A speculation relating the genetic code and the evolutionary process.
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Biological Evolution↗
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pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective.
Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of CQR argues that investigations into these mechanisms are of little value. We propose, to the contrary, that the reconstruction of the evolutionary and molecular events underlying CQR is important at many levels, including: (i) its potential to assist in the development of rational approaches to thwart future drug resistances; (ii) the stimulation of the use of CQ-like compounds in drug combinations for new therapeutic approaches; and (iii) the consideration of how the CQ-selected genome will function as the context in which current and future drugs will act, particularly in light of the many reports of multidrug resistance. The purpose of this review is to highlight, discuss and in some cases challenge the interpretations of recent findings on CQR. We consider the natural function of the PfCRT protein, the role of multiple genes and "genetic background" in the CQR mechanism, and the evolution of CQR in parasite populations. Genetic transformation techniques are improving in P. falciparum and continue to provide important insight into CQR. Here, we also discuss more subtle, yet important pharmacological approaches that may have been overlooked in a traditional "gene for drug resistance" way of thinking.
Animals↗
Evolutionary changes in the genetic code.
The genetic code has been influenced by directional mutation pressure affecting the base composition of DNA, sometimes in the direction of increased GC content and at other times, in the direction of AT. Such pressure led to changes in species-specific usages of codons and tRNA anticodons, and also in amino acid assignments of codons in mitochondria and in several intact organisms. These code changes are probably recent evolutionary events. The genetic code is not 'frozen', but instead it is still evolving.
Base Sequence↗
Discrepancies in population differentiation at microsatellites, mitochondrial DNA and plumage colour in the pied flycatcher--inferring evolutionary processes.
Genetic differentiation between three populations of the pied flycatcher Ficedula hypoleuca (Norway, Czech Republic and Spain, respectively) was investigated at microsatellite loci and mitochondrial DNA (mtDNA) sequences and compared with the pattern of differentiation of male plumage colour. The Czech population lives sympatrically with the closely related collared flycatcher (F. albicollis) whereas the other two are allopatric. Allopatric populations are on average more conspicuously coloured than sympatric ones, a pattern that has been explained by sexual selection for conspicuous colour in allopatry and a character displacement on breeding plumage colour in sympatry that reduces the rate of hybridization with the collared flycatcher. The Czech population was genetically indistinguishable from the Norwegian population at microsatellite loci and mtDNA sequences. Recent isolation and/or gene flow may explain the lack of genetic differentiation. Accordingly, different selection on plumage colour in the two populations is either sufficiently strong so that gene flow has little impact on the pattern of colour variation, or differentiation of plumage colour occurred so recently that the (presumably) neutral, fast evolving markers employed here are unable to reflect the differentiation. Genetically, the Spanish population was significantly differentiated from the other populations, but the divergence was much more pronounced at mtDNA compared to microsatellites. This may reflect increased rate of differentiation by genetic drift at the mitochondrial, compared with the nuclear genome, caused by the smaller effective population size of the former genome. In accordance with this interpretation, a genetic pattern consistent with effects of small population size in the Spanish population (genetic drift and inbreeding) were also apparent at the microsatellites, namely reduced allelic diversity and heterozygous deficiency.
Animals↗
Genetic characterization of six parasitic protozoa: parity between random-primer DNA typing and multilocus enzyme electrophoresis.
We have assayed genetic polymorphisms in several species of parasitic protozoa by means of random amplified polymorphic DNA (RAPD). One goal was to ascertain the suitability of RAPD markers for investigating genetic and evolutionary problems, particularly in organisms, such as the parasitic protozoa, unsuitable for traditional methods of genetic analysis. Another goal was to test certain hypotheses concerning Trypanosoma cruzi, and other protozoa, that have been established by multilocus enzyme electrophoresis. The RAPD results corroborate the hypothesis that the population structure of T. cruzi is clonal and yield a phylogeny of the clonal lineages in agreement with the one obtained by enzyme electrophoresis. This parity between the two sets of results confirms that RAPD markers are reliable genetic markers. The RAPD markers are also suitable for reconstructing species phylogenies and as diagnostic characters of species and subspecific lineages. The number of DNA polymorphisms that can be detected by the RAPD method seems virtually unlimited, since the number of primers can be increased effectively at will. The RAPD method is well suited for investigating genetic and evolutionary questions in certain organisms, because it is cost effective and demands no previous genetic knowledge about the organism.
