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Evolution of Evolution
Genomic Strategies for Evolutionary Adaptation:
The rate, location and extent of genetic variation is not monotonousLynn Helena Caporale
Sherman Square
New York, N.Y. 10023
212-877-9653 (phone and fax)
caporale@usa.netAbstract
The probability of mutation differs in different organisms, different tissues, different physiological states, and at different positions in the genome. This variation in the rate of genetic change arises from the effects a nucleic acid sequence has on the nucleic acid's structure, the activity and fidelity of enzymes that copy, repair, and recombine it, and the probability of insertion of mobile elements. The fidelity of enzyme complexes that copy, move, and repair nucleic acids differ among each other and differ along the sequence of each substrate.
As a property of biological organisms, the rate, extent and location of genetic change has experienced natural selection. Thus, sites in the genome at which genetic variation would be most damaging are under pressure to evolve lower rates of mutation; conversely, exploration of sequence variation may be increased at certain locations in the genome, as is seen in the immune system. Recognition signals can target genetic exploration to sequences that genomes have "learned", through natural selection, have the highest potential to yield new functions. The efficiency with which populations of organisms adapt to novel environments falls under natural selection, and has evolved.
Genome-encoded information that modulates the rate of genetic variation can be found in the sequences of introns and intergenic regions. In addition, because the genetic code is degenerate, information can evolve within protein coding regions to modulate the probability of genetic variation at sites within a gene.
Introduction
For the past three decades, knowledge of the 64 codon genetic code has allowed us to translate the sequence of protein coding regions in terms of letters and words. But a more sophisticated reader gathers concepts from the text. The explosion in DNA sequences available for analysis, including the entire genome of certain organisms, and the growing sophistication of computational tools, increasingly allows us to direct broad, "conceptual", questions to the information in these databases (Moxon 1995, Tamames et al. 1996).
Among higher-level concepts expressed by the genome of an organism are strategies for differentiation, and interacting pathways (neuronal, hormonal, inflammatory, immune, stress) by which to respond effectively to alterations in the environment during the life of the individual.
It is the purpose of this discussion to focus attention on an additional strategy encoded in a genome, and to provide a conceptual framework through which to view the expanding DNA sequence databases. This framework supports exploration of what must be a central feature of evolution: the efficiency with which a lineage of organisms is able to adapt to a new environment itself undergoes natural selection; that is, evolution is a biological function of populations of organisms, challenged by natural selection. Strategies for efficient adaptation evolve.
Nucleic acid sequence-dependent effects on the rate of genetic variation
The adjective frequently applied to the process of "mutation" is "random". However the probability of genetic change is not identical for every nucleotide in a genome. DNA sequence affects DNA structure (Rich, 1982), the fidelity of DNA polymerase (Roberts et al, 1993), and mismatch repair processes (Gläsner et al 1995). The copying of RNA retrotransposons exhibits decreased and non-random fidelity patterns (Gabriel et al, 1996). Also at the RNA level, sequence-dependent genetic variation results from induction of enzymes that edit RNA (Simpson and Maslov, 1994).
Because polymerase fidelity is sequence context-dependent, the fidelity of a polymerase that repeatedly copies a given DNA sequence will affect the evolution of that DNA sequence. Nucleotide sequences for which polymerase fidelity is high will, after many rounds of replication, be more conserved than sequences for which polymerase fidelity is lower.
Similarly, targeted mismatch repair (an enzymatic process that "corrects" one strand of DNA when the complementary base on the other strand does not obey A/T G/C pairing), when biased with respect to the direction of "repair", can result in nonrandom genetic alteration (Gläsner et al 1995).
Certain mutations arise by "correction", to palindromic DNA, of quasipalindromic secondary structures formed on the lagging strand when it becomes single-stranded during nucleic acid replication. Thus, context-dependent effects upon genetic variation include mutations that appear to have been "templated" by neighboring DNA sequences, with specific DNA sequences associated with mutation "hotspots" and other "predictable" genetic alterations (Glickman and Ripley, 1984; Trinh and Sinden, 1991, Rosche et al. 1997) with implications for human genetic disease (Gordenin et al. 1997).
The insertion and excision of DNA sequences is regulated in a wide range of organisms (Schläppi et al. 1993) with mobile elements often targeted to specific classes of sequences. For example, the activity of transposable elements mariner is affected by the elements' nucleotide sequences, by adjacent flanking sequences, and by longer-range position effects (Medhora et al. 1991); the behavior of these elements in turn affects the stability of other sequences (Morgan 1995).
A variety of enzymatic mechanisms for genetic variation have evolved with qualitatively different effects (Arber 1997); these mechanisms modulate local nucleotide variation, rearrange DNA sequences present in the genome, and enable the acquisition of new DNA sequences through horizontal gene transfer (Kidwell 1993, Hartl 1997). Thus, evolution can work on a far more colorful palette than simple random nucleotide change.
