BookAlex Pollen.
Understanding the genetic changes responsible for the evolution of human traits is a major goal of biology. One of the most distinctive human traits is the dramatic expansion of the forebrain that has occurred over the last six million years. Whole genome sequencing projects have identified millions of genomic differences that separate human and chimpanzee (Chimpanzee Sequencing and Analysis Consortium, 2005). However, connecting particular mutations to evolved human traits such as brain size remains challenging due to the vast number of mutations that have accumulated (Varki and Altheide 2005; Sikela, 2006). Nonetheless, recent evolutionary genetic studies are identifying the most prevalent types of genetic mechanisms contributing to evolved traits in natural populations, and studies of comparative and molecular development are providing an emerging picture for mechanisms by which human brain expansion could have occurred. By combining insights from evolutionary genetics and developmental neurobiology, this thesis aims to identify genomic differences that are particularly likely to have contributed to the evolutionary expansion of the human brain. First, this thesis provides evidence for the role of cis-regulatory mutations in the evolution of natural populations of stickleback fish. Next, this thesis describes a genomic screen we conducted identifying 510 deletions likely to remove cis-regulatory enhancers from the human genome. One of these deletions removes a developmental ventral forebrain enhancer near the tumor suppressor gene GADD45g, the loss of which may release a brake on cell division in particular regions of the brain during neurogenesis. A second deletion removes a developmental dorsolateral neocortex enhancer demonstrating the specificity by which evolution can affect particular regions of the brain. Finally, this thesis identifies a human enhancer near the gene BDNF that drives expression in the nail bed of the digit tips and the stomach, and could influence the distribution and function of mechanoreceptors.