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Causes and consequences of pathogenic processes in evolution: implications from experimental epilepsy in animals.

Examples from experimental epilepsy in animals are used to illustrate the view that a crucial role of the transfer of mechanisms from compensatory into pathogenic (e.g. lethal ones in the course of a disease), is played by the power of pathologic stimuli. In the genesis of epilepsy it is suggested that a critical increase of endogenous factors may underlie the conversion of the absence form of epilepsy into a generalized self-supporting form. The ability to precipitate endogenous self-augmenting mechanisms of diseases may have increased in the course of evolution. The lethal result of a serious pathogenic process leads to the suggestion that organisms cope with the disease by dying. This prevents spreading of the putative infectious disease within the population. This mechanism of disease aggravation could play a role in the survival of the species and in further evolutionary progress. This may explain why certain species may have survived in evolution and supports the theory of synthetic evolution.

Animals↗

Site-directed mutagenesis of arginine 179 of thymidylate synthase. A nonessential substrate-binding residue.

X-ray structural studies have shown that Arg-179 of thymidylate synthase is complexed to bound inorganic phosphate or to the 5'-phosphate of the bound substrate dUMP. The importance of Arg-179 to the structure/function of thymidylate synthase is also indicated by its complete conservation among the 17 thymidylate synthases thus far sequenced. In the present work, Arg-179 has been replaced by Thr, Ala, Lys, and Glu using site-directed mutagenesis with a mixture of four synthetic oligonucleotides as primers. The mutant proteins complement thymidylate synthase-deficient Escherichia coli and show high enzyme activity. Each of these mutants has been purified to homogeneity, partially sequenced to verify the mutation, and has had its steady state kinetic parameters determined. The most significant effect of all mutations is localized to a decrease in the net rate of association of thymidylate synthase with dUMP; the Lys mutant also shows an apparent increase in the dissociation constant of the folate cofactor of the reaction. The high activity in the mutant enzymes is explained by "plasticity" of the enzyme and compensatory actions of the other Arg residues. Why the Arg-179 residue has been conserved during evolution remains an open question.

Amino Acid Sequence↗

Compensatory nearly neutral mutations: selection without adaptation.

One implication of Kacser's analysis of complex metabolic systems is that mutations with small effects exist as a consequence of the typically small flux control coefficient relating enzyme activity to the rate of a metabolic process. Although a slightly detrimental mutation is somewhat less likely to become fixed by chance than a slightly favorable mutation, mutations that are slightly detrimental might be expected to be more numerous than favorable mutations owing to the previous incorporation of favorable mutations by a long history of natural selection. The result is that, as Ohta has pointed out, a significant fraction of mutations that are fixed in evolution are slightly detrimental. In the long run, the fixation of detrimental mutations in a gene increases the opportunity for the occurrence of a compensatory favorable mutation, either in the same gene or in an interacting gene. On a suitably long timescale, therefore, every gene incorporates favorable mutations that compensate for detrimental mutations previously fixed. This form of evolution is driven primarily by natural selection, but it results in no change or permanent improvement in enzymatic function.

Adaptation, Physiological↗

Direction-selective single units in the nucleus lentiformis mesencephali of the pigeon (Columba livia).

The receptive field properties of single units within the nucleus lentiformis mesencephali (LM) of the pigeon were studied using electrophysiological methods. Previous studies have suggested that the avian LM may be homologous to the nucleus of the optic tract (NOT) in mammals. Single units in the pigeon LM are similar to mammalian NOT units in that they are direction-selective, mostly for horizontal directions, velocity-selective, have large visual receptive fields and respond preferentially to large stimuli with many visual contrasts. In contrast to most reports of NOT units of mammals, more than half of pigeon LM units prefer high velocities (greater than 10 degrees/s), a large proportion (0.37) prefer non-horizontal directions, and receptive fields that are retinotopically arranged within the LM. The response properties of pigeon LM units are compared to the response properties of units within the accessory optic nucleus (the nucleus of the basal optic root or nBOR). In the avian brain, nBOR neurons respond at low velocities (0.5-5 degrees/s) and respond predominantly to vertical stimulus movement whereas LM units respond over a broader range of velocities (0.2-80 degrees/s) and respond predominantly to horizontal movements. Thus, the LM and nBOR may play different roles in the control of compensatory eye movements.

Animals↗

Deterministic, compensatory mutational events in the capsid of foot-and-mouth disease virus in response to the introduction of mutations found in viruses from persistent infections.

