Human brain evolution: from gene discovery to phenotype discovery

Abstract

The rise of comparative genomics and related technologies has added important new dimensions to the study of human evolution. Our knowledge of the genes that underwent expression changes or were targets of positive selection in human evolution is rapidly increasing, as is our knowledge of gene duplications, translocations, and deletions. It is now clear that the genetic differences between humans and chimpanzees are far more extensive than previously thought; their genomes are not 98% or 99% identical. Despite the rapid growth in our understanding of the evolution of the human genome, our understanding of the relationship between genetic changes and phenotypic changes is tenuous. This is true even for the most intensively studied gene, FOXP2, which underwent positive selection in the human terminal lineage and is thought to have played an important role in the evolution of human speech and language. In part, the difficulty of connecting genes to phenotypes reflects our generally poor knowledge of human phenotypic specializations, as well as the difficulty of interpreting the consequences of genetic changes in species that are not amenable to invasive research. On the positive side, investigations of FOXP2, along with genomewide surveys of gene-expression changes and selection-driven sequence changes, offer the opportunity for "phenotype discovery," providing clues to human phenotypic specializations that were previously unsuspected. What is more, at least some of the specializations that have been proposed are amenable to testing with noninvasive experimental techniques appropriate for the study of humans and apes.

Fig. 1.

Identifying human specializations requires, first, determining that humans differ from the chimpanzee–bonobo group (the sister group of humans), and second, determining that the difference evolved in the human lineage. The latter judgement requires evidence about the character states of outgroup taxa, such as other apes and monkeys. For practical reasons, evaluations of human specializations often use a minimal set of comparisons, involving humans, chimpanzees, and macaque monkeys (Inset). Humans and chimpanzees diverged 6 to 8 Mya, and the lineage leading to macaque monkeys diverged from the human-ape lineage ∼25 Mya. Modified from ref. .

Fig. 2.

Gene discovery starts with an unusual, heritable phenotype, and then proceeds to determine the chromosomal locus of the mutation, and finally to identify mutated gene itself. Phenotype discovery starts with species differences in genes or gene expression, identified through gene discovery, comparative genomics, or other comparative molecular methods, and proceeds to identify the biochemical, cell-biological, and other phenotypic consequences of the genetic differences.