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Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication |
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| Authors: | Dennis Megan Y Nuttle Xander Sudmant Peter H Antonacci Francesca Graves Tina A Nefedov Mikhail Rosenfeld Jill A Sajjadian Saba Malig Maika Kotkiewicz Holland Curry Cynthia J Shafer Susan Shaffer Lisa G de Jong Pieter J Wilson Richard K Eichler Evan E |
| Institution: | 1 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA 2 Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195, USA 3 The Genome Institute at Washington University, Washington University School of Medicine, St. Louis, MO 63110, USA 4 Children's Hospital Oakland Research Institute, Children's Hospital and Research Center at Oakland, Oakland, CA 94609, USA 5 Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA 6 Genetic Medicine Central California, University of California, San Francisco, Fresno, CA 93701, USA 7 Carle Clinic Association, Urbana, IL 61801, USA |
| Abstract: | 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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