Animals↗
Estimating HIV evolutionary pathways and the genetic barrier to drug resistance.
BACKGROUND: The evolution of drug-resistant viruses challenges the management of human immunodeficiency virus (HIV) infections. Understanding this evolutionary process is important for the design of effective therapeutic strategies. METHODS: We used mutagenetic trees, a family of probabilistic graphical models, to describe the accumulation of resistance-associated mutations in the viral genome. On the basis of these models, we defined the genetic barrier, a quantity that summarizes the difficulty for the virus to escape from the selective pressure of the drug by developing escape mutations. RESULTS: From HIV reverse-transcriptase sequences that had been obtained from treated patients, we derived evolutionary models for zidovudine, zidovudine plus lamivudine, and zidovudine plus didanosine. The genetic barriers to resistance to zidovudine, stavudine, lamivudine, and didanosine, for the above 3 regimens, were computed and analyzed. We found both the mode and the rate of development of resistance to be heterogeneous. The genetic barrier to zidovudine resistance was increased if lamivudine was added to zidovudine but was decreased for didanosine. The barrier to lamivudine resistance was maintained with zidovudine plus didanosine, whereas the barrier to didanosine resistance was reduced most with zidovudine plus lamivudine. CONCLUSION: Mutagenetic trees provide a quantitative picture of the evolution of drug resistance. The genetic barrier is a useful tool for design of effective treatment strategies.
Anti-HIV Agents↗
Genetic code redundancy and the evolutionary stability of protein secondary structure.
The genetic code has an inherent bias towards some amino acids because of the variable number of synonymous codons per amino acid. The extent to which these biases are expressed in protein secondary structure is described through the analysis of the overall amino acid compositions of the alpha-helix, beta-sheet, beta-turn and random coil segments elucidated by X-ray crystallography. Given the concept of neutral mutation in proteins, the allocation of synonyms in the genetic code appears to protect secondary structures from amino acid changes and discourages the appearance of chemically complex residues. The level of protection is similar for each structural form, despite their clear preferences for certain amino acids. The organization of the code is therefore relevant to the preservation of conformation seen in the evolution of many protein families.
Amino Acids↗
Single-nucleotide polymorphisms, haplotypes, and their relevance to pharmacogenetics.
Recognition that there is a vast quantity of human genetic variation has had a pervasive impact on modern medicine, facilitating the identification of scores of genes that underlie monogenic clinical disorders, as well as genes involved in complex disease processes. The next logical step for human genetics is the exploration and elucidation of genes involved in differential pharmacological response: responders, nonresponders, and those with adverse side effects. An understanding of the role that genes have in pharmacological response is the cornerstone of personalized medicine. Pharmacogenetic activities have swiftly embraced these tenets, leading to a proliferation of resources and approaches meant to enable and expedite targeted drug discovery and development. To realize the potential of these efforts, it will be necessary to incorporate a better understanding of the population genetic and evolutionary processes that have shaped genetic variation in modern humans. This article introduces these concepts to provide context and guidelines for the use of this variation (primarily single-nucleotide polymorphisms and haplotypes) in pharmacogenetics.
Genetics, Population↗
[Low genetic differentiation and close evolutionary connection between Anas platyrhynchos and Anas poecilorhyncha: data from RAPD-PCR analysis].
