Effects of a change in the level of inbreeding on the genetic load

"The effects of inbreeding may not be as noticeable in the first generation as the invigoration immediately apparent after crossing". This statement, published in 1919, has received little attention, and has apparently never been tested empirically, although the reduction of the genetic load of populations by inbreeding is well known in theoretical terms. Because inbreeding increases homozygosity, and hence the effectiveness of selection against recessive or partially recessive detrimental alleles, changes in levels of inbreeding can lead to a reduction in the frequencies of such mutant alleles. This results in equilibration at higher population mean fitness and is referred to as 'purging' populations of their genetic load. Severe inbreeding can also reduce genetic load due to overdominant alleles, provided selection coefficients are not symmetrical at all loci, because alleles giving lower fitness will be reduced in frequency at equilibrium. With either fitness model, however, reduction in genetic load takes time, and the initial effect of an increase in inbreeding is reduced fitness due to homozygosity. There are few data relating to the extent to which fitness is reduced during inbreeding in a set of lines and to how long the reduction lasts before increasing again to the initial level, or higher. Inbreeding experiments involving sib mating in mice and Drosophila subobscura, and successive bottlenecks in house flies have yielded some evidence consistent with the purging hypothesis. Here, we report results of an experiment demonstrating a prolonged time-course of recovery of mean fitness under self-fertilization of a naturally outcrossing plant, and also compare our results with expectations derived by computer calculations. Our results show that the genetic load present in an outcrossing population can be explained only with a high mutation rate to partially recessive deleterious alleles, and that inbreeding purges the population of mutant alleles.     

Genetic factors in neurotoxicology and neuropharmacology: A critical evaluation of the use of genetics as a research tool

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.     

Gigantecin: A novel antimitotic and cytotoxic acetogenin,with nonadjacent tetrahydrofuran rings,fromGoniothalamus giganteus (Annonaceae)

Summary Gigantecin (I), a novel tetrahydroxy-di-tetrahydrofuran fatty acid -lactone (acetogenin), was isolated from an ethanolic extract of the stem bark ofGoniothalamus giganteus Hook. f., Thomas (Annonaceae), by means of activity-directed fractionation (brine shrimp lethality test). This new compound is extremely cytotoxic to human tumor cells, inhibits crown gall tumors on potato discs, and is active in an assay designed to detect antimitotic agents (9 ASK).     

Amino-acid synthesis in carbonaceous meteorites by aqueous alteration of polycyclic aromatic hydrocarbons

It has been suggested that amino acids and other organic compounds found in carbonaceous meteorites formed by aqueous alteration in the meteorite parent bodies. Observations of carbonaceous material in interstellar grains and interplanetary dust particles indicate that condensed organic compounds may have been present in meteorite parent bodies at the time of aqueous alteration. One group of compounds thought to be representative of this carbonaceous material is the polycyclic aromatic hydrocarbons (PAHs). Recently it was proposed that PAHs condense on SiC grains in the molecular envelopes of carbon-rich red-giant stars, which would allow for their subsequent incorporation into meteorite parent bodies during accretion. This incorporation mechanism is supported by the identification of SiC grains in carbonaceous chondrites. The possibility therefore exists that PAHs, and/or other condensed organic compounds, represent the starting material for aqueous alteration which leads to the formation of amino acids and other water-soluble organic compounds. Here we present calculations of the distribution of aqueous organic compounds in metastable equilibrium with representative PAHs as functions of the fugacities of O2, CO2 and NH3. The results reported here for pyrene and fluoranthene, two PAHs with different structures but the same stoichiometry, differ greatly but indicate that the formation of amino and carboxylic acids is energetically favourable at probable parent-body alteration conditions. The actual reaction mechanisms involved could be revealed by consideration of isotope data for PAHs, amino acids, other organic compounds and carbonates in carbonaceous chondrites.     

A user designer-based systems methodology

This paper develops the argument that in organizational redesign it is desirable to utilize user-designers as the architects for the redesign. A methodology is developed which emphasizes the use of ideal systems models by user-designers to plan for the organization's future. The methodology involves the creation of an ideal system model, then an analysis of the present system through the creation of root definitions and process models of the existing system. Then root definitions and process models for the idealized system are created. Finally, the two are compared and desirable changes are generated which bring the existing system toward the idealized.     

Error rates in quadratic discrimination with constraints on the covariance matrices

In multivariate discrimination of several normal populations, the optimal classification procedure is based on quadratic discriminant functions. We compare expected error rates of the quadratic classification procedure if the covariance matrices are estimated under the following four models: (i) arbitrary covariance matrices, (ii) common principal components, (iii) proportional covariance matrices, and (iv) identical covariance matrices. Using Monte Carlo simulation to estimate expected error rates, we study the performance of the four discrimination procedures for five different parameter setups corresponding to standard situations that have been used in the literature. The procedures are examined for sample sizes ranging from 10 to 60, and for two to four groups. Our results quantify the extent to which a parsimonious method reduces error rates, and demonstrate that choosing a simple method of discrimination is often beneficial even if the underlying model assumptions are wrong.The authors wish to thank the editor and three referees for their helpful comments on the first draft of this article. M. J. Schmid supported by grants no. 2.724-0.85 and 2.038-0.86 of the Swiss National Science Foundation.     

<Emphasis Type="Italic">Naja siamensis</Emphasis>, a cryptic species of venomous snake revealed by mtDNA sequencing

Because of possible variation in venom composition, an understanding of venomous snake systematics is of great importance for the optimization of antivenom treatment of snakebite patients. Intraspecific variation in the morphology of many venomous snakes complicates the definition and indentification of some species when allopatric populations are involved. Selectively neutral or near-neutral mtDNA sequences can reveal evolutionary relationships obscured by ecogenetically-caused morphological variation. We use comparative sequencing of the cytochrome oxidase subunit 1 gene to reveal the existence of a widespread, cryptic species of spiting cobra from southeast Asia. This species,Naja siamensis, is widely sympatric with other Asiatic cobra species. This may be of considerable medical significance, and calls for further research into venom composition in Asiatic cobras.     

Variability of sterol utilization in stored-products insects

A comparison of sterol utilization by 3 stored-products insects revealed very different capabilities. The fluor beetle,Tribolium castaneum dealkylates and converts dietary sitosterol to about equal amounts of cholesterol (43.7%) and 7-dehydrocholeterol (39.8%), whereas another flour beetle,Tenebrio molitor, produces considerably less 7-dehydrocholesterol (16.8%) and relatively more cholesterol (66.7%) from sitosterol. The lepidopteran,Plodia interpunctella, utilized dietary sterol very similar to plant-feeding lepidoptera, producing primarily cholesterol (86.5%) from sitosterol.