Longer metaphase and fewer chromosome segregation errors in modern human than Neandertal brain development

Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.

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“…We refer readers to Mora-Bermúdez et al, 2022 who show an effect of the missense changes in KIF18A and KNL1 on the prolongation of metaphase.…”

Section: Discussionmentioning

confidence: 99%

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

Peyrégne

Kelso

Peter

et al. 2022

eLife

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“…In the case of human APs undergoing expansion, a minimization of chromosome segregation errors due to metaphase prolongation would have consequences for the entire progeny of APs, that is, BPs as well as cortical neurons and glial cells. Recent data has brought strong support to these concepts ( Mora-Bermúdez et al, 2022 ).…”

Section: Temporal Differences In Neocortical Stem and Progenitor Cell...mentioning

confidence: 93%

“…Also, the six amino acid variants found in Neandertals are identical to those found in chimpanzees and other non-human great apes. Recent data has shown that the functions of these coding differences between modern and archaic humans are related to the metaphase prolongation observed in modern human vs. chimpanzee and orang-utan organoid APs ( Mora-Bermúdez et al, 2016a , 2022 ).…”

Section: Evolutionary Aspects—are There Differences In Key Players Of...mentioning

confidence: 99%

What Are the Human-Specific Aspects of Neocortex Development?

Mora-Bermúdez

Huttner

2022

Front. Neurosci.

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When considering what makes us human, the development of the neocortex, the seat of our higher cognitive abilities, is of central importance. Throughout this complex developmental process, neocortical stem and progenitor cells (NSPCs) exert a priming role in determining neocortical tissue fate, through a series of cellular and molecular events. In this Perspective article, we address five questions of relevance for potentially human-specific aspects of NSPCs, (i) Are there human-specific NSPC subtypes? (ii) What is the functional significance of the known temporal differences in NSPC dynamics between human and other great apes? (iii) Are there functional interactions between the human-specific genes preferentially expressed in NSPCs? (iv) Do humans amplify certain metabolic pathways for NSPC proliferation? and finally (v) Have differences evolved during human evolution, notably between modern humans and Neandertals, that affect the performance of key genes operating in NSPCs? We discuss potential implications inherent to these questions, and suggest experimental approaches on how to answer them, hoping to provide incentives to further understand key issues of human cortical development.

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“…These organoids exhibited changes in organoid morphology and neuronal activity ( Trujillo et al, 2021 ). Recently, Mora-Bermudez and others introduced specific ancestral variants involved in mitotic spindle and kinetochore function in organoids and showed shorter metaphase of apical progenitors compared to the longer metaphase of non-mutated modern human organoids ( Mora-Bermúdez et al, 2022 ). It is interesting to speculate that such evolutionary differences between modern humans and ancestral human species might also be linked to bRG development and function.…”

Section: What Have Organoids Told Us About Brg?mentioning

confidence: 99%

Forebrain Organoids to Model the Cell Biology of Basal Radial Glia in Neurodevelopmental Disorders and Brain Evolution

Don

Kalebic

2022

Front. Cell Dev. Biol.

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The acquisition of higher intellectual abilities that distinguish humans from their closest relatives correlates greatly with the expansion of the cerebral cortex. This expansion is a consequence of an increase in neuronal cell production driven by the higher proliferative capacity of neural progenitor cells, in particular basal radial glia (bRG). Furthermore, when the proliferation of neural progenitor cells is impaired and the final neuronal output is altered, severe neurodevelopmental disorders can arise. To effectively study the cell biology of human bRG, genetically accessible human experimental models are needed. With the pioneering success to isolate and culture pluripotent stem cells in vitro, we can now routinely investigate the developing human cerebral cortex in a dish using three-dimensional multicellular structures called organoids. Here, we will review the molecular and cell biological features of bRG that have recently been elucidated using brain organoids. We will further focus on the application of this simple model system to study in a mechanistically actionable way the molecular and cellular events in bRG that can lead to the onset of various neurodevelopmental diseases.

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Longer metaphase and fewer chromosome segregation errors in modern human than Neandertal brain development

Cited by 5 publications

References 61 publications

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

What Are the Human-Specific Aspects of Neocortex Development?

Forebrain Organoids to Model the Cell Biology of Basal Radial Glia in Neurodevelopmental Disorders and Brain Evolution

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