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PubMed1996

Cardiovascular characterization of pyrrolo[2,1-d][1,5]benzothiazepine derivatives binding selectively to the peripheral-type benzodiazepine receptor (PBR): from dual PBR affinity and calcium antagonist activity to novel and selective calcium entry blockers.

The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]-benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3, 7-20), were subjected to calcium channel receptor binding assay. Some of these compounds showed an unexpected potency in displacing the binding of [3H]nitrendipine from L-type calcium channels, much higher than that reported for PK 11195 and Ro 5-4864 and equal to or higher than that of reference calcium antagonists such as verapamil and (+)-cis-diltiazem. Specifically, in rat cortex homogenate, our prototypic PBR ligand 7-acetoxy-6-(p-methoxyphenyl)pyrrolo[2,1-d][1,5]benzothiazepine (3) showed an IC50 equal to 0.13 nM for inhibition of [3H]nitrendipine binding. Furthermore, in functional studies this compound displayed a clear-cut selectivity for cardiac over vascular tissue. Comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using isolated guinea pig left atria, revealed that 3 displayed higher selectivity than the reference (+)-cis-diltiazem. Thus, the pyrrolobenzothiazepine 3 might represent a new tool for characterizing the relationship between the PBR and cardiac function. Furthermore, we have also investigated the structural dependence of binding to PBR and L-type calcium channels, and this study allowed us to identify a new class of potent calcium channel blockers selective for cardiac over vascular tissue, with no affinity for PBR. A number of structure-activity relationship trends have been identified, and a possible explanation is advanced in order to account for the observed differences in selectivity. Three structural features, namely, (i) the saturation of the C(6)-C(7) double bond, with a consequent higher molecular flexibility, (ii) the presence of a substituent in the benzofused ring, and (iii) a basic side chain at C-10 of the pyrrolobenzothiazepine ring system, were found to be responsible for potent L-type calcium channel antagonism and clear-cut selectivity for cardiac over vascular tissue. Among the synthesized compounds the pyrrolobenzothiazepine 62 was found to be the most promising selective calcium channel blocker. Additionally, the molecular structure determination of the key intermediate 48 by X-ray diffraction, molecular modeling, and NMR analysis is reported.

Animals↗
PubMed2002

Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands.

CD4+ T cells are positively selected in the thymus on peptides presented in the context of major histocompatibility complex class II molecules expressed on cortical thymic epithelial cells. Molecules regulating this peptide presentation play a role in determining the outcome of positive selection. Cathepsin L mediates invariant chain processing in cortical thymic epithelial cells, and animals of the I-A(b) haplotype deficient in this enzyme exhibit impaired CD4+ T cell selection. To determine whether the selection defect is due solely to the block in invariant chain cleavage we analyzed cathepsin L-deficient mice expressing the I-A(q) haplotype which has little dependence upon invariant chain processing for peptide presentation. Our data indicate the cathepsin L defect in CD4+ T cell selection is haplotype independent, and thus imply it is independent of invariant chain degradation. This was confirmed by analysis of I-A(b) mice deficient in both cathepsin L and invariant chain. We show that the defect in positive selection in the cathepsin L-/- thymus is specific for CD4+ T cells that can be selected in a wild-type and provide evidence that the repertoire of T cells selected differs from that in wild-type mice, suggesting cortical thymic epithelial cells in cathepsin L knockout mice express an altered peptide repertoire. Thus, we propose a novel role for cathepsin L in regulating positive selection by generating the major histocompatibility complex class II bound peptide ligands presented by cortical thymic epithelial cells.

Animals↗
PubMed2004

Effects of selective and non-selective endothelin receptor blockade on ET-1-induced pressor response in the hamster.

In order to assess the physiological balance existing between vasoconstrictor and vasodilator endothelin-B receptor actions associated with their dual locations (i.e. on vascular smooth muscle and endothelial cells), we investigated the effects of selective and non-selective endothelin receptor antagonists on endothelin-1-induced increase in blood pressure. Atrasentan (a selective endothelin-A receptor antagonist; 6 mg/kg) and A-192621 (a selective endothelin-B receptor antagonist; 0.03, 0.3, or 30 mg/kg) were administered intravenously to anaesthetized Syrian Golden hamsters, alone or in combination, to induce respectively selective or non-selective receptor antagonism. Atrasentan partially blocked the blood pressure response induced by endothelin-1 (0.5 nmol/kg), whereas a selective endothelin-B receptor antagonism potentiated this response, independently of the dose of A-192621. Interestingly, combination of the very low dose of A-192621 (which selectively blocked putatively endothelium-located endothelin-B receptors) with atrasentan, suppressed the protective effect previously observed with atrasentan alone. Nevertheless, combination of atrasentan with the two highest doses of A-192621 tested, dose-dependently reduced the response triggered by endothelin-1. Our results suggest that endothelial endothelin-B receptors are important to control the vascular reactivity to endothelin-1. Furthermore, our data suggest that the efficacy of a non-selective endothelin-A/ endothelin-B receptor antagonist relies upon its potency to block endothelin-B receptors in the hamster.

