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PubMed1995

Pharmacological analysis of heartbeat in Drosophila.

Analysis of the mechanisms underlying cardiac excitability can be facilitated greatly by mutations that disrupt ion channels and receptors involved in this excitability. With an extensive repertoire of such mutations, Drosophila provides the best available genetic model for these studies. However, the use of Drosophila for this purpose has been severely handicapped by lack of a suitable preparation of heart and a complete lack of knowledge about the ionic currents that underlie its excitability. We describe a simple preparation to measure heartbeat in Drosophila. This preparation was used to ask if heartbeat in Drosophila is myogenic in origin, and to determine the types of ion channels involved in influencing the heart rate. Tetrodotoxin, even at a high concentration of 40 microM, did not affect heart rate, indicating that heartbeat may be myogenic in origin and that it may not be determined by Na+ channels. Heart rate was affected by PN200-110, verapamil, and diltiazem, which block vertebrate L-type Ca2+ channels. Thus, L-type channels, which contribute to the prolonged plateau of action potentials in vertebrate heart, may play a role in Drosophila cardiac excitability. It also suggests that Drosophila heart is subject to a similar intervention by organic Ca2+ channel blockers as the vertebrate heart. A role for K+ currents in the function of Drosophila heart was suggested by an effect of tetraethylammonium, which blocks all the four identified K+ currents in the larval body wall muscles, and quinidine, which blocks the delayed rectifier K+ current in these muscles. The preparation described here also provides an extremely simple method for identifying mutations that affect heart rate. Such mutations and pharmacological agents will be very useful for analyzing molecular components of cardiac excitability in Drosophila.

Action Potentials↗
PubMed1995

A genetical theory of species selection.

Species selection, differential rates of speciation or extinction resulting from species level characters, is often invoked as the main mechanism of macroevolution that is not simply an extension of microevolutionary processes. So long as we are careful in defining "species", the logic of species selection is sound. This does not mean, however, that this process can influence evolutionary dynamics under realistic conditions. The principal challenge to the efficacy of species selection as an evolutionary mechanism is the idea that selection between individuals within species will be so much more efficient as to swamp out any effects of selection between species. To assess this, a genetic model is constructed that includes simultaneous selection within and between species, and this is used to ask: under what conditions could species selection influence evolutionary dynamics, even in the face of opposing selection between individuals? The model shows that the efficacy of species selection is strongly determined by the time between speciation events (measured in individual generations), the mutation rate of the character under consideration, and the initial size of a newly formed reproductively isolated population. Data indicate that a few studied lineages have shown sufficiently high speciation rates to make species selection an important mechanism in the evolution of characters with mutation rates on the order of 10(-6) per generation. Quantitative characters, such as body size, generally change too readily for species selection to be relevant to their evolution. Complex characters, however, may be good candidates to be influenced by species selection. The interaction of selection within and between species can be subtle, with individual selection looking, from the standpoint of a species, very much like development of an individual. Furthermore, selection between individuals may be the main process assembling complex adaptations, while species selection allows them to persist over long periods of time.

Animals↗
PubMed1998

Evolution of segregation distortion: potential for a high degree of polymorphism.

By means of a population genetical model, we study the evolution of segregation distortion. Most models of segregation distortion focus on a single distorter allele. In contrast, we consider the competition between a large number of distorters. Motivated by systems as the t complex of the house mouse or the Sd complex of Drosophila melanogaster, we assume that there is some "complementation" between distorter alleles, i.e. that the fitness of individuals heterozygous for two distorter alleles is higher than the fitness of homozygous individuals. In the presence of complementation, the most efficient distorter allele with the highest segregation ratio often does not outcompete less efficient distorters. In fact, our results show that coexistence of a large number of distorter alleles is more typical than the competitive exclusion of less efficient distorters by a single superior allele. We first consider the analytically tractable system where all distorters show the same amount of complementation. In this case, all distorters with a segregation ratio higher than a certain critical value will persist, resulting in a polymorphic population where the average segregation ratio is only slightly larger than 0.5. If the degree of complementation varies, there may be more than one stable equilibrium, and the outcome of competition may depend on the initial conditions. Motivated by empirical examples, we also consider the case that the distorting ability of an allele is negatively related to its effects on individual fitness. Interestingly, the outcome of competition depends crucially on details of such a trade-off. We conclude that verbal arguments are insufficient to predict the evolution of segregation distortion.