The evolution of foot-and-mouth disease virus (FMDV) (biological clone C-S8c1) in persistently infected cells led to the emergence of a variant (R100) that displayed increased virulence, reduced stability, and other modified phenotypic traits. Some mutations fixed in the R100 genome involved a cluster of highly conserved residues around the capsid pores that participate in interactions with each other and/or between capsid protomers. We have investigated phenotypic and genotypic changes that occurred when these replacements were introduced into the C-S8c1 capsid. The C3007V and M3014L mutations exerted no effect on plaque size or viral yield during lytic infections, or on virion stability, but led to a reduction in biological fitness; the D3009A mutation caused drastic reductions in plaque size and viability. Remarkably, competition of the C3007V mutant with the nonmutated virus invariably resulted in the fixation of the D3009A mutation in the C3007V capsid. In turn, the presence of the D3009A mutation invariably led to the fixation of the M3014L mutation. In both cases, two individually disadvantageous mutations led, together, to an increase in fitness, as the double mutants outcompeted the nonmutated genotype. The higher fitness of C3007V/D3009A was related to a faster multiplication rate. These observations provide evidence for a chain of linked, compensatory mutational events in a defined region of the FMDV capsid. Furthermore, they indicate that the clustering of unique amino acid replacements in viruses from persistent infections may also occur in cytolytic infections in response to changes caused by previous mutations without an involvement of the new mutations in the adaptation to a different environment.

Adaptation, Physiological↗

Fitness of RNA virus decreased by Muller's ratchet.

Why sex exists remains an unsolved problem in biology. If mutations are on the average deleterious, a high mutation rate can account for the evolution of sex. One form of this mutational hypothesis is Muller's ratchet. If the mutation rate is high, mutation-free individuals become rare and they can be lost by genetic drift in small populations. In asexual populations, as Muller noted, the loss is irreversible and the load of deleterious mutations increases in a ratchet-like manner with the successive loss of the least-mutated individuals. Sex can be advantageous because it increases the fitness of sexual populations by re-creating mutation-free individuals from mutated individuals and stops (or slows) Muller's ratchet. Although Muller's ratchet is an appealing hypothesis, it has been investigated and documented experimentally in only one group of organisms--ciliated protozoa. I initiated a study to examine the role of Muller's ratchet on the evolution of sex in RNA viruses and report here a significant decrease in fitness due to Muller's ratchet in 20 lineages of the RNA bacteriophage phi 6. These results show that deleterious mutations are generated at a sufficiently high rate to advance Muller's ratchet in an RNA virus and that beneficial, backward and compensatory mutations cannot stop the ratchet in the observed range of fitness decrease.

Bacteriophages↗

Delineation of an evolutionary salvage pathway by compensatory mutations of a defective lysozyme.

Model-free approaches (random mutagenesis, DNA shuffling) in combination with more "rational," three-dimensional information-guided randomization have been used for directed evolution of lysozyme activity in a defective T4 lysozyme mutant. A specialized lysozyme cloning vector phage, derived from phage lambda, depends upon T4 lysozyme function for its ability to form plaques. The substitution W138P in T4 lysozyme totally abolishes its plaque-forming ability. Compensating mutations in W138P T4 lysozyme after sequential random mutagenesis of the whole gene as well as after targeted randomization of residues in the vicinity of Trp138 were selected. In a second stage, these mutations were randomly recombined by the recombinatorial PCR method of DNA shuffling. Shuffled and selected W138P T4 lysozyme variants provide the hybrid lambda phage with sufficient lysozyme activity to produce normal-size plaques, even at elevated temperature (42 degrees C). The individual mutations with the highest compensatory information for W138P repair are the substitutions A146F and A146M, selected after targeted randomization of three residues in the neighborhood of Trp138 by combinatorial mutagenesis. The best evolved W138P T4 lysozymes, however, accumulated mutations originating from both randomly mutagenized as well as target-randomized variants.

Bacteriophage T4↗

Maintenance of aphid clonal lineages: images of immortality?

