Comment on “Reintroduction of the archaic variant of
            <i>NOVA1</i>
            in cortical organoids alters neurodevelopment”

Maričić, Tomislav; Helmbrecht, Nelly; Riesenberg, Stephan; Macak, Dominik; Kanis, Philipp; Lackner, Martin; Pugach-Matveeva, Agrafena Daria; Pääbo, Svante

doi:10.1126/science.abi6060

Cited by 22 publications

(16 citation statements)

References 6 publications

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“…For example, human organoids with the ancestral amino acid variant of splicing regulator NOVA1 (isoleucine instead of valine) were reported to be smaller and have more cell death, to have a more uneven external surface, and to have gene expression differences in synaptic and glutamatergic markers compared to those with the modern human variant ( Trujillo et al, 2021 ). However, it has been questioned whether these phenotypes were really due to the single amino acid substitution in NOVA1 ( Herai et al, 2021 ; Maricic et al, 2021 ).…”

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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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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“…These events are likely detrimental and can lead to haploinsufficiency or to the production of a dysfunctional protein. For example, in a recent study, a CRISPR/Cas9-edited clone was falsely identified as homozygous, while, in fact, a small deletion prevented proper sequencing of targeted region (Herai et al, 2021;Maricic et al, 2021;Trujillo et al, 2021). Moreover, the genetic consequences of copy-neutral LOH, which we identified in another falsely corrected clone, are not limited to the target locus, as LOH can uncover recessive alleles and elicit long-range transcriptional consequences.…”

Section: Discussionmentioning

confidence: 80%

Homozygous might be hemizygous: CRISPR/Cas9 editing in iPSCs results in detrimental on-target defects that escape standard quality controls

et al. 2022

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“…A concern when performing genome editing is unintended effects that may affect the target sites, notably deletions ( 43 , 48 ) that may not be detected when the target site is sequenced ( 49 ). To exclude this, we determined the copy number of the locus after editing and verified that polymorphic positions up- and downstream of each site remained heterozygous after editing.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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Since the ancestors of modern humans separated from those of Neanderthals, around 100 amino acid substitutions spread to essentially all modern humans. The biological significance of these changes is largely unknown. Here, we examine all six such amino acid substitutions in three proteins known to have key roles in kinetochore function and chromosome segregation and to be highly expressed in the stem cells of the developing neocortex. When we introduce these modern human-specific substitutions in mice, three substitutions in two of these proteins, KIF18a and KNL1, cause metaphase prolongation and fewer chromosome segregation errors in apical progenitors of the developing neocortex. Conversely, the ancestral substitutions cause shorter metaphase length and more chromosome segregation errors in human brain organoids, similar to what we find in chimpanzee organoids. These results imply that the fidelity of chromosome segregation during neocortex development improved in modern humans after their divergence from Neanderthals.

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Comment on “Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment”

Cited by 22 publications

References 6 publications

What Are the Human-Specific Aspects of Neocortex Development?

What Are the Human-Specific Aspects of Neocortex Development?

Homozygous might be hemizygous: CRISPR/Cas9 editing in iPSCs results in detrimental on-target defects that escape standard quality controls

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

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