Human Accelerated Regions (HARs) and Changes in Conserved Sequences

Conserved sequence refers to regions of DNA that have been unchanged or minimally changed throughout mammalian evolution, including that of the primate lineage. A great deal of research has been performed looking for human-specific changes in these conserved regions, and the body of evidence led to the definition of Human Accelerated Regions (HARs), regions of evolutionarily conserved sequence that are significantly changed in humans. 49 such regions have been defined. In addition to studies of HARs, work focusing specifically on genomic loss has found 500 deletions specific to humans in otherwise conserved sequences.

These changes in highly conserved regions are theoried to influence human-specific phenotypic features significantly, and the majority of HARs and human-specific deletions are found in non-coding regulatory regions involved in gene expression. Many of the HAR sequences are predicted to be enhancers and other regulatory signals, while others may encode structural sites and RNA genes. Additionally, many changes in HARs are predicted to have created or destroyed transcription factor genes. Further examination of the HARs most divergent from ancestral sequences has shown that HAR1 is a novel RNA gene expressed in the neocortex during development, and that HAR2 is a limb enhancer with human-specific gene expression in the embryonic hand.

Recent work examining HARs in the context of Neandertal and Denisovan genomes has suggested that mutations in HARs have come to fixation faster in the human genome than other non-HAR genomic mutations, and that HAR substitutions tend to occur episodically over time. 8% of these HAR substitutions were not found in either archaic hominin genome, suggesting that they had not yet become fixed in the genome of the common ancestor of modern humans and archaic hominins.

A study examining intragenic clustering of human accelerated elements found that the transcription factor neuronal PAS domain-containing protein 3 (NPAS3) has the largest population of noncoding-accelerated regions. NPAS3 is active during mammalian brain development and the human accelerated elements within this locus predominantly appear to act as transcriptional enhancers and thus may have influence human brain evolution.