Principles of Protein Structure - H. Schulz 1982

Protein Evolution
Protein Specialization
Frequency of Tolerated Mutations

Biological specialization is established through random Mutations followed by Selection. Mutations occurring in the DNA are of primary importance. Table 9.1 lists approximate DNA mutation rates for higher organisms. In these organisms, the rates of permissible mutations at the DNA level do not significantly affect protein selection, since the structural regions [78, 475] encoding Proteins comprise less than 10% of the DNA (sec. 4.1). Nevertheless, it has been established that DNA is homogeneous within a single species [476, 477], which indicates the existence of some selection operating at the DNA level as well. The question of whether this homogeneity is determined by a small ancestral population and a low "Genetic Drift" (the non-Darwinian hypothesis supported by "neutralists" [144, 478—480]) or whether it reflects the selection of the best-adapted DNA of a given species (the Darwinian hypothesis supported by "selectionists") remains a subject of debate (cf. [481, 482]).

Class="center">Table 9.1 Rates of macromolecular evolution^a

^a All values are rough estimates and may represent atypical cases. DNA here denotes non-repetitive DNA.

Genetic distance is measured in PAM units. At the macromolecular level, the mutation fixation rate (also referred to as The rate of acceptance) is generally expressed as the number of accepted point mutations per codon per 10¹⁰ years, which is numerically equivalent to the percentage of fixed point mutations per 10⁸ years. The percentage of fixed point mutations (the PAM unit) is a universally accepted measure of evolutionary distance. The reciprocal of the fixation rate is the "unit evolutionary period," i.e., the number of years required for one fixed codon change per 100 residues to occur.

Selection of nucleotide sequences operates at the DNA level. Due to the degeneracy of METABOLISM/28.html">The Genetic Code, only 75% of all mutations in the structural region of DNA affect the protein sequence [144, 483]. The remaining 25% constitute so-called silent mutations, in which different codons specify the same amino acid (Fig. 1.5, b). Since all codons for a given amino acid are utilized (albeit with varying frequencies [12, 13, 145]), there are no constraints at the protein level, and the rates of silent mutations should be approximately 25% of the maximum DNA mutation rates. The mutation rates of Messenger RNA (mRNA) encoding hemoglobin chains [484, 485] are approximately one-quarter of the mutation rates of hypervariable DNA nucleotide sequences (Table 9.1). Thus, it appears to correspond to the maximum rates of silent mutations. The silent mutation rate of histone IV mRNA is three times lower than that of hemoglobin mRNA (Table 9.1). A single sea urchin Cell contains 1,200 copies of active histone IV genes [487]; the corresponding 1,200 tRNA sequences appear to be homologous within a given species [486], although they differ among species. This fact serves as further evidence that the selection of nucleotide sequences occurs at the DNA level.

Selection at the protein level is generally significantly more constrained than at the DNA level. This is evident from a comparison of The amino acid substitution rates in hemoglobin and histone IV with the rates of silent mutations in the corresponding tRNAs (Table 9.1). Substitution rates vary widely across different proteins. Comparing the extreme cases—Histones IV and hypervariable protein segments—their substitution rates differ by three orders of magnitude (Table 9.1). Such differences indicate that preserving The Structure of a given protein is crucial for its biological function. Histone IV is encoded within the central part of the DNA, and any alteration in its Amino Acids can lead to catastrophic consequences. The evolution of histone IV strictly follows the Darwinian pathway; mutations are practically never fixed. In contrast, the hypervariable region of Ribonuclease apparently lacks a specific function [488], and changes within it are fixed much more readily. In this case, a non-Darwinian pathway of evolution can be assumed [489].