Artificial cloning and ancient asexuals have impacted upon both scientific and lay thinking in applied and theoretical fields as diverse as medicine and evolution. Hence, this is an opportune time to promote debate and discussion on what maintains a clonal lineage. The genetic fidelity of a clone has been discussed in detail elsewhere [Genet. Res. 79 (2002) 1; Biol. J. Linnean Soc. 79 (2003) 3]. In this paper, we focus on the lineage integrity (=longevity), or physiological lifespan of a clone with respect to senesce in relation to factors controlling telomere functioning. Aspects of cell line research pertinent to eukaryotic clonal lineages are discussed and, in particular, we try to extrapolate aspects of this research and apply it to apomictic (=mitotic) aphid lineages to suggest how they may be maintained. Analogies are made between single cells and individual aphids that senescence through a generation, whilst the respective lineages persist for finite periods, unless that is, compensatory mechanisms have evolved allowing immortality in the one and ancient asexuality in the other. Such comparison may allow fresh insights into the mechanisms of clonal lineage maintenance and evolution. We hypothesise that: (1). the cause of extinction in eukaryotic clonal lineages is due to deleterious effects on key regions of the genome, the chromosomal telomere being one such site; (2). recombination acts as a common mechanism to reset telomere functioning, perhaps more fundamental than its utility to reduce genetic load and maintain adaptability; and (3). ancient lineages persist through time as a function of group-specific compensatory mechanisms that maintain telomere integrity.

Aging↗

Self-imposed silence: parental antagonism and the evolution of X-chromosome inactivation.

A model is proposed for the evolution of X-chromosome inactivation (XCI) in which natural selection initially favors the silencing of paternally derived alleles of X-linked demand inhibitors. The compensatory upregulation of maternally derived alleles establishes a requirement for monoallelic expression in females. For this reason, XCI is self-reinforcing once established. However, inactivation of a particular X chromosome is not. Random XCI (rXCI) is favored over paternal XCI because rXCI reduces the costs of functional hemizygosity in females. Once present, rXCI favors the evolution of locus-by-locus imprinting of X-linked loci, which creates an evolutionary dynamic in which different chromosomes compete to remain active.

Animals↗

Observing development through evolutionary eyes: a practical approach.

An argument is made that only through a detailed comparison of mutational mechanisms underlying the evolution of the genetic systems governing development, can the 'logic' of individual development be fully comprehended. To do this, it is essential to choose two or more genes (or their products) that interact in the establishment of a given function, and to compare the molecular basis of that interaction in closely related species. The rationale to this approach arises from observations of molecular co-evolution between interacting partners involved with given functions which have led to species specificity in the manner in which such functions are effected. Molecular coevolution reveals that divergence in sequence can be tolerated whilst biological functions are maintained, not because it is neutral and dispensable but because successful, compensatory changes can evolve in eukaryotic genomes that are in continuous states of flux.

Animals↗

Kinetics of nigral degeneration in a chronic model of MPTP-treated mice.

The chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model we have developed in monkey reproduces all the cardinal features of Parkinson's disease, and, in particular the characteristic slow evolution of clinical signs. We still know little, however, of the kinetics of the nigral degeneration induced. This present study charts the progressive destruction of tyrosine hydroxylase-immunoreactive neurones in mice treated daily with low doses of MPTP for 20 days. Our results show that the neuronal death rate is initially high, subsequently decreases, and stabilizes. This new protocol thus mirrors closely the pattern of evolution assumed to be that of Parkinson's disease and should prove useful for studies on neuroprotection and compensatory mechanisms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Paleoproterozoic snowball earth: extreme climatic and geochemical global change and its biological consequences.

Geological, geophysical, and geochemical data support a theory that Earth experienced several intervals of intense, global glaciation ("snowball Earth" conditions) during Precambrian time. This snowball model predicts that postglacial, greenhouse-induced warming would lead to the deposition of banded iron formations and cap carbonates. Although global glaciation would have drastically curtailed biological productivity, melting of the oceanic ice would also have induced a cyanobacterial bloom, leading to an oxygen spike in the euphotic zone and to the oxidative precipitation of iron and manganese. A Paleoproterozoic snowball Earth at 2.4 Giga-annum before present (Ga) immediately precedes the Kalahari Manganese Field in southern Africa, suggesting that this rapid and massive change in global climate was responsible for its deposition. As large quantities of O(2) are needed to precipitate this Mn, photosystem II and oxygen radical protection mechanisms must have evolved before 2.4 Ga. This geochemical event may have triggered a compensatory evolutionary branching in the Fe/Mn superoxide dismutase enzyme, providing a Paleoproterozoic calibration point for studies of molecular evolution.

Africa↗

Miniaturization, genome size and the origin of functional constraints in the visual system of salamanders.