Leveraging Genetic Experience: Duplication of genes and fragments of genes
Adaptation to environmental challenges can be expedited by harnessing preexisting information, whether present in the organism or in the environment. The spread of antibiotic resistance on plasmids (Arber, 1997; Shapiro, 1992) illustrates the power of a strategy that has evolved for capturing useful genetic information. Plasmids are an evolutionary innovation that allows bacteria to sample DNA from neighboring organisms; antibiotic-resistant populations expand more rapidly using plasmids than via bacteria descendent from individual successful random mutants.
A more general strategy for leveraging useful genetic information is through duplication, followed by variation, of functional segments of DNA. Examination of protein structure (Walsh and Neurath, 1964) reveals duplication of genes, or regions within genes, as an important mechanism of evolution. Large gene families have evolved, encoding structurally homologous proteins (see, e.g. www.sanger.ac.uk/pfam/browse.shtml).
A familiar example, the serine proteases, comprise a large family of protein endohydrolases (Stroud, 1974); their conserved three-dimensional framework aligns an "oxyanion hole", which polarizes the scissile bond of the protein or peptide substrate, with an appropriately-positioned serine residue; this serine is unusually nucleophilic due to its position as part of a catalytic triad with histidine and aspartic acid.
Once the first serine protease evolved, something with broader evolutionary implications than a single serine protease was evolving. A genetic "concept" of how to achieve targeted protease activity using the nucleophilic potential of the serine hydroxyl group had evolved. If the original serine protease was not very rapid or selective, duplicates could evolve with more targeted activity. A lineage that explores variation around a functional framework will have a strong selective advantage over populations that must test every mutation and every insertion site.
Additional functions (e.g., for coagulation proteases, the ability to bind to the platelet surface) evolve by combination of DNA encoding a serine protease domain with DNA encoding other functions (Furie and Furie, 1988).
Regulatory regions also can be duplicated and moved to new loci, thus facilitating the exploration of the phenotypic results of linking, through regulation, sets of structurally unlinked loci (Ruddle et al. 1994, Schläppi et al. 1993, Shapiro, 1992, Arber 1997, Halder et al. 1995). Antigenic conversion in trypanosomes illustrates the rotation of a set of genes into the influence of a regulatory region (Borst and Cross 1982), a strategy that protects the parasite from host defenses.
Much as the use of interchangeable parts enabled the industrial revolution (Hays, 1957) the use of "interchangeable" DNA sequence fragments as raw materials represents an efficient path to the evolution of functionally useful combinations of structures. As useful units evolve from patching of sequences, these larger units, whether structural or regulatory, can in turn be duplicated (Ruddle et al. 1994), and form the basis of a new "family". Functional regions of DNA ranging in size from gene fragments (Gilbert 1978, Martin 1997) to, perhaps, entire genomes (Wolfe and Shields, 1997) appear to have been copied and/or pasted together. The first example of a truly patchwork gene to be sequenced, the LDL receptor, is made up of exons that are homologous to a diverse set of individual proteins (Südhof, 1985). Patchwork genes evolve through combination of diverse structural motifs and functional domains.
Evolution of the biochemical capability to duplicate functional genes and other pieces of DNA can be seen as an example of what has been termed second order selection, that is, selection of functions that ensure a certain degree of genetic diversity in a population, facilitating adaptation to a changing environment (Arber 1993 and 1997).
Gene families exhibit a nonrandom pattern of genetic variation
When proteins within a gene family are compared, certain sequence regions exhibit much higher conservation than other regions (see e.g. Hill and Hastie, 1987, Horrevoets et al. 1993). It generally is accepted that the fixation, over a neutral background (Kimura 1979, Ohta 1996, Kreitman 1996), of a higher percentage of alterations in certain regions is a result of random mutation followed by selection for those individual variants that alter the protein sequence in such a way as to provide a phenotypic advantage, and selection against those individual variants that are destructive of function.
That is, for serine proteases, the relative conservation of the protein sequence of scaffold and catalytic residues is said to be explained by the statement that genetic alterations that damage the conserved 3-dimensional protein scaffold, or which remove key catalytic residues, would be selected against in the evolution of each individual protease.
Such an analysis assumes an equal probability of genetic alteration at any position in the duplicated gene (i.e. mutation is random with respect to position in the gene), so that a mutation is, for example, just as likely to knock out the active site serine, destroying the serine protease activity, as it is to alter an amino acid in the specificity binding site, creating a new serine protease.
Thus, while it is accepted that protein families evolve by duplication, mutation, and selection (i.e. taking advantage of preexisting genetic information rather than by convergent evolution by mutation from a random sequence), it still is generally assumed that the mutation process itself within protein families is random with respect to DNA sequence.
However, a more efficient process than nucleotide-by-nucleotide trial and error would evolve. Consider two populations of organisms with different DNA sequences underlying identical serine protease protein sequences; for one population (for example due to differences in polymerase fidelity, mismatch repair, or recombination frequency) the underlying DNA sequence might be more likely to vary at the active site serine compared to specificity determining residues; for the other, the underlying DNA sequence might be less stable at the specificity-determining residues.
