Table 1. A summary of the evolutionary history, subcellular localization, molecular mechanisms, and neurodevelopmental effects of genes exhibiting human-specific features.

Gene name(s)	Human-specific feature	Evolutionary mechanism/origin	Subcellular compartment	Neurodevelopmental effect	Molecular mechanism
ARGAPH11B	Only present in human genome	Segmental duplication of ARGAPH11A; novel carboxy-terminal amino acid sequence due to a novel splice donor site	Mitochondrion	Increased BP proliferation, subsequent higher neuron numbers, induction of cortical expansion and folding, improved memory flexibility	Increase in mitochondrial Ca2+ concentration leading to enhanced glutaminolysis
CROCCP2	Paralogous loci present in the Catarrhini group; Expression during corticogenesis is proposed to be unique to humans	Partial segmental duplication of the ancestral gene CROCC	Cytoplasm (with perinuclear localization, presumably at the Golgi apparatus)	Increased AP and BP proliferation, subsequent increase in neuron numbers	Inhibition of IFT20 resulting into decreased ciliogenesis and activation of mTOR pathway (for BPs)
hTKTL1	Present in mammals; modern human-specific version	Modern-human specific substitution of lysine with arginine due to a single nucleotide mutation	Cytoplasm	Increased bRG abundance, subsequent higher neuron numbers	Upregulation of the pentose phosphate pathway and fatty acid synthesis
KIF18A and KNL1	Widely conserved genes; modern human-specific versions	One and two modern human-specific amino acid substitutions respectively	Kinetochore	Metaphase prolongation and improved chromosome segregation fidelity in APs	Regulation of chromosome positioning and kinetochore microtubule attachment during mitosis
NOTCH2NLA-C	Only present in human genome	Multiple segmental duplication rounds of the ancestral NOTCH2NLR; Three human-specific paralogous (NOTCH2NLA, -B, -C)	Cytoplasm (suggested to be secreted)	Increased AP proliferation, delayed neuronal differentiation (for NOTCH2NLB), increased bIP proliferation (for NOTCH2NLA)	Activation of Notch signaling
SP0535	Only present in human genome	De novo origin; single-base mutation and stop codon escape due to a two-base deletion in the human ENST00000370535 locus	Cytoplasm	Increased proliferation of APs, elevated number of bIPs, subsequently higher number of neurons, induction of cortical expansion and folding	Increase of Src phosphorylation (associated with cell proliferation) via releasing it from ATP1A1-Src complex
SRGAP2C	Only present in human genome	Incomplete segmental duplication of SRGAP2A (its “grandmother”), subsequent duplication of SRGAP2B (its “mother”); loss of SH3 and Rho-GAP domains	Cytoplasm (dendrites of cortical neurons)	Increased progenitor proliferation; induction of “human-like” developmental features as sustained radial migration, neoteny of spine and synapse development, delayed myelination, increased spine size and density, increased synaptic density, prolongation of brain development; cognitive improvements	Functional inhibition of the ancestral SRGAP2A via physical heterodimerization
TBC1D3	Present in Simian genomes but copy number and organization vary; human-specific carboxy-terminal amino acid sequence	Large-scale chromosomal rearrangements and duplication events suggestive of independent expansion in each lineage	Nucleus in oSVZ cells, cytoplasm/membrane in VZ/iSVZ and CP cells	aRG delamination and bRG proliferation, induction of cortical folding	Proposed theories include: (i) Activation of IGF and EGF pathways; (ii) inhibition of G9a-facilitated H3K9me2