During their evolution, many species of lungless salamanders (fam. Plethodontidae) have experienced a great increase in genome size and consequently in the size of their cells, including sensory receptors and neurons. In addition, some have become extremely miniaturized. The consequences of these events and the morphological compensatory processes are studied in the visual system of juvenile and adult salamanders.

Animals↗

Experimental genomic evolution: extensive compensation for loss of DNA ligase activity in a virus.

Deletion of the viral ligase gene drastically reduced the fitness of bacteriophage T7 on a ligase-deficient host. Viral evolution recovered much of this fitness during long-term passage, but the final fitness remained below that of the intact virus. Compensatory changes occurred chiefly in genes involved in DNA metabolism: the viral endonuclease, helicase, and DNA polymerase. Two other compensatory changes of unknown function also occurred. Using a method to distinguish compensatory mutations from other beneficial mutations, five additional substitutions from the recovery were shown to enhance adaptation to culture conditions and were not compensatory for the deletion. In contrast to the few previous studies of viral recovery from deletions, the compensatory changes in T7 did not restore the deletion or duplicate major regions of the genome. The ability of this deleted genome to recover much of the lost fitness via mutations in its remaining genes reveals a considerable evolutionary potential to modify the interactions of its elements in maintaining an essential set of functions.

Adaptation, Physiological↗

Genetic conflicts over sex ratio: mite-endosymbiont interactions.

Nucleocytoplasmic genetic conflicts arise as a result of asymmetric transmission of cytoplasmic and nuclear genes. Spread of a cytoplasmic element promoting female-biased sex ratios creates selection on nuclear genes for mechanisms that decrease the bias. Here we investigate the conflict over sex ratio between the cytoplasmic bacterium Wolbachia and the two-spotted spider mite Tetranychus urticae Koch. We show that, first, infected females produce significantly more female-biased sex ratios than uninfected (cured) females. Second, this effect is not due to parthenogenesis, male killing, or feminization, phenotypes commonly associated with infection by Wolbachia. Third, sex ratio is a trait with a heritable component in this species; thus, it can evolve under selection. Fourth, the sex ratio produced by uninfected (cured) females changes over time, approaching the sex ratio produced by females from the infected culture. On the basis of these results, we suggest that after sex ratio manipulation by Wolbachia, a host compensatory mechanism evolved that allows infected females to produce the sex ratio favored by nuclear genes. We discuss the evolution of "mutualism" with respect to the evolution of host mechanisms that compensate for effects induced by vertically transmitted "parasites."

Animals↗

Different patterns of atherosclerotic remodeling in the thoracic and abdominal aorta.

PURPOSE: To investigate the relationship between the vascular diameter and the extent and histologic characteristics of atherosclerosis in the thoracic and abdominal aortas of patients who died of atherosclerotic disease. METHOD: We measured the vascular diameter and evaluated the percentage atrophy of the medial layer of the thoracic and abdominal aortas of 19 patients who died due to atherosclerotic disease. The extent of plaques, calcification, ulceration, thrombosis, and the amount of fat in the plaques were evaluated semiquantitatively. RESULTS: Atherosclerosis was more severe in the abdominal than the thoracic aorta as indicated by the higher sum of the macroscopic scores (P = .02) and the higher percentage atrophy of the medial layer (P < .001). The diameter of the thoracic, but not of the abdominal aorta, correlated with age (r = 0.56; P = .01), plaque score (r = 0.59; P = .008), calcification score (r = 0.749; P < .001), and fat score (r = 0.48; P = .04). Multiple linear regression showed that age (P = .06) and calcification score (P = .001) were the parameters with the strongest association to thoracic aorta diameter. CONCLUSION: There are some differences regarding atherosclerosis in the thoracic compared to the abdominal aorta. Progressive thoracic aorta atherosclerosis is associated with fat deposition in the plaques, inducing arterial dilation. In the abdominal aorta, atherosclerosis can either have a similar evolution or be associated with less fat deposition in the arterial wall, which would result in more rigidity, hindering compensatory arterial enlargement.

Aged↗

Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality.

