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 approximately 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.

Figure 1. Comparison of Substitution Rates in HAR1–HAR5

For each HAR element, the estimated substitution rate is indicated by a circle for the human lineage and by a triangle for the chimp lineage. As a benchmark, background human-chimp substitution rates estimated from 4d sites in ENCODE regions [39] are marked with vertical lines, solid red for the genome-wide neutral rate, and dotted blue for the neutral rate in final chromosome bands. The chimp rates in all five elements fall well below the human rates, which exceed the background rates by as much as an order of magnitude. H, human; C, chimp.

Figure 2. Substitution Bias and Acceleration

W→S substitutions (red) increase with acceleration, while S→W substitutions (blue) do not. (A) Proportion of all bases that have W→S and S→W changes versus acceleration in our genome-wide scan of 34,498 elements. The mean proportion of each type of substitution is plotted for four groups based on the amount of acceleration as quantified by the LRT: extreme (p < 4.5e−4), high (4.5e−4 ≤ p < 0.05), medium (0.05 ≤ p < 0.1), and low (p ≤ 0.1). These groups correspond to HAR1–HAR5, HAR6–HAR49, HAR50–HAR202, and the remaining ~34,000 conserved elements. The normal 95% confidence interval for each mean is shown with dotted lines. These are estimates of the unconditional probability P(human = S, ancestor = W) that a base is strong in human and weak in the ancestral consensus sequence, and vice versa. The differences between substitution types are statistically significant in the extreme and high groups. (B) The same plot, but dividing by the proportion of ancestral bases that are weak or strong. These are estimates of the conditional probability P(human = S| ancestor = W) that a base is strong in human, given that the ancestral base is weak, and vice versa. The differences between substitution types are significant in the extreme group only.