Using RAPD-PCR, we examined genetic diversity and phylogenetic relationships in two groups of river ducks: Anas platyrhynchos, A. poecilorhyncha, A. strepera and A. crecca, A. formosa, A. querquedula. Molecular taxon-specific markers were found for teals (A. crecca, A. formosa, A. querquedula) and gadwall (A. strepera). Each of the species examined was shown to exhibit high genetic diversity. The mean levels of intraspecific genetic polymorphism in the groups of mallards (P = 77%) and teals (P = 74.5%) were approximately equal whereas the mean interspecific genetic distances in teals were significantly higher than in mallards (D = 0.432 and D = 0.336, respectively). The levels of interspecific genetic differentiation in the species groups were also different. The genetic distances between the teal species and between gadwall and mallards were equal to 0.668-0.971 while the genetic distance between mallard A. platyrhynchos and spot-billed duck A. poecilorhyncha was 0.401, which slightly exceeds the intraspecific values for mallards (0.356-0.377). The RAPD patterns for this species pair showed high variability and a lack of fixed differences. This was adequately reflected on both intra- and interspecific differences and on phylogenetic constructions in which the morphological species did not form their own clusters but were intermixed. In contrast to mallards, the other species, which showed high genetic variability, were reliably separated in phenogenetic and phylogenetic reconstructions. The possible explanations of the low genetic differentiation of A. platyrhynchos and A. poecilorhyncha are discussed.
Animals↗
Genetically fixed characters and evolutionary divergence.
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Africa↗
Evolutionary experiments on mate recognition in the Drosophila serrata species complex.
It is becoming increasingly apparent that at least some aspects of the evolution of mate recognition may be amenable to manipulation in evolutionary experiments. Quantitative genetic analyses that focus on the genetic consequences of evolutionary processes that result in mate recognition evolution may eventually provide an understanding of the genetic basis of the process of speciation. We review a series of experiments that have attempted to determine the genetic basis of the response to natural and sexual selection on mate recognition in the Drosophila serrata species complex. The genetic basis of mate recognition has been investigated at three levels: (1) between the species of D. serrata and D. birchii using interspecific hybrids, (2) between populations of D. serrata that are sympatric and allopatric with respect to D. birchii, and (3) within populations of D. serrata. These experiments suggest that it may be possible to use evolutionary experiments to observe important events such as the reinforcement of mate recognition, or the generation of the genetic associations that are central to many sexual selection models.
Animals↗
Patterns of human genetic diversity: implications for human evolutionary history and disease.
Since the completion of the human genome sequencing project, the discovery and characterization of human genetic variation is a principal focus for future research. Comparative studies across ethnically diverse human populations and across human and nonhuman primate species is important for reconstructing human evolutionary history and for understanding the genetic basis of human disease. In this review, we summarize data on patterns of human genetic diversity and the evolutionary forces (mutation, genetic drift, migration, and selection) that have shaped these patterns of variation across both human populations and the genome. African population samples typically have higher levels of genetic diversity, a complex population substructure, and low levels of linkage disequilibrium (LD) relative to non-African populations. We discuss these differences and their implications for mapping disease genes and for understanding how population and genomic diversity have been important in the evolution, differentiation, and adaptation of humans.
Biological Evolution↗
Four letters in the genetic alphabet: a frozen evolutionary optimum?
Piccirilli et al. (Nature, Lond. 343, 33-37 (1990)) have shown experimentally that the replicatable introduction of new base pairs into the genetic alphabet is chemically feasible. The fact that our current genetic alphabet uses only two base pairs can be explained provided that this basic feature of organisms became fixed in an RNA world utilizing ribozymes rather than protein enzymes. The fitness of such ribo-organisms is determined by two factors: replication fidelity and overall catalytic efficiency (basic metabolic or growth rate). Replication fidelity is shown to decrease roughly exponentially, and catalytic efficiency is shown to increase with diminishing returns, with the number of letters for a fixed genome length; hence their product, i.e. fitness, gives rise to a set of values with an optimum. Under a wide range of parameter values the optimum rests at two base pairs. The chemical identity of the particular choice in our genetic alphabet can also be rationalized. This optimum is considered frozen, as currently the dominant catalysts are proteins rather than RNAs.
Base Composition↗
[The work of Richard Goldschmidt: an attempt at a synthesis of genetics, developmental biology, and evolutionary theory surrounding the concept of homeosis].