Mortality in sepsis remains unacceptably high and attempts to modulate the inflammatory response failed to improve survival. Previous reports postulated that the sepsis-triggered immunological cascade is multimodal: initial systemic inflammatory response syndrome (SIRS; excessive pro-, but no/low anti-inflammatory plasma mediators), intermediate homeostasis with a mixed anti-inflammatory response syndrome (MARS; both pro- and anti-inflammatory mediators) and final compensatory anti-inflammatory response syndrome (CARS; excessive anti-, but no/low proinflammatory mediators). To verify this, we examined the evolution of the inflammatory response during the early phase of murine sepsis by repetitive blood sampling of septic animals. Increased plasma concentrations of proinflammatory (IL-6, TNF, IL-1beta, KC, MIP-2, MCP-1, and eotaxin) and anti-inflammatory (TNF soluble receptors, IL-10, IL-1 receptor antagonist) cytokines were observed in early deaths (days 1-5). These elevations occurred simultaneously for both the pro- and anti-inflammatory mediators. Plasma levels of IL-6 (26 ng/ml), TNF-alpha (12 ng/ml), KC (33 ng/ml), MIP-2 (14 ng/ml), IL-1 receptor antagonist (65 ng/ml), TNF soluble receptor I (3 ng/ml), and TNF soluble receptor II (14 ng/ml) accurately predicted mortality within 24 h. In contrast, these parameters were not elevated in either the late-deaths (day 6-28) or survivors. Surprisingly, either pro- or anti-inflammatory cytokines were also reliable in predicting mortality up to 48 h before outcome. These data demonstrate that the initial inflammatory response directly correlates to early but not late sepsis mortality. This multifaceted response questions the use of a simple proinflammatory cytokine measurement for classifying the inflammatory status during sepsis.

Animals↗

[Diagnosing eating disorders: presentation of a new diagnostic test and an initial epidemiological study of eating disorders in adolescents].

Precise diagnosis of eating disorders has long been problematic. First off, although the DSM IV provides clear criteria, these are applicable to a very narrow range of disorders. Subclinical disorders, although well defined in the literature, are difficult to diagnose as no tool has been previously available. These subclinical disorders are particularly important if one considers that they are often precursors to more serious and life-threatening eating disorders. In addition, choice of diagnostic tool for eating disorders has also long been the cause of difficulty for both researchers and clinicians. Although interviews are favored for their in-depth approach, they are sometimes difficult to implement and often too long and costly to use on a regular basis. Most available questionnaires are limited by their approach to one or two diagnostic categories, and again, until now, no tool has fully addressed the issue of subclinical disorders. The goal of this work was to translate and use a new questionnaire, The Questionnaire for Eating Disorders (Q-EDD), which was developed in the United States and based on both DSM IV criteria as well as carefully developed subclinical disorder criteria. The Q-EDD can identify the major eating disorder categories while at the same time distinguishing between different qualities in each (for example restricting versus compensatory anorexia). Moreover, the Q-EDD can identify several subclinical disorder categories, providing useful insight into potentially dangerous evolution of these disorders. In collaboration with one of the original authors, the questionnaire was translated into French with careful attention to DSM IV criteria in order to preserve its original validity. The questionnaire was read by several professionals in psychology as well as lay people to assure its face validity and ease of use. Once the questionnaire was adequately translated and corrected, it was used for an epidemiological study with a large sample of adolescents and young adults (n=1 001) from several Junior High and High Schools in the greater metropolitan area of Toulouse, France. The schools were located in a variety of neighborhoods and represented a wide range of population, some of them being more academic oriented, others being more oriented towards practical training. The population was composed of 703 females and 298 males, with an average age of 17.06 years. In addition, the population included several different ethnic categories, all of which are similarly represented in the general French population. The results from the Q-EDD showed levels of various clinical disorders to replicate data from previous epidemiological studies with 1.5% of the population suffering from a serious clinical DSM IV disorder; 7.9% suffering from DSM IV disorders NOS; and 20.9% suffering subclinical disorders. In addition to this finding of 30% of the population with an eating disorder, it was noted that a large number of these young people fell into the severe underweight and low weight categories. Indeed, nearly 10% of this group were within the weight criteria for anorexia, despite the fact that they did not meet the other criteria. This finding seemed to warrant additional investigation, and as a result, a different cut-off for severe underweight was established using literature references; this cut-off was set at the 10(th) percentile for BMI based on age. Yet, even with this new cut-off, 6% of this population still met a severe underweight criteria suggestive of anorexic pathology. These results led to the formulation of 2 hypotheses to explain this finding, the first of which examines morphological differences, the second of which suggests cultural differences in terms of eating habits and diet. The French version of the Q-EDD appears to follow the psychometric properties of the original version, moreover it provides useful and rich data regarding eating disorders in a format that is simple and efficient.

Adolescent↗