Evidence for the adaptive evolution of mutation rates.

The evidence for the adaptive optimization of mutation rates is much stronger in the case of heritable local mutators. All known local mutators are the result of unique sequence characteristics that predispose specific regions of the genome to particular types of mutation. The best examples come from investigations of pathogenesis, presumably because pathogenesis results in very strong selective pressures favoring high rates of specific types of mutations. Hypermutable sequences generate antigen diversity in pathogens and antibody diversity in hosts. The best known of these are the “contingency loci” of pathogenic prokaryotes, which produce highly specific tuning of mutation rates in particular genes.Contingency loci are antigen- and phase-determinant genes in pathogenic bacteria that switch between functional (on) and nonfunctional (off) states at very high rates (Figure 1Figure 1). In many cases, the genes being switched on and off are primary antigenic determinants, resulting in a pathogen that can vary its antigenic signature abruptly without suffering an increased rate of mutation elsewhere. This switching behavior results from the mutational properties of tandem repetitive DNA (microsatellites) located within the gene or its associated controlling elements (Moxon et al. 1994xMoxon, E.R, Rainey, P.B, Nowak, M.A, and Lenski, R.E. Curr. Biol. 1994; 4: 24–33Abstract | Full Text | Full Text PDF | PubMed | Scopus (455)See all ReferencesMoxon et al. 1994). Microsatellites experience high rates of single-motif insertion and deletion mutations through replication slippage. This generates a high rate of alternating loss-of-function and reversion mutations, which is highly adaptive for the pathogens that carry them.Figure 1General Model of Functional Variability Driven by Hypermutable Microsatellites in Prokaryotic Contingency LociAntigen- and phase-determinant genes containing nontriplet microsatellites turn on and off at high rates due to replication slippage mutations that cause repeat-number changes in the microsatellite. These mutations occur at very high rates (μ ≅ 10-3).View Large Image | View Hi-Res Image | Download PowerPoint SlideAlthough the genes that are controlled by contingency repeats in different organisms are often involved in anti-genicity, the proteins they code for are very diverse, and the repetitive DNAs driving hypermutability are diverse as well (Moxon and Wills 1999xMoxon, E.R and Wills, C. Sci. Am. 1999; 280: 72–77CrossrefSee all ReferencesMoxon and Wills 1999). Most contingency repeats are the longest microsatellite DNAs in their respective prokaryotic genomes, suggesting that they did not arise at these locations by chance. Thus, repetitivity itself is evolving in these sequences, and microsatellites have independently been selected for their mutability many times in response to similar selective pressures.Local mutator systems have evolved in eukaryotic organisms, but some are very different from contingency loci (Deitsch et al. 1997xDeitsch, K.W, Moxon, E.R, and Wellems, T.E. Microbiol. Mol. Biol. Rev. 1997; 61: 281–293See all ReferencesDeitsch et al. 1997). Many of these systems do not generate heritable, germline mutations but rather employ mutational mechanisms that effectively decouple the consequences of hypermutation from the process of long-term evolution. The best characterized example is mammalian antibody diversification by somatic hypermutation. Other systems, such as the cassette-switching system involved in trypanosome antigenic hypervariability, do give rise to heritable mutations, but these mutations too are strictly confined to certain parts of the genome (Figure 2Figure 2).Figure 2Two Ways in which Eukaryotes Have Modified the Rate at which They Produce New Genetic Variants(A) Karl Hogstrand and Jan Bohme have found that regions of mouse MHC genes that are unusually rich in CpG doublets preferentially act as donors and recipients for gene conversion. CpG doublets are generally repressed in eukaryotic genomes and may be retained at these locations specifically for their ability to increase the mutation rate. Conversions in such genes account for a substantial fraction of the new MHC alleles in mice. (Modified from Figure 1Figure 1 of Hogstrand and Bohme [1999].)(B) The expressed variant surface glycoprotein (VSG) genes of trypanosomes change continually during an infection. Expressed antigen alleles (often mosaics) are generated using genetic information (cassettes) stored elsewhere in the genome. The cassettes themselves remain unchanged.View Large Image | View Hi-Res Image | Download PowerPoint SlideThese systems are much more complex and highly regulated than bacterial contingency genes, and it is clear that they have evolved specifically to increase the rate of mutation in localized parts of the genome. Other eukaryotic local mutators, such as the CpG island-associated gene conversions generating diversity at the MHC locus, generate germline genetic changes in a manner more similar to that seen in contingency loci (Figure 2Figure 2). The existence of all of these systems demonstrates that adaptive evolution can produce highly specific mutators in eukaryotes.The high mutation rates experienced in prokaryotic contingency genes and in their eukaryotic counterparts are determined only by the unique sequence characteristics of the genes themselves. The evolution of local mutators does not depend on linkage or population size, factors that can interfere with fixation of global mutators. Local mutators also carry no cost resulting from increased rates of deleterious mutation elsewhere in the genome. The evolution of adaptively variable antigenic determinants in pathogens generates tremendous selective pressure on their hosts to evolve adaptively variable immune defenses, and vice versa. This is an optimal situation for the evolution of mutators (Haraguchi and Sasaki 1996xHaraguchi, Y and Sasaki, A. J. Theor. Biol. 1996; 183: 121–137Crossref | Scopus (28)See all ReferencesHaraguchi and Sasaki 1996).Factors other than host-pathogen interactions may be spurring the evolution of local mutators. Coding-region triplet-repeat microsatellites, which are both common and hypervariable in higher eukaryotes, may provide genetic variability that allows selective fine tuning of protein function (King et al. 1997xKing, D.G, Soller, M, and Kashi, Y. Endeavour. 1997; 21: 36–40Crossref | Scopus (78)See all ReferencesKing et al. 1997). Single-repeat length mutations in these microsatellites alter the length of repetitive amino acid tracts within protein products without generating frameshift mutations. Among humans, some of the longest coding triplet-repeat microsatellites occur in or near proteins that affect neural function, and some of these are long enough to become highly unstable, resulting in genetic disorders such as Fragile X syndrome, Huntington's disease, and spinocerebellar ataxia. Because the human brain has recently undergone considerable directional selection, it is possible that the deleterious effects of these long microsatellites have been counterbalanced, either by second-order selection acting through highly adaptive mutations generated by these hypermutable repeats or by hitchhiking with strongly selected adaptations generated independently of the microsatellites but tightly linked to them. It may soon be feasible to distinguish between these possibilities, through comparisons between the human and chimpanzee genomes.Local mutators do not predict the future, even though they do preferentially produce the very types of mutations likely to increase survival. Hypervariability evolved in antigenic contingency genes because it allowed the ancestors of today's pathogens to repeatedly escape immune clearance by their hosts. Because host immune responses confront pathogens with variable environments that have strong elements of predictability, mutational mechanisms in the pathogens have evolved to generate an appropriately variable antigenic repertoire. The hosts' immune systems have also evolved local mutators of various kinds, in response to pathogen variability. The key is the element of predictability in these interactions. If general environmental change also has elements of predictability, global mutation rates may have evolved toward optimal levels, but such optimization has not yet been clearly demonstrated.‡To whom correspondence should be addressed (e-mail: dmetzgar@biomail.ucsd.edu).