The role of an ethics advisory board in self-regulation.
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Ethics, Medical↗
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The current ethical controversy over reproductive medicine: prenatal diagnosis.
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Ethics, Medical↗
Ancestral inbreeding only minimally affects inbreeding depression in mammalian populations.
Inbreeding depression can be reduced, or purged, by selection against deleterious alleles. This prediction is the basis of the recommendation that captive wildlife populations suffering from inbreeding depression be intentionally bred from healthy inbred animals. Yet data on the effectiveness of purging inbreeding depression are few. In this study I present and use two different regression models (an ancestral inbreeding model and a lethal recessive model) to test for the presence of purging effects in 25 captive mammalian populations. Fitness components examined were neonatal survival, survival from neonate to weaning, and litter size. In only one species was purging statistically significant. However, 15 of 17 species that showed inbreeding depression exhibited a slight decline in inbreeding depression in neonatal survival among descendants of inbred animals. These results show a small but highly significant trend of purging on neonatal survival. No trends in purging effects were observed in weaning survival or litter size. The effects were not likely to be strong enough to be of practical use in eliminating inbreeding depression.
Animals↗
Genetic error, sex, and diploidy.
Mathematical models and experiments on transformation are reported testing the hypothesis that sex and diploidy evolved as a DNA repair system. The models focus on the origin of diploidy and sex by studying selection between asexual haploids, sexual haploids, and diploids. Haploid cells are efficient replicators, while diploid cells are resistance to damage. A sexual haploid may combine the advantages of both: spending much of its life cycle in the haploid state, then temporarily fusing to become diploid, followed by splitting to the haploid state. During the diploid state DNA damage can be repaired, since there are two copies of the gene in the cell and one copy is presumed to be undamaged. Five basic rate parameters are employed: birth and death; genomic damage (for the haploids alone); and, for the sexual cell, fusion and splitting. Parameter space bifurcation diagrams for the equilibria are drawn, and solutions of the equations are described in terms of these diagrams. Each type of cell has a region of the parameter space that it occupies exclusively (given its initial presence in the competition). The haploid wins in environments characterized by low damage. The diploid wins in environments characterized by high damage, low mortality, and abundant resources. In general, only a single type of cell occupies a given portion of the space. We find, however, that competitive coexistence of an asexual diploid and sexual haploid is possible in spite of the fact that they are competing for a single resource (nucleotide building blocks). Sex can increase from rarity if matings occur with asexual cells. Only sex can cope with both high mortality and high damage. We then turn to natural bacterial transformation as a model system for the experimental study of sex. Natural transformation in distributed widely, but apparently sparsely, in all bacterial groups. A very preliminary phylogenetic analysis of the bacilli and related species indicates that transformation is probably not a diversifying force in bacterial evolution. However, it is difficult to be sure because of the ambiguity surrounding negative data. Experiments with the bacterium Bacillus subtilis indicate that transformation frequencies respond adaptively to DNA damage if homologous donor DNA is used. Several specific hypotheses for this response are considered. Recent work in other labs on the evolution of transformation is discussed from the point of view of the hypothesis that transformation functions in DNA repair.
DNA Repair↗
Loss of meiosis in Aspergillus.
If strictly mitotic asexual fungi lack recombination, the conventional view predicts that they are recent derivatives from older meiotic lineages. We tested this by inferring phylogenetic relationships among closely related meiotic and strictly mitotic taxa with Aspergillus conidial (mitotic) states. Phylogenies were constructed by using DNA sequences from the mitochondrial small ribosomal subunit, the nuclear ribosomal internal transcribed spacers, and the nuclear 5.8S ribosomal gene. Over 920 bp of sequence was analyzed for each taxon. Phylogenetic analysis of both the mitochondrial and nuclear data sets showed at least four clades that possess both meiotic and strictly mitotic taxa. These results support the hypothesis that strictly mitotic lineages arise frequently from more ancient meiotic lineages with Aspergillus conidial states. Many of the strictly mitotic species examined retained characters that may be vestiges of a meiotic state, including the production of sclerotia, sclerotium-like structures, and hülle cells.
