Novel brain-expressed noncoding RNA, HSTR1, identified at a human-specific variable number tandem repeat locus with a human accelerated region

The evolutionary conserved genomic sequences that have acquired significantly increased number of nucleotide substitutions specifically in the human lineage, called human accelerated regions (HARs), have been identified as candidate genomic regions that have contributed to the evolution of human-specific traits. A number of HARs were indeed shown to have novel enhancer activity and be associated with human-specific brain development and with cognition and social behavior. It is therefore of great importance to investigate the details of genomic function of each HAR to understand the roles of HARs as critical contributors to the genetic basis of human evolution. In this study, we identified a previously unannotated brain-expressed noncoding RNA gene, HSTR1, at a human-specific tandem repeat locus. Notably, the 5' flanking sequence of HSTR1 showed the signature of HARs and the dramatic human-specific enhancement of promoter activity, providing the evidence of positive selection to increase the expression level of HSTR1 during human evolution. We also revealed that the tandem repeat number in HSTR1 was highly variable among individual alleles and affected the stability of HSTR1 RNA, suggesting variation in the activity of HSTR1 between human individuals. Our work thus provides a novel candidate gene that potentially contributed to the evolution of the human brain. It may also underpin some of the variation between human brains.