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Biological Evolution↗
Genetic diversity and the evolutionary history of plant immunity genes in two species of Zea.
Plant pathogenesis-related genes (PR genes) code for enzymes, enzyme inhibitors, and other peptides that confer resistance to pathogens and herbivores. Although several PR genes have been the subject of molecular population genetic analyses, a general understanding of their long-term evolutionary dynamics remains incomplete. Here we analyze sequence data from 17 PR genes from two closely related teosinte species of central Mexico. In addition to testing whether patterns of diversity at individual loci depart from expectations under a neutral model, we compared patterns of diversity at defense genes, as a class, to nondefense genes. In Zea diploperennis, the majority of defense genes have patterns of diversity consistent with neutral expectations while at least two genes showed evidence of recent positive selection consistent with arms-race models of antagonistic coevolution. In Zea mays ssp. parviglumis, by contrast, analyses of both defense and nondefense genes revealed strong and consistent departures from the neutral model, suggestive of nonequilibrium population dynamics or population structure. Nevertheless, we found a significant excess of replacement polymorphism in defense genes compared to nondefense genes. Although we cannot exclude relaxed selective constraint as an explanation, our results are consistent with temporally variable (transient or episodic) selection or geographically variable selection acting on parviglumis defense genes. The different patterns of diversity found in the two Zea species may be explained by parviglumis' greater distribution and population structure together with geographic variation in selection.
Base Sequence↗
Sex-specific genetic structure in Schistosoma mansoni: evolutionary and epidemiological implications.
We studied the population genetic structure of 360 and 1247 adult Schistosoma mansoni using seven microsatellite and seven random amplified polymorphic DNA (RAPD) markers, respectively. Parasites were collected from their natural definitive host Rattus rattus in Guadeloupe (West Indies). We found a sex-specific genetic structure, a pattern never before reported in a parasitic organism. Male genotypes were more randomly distributed among rats than female genotypes. This interpretation was consistent with a lower differentiation between hosts for males relative to females, the higher genetic similarity between females in the same host and the observed local (i.e. within-individual-host) differences in allele frequencies between the two sexes. We discuss our results using ecological and immunological perspectives on host-parasite relationships. These results change our view on the epidemiology of schistosomiasis, a serious disease affecting humans in African and American intertropical zones.
Animals↗
Early fixation of an optimal genetic code.
The evolutionary forces that produced the canonical genetic code before the last universal ancestor remain obscure. One hypothesis is that the arrangement of amino acid/codon assignments results from selection to minimize the effects of errors (e.g., mistranslation and mutation) on resulting proteins. If amino acid similarity is measured as polarity, the canonical code does indeed outperform most theoretical alternatives. However, this finding does not hold for other amino acid properties, ignores plausible restrictions on possible code structure, and does not address the naturally occurring nonstandard genetic codes. Finally, other analyses have shown that significantly better code structures are possible. Here, we show that if theoretically possible code structures are limited to reflect plausible biological constraints, and amino acid similarity is quantified using empirical data of substitution frequencies, the canonical code is at or very close to a global optimum for error minimization across plausible parameter space. This result is robust to variation in the methods and assumptions of the analysis. Although significantly better codes do exist under some assumptions, they are extremely rare and thus consistent with reports of an adaptive code: previous analyses which suggest otherwise derive from a misleading metric. However, all extant, naturally occurring, secondarily derived, nonstandard genetic codes do appear less adaptive. The arrangement of amino acid assignments to the codons of the standard genetic code appears to be a direct product of natural selection for a system that minimizes the phenotypic impact of genetic error. Potential criticisms of previous analyses appear to be without substance. That known variants of the standard genetic code appear less adaptive suggests that different evolutionary factors predominated before and after fixation of the canonical code. While the evidence for an adaptive code is clear, the process by which the code achieved this optimization requires further attention.
Amino Acids↗
[Non-universal genetic codes and their evolutionary processes].
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Amino Acid Sequence↗