The lineage of organisms for which fidelity of the relevant polymerase was highest for the catalytic triad and structural framework, and lowest around the selectivity-determining region for the newly duplicated copy, would be at an advantage over a lineage in which the reverse was true. The favored lineage (and its descendants) would be more likely to evolve new serine proteases and less likely to simply knock out the serine protease function.
In other words, just as individual organisms are at a selective advantage if their DNA encodes "better" amino acid sequences, populations of organisms with DNA sequences that facilitate exploration of useful sequence variation also would be at a selective advantage. As the "winners", these populations would be expected to be among us today, in fact would include us (Caporale 1995 and 1984).
Context-dependent Modulation of Genetic Variation
Cells devote significant resources to protecting themselves against random genetic variation, for example through proofreading and mismatch repair, and have the capacity to set the level of background localized mutability by adjusting the activity of repair systems (Arber 1993 and 1997, Shapiro 1996).
Viruses have evolved mutation rates that differ from that of their hosts (Santos and Drake, 1984). Polymerase fidelity plays a role in adaptation, and thus falls under selective pressure. Viral polymerase fidelity often is low by mammalian standards. The low fidelity of the HIV reverse transcriptase (Peliska and Benkovic 1994) presents a challenge to the host's immune system (and to the pharmaceutical industry), as HIV rapidly evolves resistant variants of molecules recognized by the immune system or targeted with drugs. Under selective pressure from the nucleoside analogue (-)2',3'-dideoxy-3'-thiacytidine (3TC), a reverse transcriptase mutant (M184V) emerges; this mutant copies the HIV genome with increased fidelity compared to the wild type polymerase; this mutant enzyme emerges because it is able to replicate in the presence of 3TC, but its increased fidelity compared to the wild-type enzyme is otherwise a disadvantage to the virus in its battle against the host immune system (and in its battle against the efforts of pharmaceutical company chemists). The increased fidelity of the M184V polymerase, by decreasing the rate of appearance of viral variants that can resist drugs and lose epitopes recognized by the immune response, is thought to contribute to the efficacy of 3TC in the clinic (Wainberg et al. 1996).
In bacteria, alleles that increase the mutation rate have been observed to accelerate the rate at which bacteria adapt to a changing environment (Moxon and Thaler 1997, Taddei et al. 1997). Mechanisms that increase and decrease genetic variation depending upon the "fit" to the environment of the organism (e.g. stress or stationary phase vs. log growth) provide a selective advantage (Foster et al. 1996).
Novel polymerases and biased mismatch "repair" enzymes that exhibit different fidelity spectra can be induced in different cell lineages at different times. Thus sequence-context-dependent effects on the rate, type, and extent of genetic alteration has an additional extremely important dependence upon cell context. Much as a shifting array of metabolic enzymes is induced as the organism's environment changes, special sets of genes for manipulating nucleic acids may be induced under conditions of stress and/or in populations of germ cells.
Regulated, Targeted, Genetic Variation: Immune System Genes as a Paradigm
The immune system provides dramatic evidence that biochemical mechanisms that generate genetic variability can be organized to respond effectively to novel challenges in the environment (Tonegawa, 1983; Rowen et al. 1996).
At a systems level, immunoglobulin DNA can be viewed as a library of DNA sequences that encode binding domains, which can be linked to create a functional protein. Specific recognition signals have evolved to direct functional combination of immunoglobulin gene fragments, and to further focus genetic variation where it is most needed, within that region of the gene sequence responsible for encoding selective recognition of an infectious organism.
Enzymes induced in immune cell lineages remove a "variable" (V) region (marked by a recombination signal sequence) from the library and join it to a "constant" (C) region. In addition to the large number of available V regions, further sequence variation in this binding region arises from the selection of one of several possible sites of joining (J regions); yet more variation is encoded in this system, as the precise site of the V/JC junction is flexible within the 3 bases of the codon at the V/J splice site; thus, a recombination system has evolved that targets sequence variation to the stretch of DNA that must "learn" to encode a protein sequence that binds an antigen selectively and potently. (Variability at this binding site is increased further in heavy chain and T-cell receptor gene families by the addition and deletion of nucleotides at a (V/D/J) junction.)
The antigen-binding V region is in a genetic context in which it accumulates mutations far more quickly than does the C region that forms part of the same new gene. The rate of genetic variation of the assembled gene is not monotonous; certain codons within the relocated "variable" portion of the gene vary at a yet higher rate ("hypermutation"), possibly due to targeted "repair". It is very important to note that this increased mutation occurs in the absence of selection for increased antigen binding affinity; indeed, genes that do not encode immunoglobulin sequences, placed into the variable context (i.e. the context into which the V region is moved) also experience hypermutation (Betz et al 1993, Yelamos et al. 1995). Thus, a genetic system has evolved that exhibits hypermutability at certain positions within the coding region of a gene focusing variation to a binding recognition site that distinguishes different gene family members and away from sequence regions that are conserved in the gene family. In some species, different mechanisms have evolved to focus genetic variation to the v regions; rather than recombination, patches of sequence are "pasted in" to the v regions through gene conversion (McCormack et al. 1993, Fuschiotti et al. 1997, Parng et al. 1996).
