Forces Shaping the Fastest Evolving Regions in the Human Genome

Comparative genomics allow us to search the human genome for segments that were extensively changed in the last ~5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements are dramatically changed in human but not in other primates, with seven times more substitutions in human than in chimp. The accelerated elements, and in particular the top five, show a strong bias for adenine and thymine to guanine and cytosine nucleotide changes and are disproportionately located in high recombination and high guanine and cytosine content environments near telomeres, suggesting either biased gene conversion or isochore selection. In addition, there is some evidence of directional selection in the regions containing the two most accelerated regions. A combination of evolutionary forces has contributed to accelerated evolution of the fastest evolving elements in the human genome.
Synopsis Studies of differences between the chimpanzee and human genomes have focused on protein-coding genes. However, examples of amino acid changes between chimp and human have not been able to explain most of the phenotypic differences between us and our fellow hominoids. King and Wilson (1975) proposed that the main differences between chimps and humans will be found in non-coding regulatory DNA. Consistent with this hypothesis, recent whole-genome scans for evolutionarily conserved DNA elements that have evolved rapidly since our divergence from the chimp-human ancestor have discovered largely non-coding regions. The authors investigate a carefully screened set of 202 such human accelerated regions (HARs). Most of these HARs do not code for proteins, but instead are located in introns and intergenic regions near protein-coding genes. The set of genes near HARs is enriched for transcription factors, suggesting that the HARs may play important roles in gene regulation. This study also discovers a striking adenine and thymine to guanine and cytosine bias among the human-specific changes in HARs. This suggests the involvement of biased gene conversion or a selective force to increase guanine and cytosine content. Some HARs may also have been under positive selection. Hence, there is likely more than one evolutionary force shaping the fastest evolving regions of the human genome.