HARs: History, Functions, and Role in the Evolution and Pathogenesis of Human Diseases

Abstract

Abstract—: It is thought that changes in mechanisms of gene regulation have played the critical role in human evolution, rather than changes in protein-coding sequences. Recent studies have discovered a special class of genome elements, human accelerated regions (HARs). These elements are conserved non-coding DNA sequences of mammals that have been accumulating human-specific mutations throughout the evolution. Starting from their discovery, the actual role of HARs in human evolution has remained unclear, since they are almost exclusively represented by non-coding sequences with no annotations. It is now known that HAR elements are enriched with binding motifs of transcription factors and histone markers of active chromatin. Recent investigations using functional genomics, computational methods, and genetic analysis have demonstrated that many HARs participate in the genetic regulation of development and have made a major contribution to the evolution of the human brain—in particular, the enlargement of the cerebral cortex. Furthermore, there is much evidence that there is relationship between the polymorphisms of HAR sequences and development of various neurological diseases, such as autism spectrum disorders, schizophrenia, and Huntington’s disease. Such functional methods of analysis as massively parallel reporter assay and screenings using the CRISPR system significantly increase the amount of described regulatory elements specific for human beings. Further investigation of HARs and other evolutionary dynamic genome regions might clarify sophisticated evolutionary changes underlying the unique cytoarchitecture and cognitive abilities of the human brain. Here, we have elucidated the approaches to HAR identification in the genome and their role in regulation of gene activity and effect on the evolution of the human brain and reviewed certain pathological effects of mutations in HAR sequences.