Animals↗
PubMed1995

Differential effects of non-selective and selective phosphodiesterase inhibitors on human eosinophil functions.

1. The effect of non-selective (3-isobutyl-1-methylxanthine, IBMX; theophylline) and type IV- or type III/IV-selective (rolipram, RP 73401; zardaverine, tolafentrine) phosphodiesterase (PDE) inhibitors on human eosinophil functions was investigated. 2. For this purpose human eosinophils were purified from blood of healthy donors by a magnetic cell separation (MACS) technique to a purity > or = 99%. From the stimuli investigated (complement C5a; N-formyl-methionyl-leucyl-phenylalanine, fMLP; platelet activating factor, PAF; opsonized zymosan) C5a was selected to test the influence of the above mentioned compounds on secretion of granule constituents (eosinophil cationic protein, ECP; eosinophil-derived neurotoxin, EDN) as well as on formation of reactive oxygen species measured by luminol-enhanced chemiluminescence in intact cells. For comparison, inhibition of PDE IV activity in the cytosol of disrupted cells, which contains about 75% of total PDE IV activity, was determined. 3. Both theophylline and IBMX inhibited the two cell responses with IC50 values which were in the range of their IC50 values obtained for inhibition of PDE IV activity in the cell-free system. The beta 2-adrenoceptor agonist, salbutamol (1 mumol l-1), which by itself did not substantially influence the two cell responses, only marginally improved the potency of theophylline and IBMX in inhibiting ECP/EDN secretion. Only the IC50 value of IBMX for inhibition of chemiluminescence was lowered by about one order of magnitude in the presence of salbutamol. 4. In contrast, none of the selective PDE inhibitors tested substantially inhibited the two cell responses at concentrations up to 10 mumol l-1. This was surprising because all of the compounds investigated inhibited PDE IV activity in the cell-free system with IC50 values which were at least 30 fold lower than the highest concentration of the compounds used with intact cells. In combination with salbutamol, however, both ECP/EDN secretion and chemiluminescence was inhibited by rolipram and zardaverine with IC50 values similar to the IC50 values for inhibition of PDE IV activity. Although RP 73401 and tolafentrine also inhibited both cell responses in the presence of salbutamol, the potency of these two compounds in inhibiting eosinophil function in intact cells was at least two orders of magnitude lower than would have been expected from the inhibition of PDE IV activity in the cell-free system. 5. These results indicate that (i) C5a-stimulated human eosinophils are sensitive to inhibition by then on-selective PDE inhibitors theophylline and IBMX, (ii) the inhibitory effect of these non-selective PDE inhibitors cannot be mimicked by selective PDE IV or PDE III/IV inhibitors although human eosinophils almost exclusively contain PDE IV; (iii) the selective PDE inhibitors need an additional cyclic AMP trigger like a beta 2-adrenoceptor agonist to be effective; but (iv) under the latter conditions inhibition of cell responses in intact cells does not correspond to inhibition of PDE IV activity in the cell-free system.6. We conclude that the non-selective PDE-inhibiting xanthines may inhibit C5a-stimulated human eosinophil responses by other action(s) in addition to PDE IV inhibition, and that inhibition of PDE IV activity in the cell-free system by the selective inhibitors may not generally represent the potency of the compounds in intact cells.

1-Methyl-3-isobutylxanthine↗
PubMed1975

A controlled, randomized trial of highly selective vagotomy versus selective vagotomy and pyloroplasty in the treatment of duodenal ulcer.

The results of highly selective vagotomy without drainage and selective vagotomy with pyloroplasty for duodenal ulcer were compared in a randomized, controlled trial of a series of 100 patients. The frequency of dumping, diarrhoea, and epigastric fullness was significantly lower after highly selective (6, 6, and 8 percent) than after selective vagotomy (30, 20, and 28 percent) one year after the operations. Recurrent and persisting duodenal ulcers appearing from one to four years after the operations were significantly more frequent after highly selective (22 percent) than after selective vagotomy (8 percent). No significant relationships were found between recurrent ulceration and gastric acid secretion measurements after the two operations. The Hollander response was early positive in 28 percent and late positive in 30 percent of the patients subjected to highly selective vagotomy, while the corresponding figures after selective vagotomy were 26 and 32 percent. The overall clinical results of the two operations were not different according to the classification of Visick. Excluding the patients with recurrence resulted in significantly better clinical results after highly selective vagotomy.

Adult↗
PubMed2005

Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure.

