Inhibition of SRGAP2 Function by Its Human-Specific Paralogs Induces Neoteny during Spine Maturation

Structural genomic variations represent a major driving force of evolution, and a burst of large segmental gene duplications occurred in the human lineage during its separation from nonhuman primates. SRGAP2, a gene recently implicated in neocortical development, has undergone two human-specific duplications. Here, we find that both duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain. SRGAP2C is expressed in the developing and adult human brain and dimerizes with ancestral SRGAP2 to inhibit its function. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. Expression of SRGAP2C phenocopies SRGAP2 deficiency. It underlies sustained radial migration and leads to the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex and plays an important role during human brain development. [Display omitted] ► SRGAP2 has undergone two partial duplications, specifically in the human genome ► One copy (SRGAP2C) is expressed in the human brain and antagonizes ancestral SRGAP2 ► Ancestral SRGAP2 promotes dendritic spine maturation and limits spine density in vivo ► Human SRGAP2C induces neoteny and leads to higher density of spines with longer necks A truncated duplicate gene present only in humans antagonizes the function of its parental paralog in neural development, leading to human-specific neuronal features such as increased dendritic spine density.