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Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection

Figure 7

Functional mutations associated with DHS gains and losses.

(a–e) Scatterplots showing the enrichment of AP1 motif matches in species with increased hypersensitivity. Each “x” represents a single DHS site. (a–c) positive values on each axis indicate better motif matches on the human branch. For these regions, points in the upper-right quadrant are regions where the AP1 motif scores better in human than either chimp or macaque, where the lower left represent AP1 motif scores worse in human. The number of DHS sites in these quadrants are indicated. (d–e) For chimp gain and loss regions, positive values for each axis indicate a better motif match in the chimp branch. (f) The AP1 motif from JASPAR and an example alignment of a representative human gain region representing a point along the diagonal in the upper-right quadrant in panel a. (g) Boxplots summarizing the results from AP1 and three other motifs. The boxplots show the distribution of (combined) log-ratios (relative to the appropriate species). P values for differences relative to common regions are significant (asterisk) in all 4 comparisons: human DHS gains, P<10−31; human DHS losses P<10−3; chimp DHS gains, P<10−13; chimp DHS losses, P<10−8 (Materials and Methods). In AP1, the significant trends illustrate the same principal observed in panels a–e. Most other transcription factors have plots that show no pattern in motif score among species, such as SP1 and SOX10 (Supplemental data file 3 in Dataset S1). ZEB1, a transcriptional repressor, displays an inverse relationship with hypersensitivity.

Figure 7