Aspergillus↗
Interspecies transfer of female mitochondrial DNA is coupled with role-reversals and departure from neutrality in the mussel Mytilus trossulus.
Mussels of the genus Mytilus have distinct and highly diverged male and female mitochondrial DNA (mtDNA) genomes with separate routes of inheritance. Previous studies of European populations of Mytilus trossulus demonstrated that 33% of males are heteroplasmic for a second mtDNA genome of increased length and that hybridization with Mytilus edulis does not block mtDNA introgression, in contrast to reports for American populations. Here, we demonstrate that the female mtDNA type of M. edulis has replaced the resident female mtDNA type of European M. trossulus. This is supported by COIII sequence data indicating that the female mtDNA of European M. trossulus is very similar to that of M. edulis and that in phylogenetic trees, the mtDNAs of these two species cluster together but separately from American M. trossulus sequences, the latter not being disturbed by introgressive hybridization. We also provide evidence that the mtDNA genome of increased length found in heteroplasmic males of European M. trossulus derives from a recent partition of an introgressed M. edulis female type into the male route of transmission. Neutrality tests reveal that European populations of M. trossulus display an excess of replacement polymorphism within the female mtDNA type with respect to conspecific American populations, as well as a significant excess of rare variants, of a similar magnitude to those previously reported for the invading European M. edulis mtDNA. Results are consistent with a nearly neutral model of molecular evolution and suggest that selection acting on European M. trossulus mtDNA is largely independent of the nuclear genetic background.
Americas↗
Molecular evolution of the period gene in Drosophila athabasca.
We measured nucleotide variability within and between the three semispecies of the Drosophila athabasca complex, at the period (per) gene by using a polymerase chain reaction-based four-cutter restriction-enzyme analysis. The levels of polymorphism varied considerably between the three semispecies. Our results for per, combined with previous data for X-linked allozymes, suggest that the X chromosome in the western-northern semispecies is less variable than expected under an equilibrium-neutral model. Both the pattern of divergence between the semispecies and a cladistic clustering of per haplotypes support the previously hypothesized grouping of eastern A and eastern B as the two most recently diverged semispecies. A 21-bp in-frame segment in the region of per which shares sequence similarity with the neuronal development gene single minded is deleted in all eastern A and eastern B flies examined but is present in all of the western-northern flies and all other published per sequences. Despite these hints that there may be significant differences at the per gene between the semispecies, especially the western-northern group versus the two eastern groups, there is no compelling evidence that per is involved in the mating song differences between the semispecies.
Animals↗
Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: Preclinical experience.
Docetaxel is a taxoid which is currently in phase II/III clinical trials in Europe, the US and Japan. It was found to promote tubulin assembly in microtubules and to inhibit their depolymerization. In vitro, the docetaxel concentrations required to reduce murine and human cell survival by 50% ranged from 4 to 35 ng/ml and the cytotoxic effects were greater on proliferating than on non-proliferating cells. It was also found to be cytotoxic on fresh human tumor biopsies. In vivo, the drug was found to be schedule independent. A total of 13/14 murine transplantable tumors were found very sensitive to i.v. docetaxel and complete regressions of advanced stage tumors were obtained. Activity was also observed in 15/16 human tumor xenografts in nude mice at an advanced stage. In combination studies, synergism was observed in vivo with 5-fluorouracil, cyclophosphamide and etoposide. Pharmacokinetic evaluation revealed linear pharmacokinetics in tumor-bearing mice. There was a good tumor retention with a 22 h elimination half-life. Plasma protein binding ranged from 76 to 89%. Preclinical toxicology evaluation of docetaxel included single-dose toxicity in rats, mice and dogs, 5-day toxicity in mice and dogs, intermittent-dose toxicity in rats, dogs and monkeys, genetic and reproductive toxicity, as well as investigation of the irritation and sensitization potential. The principal toxicities were hematopoietic (all species), gastrointestinal (dog, monkey) and neuromotor (mice). Dogs appeared to be the most sensitive species. The clinical entry dose of 5 mg/m2 was based on one-third of the 'toxic dose low' in dogs (15 mg/m2).
