{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman‐specific NOTCH2NL paralogs are prominently expressed in radial glia, where they modulate Notch signaling by directly interacting with Notch receptors. By enhancing Notch pathway activity, these genes delay the differentiation of neuronal progenitors, thereby extending the period of cortical stem cell proliferation and contributing to the expansion of the human neocortex. Importantly, variations in NOTCH2NL dosage have been linked to neurodevelopmental disorders, with duplications at the 1q21.1 locus associated with macrocephaly and autism, and deletions linked to microcephaly and schizophrenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \n"}, {"type": "p", "children": [{"type": "t", "text": "\nComparative evolutionary analyses reveal that archaic hominins such as Neanderthals and Denisovans harbored unique protein‐coding variants and gene configurations within the NOTCH2NL family. These differences may have altered the capacity of NOTCH2NL to activate Notch signaling, suggesting that shifts in its functional output contributed to divergent patterns of brain development and evolution among hominin lineages."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n \n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther genetic scrutiny in modern human populations indicates ongoing adaptive evolution of NOTCH2NL, with structural variants emerging that modulate its expression levels toward an optimal dosage. This balance appears critical for maximizing the benefits of increased neuronal production while minimizing the risk of genomic instability and associated neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"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": "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"}]}]}]}