Transcriptional Enhancers in the FOXP2 Locus Underwent Accelerated Evolution in the Human Lineage.

Unique human features, such as complex language, are the result of molecular evolutionary changes that modified developmental programs of our brain. The human-specific evolution of the forkhead box P2 (FOXP2) gene-coding region has been linked to the emergence of speech and language in the human kind. However, little is known about how the expression of FOXP2 is regulated and whether its regulatory machinery evolved in a lineage-specific manner in humans. In order to identify FOXP2 regulatory regions containing human-specific changes, we used databases of human-accelerated noncoding sequences or HARs. We found that the topologically associating domain determined using developing human cerebral cortex containing the FOXP2 locus includes two clusters of 12 HARs, placing the locus occupied by FOXP2 among the top regions showing fast acceleration rates in noncoding regions in the human genome. Using in vivo enhancer assays in zebrafish, we found that at least five FOXP2-HARs behave as transcriptional enhancers throughout different developmental stages. In addition, we found that at least two FOXP2-HARs direct the expression of the reporter gene EGFP to foxP2-expressing regions and cells. Moreover, we uncovered two FOXP2-HARs showing reporter expression gain of function in the nervous system when compared with the chimpanzee ortholog sequences. Our results indicate that regulatory sequences in the FOXP2 locus underwent a human-specific evolutionary process suggesting that the transcriptional machinery controlling this gene could have also evolved differentially in the human lineage.

Spectrin ßV adaptive mutations and changes in subcellular location correlate with emergence of hair cell electromotility in mammalians.

The remarkable hearing capacities of mammals arise from various evolutionary innovations. These include the cochlear outer hair cells and their singular feature, somatic electromotility, i.e., the ability of their cylindrical cell body to shorten and elongate upon cell depolarization and hyperpolarization, respectively. To shed light on the processes underlying the emergence of electromotility, we focused on the ßV giant spectrin, a major component of the outer hair cells' cortical cytoskeleton. We identified strong signatures of adaptive evolution at multiple sites along the spectrin-ßV amino acid sequence in the lineage leading to mammals, together with substantial differences in the subcellular location of this protein between the frog and the mouse inner ear hair cells. In frog hair cells, spectrin ßV was invariably detected near the apical junctional complex and above the cuticular plate, a dense F-actin meshwork located underneath the apical plasma membrane. In the mouse, the protein had a broad punctate cytoplasmic distribution in the vestibular hair cells, whereas it was detected in the entire lateral wall of cochlear outer hair cells and had an intermediary distribution (both cytoplasmic and cortical, but restricted to the cell apical region) in cochlear inner hair cells. Our results support a scenario where the singular organization of the outer hair cells' cortical cytoskeleton may have emerged from molecular networks initially involved in membrane trafficking, which were present near the apical junctional complex in the hair cells of mammalian ancestors and would have subsequently expanded to the entire lateral wall in outer hair cells.

Genetic Mechanisms Underlying Cortical Evolution in Mammals.

The remarkable sensory, motor, and cognitive abilities of mammals mainly depend on the neocortex. Thus, the emergence of the six-layered neocortex in reptilian ancestors of mammals constitutes a fundamental evolutionary landmark. The mammalian cortex is a columnar epithelium of densely packed cells organized in layers where neurons are generated mainly in the subventricular zone in successive waves throughout development. Newborn cells move away from their site of neurogenesis through radial or tangential migration to reach their specific destination closer to the pial surface of the same or different cortical area. Interestingly, the genetic programs underlying neocortical development diversified in different mammalian lineages. In this work, I will review several recent studies that characterized how distinct transcriptional programs relate to the development and functional organization of the neocortex across diverse mammalian lineages. In some primates such as the anthropoids, the neocortex became extremely large, especially in humans where it comprises around 80% of the brain. It has been hypothesized that the massive expansion of the cortical surface and elaboration of its connections in the human lineage, has enabled our unique cognitive capacities including abstract thinking, long-term planning, verbal language and elaborated tool making capabilities. I will also analyze the lineage-specific genetic changes that could have led to the modification of key neurodevelopmental events, including regulation of cell number, neuronal migration, and differentiation into specific phenotypes, in order to shed light on the evolutionary mechanisms underlying the diversity of mammalian brains including the human brain.