Animals↗
Toxicological assessment of gadoversetamide injection (OptiMARK), a new contrast-enhancement agent for use in magnetic resonance imaging.
RATIONALE AND OBJECTIVES: A series of preclinical tests were undertaken during the developmental process to determine the safety profile of gadoversetamide injection (OptiMARK). METHODS: Acute intravenous, acute intracisternal, and repeated-dose toxicities; cardiovascular effects; and genetic and reproductive toxicology characteristics were assessed in several animal species. RESULTS: Gadoversetamide injection demonstrated an acute intravenous median lethal dose of 25 to 28 mmol/kg and a maximum nonlethal dose of 14 mmol/kg in mice. In the dog, acute administration of gadoversetamide injection showed a no observable effect level at 3 mmol/kg. Dosed daily for 4 weeks, gadoversetamide injection (0.1 mmol x kg(-1) x d(-1)) caused no serious irreversible changes in any organs in rats and dogs. At a dose of 0.1 mmol/kg, gadoversetamide injection caused no significant (P < 0.05) changes in cardiovascular function in anesthetized dogs. Gadoversetamide injection showed no mutagenic activity. Fertility, reproductive performance, and postnatal fetal development were not affected at doses up to 0.5 mmol x kg(-1) x d(-1) in the rat. No teratogenicity was observed at doses up to 4.2 mmol x kg(-1) x d(-1) in the rat and up to 1.6 mmol x kg(-1) x d(-1) in the rabbit. CONCLUSIONS: Data from our toxicological assessment demonstrate the safety of gadoversetamide injection in a number of animal species at doses exceeding the intended human clinical dose.
Abnormalities, Drug-Induced↗
Pregnancy in the postmenopause: how far can assisted reproductive technology be trusted?
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Adult↗
Ethical considerations in the treatment of cystic fibrosis.
Over the last several decades, rapid medical advancement in the treatment of persons with cystic fibrosis (CF) has brought with it a number of ethical concerns. The increasing life expectancy of persons with CF has made transitions in care increasingly common. This change in life expectancy along with advances in assisted reproductive technologies has focused attention on reproductive decision making in CF. Living lobar lung transplantation, although technically developed, remains ethically problematic. The understanding of ethical issues arising in the treatment of CF is crucial to providing optimal care.
Cystic Fibrosis↗
Impact of direct-to-consumer advertising for hereditary breast cancer testing on genetic services at a managed care organization: a naturally-occurring experiment.
PURPOSE: To describe the impact of Myriad Genetics, Inc.'s direct-to-consumer advertising (DTC-ad) campaign on cancer genetic services within two Managed Care Organizations, Kaiser Permanente Colorado (KPCO), Denver, Colorado, where the ad campaign occurred, and Henry Ford Health System (HFHS), Detroit, Michigan, where there were no advertisements. METHODS: The main outcome measures were the changes in number and pretest mutation probability of referrals approved for cancer genetic services at KPCO and HFHS during the campaign versus the year prior, and mutation probability of those undergoing testing. RESULTS: At KPCO, referrals increased 244% during the DTC-ad compared to the same time period a year earlier (P value<0.001). The proportion of referrals at high pretest probability of a mutation (10% or greater) dropped from 69% the previous year to 48% during the campaign (P value<0.001). There was no significant change in pretest mutation probability among women who underwent testing between the two time periods. HFHS reported no significant change between the two time periods for numbers or mutation probability of referrals, or for mutation probability of women tested. CONCLUSION: The DTC-ad caused significant increase in demand for cancer genetic services. In the face of potential future DTC-ad for inherited cancer risk, providers and payers need to consider the delivery of genetic services and genetic education for persons of all risk levels.
Adult↗
The evolutionary genetics of sexual systems in flowering plants.
Population genetic studies of the evolution of breeding systems in flowering plants are reviewed. The selective advantage of a gene's increasing the selfing rate is stressed. In the evolution of outbreeding mechanisms, some strong disadvantage to selfing must therefore be acting; it is suggested that this disadvantage is inbreeding depression. Populations with no absolute barrier to selfing, and with intermediate levels of self-fertilization, appear to be the most likely starting state for the evolution of outbreeding mechanisms. There is some evidence for inbreeding depression in such populations. The evolution of distyly and dioecy are considered in some detail. An explanation for the existence of supergenes controlling these systems is proposed. The breakdown of distyly and tristyly are also considered. The evolution of recombination rates in selfing and outcrossing species is examined briefly.