Once a functional active binding region has been attached to an effector (C) region, "switch" sequences facilitate replacement of the effector region by other C regions, which encode distinct effector functions (Stavnezner 1996). Thus a newly-evolved ligand binding domain can be harnessed to expose this ligand to different effector functions (e.g. binding to macrophages, release of histamine).
Thus, in the evolution of an antibody response, enzymes attach candidate binding regions to conserved effector regions in a functional orientation, focus variation in a region of DNA important for selectivity, and switch functional binding site sequences to sequences with different conserved effector roles. The immune system illustrates the power of inducible, creative enzymes that are targeted to appropriate places in the genome by specific signals, enabling an increase in the rate of productive sequence-dependent, context-dependent, genetic variation.
A wider role for regulated genetic variation?
It is reasonable to consider that mechanisms, induced in lymphocyte populations to introduce variation into immunoglobulin and T-cell receptor genes to facilitate effective responses to the onslaught of pathogenic organisms, may be adaptations of mechanisms that first evolved in the germ line, enabling populations to respond to other selective pressures.
Polymerase complexes that copy and move nucleotide sequences, and new contexts into which sequences are placed, may attract enzymes that have distinct and/or decreased fidelity and/or biased or inaccurate mismatch repair. Contexts into which new sequences are moved can be labeled in a heritable but reversible manner (Fedoroff et al. 1995, Pfeifer and Tilghman 1994). Thus, genetic machinery is available that would allow a newly-duplicated and or relocated gene to experience higher rates of variation, with sequence-dependent hotspots of variation, in the germ cell lineage, expediting exploration of the potential usefulness of the duplicated sequence.
Indeed, immunoglobulins and T-cell receptors are not the only gene families in which the extent of sequence variation is very different between the amino and carboxyl terminal regions of the proteins (see e.g. the discussion of the hedgehog protein family in Kumar et al. 1996). The observed pattern of genetic variation in such gene families could be explained by increased exploration of variation in focused regions of a gene during meiosis and mitosis in the germ line, drawing upon enzymatic machinery of the type used in somatic generation of diversity in the immune system, rather than by monotonous mutation followed by selection.
Gene conversion has been proposed to explain the observed accelerated evolution of synonymous codons in the serine protease kallikrein (Wines et al. 1991, Ohta 1994). Retrotransposition at double-strand breaks has been proposed to play a role in gene conversion (Derr and Strathern 1993). Gene conversion facilitates evaluation of sequence fragments at a targeted location, and can spread successful variants through a gene family (Ohta and Dover 1983). The source of sequences for gene conversion may be other functional gene family members, but "pseudogenes" may serve as a reservoir of sequence options.
Enzymatic machinery such as that demonstrated to operate in the immune system, would enable populations of organisms to explore, in meiotic and/or germ line mitotic divisions, the potential value, in a given environment, of the fruits of specific types of genetic alteration.
This analysis suggests induction of related genes in meiosis and in immune cell lineages, as has been observed (Xu et al. 1996), and anticipates the discovery of unique targeting sequences in appropriate positions in the genome. Z-DNA sequences, associated with class switch in the immunoglobulins and antigenic variation in trypanosomes, have long been proposed to have a general role in promoting genetic recombination (see e.g. Smith and Moss 1994).
Indeed, mechanisms that increase recombination and combinatorial information exchange are induced during meiosis (Ohta et al. 1998, Schwacha and Kleckner 1997). Perhaps the most dramatic demonstration that DNA sequence can be altered in a regulated, massive, and non-random manner after mating is provided by the protozoan Oxytrichia, which completely reorganizes its genetic apparatus in the formation of a new macronucleus in the cell generation after mating, fragmenting the germ-line chromosomes into thousands of pieces and then reassembling a subset (DuBois and Prescott 1997)
Analysis of the set of enzymes for manipulating nucleic acids induced in germ cells, and the set of genetic alterations observed in these lineages is an important area of focus for further investigation (Huang et al. 1995, Murti et al. 1995). Another informative, and now accessible, area for analysis is the information content of nucleotide sequences within gene families. Statistical tools available to query DNA sequence databases have revealed increased and decreased frequencies of use of certain DNA sequences (Karlin 1994, Trifonov 1989); such analysis can uncover footprints of past genetic events and possible signal sequences recognized by modulatory enzymes.
The Degeneracy of the Genetic Code allows additional messages to be transmitted through a protein coding region
While signals that modulate the rate of variation of a gene may be found in introns and intergenic regions, such information also can evolve within a protein-coding sequence.
