Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication

Megan Dennis, Xander Nuttle, Peter H. Sudmant, Francesca Antonacci, Tina A. Graves, Mikhail Nefedov, Jill A. Rosenfeld, Saba Sajjadian, Maika Malig, Holland Kotkiewicz, Cynthia J. Curry, Susan Shafer, Lisa G. Shaffer, Pieter J. De Jong, Richard K. Wilson, Evan E. Eichler

Research output: Contribution to journalArticlepeer-review

240 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)912-922
Number of pages11
Issue number4
StatePublished - May 11 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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