Biological Evolution↗
A polygenic model for the evolution and maintenance of conditional strategies.
We develop a genetic model for conditional strategies which places such strategies in the context of phenotypic plasticity. The model, which treats conditional strategies as polygenic threshold traits, indicates that, given requisite genetic variation in reaction norms, conditional strategies will evolve to their optimum level and be maintained by stabilizing selection, provided environmental variation results in a fitness trade-off for the alternative conditional phenotypes. The precise value for the evolutionary optimum is found to depend primarily on the probability density function of the environmental variation that influences the production of the conditional phenotypes and the magnitude of the fitness trade-offs of the conditional phenotypes across such environmental variation. The model is tested by application to three well-studied conditional strategies. In each case the predictions of the model are in good agreement with the results of these studies.
Animals↗
A model of gender modification in gynodioecious plants.
The conditions under which hermaphrodites in gynodioecious populations might evolve increased allocation to male function are important for understanding the evolution of plant mating systems. A model is presented here that investigates these conditions under the assumptions that sex determination is nucleo-cytoplasmic and polymorphism is maintained by population subdivision. It is found that modifiers affecting the sex allocation in gynodioecious populations can invade under restrictive conditions, and that under these conditions hermaphroditism no longer is an evolutionary stable strategy. The reasons for the differences between this and related models are discussed.
Alleles↗
Models of selective mating and the initiation of the Fisherian process.
The effects of various rules of selective mating on the initial stages of Fisherian sexual selection are investigated. A comparison of three models of selective mating, fixed relative preference, best of N males and absolute preference is provided, with a special emphasis on their mathematical properties. Using a two-locus haploid model of sexual selection in a polygamous population, I show that the absolute preference rule of selective mating may lower the threshold frequency of the preference trait, required for the initiation of the Fisherian process, as low as zero. This was not observed in the previous analyses with fixed relative preference or best of N male rules. It is then argued that absolute preference may cause the initiations of the Fisherian process more easily without introducing additional assumptions such as pleiotropy or random genetic drift. Some problems associated with the mating rule are also discussed.
Animals↗
Inbreeding depression influences lifetime breeding success in a wild population of red deer (Cervus elaphus).
Evolutionary and conservation biologists have a long-standing interest in the consequences of inbreeding. It is generally recognized that inbred individuals may experience reduced fitness or inbreeding depression. By the same token, relatively outbred individuals can have greater than average fitness, i.e. heterosis. However, nearly all of the empirical evidence for inbreeding depression comes from laboratory or domestic species. Inbreeding depression and heterosis are difficult to detect in natural populations due to the difficulties in establishing pedigrees. An alternative method is to correlate heterozygosity, which is measured using genetic markers, with a trait related to fitness. The typically studied traits, such as juvenile survival and growth rates, either cover only early life or are weakly correlated with lifetime breeding success (LBS). In this paper we show that heterozygosity is positively associated with male and female adult LBS in a wild population of red deer (Cervus elaphus) on the Isle of Rum, Scotland. To the authors' knowledge, this is the first time that inbreeding depression and/or heterosis have been detected for a trait highly correlated with overall fitness in both sexes in a wild population.
Animals↗
Sympatric speciation: compliance with phenotype diversification from a single genotype.
A novel mechanism for sympatric speciation that takes into account complex bioprocesses within each individual organism is proposed. According to dynamical systems theory, organisms with identical genotypes can possess differentiated physiological states and may coexist 'symbiotically' through appropriate mutual interaction. With mutations, the phenotypically differentiated organisms gradually come to possess distinct genotypes while maintaining their symbiotic relationship. This symbiotic speciation is robust against sexual recombination, because offspring of mixed parentage with intermediate genotypes are less fit than their parents. This leads to sterility of the hybrid. Accordingly, a basis for mating preference also arises.
Biological Evolution↗