Genetic bases of human unique traits

Abstract

Being human, we possess unique biological features, such as the big brain, upright walking and sophisticated language, which set us apart from our close relatives, the non-human primates since our divergence from the Pan lineage approximately 5 million years ago. Scientists have attempted to solve the mystery of our unique phenotypic traits with approaches from paleoanthropology, anatomy, psychology, behavior and social cognition etc. However, the answers are embedded in our genetic makeup. What are the genetic changes in our genome that make us human? By comparing the genomes of humans and nonhuman primates, scientists have identified a lot of genetic changes that might have contributed to the human-specific traits. These genetic changes work at different genetic levels, including sequence changes in protein-coding genes, gene expression changes, gene losses and gene duplications. Natural selection is the driving force pushing fixation of these genetic changes during human evolution, and they may have important contribution to human’s unique phenotypes. In this review, we mainly discuss the relationship between human-specific phenotypes and genetic changes. We summarize our current findings and understandings of genes with human-specific mutations and their possible functional effects. For example, a set of brain-size regulating genes have been identified and many of them showed strong signatures of Darwinian positive selection during primate evolution and human origin. These human-specific mutations likely work their ways through human brain development and eventually form a large brain. Another fascinating example is the language gene FOXP2 that has two human specific mutations, which may lead to a unique developmental pattern change of the human brain region responsible for human language ability. Furthermore, besides protein coding genes, there are other genetic changes, and many identified fast-evolving regions in the human genome are not located in the coding sequences. Instead they are distributed in regulatory sequences likely involved in gene expression regulation which affect the temporal and spatial pattern of human development. Finally, we introduce the recent advance of technologies that can be used to study the functional outcomes of the human specific mutations. These technologies provide useful tools that may reproduce the scenes of human evolution in the laboratory. The in vitro analysis of humanized iPSCs can to some extend mimic the in vivo development of the human brain. Notably, the newly developed gene editing tools including CRISPR-Cas9 and TALEN are promising in studying the human-specific traits using transgenic animal models, especially the transgenic monkey models which may provide much more mechanistic information than the traditional mouse model. The human-specific genetic changes accumulated during human evolution occurred at different levels, but they must work together to produce the human-specific traits. Future studies may establish the links by figuring out how changes at different genetic levels coordinate with each other to make us human.