Fig. 1.
The complementary nature of evolutionary, biochemical, and genetic evidence. The outer circle represents the human genome. Blue discs represent DNA sequences acted upon biochemically and partitioned by their levels of signal [combined 10th percentiles of different ENCODE data types for high, combined 50th percentiles for medium, and all significant signals for low (see Reconciling Genetic, Evolutionary, and Biochemical Estimates and Fig. 2)]. The red circle represents, at the same scale, DNA with signatures of evolutionary constraint (GERP++ elements derived from 34mammal alignments). Overlaps among the sequences having biochemical and evolutionarily evidence were computed in this work (Fig. 3 and SI Methods). The small purple circle represents protein-coding nucleotides (Gencode). The green shaded domain conceptually represents DNA that produces a phenotype upon alteration, although we lack well-developed summary estimates for the amount of genetic evidence and its relationship with the other types. This summary of our understanding in early 2014 will likely evolve substantially with more data and more refined experimental and analytical methods.