Detection of selection on the regulation of neural genes in humans

Abstract

Identifying genetic changes underlying human specific traits is one of the major goals in evolutionary studies. Recently, the rapid evolution of next generation sequencing technology has greatly increased the number of available genomes of various species. Thus, a sharp increase in the genomic data has opened a new dimension to the study of comparative genomes. However, our incomplete knowledge of noncoding regions limits the functional interpretation of underlying DNA variants. Epigenetics is known to help understanding the function of non-coding regions that are unexplainable by genetics only. Epigenomic signatures can mark the location of functional elements and provide systematic information on the spatiotemporal specificity of their regulatory activities. Thus, interpretation of genetic modifications in noncoding regulatory regions through epigenetic genetic data seem to be critical in understanding the evolutionary process of human with epigenetic data. In the thesis, I analyzed the population genomes of humans, non-human primate, and ancient human and used transcripts and epigenetic data of human and non-human primate brain cells. I found that the expression of a gene that plays an important role in sympathetic nervous system was specifically low in human and chimpanzee brain. On the basis of three-dimensional chromatin structure, I identified a cis-regulatory region for the gene. In addition, I have experimentally verified the function of the predicted regulatory region through CRISPR/Cas9 genome editing. Also, I found that the regulatory region has received a positive selection in human and chimpanzee using a variety of evolutionary statistical methods. However, human evolution has undergone dramatic changes such as transition from hunting to agriculture, therefore there is a limit to understanding human evolution only by interspecific comparisons. So, I efforted to find the recent evolutionary traces using Paleogenomics. To do this, I compared the population genomes of 12 European ancients, Neanderthal, and Denisovain with modern human. I found that for a long time under balancing selection where the variant exists has been positively selected in the modern population at a rapid rate during the recent adaptation period. I found that variants, which have been under balancing selection for a long time, are positively selected at a rapid rate in the modern population during the recent adaptation period. There was enrichment of functional changes in regulatory sequences relative to flanking genomic regions. The related genes were significantly associated with neural development, cognitive or behavioral traits, and psychiatric disorders. In conclusion, I detected selective pressure for enhanced sympathetic nervous activity in the evolution of humans. Also, through analysis of population genetics of ancient and modern people, I found that some genetic factors underlying cognitive function common in present-day humans have existed for a long time under balancing selection in ancestral populations, until they were driven to fixation during recent adaptive changes. Therefore, my results elucidate the regulatory implications of genetic modifications for human evolution and will likely facilitate further related studies.