Forces Shaping the Fastest Evolving Regions in the Human Genome

Abstract

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.

The Neutral Theory of Molecular Evolution in the Genomic Era

“…The evolution of these regulatory systems is one of the most important problems in evolutionary biology at present, but unfortunately this issue has not been studied in a comprehensive manner. A number of authors (e.g., 4,11,14,57,134,136) have studied the evolution of cis-regulatory and other elements by using statistical methods and concluded that their evolution was aided by positive selection. However, this conclusion appears to contradict the fact that these elements are generally highly conserved.…”

Human-specific genomic signatures of neocortical expansion

“…So-called human-accelerated regions (HAREs) have been increasingly implicated in cortical evolution [52,58].…”

Noncoding RNA transcription beyond annotated genes

“…Intriguingly, an independent study on expression of intergenic sequences in human and chimpanzee shows conservation of expression of noncoding RNAs in equivalent genomic positions, but not conservation of the RNA sequences, demonstrating that that noncoding RNAs are under expression constraints, particularly in brain [24]. Instead of looking for similarity of expression, Pollard and colleagues [25] looked for differences between human and chimpanzee. They analyzed genomic regions that evolve faster than neutral regions (evidence of positive selection) and identified about 200 of these regions.…”