A nucleotide sequence can encode more information than that of a single protein coding sequence. This is illustrated by many examples (Trifonov 1989, Normark et al. 1983), from the overlap of codons of two prokaryotic viral genes (Sanger et al. 1977), to the presence of sequences regulating gene expression within the protein coding region of eukaryotic genes (Ficzycz et al, 1997).
The degeneracy of the genetic code allows additional information to be transmitted through the protein coding region of the gene (Caporale, 1984). A protein coding sequence evolves under selective pressure to encode more optimal amino acids at a given position. The degeneracy of the code gives the underlying nucleotide sequence the flexibility to evolve to encode information that increases the likelihood of genetic alteration at those sites at which variation could create a new useful function, and decreases the likelihood of alteration at those sites at which variation would disturb the active scaffold or other essential residues.
Is there evidence for sequence information that regulates not only gene expression, but also gene variation, within a protein coding region? The Lyme disease spirochete Borreliae employs antigenic variation to persist in the face of an active host immune response. This variation is thought to depend upon enzymatic recognition of a conserved direct repeat in a gene encoding a surface-exposed lipoprotein (Zhang et al 1997). This direct repeat lies within the predicted coding region of the lipoprotein gene. In other words, in Borreliae, synonymous codons fall under selective pressure to conserve a direct repeat that functions at the DNA level to attract genetic variation. The existence of this type of information (along with levels of isoacceptor tRNA and constraints of mRNA secondary structure) may contribute to the observed conservation of nucleotides that, due to the degeneracy of the genetic code, are "synonymous". Synonymous changes do not alter protein sequences (Caporale 1984, Lipman and Wilbur 1985) and thus are not predicted to be constrained when only protein sequence is considered.
A genetic "concept", encoded as sequence-dependent effects on nucleic acid sequence stability, could embody the overlay of selectivity upon homology within a gene family. As is seen in the immune system, those sites at which variation would be more likely to evolve a useful function (e.g. a ligand binding site), would encode regions of higher genetic flexibility. Those residues that must be conserved to maintain the common function (where variation would disturb the active scaffold, destroy a catalytic residue, or eliminate interaction with downstream effectors), would be encoded as regions of lower genetic flexibility (Caporale 1984).
The genomic "concept", shared among genes encoding members of a gene family, would focus genetic exploration of the functional potential of that family (see e.g. Valentine et al. 1996) in more productive directions, and thus would facilitate the adaptation of populations to environmental challenges.
Information modulating genetic variation may involve not just the sequences themselves, but relationship between neighboring sequences and/or other sequence-dependent effects on DNA structure. As our understanding of genomes becomes more sophisticated, we will increasingly be able to recognize such signals. For example, initially the insertion sites for Ty transposons, while clearly nonrandom in that they avoided coding regions, had no obvious sequence relationship. Later, it was understood that such sites all were recognized by the enzyme Pol III (Devine and Boeke 1996). More recently, genes associated with virulence in H. influenzae were identified based upon a search of the organism's genome filtered through the hypothesis that DNA repeats would facilitate slippage associated with protein phase variation (Hood et al. 1996).
Summary: Genomes encode efficient strategies of evolution
With mutation and selection, we understand evolution, but only in part. It is hard to conceive of such a process as random individual nucleotide changes generating so many diverse, successful lifeforms, but we assure ourselves that there was so much time available, more than we can conceive of, that can account for it all.
However, reminiscent of the experience of those of us who were children prior to acceptance of plate tectonics, and who insisted that the east coast of the Americas fit perfectly to the west coast of Europe and Africa, we sense that we might be missing an important part of the story.
An overarching principle of evolution, which has been overlooked in most discussions, makes the tremendous diversity, with its extensive underlying biochemical homologies, more comprehensible. This principle is that evolutionary strategies evolve that make the process of evolution more efficient. An important strategy is one that modulates the rate, type, and extent of genetic variation in a cell-type and nucleic acid sequence-dependent manner (Caporale 1984).
Enzymes that affect the fidelity of replication and/or mismatch repair have been shown to be induced in special circumstances. Gene segments (e.g. immunoglobulin V regions) can be moved into contexts in which genetic alteration is more rapid. The location, timing, extent, and type of genetic variation can be regulated and modulated.
Much as a protein coding sequence evolves through selection to encode more optimal amino acids, genomes encoding gene families in which genetic alterations are more likely to occur in residues that explore new selectivities, and less likely to occur in the scaffold and at essential active site residues, would tend to have been selected for evolution.
In other words, a "concept" of a functional member of a gene family could evolve to be expressed through a linear DNA sequence. As a protein duplicates and evolves, its progeny would retain such "conceptual" information, facilitating efficient sequence exploration (as illustrated by the divergence of heavy, lambda, kappa and T cell receptor loci from a primordial immunoglobulin domain structure, which retain appropriately located recombination and diversity-targeting signals). Generic mechanisms are likely to be maintained in the genome to distinguish protected and exploratory regions in multiple evolving gene families.
