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Ontophyletics of the nervous system: eyeless mutants illustrate how ontogenetic buffer mechanisms channel evolution.

Genetics and molecular biology have shown the mechanisms that allow the genome to provide both the continuity and the variation from generation to generation within a phylogeny. Embryology and developmental biology show the mechanisms that turn the genome into an organism. Mutations, the basis for evolutionary change, cannot in themselves ensure concordance between their products and the products of unchanged genes. Thus, mutations will not necessarily produce a viable organism. On the other hand, ontogenetic buffer mechanisms normally maintain concordance in the developing organism. In addition, ontogenetic buffer mechanisms can integrate discordant mutations into viable organisms that can then be perpetuated during evolution. The evolutionary role of one ontogenetic buffer mechanism, compensatory innervation, is well illustrated in the anopthalmic mutant mouse. In the anopthalmic mouse, a single gene mutation removes afferent axons of the dorsal lateral geniculate nucleus, and compensatory innervation by another population of axons ensures that the dorsal lateral geniculate remains integrated into the central nervous system. Within each organism's ontogeny is a hierarchy of sources of compensatory innervation, and this hierarchy will determine how any particular deafferentating mutation will be buffered. In this way, an ontogeny can channel the phylogeny of which it is a member.

Animals

Pyruvate kinase deficiency hemolytic anemia: enzymatic characterization studies in twelve patients.

Erythrocyte pyruvate kinase from twelve patients with hereditary erythrocyte pyruvate kinase (PK) deficiency was investigated according to the recommended methods for the characterization of red cell pyruvate kinase variants. Family members were also studied. Abnormalities were frequently noted in the affinity for the substrate, phosphoenolpyruvate; allosteric activator, fructose-1,6-diphosphate; allosteric inhibitor, ATP; and also in heat stability and electrophoretic pattern. Several different PK variants were identified. Polyacrylamide gel electrophoresis revealed the presence of immature activity bands in the red cells of some patients. These bands presumably represent residuals of isozymes produced during the evolution of erythrocyte PK, and may occur as a compensatory mechanism for the defective isozyme.

Adenosine Triphosphate

Secondary structure constraints on the evolution of Drosophila 28 S ribosomal RNA expansion segments.

Eukaryotic ribosomal RNA genes contain rapidly evolving regions of unknown function termed expansion segments. We present the comparative analysis of the primary and secondary structure of two expansion segments from the large subunit rRNA gene of ten species of Drosophila and the tsetse fly species Glossina morsitans morsitans. At the primary sequence level, most of the differences observed in the sequences obtained are single base substitutions. This is in marked contrast with observations in vertebrate species in which the insertion or deletion of repetitive motifs, probably generated by a DNA-slippage mechanism, is a major factor in the evolution of these regions. The secondary structure of the two regions, supported by multiple compensatory base changes, is highly conserved between the species examined and supports the existence of a general folding pattern for all eukaryotes. Intriguingly, the evolutionary rate of expansion segments is very slow relative to other genic and non-genic regions of the Drosophila genome. These results suggest that the evolution of expansion segments in the rDNA multigene family is a balance between the homogenization of new mutations by unequal crossing over and a combination of selection against some such mutations per se and selection for subsequent compensatory mutations, in order to maintain a particular RNA secondary structure.

Animals

Myocardial hypertrophy and cardiac failure: a complex interrelationship.

The interrelationship between myocardial hypertrophy and myocardial function is a complex one. In patients with essential hypertension, the appearance of left ventricular hypertrophy may be an ominous sign, often presaging the evolution of congestive heart failure. In other settings, such as valvular heart disease, congestive cardiomyopathy, and ischemic heart disease, myocardial hypertrophy serves as a compensatory mechanism in response to excessive loading conditions. This article reviews experimental and clinical data concerning the evolution of hypertrophy and its relationship to myocardial function.

Animals

Sequential antibiotic exposure restores antibiotic susceptibility.

