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

Abstract

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.

Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution

“…This model provided evidence that the human changes influence exploratory and learning behaviours linked to modifications to medium spiny neurons coordinating cortico-striatal networks 163 , 179 . Similarly, recent studies have begun to explore the physiological consequences of modern human-specific mutations in mouse models and cell lines 109 , 180 , 181 . Finally, mouse models have been used to link the human-specific inactivation of the CMAH gene that is necessary for synthesis of N -glycolylneuraminic acid to changes in immune response 182 and muscle fatigue 183 , which have implications for human traits.…”

Paleoanthropology of cognition: an overview on Hominins brain evolution

“…To date few of these changes have been deciphered, but several are involved in brain development and connectivity. The modern variants of KIF18a and KNL1 are proven to cause metaphase prolongation and fewer chromosome segregation errors during cell divisions in apical progenitors of developing neocortex [33]. The modern version of TKTL1 results in an increase in cortical neuron production and increases the ability of the basal radial glia to self-amplify [34].…”

“…A ce jour, peu de ces mutations ont été décryptées, mais plusieurs d'entre elles sont impliquées dans le développement et la mise en place de la connectivité du cerveau. Il a été démontré que les variantes modernes de KIF18a et KNL1 provoquent une prolongation de la métaphase et moins d'erreurs de ségrégation chromosomique lors des divisions cellulaires dans les progéniteurs apicaux du néocortex en développement [33]. La version moderne de TKTL1 entraîne elle une augmentation de la production de neurones corticaux et accroît la capacité de la glie radiaire basale à s'auto-amplifier [34].…”

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

“…Thanks to the discovery of somatic reprogramming factors, it is possible to derive brain organoids from many species, including great apes [ 256 , 257 , 258 , 259 ]. By comparing organoid differentiations from human and chimpanzee, Mora-Bermudez et al identified differences in cell cycle kinetics between species [ 260 ] and identified candidate modern human-specific causative mutations [ 261 ]. Pollen et al demonstrated that organoids derived from non-human primates recapitulate cross-species gene expression differences observed in primary tissue and identified changes in mTOR signaling pathway activation [ 32 ].…”