Alleles↗
PubMed1998

The cost of sex revisited: effects of male gamete output of hermaphrodites that are asexual in their female capacity.

The genetic cost of sexual reproduction has been attributed to two causes in mathematical formulations: male function or genome dilution. We develop and analyse a genetic model that shows that both costs occur, depending upon the conditions. The model differs from previous formulations in that the level of output and fertilization success of male gametes produced by hermaphrodites that are asexual in their female function (henceforth "parthenogenetic hermaphrodites") are treated as variables, rather than constants fixed at 0 or 1, as has previously been the case. By expressing the cost of sex in terms of per capita egg loss of sexual individuals and parthenogenetic hermaphrodites, we partition the cost into components due to male function and genome dilution. Which component dominates the cost of sex depends upon the relative male gamete output of the parthenogenetic hermaphrodites. The cost of sex is observed to increase, or remain unchanged in some marginal cases, with increases in (i) frequency of parthenogenetic hermaphrodites, (ii) fertilization success of male gametes produced by parthenogenetic hermaphrodites and (iii) potential eggs lost by diverting resources to male gamete production. In certain situations, parthenogenetic hermaphrodites with an intermediate level of male gamete output have the greatest fitness advantage over sexual individuals. If heritable variation for levels of male gamete output exists among parthenogenetic hermaphrodites, this raises the possibility of the evolution of optimal levels of male gamete production by parthenogenetic hermaphrodites through natural selection, in situations of recurring invasion of asexual populations by propagules from sexual populations, a scenario that is increasingly being appreciated as potentially fairly likely to occur in nature.

Animals↗
PubMed2000

Optimal sex ratios in structured populations.

In this paper, we develop a general method to determine evolutionary equilibrium sex ratios and to check evolutionary stability, continuous stability and invadability in exact genetic models with or without dominance. This method is then applied to three kinds of models for structured populations: the first one concerns Hamilton's LMC model, except that only a fraction beta of female offspring mate with male offspring born in the same colonies, while a fraction 1-beta mate with male offspring chosen at random within the whole population; in the second model, it is assumed that partial dispersal of inseminated females occurs after mating; in the third model, partial dispersal of male and female offspring occurs before mating. In the first model, the effect of population regulation is studied while, in the other models, two kinds of dispersal are considered: proportional and uniform.

Animals↗
PubMed1994

Cultural transmission of a sign language when deafness is caused by recessive alleles at two independent loci.

Two unlinked autosomal loci are assumed to affect the ability to hear in such a way that homozygosity for the recessive allele at either locus causes deafness. The five deaf genotypes are subject to the same negative selection due to a lower likelihood of marriage, but unmarried deaf persons remain socially active and participate in the cultural transmission of sign languages. Marriages are assortative for deafness or for hearing, and mutation occurs irreversibly from the dominant to recessive allele at each locus at the same rate. At mutation-selection balance, the fully polymorphic equilibrium is symmetrical. Based on this genetic model, we consider the relative importance of various forms of cultural transmission as they affect the persistence of sign languages. Horizontal transmission is shown to be effective when deaf children are able to interact with many peers. This observation is especially pertinent if assortative meeting of deaf children occurs, for example, at schools for the deaf. Oblique transmission can also be effective, but the literature suggests that this kind of transmission plays only a minor role. It is necessary, however, that some form of cultural transmission occur between generations. Thus, vertical transmission is a critical factor, despite the fact that parent-child transmission is often interrupted due to the recessive inheritance of deafness. In particular, the contribution of vertical transmission is enhanced by assortative mating for deafness.

Child Development↗
PubMed2000

A generalization of Pontryagin's maximum principle for dynamic evolutionary games among relatives.

We present two theorems that generalize Pontryagin's maximum principle to the setting of dynamic evolutionary games between genetically related individuals. The two theorems correspond to two types of interactions among individuals: patch-structured populations in which individuals locally "play the field" and pairwise interactions. These generalizations can be used in the same way that Pontryagin's maximum principle is used and they are valid for diploid organisms under a single locus, diallelic genetic model. These generalizations involve an interesting, dynamic version of Hamilton's Rule from inclusive fitness theory. We illustrate how these theoretical results can be applied by modeling the evolution of lifetime resource allocation to growth and reproduction in an annual plant when there is competition for resources among related individuals.

Biological Evolution↗
PubMed1984

Genetics of urinary pepsinogen: a new hypothesis.