BACKGROUND: The prevalence of antibiotic resistance continues to rise, rendering many valuable antimicrobial drugs ineffective. Pairwise cyclic antibiotic therapy, where treatment is rapidly switched between two antibiotics, has been demonstrated in vitro to limit the evolution of antibiotic resistance. However, what happens when resistance inevitably evolves to one of the drugs? METHODS: In this study, we perform over 450 evolution experiments to test the resilience of four proposed cyclic therapies. We use soft agar gradient evolution and 'flat plates' to identify resistance trade-offs that are resilient to compensatory mitigation. Resensitizations were detected by antimicrobial susceptibility assays, and their mechanistic underpinnings were elucidated via genomic and phenotypic analyses. RESULTS: Resistance evolves readily and collateral sensitivity (CS) (where resistance to drug A leads to hypersensitivity to drug B) does not hinder the evolution of multidrug resistance and does not predict or promote resensitization. However, if resistance to drug B increases susceptibility to A, a phenomenon we term backward CS, resistance to A can be reduced or even reversed. For example, we show that Escherichia coli cells frequently become hypersensitive to β-lactams upon aminoglycoside resistance acquisition, due to conflicting modifications to the proton motive force and efflux pumps. We also find for the first time that polymyxin B resistance can be entirely reversed by exposure to tigecycline, through the acquisition of compensatory mutations that reduce the fitness penalty of tigecycline resistance. CONCLUSIONS: The longevity of drug cycling protocols can be significantly improved by leveraging backwards CS to resensitize cells as antibiotic resistance evolves.

Anti-Bacterial Agents

A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis.

Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE-associated fitness remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, representing a vast reservoir of potential targets for novel antimicrobial intervention. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory "bypass" mechanisms. Together, these findings provide a comprehensive, genome-wide map of the bacterial niche-requirements for streptococcal infective endocarditis.

Animals

[Comparative analysis of blood coagulation and various indicators of microcirculation in patients with coronary arteriosclerosis and hypertension in the age aspect].

In patients with hypertensive disease and coronary atherosclerosis the blood-clotting potential increases on account of a rise in the level of procoagulants and inhibition of fibrinolysis. Age-specific differences in the characteristics of the coagulation and fibrinolytic system of the blood are levelled out parallel with the development of atherosclerosis and progressive evolution of hypertensive disease. In patients of advanced age a tendency toward a compensatory increased activity of erythrocytic anticoagulation factors is noted, finding its expression in a drop of the procoagulants level, and increase of anticoagulants and in a rising fibrinolytic activity. Changes in the state of the conjunctival microcirculation and the retinal hemodynamics correlate with the intensity of the pathological process and shifts in the blood coagulation system.

Adaptation, Physiological

Complete sequences of the rRNA genes of Drosophila melanogaster.

In this, the first of three papers, we present the sequence of the ribosomal RNA (rRNA) genes of Drosophila melanogaster. The gene regions of D. melanogaster rDNA encode four individual rRNAs: 18S (1,995 nt), 5.8S (123 nt), 2S (30 nt), and 28S (3,945 nt). The ribosomal DNA (rDNA) repeat of D. melanogaster is AT rich (65.9% overall), with the spacers being particularly AT rich. Analysis of DNA simplicity reveals that, in contrast to the intergenic spacer (IGS) and the external transcribed spacer (ETS), most of the rRNA gene regions have been refractory to the action of slippage-like events, with the exception of the 28S rRNA gene expansion segments. It would seem that the 28S rRNA can accommodate the products of slippage-like events without loss of activity. In the following two papers we analyze the effects of sequence divergence on the evolution of (1) the 28S gene "expansion segments" and (2) the 28S and 18S rRNA secondary structures among eukaryotic species, respectively. Our detailed analyses reveal, in addition to unequal crossing-over, (1) the involvement of slippage and biased mutation in the evolution of the rDNA multigene family and (2) the molecular coevolution of both expansion segments and the nucleotides involved with compensatory changes required to maintain secondary structures of RNA.

Animals

Population consequences of mutagenesis and antimutagenesis.