Populations of organisms that can adapt more efficiently to novel niches would be at a selective advantage in entry into new niches. Jumps in efficiency, made possible by development of novel efficient evolutionary strategies, could fuel apparent saltatory expansion of species as each innovation evolved.
With its ability to employ interchangeable parts, and to direct variation to certain sequences, it is possible that for two decades the immune response has been waving in our faces examples of genetic mechanisms for focused variation that operate widely in the germ line.
Indeed, given the known sequence-dependent effects of enzymes that act on nucleic acids, and the known specificity of mobile elements with respect to sequence, the rate of genetic variation within a genome cannot be independent of sequence context. It would be difficult to argue that such inducible, sequence-context dependent effects on genetic variation cannot escape the influence of natural selection.
Biochemical mechanisms that increase the probability of constructive vs. destructive genetic alterations would provide a selective advantage to populations in which such mechanisms evolved and thus should have been selected for in evolution. As genome-encoded strategies evolve, enabling some populations to become more efficient at exploring possible adaptations to novel environments, the efficiency of evolutionary adaptation evolves.
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Acknowledgments: I would like to thank Werner Arber for his input and for sharing his thoughts with me prior to publication, and Jim Shapiro for his comments on an earlier version of this manuscript.
References
Arber, W. Evolution of prokaryotic genomes Gene 135:49-56 (1993)
Arber, W. (1997) The involvement of genetic and environmental factors in the evolution of bacteria Enciclopeida Italiana (in press)
Betz, A., C. Rada, R. Pannell, C. Milstein and M. Neuberger. Specificity of the antibody hypermutation mechanism: Clustering, polarity, and specific hot spots. Proc. Natl. Acad. Sci. USA 90:2385-2388 (1993)
Borst, P. and Cross, G.A.M. (1982) Molecular Basis for Trypanosome Antigenic Variation Cell 29:291-303
Caporale, L.H. Is there a higher level genetic code that directs evolution? Mol. Cell. Biochem. 64: 5-13 (1984)
Caporale, L.H. Chemical Ecology. Proc. Natl. Acad. Sci. USA 92:75-82 (1995)
Derr LK; Strathern JN (1993) A role for reverse transcripts in gene conversion Nature 36:1170-3
Devine SE and Boeke JD (1996);Integration of the yeast retrotransposon Ty1 is targeted to regions upstream of genes transcribed by RNA polymerase III. Genes Dev 10: 620-33
DuBois ML and Prescott DM, Volatility of internal eliminated segments in germ line genes of hypotrichous ciliates. Mol Cell Biol 1997 Jan: 326-37
Ficzycz, A., Kaludov, N.K., Lele, Z., Hurt, M.M., and Ovsenek, N. A Conserved Element in the Protein-Coding Sequence is Required for Normal Expression of Replication-Dependent Histone Genes in Developing Xenopus Embryos. Dev. Biol. 182:21-32 (1997)
Fedoroff, N., Schläppi M, and Raina, R. (1995) Epigenetic regulation of the maize Spm transposon BioEssays 17:291-297
Foster PL; Trimarchi JM; Maurer RA Two enzymes, both of which process recombination intermediates, have opposite effects on adaptive mutation in Escherichia coli Genetics 142: 25-37 (1996)
Furie, B. and Furie, B.C. The Molecular Basis of Blood Coagulation Cell 53: 505-518 (1988)
Fuschiotti, P., Fitts, M.G., Pospisil, R., Weinstein, P. D., and Mage, R. G. 1997 RAG1 and RAG2 in Developing Rabbit Appendix Subpopulations (1997) J. Immunol. 158:55-64
Gabriel, A., Willems, M. Mules, E.H. and Boeke, J.D. Replication infidelity during a cycle of Ty1 retrotransposition. Proc. Natl. Acad. Sci. USA 93:7767-7771 (1996)
Gaunt, S.J. (1991) Expression patterns of mouse Hox genes: clues to an understanding of developmental and evolutionary strategies Bioessays 13:505-513
Gilbert, W. (1978) Why genes in pieces? Nature 271 501
Gläsner, W., R. Merkel, V. Schellenberger and H-J Fritz Substrate Preferences of Vsr DNA Mismatch Endonuclease and their Consequences for the Evolution of the Escherichia Coli K12 genome. J. Mol. Biol. 245:1-7 (1995)
Glickman, B.W. and Ripley, L.S. Structural intermediates of deletion mutagenesis: A role for palindromic DNA Proc. Natl. Acad. Sci. USA 81:512-516 (1984)
Gordenin, D.A., Kunkel, T.A., and Resnick, M.A. (1997) Repeat expansion-all in a flap? Nature Genetics 16:116-118
