section: Introductionmentioning

confidence: 99%

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

Libé-Philippot,

Lejeune,

Wierda

et al. 2023

Cell

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Genetic architecture of human brain evolution

Cited by 11 publications

References 89 publications

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

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