A new genetic model is proposed to explain the inheritance of the urinary pepsinogen (PG1) polymorphism. Each main fraction, 3, 4 and 5, in the multibanded electrophoretic pattern, is determined by its own specific gene, B, C and D respectively. The intensity ratio of the fractions is principally determined by the number of gene copies. Accordingly, the PG1 phenotypes are determined by gene combinations, haplotypes, some of which may be identical to alleles in previous one locus models. Some critical families, not interpretable using previous genetic models, are presented to support the hypothesis. Preliminary population data from the Netherlands are described. The molecular background of this polymorphism and its relevance for gastric (pre)malignancy is discussed.

Adult↗
PubMed1985

Further segregation analysis of the fragile X syndrome with special reference to transmitting males.

A new series of 96 pedigrees with the fra(X) syndrome was analysed using complex segregation analysis with pointers, defining affection as any degree of mental impairment. These families were found to exhibit the same segregation pattern as the first series of 110 pedigrees (Sherman et al. 1984). The best estimate for penetrance of mental impairment in males was 79% and in females was 35% for the combined data. Again, there was little evidence for sporadic cases among affected males. Many more intellectually normal transmitting males have been observed since the existence of such males and the concomitant need to investigate the paternal side of pedigrees was recognized. On further investigation of all 206 pedigrees from the old and new data sets, the sibships of nonexpressing males appeared to be different from those of expressing males. Our analysis, using mental impairment as the phenotype, suggested that obligate carrier mothers and daughters of intellectually normal transmitting males are rarely, if ever, mentally impaired and that the sibs of transmitting males are much less likely to be retarded than the sibs of mentally impaired males. Though mothers and daughters of transmitting males are similar in phenotype, the expression of the gene in their offspring appears to be different: the penetrance of mental impairment is higher in offspring of intellectually normal daughters of transmitting males than in offspring of intellectually normal mothers of transmitting males. The implications of these observations for genetic counseling and for genetic models of the fra(X) syndrome are discussed.

Female↗
PubMed1988

What is schizophrenia? Changing perspectives in epidemiology.

The psychotic syndrome at the core of schizophrenia appears to be invariable across cultures. The risk of morbidity also seems to vary very little from country to country and over medium periods of time. Moreover, apart from gender differences in first onset, the cumulative lifetime risk is the same in females and males. A similar epidemiological pattern is only found in pathological conditions that are characterized by a precisely defined section of a psychopathological dimension with a continuous distribution in the population, e.g. severe mental retardation being the extreme section of normally distributed IQ values. The interpretation of schizophrenic psychosis as the extreme section of a psychopathological dimension or disposition that is almost evenly distributed in all populations is supported by the fact that milder psychiatric disorders occur more frequently before the onset of the psychosis and in close relatives of schizophrenic patients. The psychopathological heterogeneity of these disorders argues against the assumption of a manifest psychopathological dimension with a continuous transition from the schizophrenic psychosis to the "normal" schizothymic personality. More probable is a continuously distributed latent vulnerability to schizophrenia--with or without a threshold effect--which in severe degrees disposes to the uniform reaction pattern of the schizophrenia syndrome. Smaller degrees of vulnerability are associated with an increased risk for milder patterns of disturbances, which are also more strongly determined by environment and personality and therefore are rather heterogeneous. These assumptions lead to other epidemiological and genetic models than Kraepelin's early concept of a disease entity does.

Female↗
PubMed1998

A loss-of-function mechanism of nigral neuron death without Lewy body formation: autosomal recessive juvenile parkinsonism (AR-JP).

We present a genetic model of selective nigral neuron death without Lewy body formation--autosomal recessive juvenile parkinsonism (AR-JP). Mapping of AR-JP gene to a single recessive locus on chromosome 6q25.2-27 is a strong indication of the idea that a loss-of-function mutation of a single gene is sufficient to cause selective nigral neuron death. The absence of Lewy body formation in AR-JP is important, because most cases of neuron death caused by loss-of-function mechanism are not accompanied by inclusion body. Our findings clearly indicate that nigral cells are critically dependent for their survival on the function of AR-JP protein. This raises an important question of whether or not AR-JP protein contributes to the downstream pathway of cell death in Parkinson's disease.

Cell Death↗
PubMed2002

Up-regulation of glutamate receptors is associated with LTP defects in the early stages of diabetes mellitus.

