{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman-specific NOTCH2NL paralogs, including NOTCH2NLB, play a pivotal role in regulating Notch signaling during cortical development. Their expression in radial glial cells enhances Notch receptor activation through allele-dependent interactions, delaying the differentiation of neuronal progenitors. Moreover, perturbations in their dosage—through either ectopic expression or deletion—have been linked with neurodevelopmental disorders, as alterations in the 1q21.1 locus are associated with conditions ranging from macrocephaly and autism to microcephaly and schizophrenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn studies of the developing human cortex, NOTCH2NLB and its paralogs have been shown to promote the clonal expansion and maintenance of cortical progenitors. Functionally, these genes act by activating the Notch pathway via inhibition of cis Delta/Notch interactions, ultimately leading to increased neuronal output and contributing to the evolutionary expansion and increased complexity of the human neocortex."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInvestigations into archaic hominid genomes reveal that unique protein-coding variants and unusual genomic configurations of the NOTCH2NL gene family exist in Neanderthals and Denisovans. These findings, together with evidence of ongoing adaptive evolution in modern humans, suggest that fine-tuning of NOTCH2NLB dosage is critical for optimal cortical development and that evolutionary pressures have acted to balance its role in promoting brain expansion against the risk of neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ian T Fiddes, Gerrald A Lodewijk, Meghan Mooring, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2018.03.051"}], "href": "https://doi.org/10.1016/j.cell.2018.03.051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29856954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29856954"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ikuo K Suzuki, David Gacquer, Roxane Van Heurck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2018.03.067"}], "href": "https://doi.org/10.1016/j.cell.2018.03.067"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29856955"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29856955"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gerrald A Lodewijk, Diana P Fernandes, Iraklis Vretzakis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Evol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molbev/msaa104"}], "href": "https://doi.org/10.1093/molbev/msaa104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32330268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32330268"}]}]}]}