Although the progress in basic understanding of mutagenesis and in techniques for precise measurement of mutation rates in test systems has been enormous, there has been very little progress in applying this information to estimates of germline mutation in humans, and even less in translating such estimates into quantitative assessments of the impact on future generations. This doesn't mean that new information about the mutation process, and antimutagens in particular, is not useful. Lowering the human mutation rate would be good, even if we can't say how good. Some simple population kinetics of a change of mutation are discussed, and it is shown that future environmental changes can be ignored if we assume that the impact of a disease on human welfare is changed by the environment in the same proportion as its effect on fitness. Since the human mutation rate appears to be much higher in males than in females, it would be especially important to find ways of reducing the male rate. The role of transposable elements in determining human spontaneous mutation rates is unknown, but unless data from experimental organisms are grossly misleading, this role may be substantial. It is sometimes argued that such responses as error-prone repair systems may be an evolutionary strategy to allow the population to try a larger repertoire of mutations in times of environmental change. They may also be a survival strategy. I suggest that, although such an evolutionary strategy may possibly be adopted in asexual organisms with a very high reproductive rate, it is very unlikely in Mendelian species with limited reproduction such as most higher animals. The amount of existing variability in a large population is so great relative to that which arises in a few generations by mutation that segregation and recombination of existing alleles would appear to be a better way of coping with changing environment. As the human age of reproduction has increased in the recent evolutionary past, it is possible that the compensatory adjustment of mutation rates has not been fast enough to keep up. Perhaps evolution of mutation rates is more determined by selection to reduce somatic mutation than by selection to reduce germinal mutation. Regardless of the answer to the question of the optimum mutation rate for long-time evolution, in my view, the optimum mutation rate from the standpoint of human welfare for the foreseeable future is zero.

Animals

[Morphologic characteristics of the liver in the postcholecystectomy syndrome].

Liver biopsies of 152 patients with post-cholecystectomy syndrome are studied. Liver alterations observed in these patients are subdivided into morphological syndromes (portal and periportal hepatitis, liver fibrosis and cirrhosis) and their evolution is investigated. Changes of intrahepatic bile ducts are studied and their adaptive-compensatory character is shown. Compensatory processes in the liver parenchyma are also investigated. Patho- and morphogenesis of alterations observed is discussed.

Adult

Kinetics of elemental content changes of bone tissue of mice during evolution under hypokinetic stress.

Concentration of 13 elements in bone tissue of mice held in tightly spaced cages for 3 wk, which caused an acute stress reaction, was determined by means of neutron activation analysis. Functionally different bone tissues of mice skeletons--the femur, accomplishing both supporting and dynamic functions; the parietal bone, being practically immovable; and the ectopic bone, newly formed under kidney capsule in the place of syngeneic bone marrow implantation--were analyzed. Similar dynamics of the elemental composition of investigated bones was found: the progressive demineralization owing to the loss of Ca, P, Mg, and Fe is accompanied by the compensatory inclusion of Sr in the bone tissues. In the ectopic bone, it was not as high. During evolution under hypokinetic stress, the microelement concentrations (Zn, Cr, Rb, Ru, Br, Co, Sb) change significantly. Results obtained form the evidence for some system character of osteoporosis at limited mobility.

Animals

[The adaptive-compensatory reactions in adjusting to space flights].

In this paper an evolutionary approach is used to substantiate the steps of life evolution on Earth towards overcoming the gravitational forces with the formation of metabolic cycles controlling the energetic of anti-G processes. The step of an adaptation to hypogravity was similar to return of surface animals to an aquatic environment. The impossibility of coming back to land was the "price" of adaptation to the aquatic environment. This phenomenon was used by the author as a logical model of human adaptation to a weightless environment. The concept of adaptation is examined from two points of view: adaptation and compensation. The scheme contains 4 steps of adaptation to space mission environments: Step I-preadaptation (phase of primary reactions); Step II-compensation of body structures not being in line with the conditions of a novel environment; Step III-the formation of parameters of an organism corresponding to the norm of adaptation to weightlessness; Step IV-the return of cosmonauts to Earth under hypergravity conditions. In compliance with these steps we consider the tasks of supporting space missions to facilitate body readaptation after return to Earth, i.e., to decrease the "price" of adaptation.

Adaptation, Physiological

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

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

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

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

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