title: Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication.
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.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, 98195, USA.
authors.forename: Megan Y
authors.initials: MY
authors.lastname: Dennis
authors.forename: Xander
authors.initials: X
authors.lastname: Nuttle
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sudmant
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonacci
authors.forename: Tina A
authors.initials: TA
authors.lastname: Graves
authors.forename: Mikhail
authors.initials: M
authors.lastname: Nefedov
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Saba
authors.initials: S
authors.lastname: Sajjadian
authors.forename: Maika
authors.initials: M
authors.lastname: Malig
authors.forename: Holland
authors.initials: H
authors.lastname: Kotkiewicz
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.forename: Susan
authors.initials: S
authors.lastname: Shafer
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: de Jong
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations; D019143:Evolution, Molecular; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005826:Genetics, Medical; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008322:Mammals / Q000235:genetics; D008969:Molecular Sequence Data; D011247:Pregnancy; D011323:Primates / Q000235:genetics*; D056916:Segmental Duplications, Genomic
chemical_list: D020690:GTPase-Activating Proteins; C501995:SRGAP2 protein, human