Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex

Abstract

Understanding the molecular basis that underlies the expansion of the neocortex during primate, and notably human, evolution requires the identification of genes that are particularly active in the neural stem and progenitor cells of the developing neocortex. Here, we have used existing transcriptome datasets to carry out a comprehensive screen for protein-coding genes preferentially expressed in progenitors of fetal human neocortex. We show that 15 human-specific genes exhibit such expression, and many of them evolved distinct neural progenitor cell-type expression profiles and levels compared to their ancestral paralogs. Functional studies on one such gene, NOTCH2NL, demonstrate its ability to promote basal progenitor proliferation in mice. An additional 35 human genes with progenitor-enriched expression are shown to have orthologs only in primates. Our study provides a resource of genes that are promising candidates to exert specific, and novel, roles in neocortical development during primate, and notably human, evolution.

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics

“…RAB6C, ZNF90, GLUD2, POTEM, POTEE, and MT1M were all upregulated over differentiation from day 24 to day +95. While the roles of many of these genes unclear, NOTCH2NL and GLUD2 have been linked to human-specific changes in brain development (39)(40)(41)(42)(43)(44)(45).…”

Using brain organoids to study human neurodevelopment, evolution and disease

“…In gyrencephalic species and in humans, the proportion of bRGs expressing TBR2 is smaller compared to mice, since in human bRGs share more similarities with aRGs than RGs do with IPs (Fietz et al, ; Florio et al, ). Although no specific bRG markers are known to distinguish aRGs from bRGs, bulk and single cell RNA sequencing showed recently that bRGs are characterized, at later developmental stages (after GW17), by the expression of the bRG markers HOPX, PTPRZ1, TNC (Florio et al, ; Nowakowski et al, ; Pollen et al, ). Nevertheless, these markers are not specific to bRGs throughout development in humans, and in mice they are also expressed in aRGs (Florio & Huttner, ; Vaid et al, ).…”

“…Although the above criteria were used to identify and distinguish aRGs and bRGs, within the bRGs population there is great variability in terms of gene expression profile or shape. Bulk or single cell RNA sequencing of the different NPC populations has contributed to the understanding of the transcriptome of the bRGs in developing brains and showed that the spatial localization of bRGs is linked with the expression of different gene sets (Florio et al, ; Florio et al, ; Nowakowski et al, ; Pollen et al, ). In particular, bRGs located in a region which will generate gyri have different gene expression profiles than bRGs located in a region which will generate sulci (de Juan et al, ).…”

“…These changes contribute to changes in the expression levels of genes, to the gene structure and thus their function, or to generation of new human enriched or human‐specific genes. Examples of such genes are the SRGAP2, ARHGAP11B, NOTCH2NL, FZD8 among others (Boyd et al, ; Dennis et al, ; Fiddes et al, ; Florio et al, ; Florio et al, ; Suzuki et al, ). Overall, it is clear that the crosstalk of biological and mechanical processes controls the folding of the cerebral cortex in gyrencephalic species or the type and morphology of the neurons.…”

“…Throughout evolution, the human cortex has greatly expanded and this is linked to increase in cognitive abilities. The main factor, known so far, controlling human cortical expansion is the increase in the proliferative capacity of the NPCs at early developmental stages (Borrell & Reillo, ; Florio et al, ; Florio & Huttner, ; Rakic, ).…”