Evolution of Human-Specific Neural SRGAP2 Genes by Incomplete Segmental Duplication

Abstract

SUMMARY Gene duplication is an important source of phenotypic change and adaptive evolution. We use a novel genomic approach to identify highly identical sequence missing from the reference genome, confirming the cortical development gene Slit-Robo Rho GTPase activating protein 2 (SRGAP2) duplicated three times 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 analysis shows SRGAP2C is the most likely duplicate to encode a functional protein and among the most fixed human-specific duplicate genes. Our data suggest a mechanism where incomplete duplication created a novel function —at birth, antagonizing parental SRGAP2 function 2–3 mya a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.

Evolution and diversity of copy number variation in the great ape lineage

“…This has led to speculation that differences in fixation and copy number polymorphism may have contributed to the phenotypic ''plasticity'' and species-specific differences between humans and great apes (Olson 1999;Varki et al 2008). While there is some evidence that fixed deletions and duplications contribute to morphological differences between humans and great apes (McLean et al 2011;Charrier et al 2012;Dennis et al 2012), a comprehensive assessment of these differences at the level of the genome has not yet been performed. Previous studies of CNV have been predominated by array comparative genomic hybridization (CGH) experiments (Fortna et al 2004;Perry et al 2006;Dumas et al 2007;Gazave et al 2011;Locke et al 2011), which provide limited size resolution, are imprecise in absolute copy number differences, and are biased by probes derived from the human reference genome.…”

Rôle de la duplication partielle du gèneSRGAP2dans l’évolution et le développement du cerveau humain

“…Cependant, le produit de cette dernière duplication (SRGAP2D) contient des délétions supplémentaires, et il est peu probable qu'il soit exprimé. Le séquençage complet du génome de plus de 600 individus sains (1 000 Genomes Project) a révélé que seuls SRGAP2A et SRGAP2C présentent un nombre fixe de copies dans le génome humain, alors que le nombre de copies de SRGAP2B varie [6]. Ceci suggère que SRGAP2B est en train de devenir un pseudogène alors que SRGAP2C est potentiellement un nouveau gène spécifiquement humain.…”

“…L'interaction entre SRGAP2A et la forme humaine tronquée SRGAP2C inhibe la fonction de SRGAP2A ( Figure 1B). Ainsi, in vivo, au cours du déve-loppement embryonnaire, SRGAP2A promeut le branchement des neurones pyramidaux, [6]. SRGAP2C inhibe la fonction de SRGAP2A en interagissant avec son domaine F-BAR [7].…”

“…Nous avons donc postulé que ces duplications pouvaient avoir contribué à certains aspects de la spéciation du cerveau humain. [6]. Cette dernière résulte de la fécondation d'un ovocyte humain énu-cléé par un spermatozoïde unique ; elle contient donc un équivalent haploïde du génome humain qui a l'avantage de ne pas présenter de variation allélique.…”

Next stop: Language. The ‘FOXP2’ gene’s journey through time

“…The importance of this gene for lung development had been described in mice even before its mutation in the KE family was linked to language, showing that FoxP2 was neither a gene unique to humans nor unique to the brain. Humanunique genes do exist (Dennis et al, 2012) but FoxP2 is not one of them. FoxP2 exist in all 274 vertebrates studied so far, and it is also among the genes whose sequence barely changed throughout vertebrate evolution.…”