the gorilla sequence agrees with the human what was the sequence of the leptin gene in the last common ancestor? The most economical assumption is that evolution minimum number of mutations consistent with the data. Thus, it seems likely that chimp TACCAACAGATCCTCACCAGTATGCCTTCCAGAAACATGATCCAAATATCCAACGACCTG protein Y  Q  Q  I  L  T  S  M  P  S  R  N  M  I  Q  I  S  N  D L the leptin sequence of the last common has followed a pathway requiring the ancestor was the same as the human and chimpanzee sequences when they agree; when they disagree, the gorilla sequence would be used as a tiebreaker. For convenience, only the first 300 nucleotides of the leptin-coding sequences are given. The remaining 141 are identical between humans and chimpanzees.
Figure 4–65 The very different rates of evolution of exons and introns, as illustrated by comparing a portion of the mouse and human leptin genes. Positions where the sequences differ by a single nucleotide substitution are boxed in green, and positions that differ by the addition or deletion of nucleotides are boxed in yellow. Note that, thanks to purifying selection, the coding sequence of the exon is much more conserved than is the adjacent intron sequence.
based on radioisotope decay in the rock formations in which fossils are found. Because the fossil record has many gaps, however, precise divergence times between species are difficult to establish, even for species that leave good fossils with distinctive morphology.
Phylogenetic trees whose timing has been calibrated according to the fossil record suggest that changes in the sequences of particular genes or proteins tend to occur at a nearly constant rate, although rates that differ from the norm by as much as twofold are observed in particular lineages. This provides us with a molecular clock for evolution—or rather a set of molecular clocks corresponding to different categories of DNA sequence. As in the example in Figure 4–65, the clock runs most rapidly and regularly in sequences that are not subject to purifying selection. These include portions of introns that lack splicing or regulatory signals, the third position in synonymous codons, and genes that have been irreversibly inactivated by mutation (the so-called pseudogenes). The clock runs most slowly for sequences that are subject to strong functional constraints—for example, the amino acid sequences of proteins that engage in specific interactions with large numbers of other proteins and whose structure is therefore highly constrained, or the nucleotide sequences that encode the RNA subunits of the ribosome, on which all protein synthesis depends.
Occasionally, rapid change is seen in a previously highly conserved sequence. As discussed later in this chapter, such episodes are especially interesting because they are thought to reflect periods of strong positive selection for mutations that have conferred a selective advantage in the particular lineage where the rapid change occurred.
The pace at which molecular clocks run during evolution is determined not only by the degree of purifying selection, but also by the mutation rate. Most notably, in animals, although not in plants, clocks based on functionally unconstrained mitochondrial DNA sequences run much faster than clocks based on functionally unconstrained nuclear sequences, because the mutation rate in animal mitochondria is exceptionally high.
Categories of DNA for which the clock runs fast are most informative for recent evolutionary events; the mitochondrial DNA clock has been used, for example, to chronicle the divergence of the Neanderthal lineage from that of modern Homo sapiens. To study more ancient evolutionary events, one must examine DNA for which the clock runs more slowly; thus the divergence of the major branches of the tree of life—bacteria, archaea, and eukaryotes—has been deduced from study of the sequences specifying ribosomal RNA.