What makes us human? In particular, during recent evolution, what genetic mechanisms have allowed the emergence of specific traits characterizing the human brain? These questions represent some of the most challenging problems remaining in biology and have fascinated generations of philosophers, sociologists, anthropologists, geneticists, neuroscientists and evolutionary biologists. The identification of the genetic mechanisms underlying human-specific brain development during evolution will transform our ability to decipher the pathophysiological mechanisms underlying neurodevelopmental disorders affecting humans such as autism or schizophrenia.
In recent years, many potential genetic mechanisms have been proposed to participate in human brain evolution. These include molecular evolution of transcription factors or changes in transcriptional regulation (Enard et al., 2002; Konopka et al., 2009), accelerated evolution of small non-coding RNAs (Pollard et al., 2006), changes in the tissue-specificity of enhancer elements (McLean et al., 2011; Prabhakar et al., 2008), or changes in patterns of alternative splicing of specific genes (Calarco et al., 2007). So far, few studies have assessed the functional consequences of these genomic changes.
Gene duplication is one of the major forces driving evolution and speciation (Ohno, 1970). Recent breakthroughs in evolutionary genomics show that a burst of gene duplications occurred in the human lineage during its separation from non-human primates approximately 6 million years ago (Bailey et al., 2002; Fortna et al., 2004; Marques-Bonet et al., 2009). This has led to the hypothesis that these evolutionarily recent gene duplications might have participated in the emergence of human-specific traits of brain development and function (Bailey and Eichler, 2006; Stankiewicz and Lupski, 2010). However, so far, this portion of the human genome has largely remained unexplored largely because, for technical reasons, it is still poorly assembled (Bailey et al., 2002). The long-term scientific goal of this project is aimed at determining the role of hominoid- and human-specific gene duplications during brain development and evolution. This is a unique scientific paradigm: the first publication determining the role of human-specific gene duplications during brain development came out of our laboratory recently (Charrier et al., 2012) and represents a milestone in our understanding of the genetic and neurobiological mechanisms underlying the emergence of human-specific traits of brain development, for example neoteny during synaptic maturation (Benavides-Piccione et al., 2002; Petanjek et al., 2011).
We first focused on SRGAP2 and its human-specific paralogs because we previously reported that this gene plays important roles during neocortical development, in particular regulating neuronal migration and dendritic branching (Guerrier et al., 2009). SRGAP2 has undergone two main human-specific duplications ((Fortna et al., 2004; Sudmant et al., 2010); see Fig. 1A). We found that the two main human-specific gene duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain involved in membrane deformation. SRGAP2C (but not SRGAP2B) is detected both at the mRNA and protein levels in the fetal and adult human brain and dimerizes through its truncated F-BAR domain with ancestral SRGAP2 but strongly inhibits its function (Charrier et al. 2012). In the mouse neocortex, we discovered that SRGAP2 is required for proper spine maturation and limits spine density in vivo (Figure 1C). Expression of SRGAP2C in cortical neurons in vivo phenocopies SRGAP2 genetic loss-of-function (Charrier et al., 2012). Remarkably, its expression in vivo, in mouse cortical pyramidal neurons, leads to the emergence of human-specific features, including neoteny of spine maturation resulting in increased density of spines with long necks. The group of Dr Evan Eichler has dated the emergence of these human-specific gene duplications to approximately 3.4 and 2.4 million years ago respectively (Dennis et al., 2012) (Figure 1A-B). Of particular interest, the second duplication that gave rise to SRGAP2C arose 2.4 mya which corresponds approximately to the time during evolution where the Australopithecus and Homo lineages diverged and in the fossil record corresponds to the beginning of brain expansion characterizing the Homo lineage (Dennis et al., 2012). These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex by slowing the rate of excitatory synapse maturation and allowing the emergence of more spines per pyramidal neuron, which is a critical feature of human pyramidal neurons (Benavides-Piccione et al., 2002).
We are currently using this new paradigm to define the expression and function of other hominoid- and human-specific gene duplications during brain development and evolution.