Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication
Open accessAbstract
Gene duplication is an important source of phenotypic change and adaptive evolution. We leverage a haploid hydatidiform mole to identify highly identical sequences missing from the reference genome, confirming that the cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) duplicated three times exclusively in humans. We show that the promoter and first nine exons of SRGAP2 duplicated from 1q32.1 (SRGAP2A) to 1q21.1 (SRGAP2B) ∼3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (SRGAP2D) ∼2.4 and ∼1 mya, respectively. Sequence and expression analyses show that SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Our data suggest a mechanism where incomplete duplication created a novel gene function-antagonizing parental SRGAP2 function-immediately "at birth" 2-3 mya, which is a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.
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The SRGAP2 gene family is composed of SRGAP2A, the ancestral gene shared by all mammals, and human-specific duplicates SRGAP2B, SRGAP2C, and SRGAP2D, which emerged through segmental duplications during hominin evolution over the past approximately 2-3 million years.
“This family is composed of SRGAP2A, the ancestral gene shared by all mammals (named SRGAP2 in non-human species), human-specific (HS) gene duplicates SRGAP2B, SRGAP2C, and SRGAP2D, which emerged through segmental duplications during hominin evolution, over the past ∼2–3 million years.25,26”
From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [25]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSRGAP2C dimerizes with SRGAP2A, acting as a dominant-negative inhibitor.
“SRGAP2C dimerizes with SRGAP2A, acting as a dominant-negative inhibitor.”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [90]
The Discussion says functional evidence suggests that partial SRGAP2 copies heterodimerize with full-length SRGAP2, creating a dominant-negative interaction. It proposes this mechanism rather than establishing it as the categorical fact stated in the claim. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThis interaction inhibits SRGAP2A's role in promoting dendritic spine maturation and limiting spine density.
“This interaction inhibits SRGAP2A’s role in promoting dendritic spine maturation and limiting spine density.”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [90]
The Discussion (page unavailable) proposes that partial SRGAP2 proteins interact with full-length SRGAP2 and act as dominant negatives, supporting inhibition of the ancestral protein. Our copy does not state that SRGAP2A promotes dendritic spine maturation or limits spine density, so it does not support those specific effects. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThis duplication resulted in a truncated version of SRGAP2A that retains the F-BAR domain but lacks the RhoGAP and SH3 domains.
“This duplication resulted in a truncated version of SRGAP2A that retains the F-BAR domain but lacks the RhoGAP and SH3 domains.”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [90]
The Results (Evolutionary history of SRGAP2; page unavailable) say the duplicated copies are predicted to produce truncated proteins carrying nearly the entire F-BAR domain, not an intact one. The Discussion says they lack other functional domains, but the passages in our copy do not identify those domains specifically as RhoGAP and SH3. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSRGAP2C is a human-specific paralog of the ancestral SRGAP2A gene, arising approximately 2.4 million years ago through an incomplete segmental duplication.
“SRGAP2C is a human-specific paralog of the ancestral SRGAP2A gene, arising approximately 2.4 million years ago through an incomplete segmental duplication.”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [90]
SRGAP2C expression leads to increased spine density and prolonged periods of synaptic development (neoteny), features associated with enhanced synaptic plasticity and cognitive abilities in humans.
“Consequently, SRGAP2C expression leads to increased spine density and prolonged periods of synaptic development (neoteny), features associated with enhanced synaptic plasticity and cognitive abilities in humans [90].”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [90]
The Results section on SRGAP2 mRNA expression reports that SRGAP2C is transcribed in human brain, and the Discussion proposes a possible antagonistic function. Neither section addresses increased spine density, prolonged synaptic development, synaptic plasticity, or cognitive abilities; searches for those effects found no supporting passage in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredHumans have four forms of SRGAP2: one ancestral form (SRGAP2A) orthologous to mouse Srgap2 and three human-specific paralogs (SRGAP2B, SRGAP2C, SRGAP2D) produced by incomplete segmental duplication.
“Mice have only one form of the Srgap2 gene, but humans have four forms: one ancestral form (SRGAP2A), which is orthologous to mouse Srgap2, and three human-specific paralogs (SRGAP2B, SRGAP2C, and SRGAP2D) that were produced by incomplete segmental duplication.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Dennis et al., 2012
The human-specific SRGAP2 paralogs emerged when the genus Homo diverged from Australopithecus 2-3 million years ago.
“Thus, the human-specific SRGAP2 paralogs emerged when the genus Homo diverged from Australopithecus 2–3 million years ago (Dennis et al., 2012).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Dennis et al., 2012
Overexpression of SRGAP2C in the mouse brain results in sustained radial migration of neurons, increased spine density, and neoteny during spine maturation, which are human-specific features of neuronal development.
“Overexpression of SRGAP2C in the mouse brain results in sustained radial migration of neurons as well as increased spine density and neoteny during spine maturation, which are human-specific features of neuronal development.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Dennis et al., 2012
SRGAP2C dimerizes with full-length SRGAP2A and inhibits SRGAP2A function in a dominant negative manner.
“With its truncated F-BAR domain, SRGAP2C dimerizes with full-length SRGAP2A and inhibits SRGAP2A function in a dominant negative manner.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Dennis et al., 2012
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- Authors
- Dennis, M. Y., Nuttle, X., Sudmant, P. H., Antonacci, F., Graves, T. A., Nefedov, M., Rosenfeld, J. A., Sajjadian, S., Malig, M., Kotkiewicz, H., Curry, C. J., Shafer, S., Shaffer, L. G., de Jong, P. J., Wilson, R. K., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Washington University in St. Louis (US)
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Eichler, Evan E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 149
- Issue
- 4
- Pages
- 912-922
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3365555
- OpenAlex
- W2008677609
- Cited by
- 407
- References
- 68
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 31 · 2023: 46 · 2022: 20 · 2021: 28 · 2020: 19 · 2019: 36 · 2018: 21 · 2017: 31 · 2016: 30 · 2015: 30 · 2014: 32 · 2013: 28 · 2012: 15
- FWCI
- 20.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health
- National Human Genome Research Institute (HG002385, P01HG004120, R01HG002385, T32HG000035)
- National Institute of General Medical Sciences (GM 058815, R01GM058815)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD071698)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- SRGAP2, gene duplication, human-specific genes, 1q21.1, cortical development, neocortex expansion, human evolution
- MeSH terms
- Animals, Female, Genetics, Medical, Humans, Hydatidiform Mole, Mammals, Molecular Sequence Data, Pregnancy, Primates, In Situ Hybridization, Fluorescence, Evolution, Molecular, GTPase-Activating Proteins, DNA Copy Number Variations, Segmental Duplications, Genomic
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