Simulation of the distribution of parental strains’ genomes in RC strains of mice

Recombinant Congenic strains (RC strains) were developed to facilitate mapping of genes influencing complex traits controlled by multiple genes. They were produced by inbreeding of the progeny derived from a second backcross from a common `donor' inbred strain to a common `background' inbred strain. Each RC strain contains a random subset of approximately 12.5% of genes from the donor strain and 87.5% of genes from the background strain. In this way the genetic control of a complex disease may be dissected into its individual components. We simulated the production of the RC strains to study to what extent they have to be characterized in order to obtain sufficient information about the distribution of the parental strains' genomes in these strains and to acquire insight into parameters influencing their effectiveness in mapping quantitative trait loci (QTLs). The donor strain genome in the RC strains is fragmented into many segments. Genetic characterization of these strains with one polymorphic marker per 3.3 centiMorgans (cM) is needed to detect 95% of the donor strain genome. The probability of a donor strain segment being located entirely in between two markers of background strain origin that are 3 cM apart (and hence escaping detection) is 0.003. Although the donor strain genome in the RC strains is split into many segments, the largest part still occurs in relatively long stretches that are mostly concentrated in fewer than 13 autosomes, the median being 9 autosomes. Thus, in mapping QTLs, the use of RC strains facilitates the detection of linkage. Received: 20 December 1996 / Accepted: 23 July 1997     

Correlated autoradiographic and ion-microscopic study of the role of iodine in the formation of “cold” follicles in young and old mice

Summary The role of iodine in the formation of cold follicles (not labeled on autoradiograms after radioiodine administration) was analysed in ICR female mice during aging and involution of thyroid hyperplasia, by use of light and electron microscopy and by comparing autoradiographic and analytical ion-microscopic images for the same follicle in serial sections. The proportion of cold and partly cold (displaying a patchy or ring labeling pattern on autoradiograms) follicles increased significantly during aging. This increase was more pronounced in old mice fed an iodine-rich diet as compared to mice fed a moderate iodine diet. Similarly, during goiter involution produced by refeeding iodine, the follicular heterogeneity of iodine metabolism was more accentuated with a high dose of iodine, regardless of the age of the mice. The follicular lumina of hot and cold follicles had the same concentration of stable iodine, as shown by analytical ion microscopy, and the cells of both types of follicles formed colloid droplets in response to TSH. Furthermore, when a goitrogenic treatment was induced in aged mice, some cold follicles persisted after 8 days, but all follicles resumed hot after 16 days. By analytical ion microscopy, ¹²⁷iodine was also found inside thyroid cells of old mice, but the cytoplasmic patches of ¹²⁷iodine were not labeled with ¹²⁵iodine. They corresponded to lipofuscin pigments and secondary lysosomes, as observed in serial sections at the electron-microscopic level. This intracellular stable iodine could constitute a slow turnover compartment not used for hormone synthesis.Portions of this work were presented at the 15th and 17th Annual Meetings of the European Thyroid Association (Stockholm 1986; Montpellier 1988). This work was supported in part by the Association de la Recherche sur le Cancer (ARC) and a cooperative programme Communauté Française de Belgique-France     

Sexually Antagonistic “Zygotic Drive” of the Sex Chromosomes

Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic “zygotic drive”, because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic “arms race” between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.     

On the origin of molecular “handedness” in living systems

Elementary particle effects (beta-decay) provide at best only a weakly handed radiation in the biologically effective energy ranges. Global magnetic effects coupled to sunlight are randomized by paleomagnetic reversals. Hence a persistent terrestrial handed bias at possible local biopoetic sites offers a more promising explanation for the origin of the "handedness" of the molecules found among living systems on earth. Magnetite in lava flows maintains a handed bias for surface catalysis through many magnetic reversals. Magnetite contaminated with sulfur has already been proposed by Granick as a biopoetic site because it provides a weak source of chemical energy derived by photochemical conversion. Indirect evidence for this hypothesis has been provided by the molecular structure of ferredoxin - a single strand of the 14 primordial amino acids wrapped around an FeS core. Lava flows have been suggested as biopoetic sites by Fox, since their temperature and chemical composition might allow for the rapid synthesis of prebiotic compounds at the surface of the primitive earth. The additional fact that magnetite in lave flows also provides a persistent handed site for surface catalysis offers a further argument for the experimental investigation of this specific biopoetic environment.     

PCR-analyzed microsatellites of the mouse genome—additional polymorphisms among ten inbred mouse strains

Eighty sequences from the mouse genome database containing microsatellites (simple sequence repeats) have been analyzed for size variation among ten different inbred strains of mice; 62/80 (77.5%) showed polymorphism of at least three alleles. We have been able to detect all the polymorphims by agarose gel electrophoresis, often running the gels for up to 3 h. Between individual pairs of mouse strains to be used in chromosomal mapping studies in our laboratory, 35–60% polymorphism occurred. There are potentially enough microsatellites within the mouse and human genome to have a marker at every 1-cM distance. This simple approach will, therefore, continue to be useful in genome mapping studies, leading eventually to high-resolution maps of both the mouse and human genomes; this should allow for physical mapping and cloning of specific genes.     

Identification of Ly 5 on the surface of ‘natural killer’ cells in normal and athymic inbred mouse strains

This report that (1) cells mediating NK activity in different inbred mouse strains selectively express one of two allelic products specified by theLy-5 locus (or a locus tightly linked to it) and (2) this surface structure may directly contribute to NK-mediated cytolysis, since Ly 5 antiserum specifically inhibits NK activity in vitro in the absence of complement.     