AIMS/HYPOTHESIS: Recent studies involving electrophysiology and immunolabelling indicate that short-term insulin treatment of hippocampal neurons in culture induces changes in glutamate receptor function, suggesting that this receptor system can be altered on a relatively rapid time scale during diabetic conditions. To investigate this hypothesis, we examined whether brain glutamate receptors and long-term potentiation are altered in the early stages of diabetes mellitus in non-obese diabetic mice, a genetic model of Type I (insulin-dependent) diabetes mellitus. METHODS: In vitro receptor autoradiography and immunoblotting were used to study the impact of diabetes on brain glutamate receptors. From an electrophysiological point of view, field potential recordings were also examined in area CA1 of hippocampal slices to determine the influence of diabetes on long-term potentiation. RESULTS: Quantitative autoradiographic analysis revealed enhanced 3H-glutamate binding to several brain regions of diabetes mice, with maximal increases in the cerebral cortex and hippocampus. Saturation kinetics within the cerebral cortex disclosed that this change of 3H-glutamate was possibly due to an increase in the maximal number of N-methyl- D-aspartate binding sites, an interpretation that was corroborated by Western blot analysis of N-methyl- D-aspartate 2A subunits. Impairment in the expression of hippocampal long-term potentiation was also observed in diabetic mice, while the failure to elicit synaptic potentiation was prevented by insulin treatment. CONCLUSION/INTERPRETATION: Because glutamate receptors are thought to be involved in several degenerative processes, our results suggest that up-regulation of these receptors in the early stages of diabetes could represent an important mechanism underlying neurological complications within the brain of diabetic patients.

Animals↗
PubMed1998

Footprints of intragenic recombination at HLA loci.

To evaluate the effect of balancing selection and intragenic recombination (or gene conversion) at six individual HLA loci, synonymous nucleotide diversity in different exon groups is examined within (pi w) and between (pi b) allelic lineages that may be defined by either serological or DNA sequence differences. Both pi values are high in exons which encode for the peptide binding region (PBR) and tend to decrease in other exons. The value of pi w is significantly smaller than that of pib in any exon of any locus. However, even pi w is much greater than nucleotide diversity at non-HLA loci. These observations provide additional strong evidence for the operation of balancing selection in PBR-encoding exons and its indirect effects on polymorphism at linked neighboring regions. It appears that allelic lineages have generally evolved in isolation but the linkage relationships within and between exons are incomplete throughout the long evolutionary history. To quantify intragenic recombination and account for the large discrepancy between the HLA and non-HLA diversity, a population genetics model is analyzed with special reference to the evolution of modern humans. The analysis suggests that the recombination rate between two sites 1000 base pairs apart is about 10(-5) per generation and that the effective size of human populations (equivalent roughly to the number of breeding individuals in a randomly mating population) has dropped from 10(5) to 10(4) in most of the Quaternary. One possibility for this reduction is discussed.

Chromosome Mapping↗
PubMed1987

An interactive program for determining tentative gene assignments from immunological data.

This paper announces an interactive program that could be useful for workers investigating new immunogenetic systems and theoreticians seeking to resolve persistent puzzling questions about systems already developed. The program seeks symbolic representations of data and its interpretations. By its ability to work with symbolizations in their most general form it is able to reveal symbolic patterns that may correspond directly to otherwise unexpected genetic models.

Immunogenetics↗
PubMed1992

Plots for examination of univariate twin data.

We discuss informative plots for univariate twin data that can be used in conjunction with twin data analyses. The plots are useful for spotting outliers, spotting possible single gene effects, and displaying the contribution of individual twin pairs to the fit of genetic models of the data. We illustrate the use of the plots on bone mineral data, and present programs for generating the plots in SAS.

Data Interpretation, Statistical↗
PubMed1985

Differential acquisition of a "working memory" task by the Roman strains of rats.

Twenty-eight male rats of the Roman strains-fourteen RHA (Roman High Avoidance) and fourteen RLA (Roman Low Avoidance)-were submitted to a positively reinforced task, the delayed reinforced alternation test (DRA), in a T-maze. Performances of RLA rats were significantly better than those of RHA; RLA rats also had higher VTE (vicarious trial and error) and spontaneous alternation (SA) scores. These data confirm the fact that RLA may acquire positively reinforced learning as rapidly, or even more rapidly, than RHA rats, and that the differences in active avoidance behavior between these strains depend more on differential freezing behavior than on learning and memory capacities. Since the delayed reinforced alternation is considered as a working memory test, our results suggest that the Roman strains could be used as a genetic model for the neurobiological study of this form of memory.

Animals↗