Halder, G., Callaerts, and Gehring, W.J. (1995) New Perspectives on eye evolution. Curr. Op. Genet Devel 5 :602-609
Hartl, D.L. (1997) Mariner Sails into Leishmania Science 276:1659-1660
Hays, S.P. The Response to Industrialism 1885-1914 The University of Chicago Press (1957)
Hill, R.E. and Hastie, N.D. Accelerated evolution in the reactive centre regions of serine protease inhibitors. Nature 326:96-99 (1987)
Holland, J.H. Hidden Order: how adaptation builds complexity Helix Books 1995
Hood, D.W., Deadman, M.E., Jennings, M.P., Bisercic, M., Fleischman, R.D., Venter, J.C., and Moxon, E.R. (1996) DNA Repeats identify novel virulence genes in Haemophilus influenzae Proc. Natl Acad Sci USA 93:11121-11125
Horrevoets, A.J.G., Tans, G., Smilde, A.E., van Zonneveld, A-J., and Pannekoek, H. Thrombin- Variable Region 1 (VR1) J. Biol Chem 268:779-782 (1993)
Huang, M-M, Erlich, H.A., Goodman, M.F., and Arnheim, N. (1995) Analysis of Mutational Changes at the HLA Locus in Single Human Sperm Human Mutation :303-310
Karlin, S., Ladunga, I. And Blaisdell, B.E. Heterogeneity of genomes: Measures and Values Proc. Natl. Acad. Sci. USA 91:12837-12841 (1994)
Kidwell, M.G. (1993) Annu. Rev. Genet. 27:235-56
Kimura M (1979) The neutral theory of molecular evolution. Sci Am, 241:98-100, 102, 108 passim
Kreitman, M (1996) The neutral theory is dead. Long live the neutral theory. BioEssays 1996 18 : 678-683.
Kumar, S., Balczarek, K.A., and Lai, Z-C. (1996) Evolution of the hedgehog Gene Family (1996) Genetics 142:965-972
Lipman, D.J. and Wilbur, W.J. (1985) Interaction of Silent and Replacement Changes in Eukaryotic Coding Sequences J. Mol. Evol. 21:161-167
Martin, W. (1997) Whence Genes http://biomednet.com/hmsbeagle/1997/01/cutedge/day1.htm#1_3
McCormack, W.T., Hurley, E.A. and Thompson, C.B. Germline maintenance of the pseudogene donor pool for somatic immunoglobulin gene conversion in chickens. Mol. Cell. Biol. 13:821-830 (1993)
Medhora M, Maruyama K, Hartl DL (1991) Molecular and functional analysis of the mariner mutator element Mos1 in Drosophila. Genetics 128 311-318
Morgan, G.T. (1995) Identification in the human genome of mobile elements spread by DNA-mediated transposition J. Mol Biol 254:1-5
Moxon ER (1995) Whole genome sequencing of pathogens: a new era in microbiology. Trends Microbiol 3:335-7
Moxon, E.R. and Thaler, DS (1997) The tinkerer's evolving tool-box Nature 387, 659-661
Murti, JR, Bumbulls, M, Schimenti (1994) Gene conversion between unlinked sequences in the germline of mice Genetics 137:837-43
Normark, S. Bergstron, S, Edlund, T., Grundstrom, T., Jaurin, B. Lindberg F.T. and Olsson O (1983). Overlapping Genes in Ann Rev Genetics 17 499-525
Ohta T (1994 ) On hypervariability at the reactive center of proteolytic enzymes and their inhibitors. J Mol Evol, 39:614-9
Ohta, T. 1996 The current significance and standing of neutral and nearly neutral theories. BioEssays 18 : 673-677.
Ohta, T. and Dover, G.A. (1983) Population genetics of multigene families that are dispersed into two or more chromosomes Proc Natl Acad Sci USA 80:4079-83
Ohta, K., Nicolas, A., Furuse, M., Nabetani, A., Ogawa, H., and Shibata, T. (1998) Mutations in the MRE11, RAD50, XRS2, and MRE2 genes alter chromatin configuration at meiotic DNA double-straded break sites in premeiotic and meiotic cells. Proc. Natl. Acad. Sci, US 95:646-651
Parng CL; Hansal S; Goldsby RA; Osborne BA; 1996 Gene conversion contributes to Ig light chain diversity in cattle. J Immunol 157: 5478-86
Peliska JA; Benkovic SJ (1994 ) Fidelity of in vitro DNA strand transfer reactions catalyzed by HIV-1 reverse transcriptase. Biochemistry, 33:3890-5,
Pfeifer, K., and Tilghman, S.M. (1994) Allele-specific gene expression in mammals: The curious case of the imprinted RNAs Genes and Development 8:1867-1874
Recchia, G.D., Hall, R.M. Gene Cassettes: a new class of mobile element. Microbiology 141:3015- (1995)
Rich, A. Right-handed and Left-Handed DNA: Conformational Information in Genetic Material. Cold Spring Harbor Symposium on Quantitative Biology 47:1 (1982)
Roberts, J.D., Nguyen, D., and Kunkel, T. Frameshift Fidelity during Replication of Double-Stranded DNA in HeLa Cell Extracts. Biochemistry 32:4083-4089 (1993)
Rosche, W.A., Trinh, T.Q. and R.R. Sinden. (1997) Leading strand specific spontaneous mutation corrects a quasipalindrome by an intermolecular strand switch mechanism. J. Mol. Biol., 269, 176-187.