Feature identification in circadian rhythms of mice strains using in vivo information

The objective of this work was to identify strain-specific characteristics from real-time measurements of circadian rhythms of two inbred mouse strains. In particular, heart rate, temperature, and activity data collected from A/J and C57BL/6J (B6) mice using telemetry are analyzed. The influence of activity on heart rate and temperature is minimized by correlation analysis followed by regression analysis. The correlation analysis is used to determine the length of the activity data filter that results in the best correlation between activity data and heart rate or temperature. After the activity data are filtered, they are used in regression analysis. The temperature and heart rate rhythms obtained as the intercepts of the regression analysis are interpreted as the zero-activity rhythms and consequently are good estimates of the circadian rhythms. The circadian temperature rhythms for the B6 mice follow a smoother cosine-like time waveform, whereas those for the A/J mice follow a more square-wave-like waveform. To quantify the difference between these two temperature rhythms, a feature based on Fourier analysis of the time-series data is used. Detrended fluctuation analysis is used to identify features in the heart rate rhythms. The results of this work show that the features for the circadian temperature and heart rate rhythms can be used as distinguishing characteristics of the A/J and B6 strains. This work provides the foundation for future studies directed at investigating the influence of chromosomal substitutions on the regulation of circadian rhythms in these two strains.     

Kinetic analysis of the “substrate protective effect” in cholinesterases of different origin

The authors’ own and literature data are summarized on interaction of 17 irreversible organophosphorus inhibitors with different types of cholinesterases (ChE): erythrocyte acetylcholinesterase (AChE), serum butyrylcholinesterase (BuChE), and cholinesterase of the Pacific squidTodarodes pacificus, in the presence of 9 substrates. The kinetic analysis of the “substrate protective effect” based on A.P. Brestkin’s equation is performed, and the current interpretation of individual components of this process is done. An essential effect of the inhibitor structure on individual phases of the reaction is revealed. Among choline substrates, only formylcholine did not show a protective effect. The inability of an uncationic substrate, phenylacetate, to regulate ChE reactivity is confirmed. Among the studied ChE, the highest substrate protective effect was revealed in the Pacific squid ChE.     

Geographic distribution of the anti-parasite trait “slave rebellion”

Social parasites exploit the brood care behavior of other species and can exert strong selection pressures on their hosts. As a consequence, hosts have developed defenses to circumvent or to lower the costs of parasitism. Recently, a novel, indirect defense trait, termed slave rebellion, has been described for hosts of a slave-making ant: Enslaved Temnothorax longispinosus workers reduce local parasite pressure by regularly killing pupae of their obligatory slavemaking parasite Protomognathus americanus. Subsequently, growth of social parasite nests is reduced, which leads to fewer raids and likely increases fitness of neighboring related host colonies. In this study, we investigate the presence and expression the slave rebellion trait in four communities. We report its presence in all parasitized communities, document strong variation in its expression between different geographic sites and discuss potential explanations for this observed variation.     

The physical basis of alpha waves in the electroencephalogram and the origin of the “Berger effect”

Synchronised activity, differing in phase in different populations of neurons, plays an important role in existing theories on the function of brain oscillations (e.g., temporal correlation hypothesis). A prerequisite for this synchronisation is that stimuli are capable of affecting (resetting) the phase of brain oscillations. Such a change in the phase of brain waves is also assumed to underlie the Berger effect: when observers open their eyes, the amplitude of EEG oscillations in the alpha band (8–13 Hz) decreases significantly. This finding is usually thought to involve a desynchronisation of activity in different neurons. For functional interpretations of brain oscillations in the visual system, it therefore seems to be crucial to find out whether or not the phase of brain oscillations can be affected by visual stimuli. To answer this question, we investigated whether alpha waves are generated by a linear or a nonlinear mechanism. If the mechanism is linear – in contrast to nonlinear ones – phases cannot be reset by a stimulus. It is shown that alpha-wave activity in the EEG comprises both linear and nonlinear components. The generation of alpha waves basically is a linear process and flash-evoked potentials are superimposed on ongoing alpha waves without resetting their phase. One nonlinear component is due to light adaptation, which contributes to the Berger effect. The results call into question theories about brain-wave function based on temporal correlation or event-related desynchronisation.Electronic Supplementary Material: Supplementary material is available for this article at     

Identification and origin of Nε-homocysteinyl-lysine isopeptide in humans and mice

Homocysteine (Hcy) metabolites, Hcy-thiolactone and N-Hcy-proteins, have been linked to the pathology of human cardiovascular and neurodegenerative diseases. Hcy-thiolactone is generated in an error-editing reaction in protein biosynthesis when Hcy is selected in place of methionine by methionyl-tRNA synthetase. N-Hcy-protein, in which Hcy is linked via isopeptide bond to ε-amino group of a protein lysine residue, forms in a post-translational reaction of Hcy-thiolactone with proteins. Here, we identify a novel metabolite, Nε-Hcy-Lys, in human and mouse plasma, and show that this metabolite is elevated in genetic (cystathionine β-synthase deficiency in humans and mice, methylenetetrahydrofolate reductase deficiency in mice) or dietary (high Met diet in mice) deficiencies in Hcy metabolism. We also show that Nε-Hcy-Lys is generated by proteolytic degradation of N-Hcy-protein in mouse liver extracts. Our data indicate that free Nε-Hcy-Lys is an important pathology-related component of Hcy metabolism in humans and mice.     

Drugs of plant origin from the “Carlo Erba” collection of the Botanical Museum in Portici “Orazio Comes”

Phytochemistry Reviews - The aim of this paper is to illustrate the origin and composition of a collection of 192 plant drugs, based on archival documents from 1932 to 1940. This unique collection...