Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis
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Abstract
Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders.
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These contained genes known to have CNVs associated with human health, including amylase (four to ten copies), β-defensin (three to seven copies, DEFB107A) and NOTCH2NLC-NOTCH2NLB (one additional copy).
“These contained genes known to have CNVs associated with human health, including amylase61 (four to ten copies), β-defensin62 (three to seven copies, DEFB107A) and NOTCH2NLC–NOTCH2NLB63 (one additional copy).”
From A draft human pangenome reference. (2023) · cites this paper as [63]
The Results section on neurodevelopmental phenotypes (page not provided) reports an additional hybrid NOTCH2NLA/B allele in a patient with a 1q21.1 duplication, supporting the one-additional-copy claim and its health context. It does not identify that additional copy as NOTCH2NLC–NOTCH2NLB; the Results section on NOTCH2NL variation discusses NOTCH2NLC copy number separately. The amylase and β-defensin examples carry different citations and are not assessed here. (LLM, conf=0.86)
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Nuttle, X., Huddleston, J., O’Roak, B. J., Antonacci, F., Fichera, M., Romano, C., Shendure, J., & Eichler, E. E. (2013) · Nature Methods · doi:10.1038/nmeth.2572 · Cited by 31 · see citing works
Self-citationSzamalek, J. M., Goidts, V., Cooper, D. N., Hameister, H., & Kehrer‐Sawatzki, H. (2006) · Human Genetics · doi:10.1007/s00439-006-0209-y · Cited by 20 · see citing works
Chang, H., Li, L., Peng, T., Li, M., Gao, L., & Xiao, X. (2016) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32502 · Cited by 7 · see citing works
Scalable Systems and Algorithms for Genomic Variant Analysis
Nothaft, F. A. (2017) · eScholarship (California Digital Library) · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
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A draft human pangenome reference.
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Segmental duplications and their variation in a complete human genome
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Developmental mechanisms underlying the evolution of human cortical circuits
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Increased mutation and gene conversion within human segmental duplications
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Self-citationA human-specific modifier of cortical connectivity and circuit function
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Cellular and Molecular Mechanisms Linking Human Cortical Development and Evolution
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- Authors
- Fiddes, I. T., Lodewijk, G. A., Mooring, M., Bosworth, C. M., Ewing, A. D., Mantalas, G. L., Novak, A. M., van den Bout, A., Bishara, A., Rosenkrantz, J. L., Lorig-Roach, R., Field, A. R., Haeussler, M., Russo, L., Bhaduri, A., Nowakowski, T. J., Pollen, A. A., Dougherty, M. L., Nuttle, X., Addor, M.-C., Zwolinski, S., Katzman, S., Kriegstein, A., Eichler, E. E., Salama, S. R., Jacobs, F. M. J., & Haussler, D.
- Affiliations
- University of California, Santa Cruz (US)
- University of Amsterdam (NL)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- University of Washington (US)
- Broad Institute (US)
- Corresponding author
- Jacobs, Frank M.J.
- Haussler, David
- ORCID
- Fiddes, Ian T.
- Lodewijk, Gerrald A.
- Mooring, Meghan
- Bosworth, Colleen M.
- Ewing, Adam D.
- Mantalas, Gary L.
- Novak, Adam M.
- Rosenkrantz, Jimi L.
- Lorig-Roach, Ryan
- Field, Andrew R.
- Haeussler, Maximilian
- Bhaduri, Aparna
- Nowakowski, Tomasz J.
- Pollen, Alex A.
- Dougherty, Max L.
- Nuttle, Xander
- Addor, Marie-Claude
- Zwolinski, Simon
- Katzman, Sol
- Kriegstein, Arnold
- Eichler, Evan E.
- Salama, Sofie R.
- Jacobs, Frank M.J.
- Haussler, David
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 173
- Issue
- 6
- Pages
- 1356-1369.e22
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5986104
- OpenAlex
- W2805663744
- Cited by
- 595
- References
- 86
- Citations by year
- 2026: 54 · 2025: 72 · 2024: 72 · 2023: 98 · 2022: 69 · 2021: 91 · 2020: 69 · 2019: 51 · 2018: 18
- FWCI
- 21.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 395 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- CIRM (T3-00006, EDUC2-08394, TG2-01157, GC1R-06673-A, GC1R-06673-B)
- Human Frontier Science Program (LT000689/2010-L, CDA00030/2016C)
- ERC (ERC-2016-StG-716035)
- NWO Earth and Life Sciences (834.12.003)
- EMBO (ALTF 292-2011)
- NIH (HG002385, F30HG009478, R01 GM109031, U41HG002371, U54HG007990)
- NCI (24074-443720)
- NIST/JIMB
- California QB3 Institute
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Notch signaling, cortical neurogenesis, radial glia, human brain evolution, paralogs, neurodevelopmental disorders, macrocephaly, microcephaly, autism spectrum disorder, schizophrenia, genomic instability
- MeSH terms
- Animals, Brain, Cell Differentiation, Cerebral Cortex, Pan troglodytes, Female, Gorilla gorilla, Humans, Neuroglia, Neurons, Signal Transduction, Gene Deletion, Sequence Analysis, RNA, Genes, Reporter, Neocortex, Receptor, Notch2, Embryonic Stem Cells, Neurogenesis, HEK293 Cells, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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