Rowen L; Koop BF; Hood L (1996) The complete 685-kilobase DNA sequence of the human beta T cell receptor locus. Science, 272:1755-62
Ruddle, F.H., Bentley, K.L., Murtha, M.T. and Risch, N. (1994) Gene loss and gain in the evolution of the vertebrates Dev Suppl. 155-61
Sanger, F., Air, G., Barrell B., Brown, N., Coulson, A.R., Fiddes, J.C., Hutchison, A. III, Slocombe, P.M., Smith, M. 1977, Nucleotide sequence of bacteriophage phi X 174 DNA Nature 265:687-695
Santos ME; Drake JW (1994) Rates of Spontaneous mutation in bacteriophage T4 are independent of host fidelity determinants. Genetics 138,:553-64
Schläppi M; Smith D; Fedoroff N TnpA trans-activates methylated maize Suppressor-mutator transposable elements in transgenic tobacco. Genetics 133: 1009-21 (1993)
Schwacha A; Kleckner N (1997) Interhomolog bias during Meiotic Recombination: Meiotic Functions promote a Highly Differentiated Interhomolog-only Pathway Cell 90:1123-1135
Shapiro (1996) http://www-polisci.mit.edu.BostonReview/BR22.1/Shapiro.html
Shapiro, J.A. Barbara McClintock, 1902-1992. BioEssays 14:791-792 (1992)
Shapiro, J.A. Natural Genetic Engineering in Evolution. Genetica 86:99-111 (1992)
Simpson, L, and Maslov, D.A. "RNA Editing and the Evolution of Parasites." Science 264:1870-1871 (1994)
Smith, P.D. and Moss, S.E. (1994) Z-DNA-forming sequences at a putative duplication site in the human annexin VI-encoding gene. Gene 138 239-242
Stavnezer, J., Immunoglobulin class switching Current Opinion in Immunology 1996, 8: 199-205.
Stroud, R.M. A Family of Protein-Cutting Proteins Scientific American 231:74-88 (1974)
Südhof TC; Goldstein JL; Brown MS; Russell DW (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228:815-22
Taddei F; Radman M; Maynard-Smith J; Toupance B; Gouyon PH; Godelle B
Role of mutator alleles in adaptive evolution Nature, 387(6634):700-2 (1997)
Tamames J; Ouzounis C; Sander C; Valencia A (1996 ) Genomes with distinct function composition FEBS Lett, 389:96-101
Teng SC; Kim B; Gabriel A; (1996) Retrotransposon reverse-transcriptase-mediated repair of chromosomal breaks. Nature 383:641-4
Tonegawa, S. Somatic Generation of Antibody Diversity Nature 302:575-581 (1983)
Trifonov, E.N. (1989) The multiple codes of nucleotide sequences Bull. Math. Biol. 51:417-32
Trinh, T.Q. and Sinden, R.B. Preferential DNA secondary structure mutagenesis in the lagging strand of replication in E. Coli. Nature 352:544-547 (1991)
Valentine, J.W., Erwin, D.H. and Joblonski, D. (1996) Developmental evolution of metazoan bodyplans: the fossil evidence. Dev. Biol 173:373-81
Wainberg MA; Drosopoulos WC; Salomon H; Hsu M; Borkow G; Parniak M; Gu Z; Song Q; Manne J; Islam S; Castriota G; Prasad VR Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science, 271:1282-5, 1996
Walsh, K.A., and Neurath, H. Trypsinogen and Chymotrypsinogen as Homologous Proteins Proc. Natl. Acad. Sci. U.S. 52:884-889 (1964)
Wines, D.R., Brady, J.M., Southard, E.M., and MacDonald, R.J. (1991) J. Mol. Evol 32:476-92
Wolfe, K.H. and Shields, D.C. (1997) Molecular evidence for an ancient duplication of the entire yeast genome Nature 387 708-713
Xu Y; Ashley T; Brainerd EE; Bronson RT; Meyn MS; Baltimore D (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma Genes Dev, 10:2411-22
Yelamos, J., Klix, N., Goyenechea, B., Lozano, F., Chui, Y.L., Gonzalez Fernandez, A., Pannell, R., Neuberger, M.S., and Milstein, C. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation Nature 376:225-229 (1995)
Zhang, J-R, Hardham, J.M., Barbour, A.G. and Norris, S.J. (1997) Antigenic Variation in Lyme Disease Borreliae by Promiscuous Recombination of VMP-like Sequence Cassettes Cell 89 , 275-285
NECSI InterJournal abstract