OBJECTIVE: To investigate the potential differential effects of selective endothelin (ET) A and dual ET-A/B receptor blockade in patients with chronic heart failure. METHODS: Nine patients with chronic heart failure (New York Heart Association class II-III) each received intravenous infusions of BQ-123 alone (selective ET-A blockade) and combined BQ-123 and BQ-788 (dual ET-A/B blockade) in a randomised, placebo controlled, three way crossover study. RESULTS: Selective ET-A blockade increased cardiac output (maximum mean (SEM) 33 (12)%, p < 0.001) and reduced mean arterial pressure (maximum -13 (4)%, p < 0.001) and systemic vascular resistance (maximum -26 (8)%, p < 0.001), without changing heart rate (p = 0.38). Dual ET-A/B blockade significantly reduced the changes in all these haemodynamic variables compared with selective ET-A blockade (p < 0.05). Selective ET-A blockade reduced pulmonary artery pressure (maximum 25 (7)%, p = 0.01) and pulmonary vascular resistance (maximum 72 (39)%, p < 0.001). However, there was no difference between these effects and those seen with dual ET-A/B blockade. Unlike selective ET-A blockade, dual ET-A/B blockade increased plasma ET-1 concentrations (by 47 (4)% with low dose and 61 (8)% with high dose, both p < 0.05). CONCLUSIONS: While there appeared to be similar reductions in pulmonary pressures with selective ET-A and dual ET-A/B blockade, selective ET-A blockade caused greater systemic vasodilatation and did not affect ET-1 clearance. In conclusion, there are significant haemodynamic differences between selective ET-A and dual ET-A/B blockade, which may determine responses in individual patients.

Adult↗
PubMed1993

Alternative methods of selection for litter size in mice: III. Response to 21 generations of selection.

Alternative methods of selection to increase litter size in mice have been practiced for 21 generations followed by six generations of relaxed selection. Three replicates were used with four selection criteria: index of components (IX:I = 1.21 x total ovulation rate + 9.05 x ova success), uterine capacity (UT), litter size (LS), and an unselected control (LC). In IX, ovulation rate and ova success were measured by number of corpora lutea and number of pups born/number of corpora lutea, respectively. In UT, uterine capacity was measured and defined as number of pups born to unilaterally ovariectomized (right ovary excised) females. Selection in LS was based on number born to unaltered dams. In all cases, number born was fully formed, live or dead pups. Pups from 16 randomly chosen LC dams and from the top 16 dams in IX, UT, and LS were selected to produce the next generation in each criterion-replicate line. Response in number born, selected criteria deviated from control, was regressed on generation number over the 21 generations of selection. Responses for the IX and LS criteria were quite similar (.14 +/- .01 and .16 +/- .01 pups per generation, respectively), whereas response in UT, with only one functional horn, was slightly lower (.09 +/- .01). The average cumulative selection differentials for IX, LS, and UT at Generation 21 were 32.78 index units, 36.38 pups, and 28.53 pups, respectively. The LC criterion had an unintentional cumulative selection differential of 3.3 pups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

The mouse defense test battery: evaluation of the effects of non-selective and BZ-1 (omega1) selective, benzodiazepine receptor ligands.

The behavioral effects of several benzodiazepine (BZ) (omega) receptor ligands were compared using the Mouse Defense Test Battery which has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. The drugs used included non-selective BZ (omega) full (clonazepam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil and imidazenil) agonists, and BZ-1 (omega1) selective (abecarnil, CL 218,872 and zolpidem) receptor ligands. With the exception of clonazepam, non-selective BZ (omega) receptor compounds only partially affected flight behaviors. The drugs reduced some but not all flight measures in response to the approaching rat, whereas clonazepam attenuated all flight reactions. In contrast to their mild and inconsistent actions on flight, the non-selective BZ (omega) receptor agonists displayed clear effects on risk assessment when subjects were chased by the rat. When contact was forced between the subject and the rat, the non-selective BZ (omega) receptor full agonists reduced defensive threat and attack reactions, while the partial agonists imidazenil and bretazenil only weakly attenuated defensive attack behavior. Similarly, after the rat had been removed from the test area, the non-selective BZ (omega) receptor full agonists displayed greater efficacy than the partial agonists in reducing escape attempts. Overall, results obtained with the selective BZ-1 (omega1) receptor ligands demonstrated either no clear effects or no specific action on defensive reactions. Taken together, these data demonstrate that: (1) non-selective BZ (omega) agonists displaying high intrinsic activity affect a wider range of defensive behaviors than non-selective BZ (omega) receptor partial agonists; (2) the defense system does not involve primarily BZ (omega) receptors containing the alpha1-subunit.

Journal Article↗
PubMed1985

Does beta 1-selective agonistic activity interfere with the antihypertensive efficacy of beta 1-selective blocking agents?

In order to investigate whether addition of beta 1-selective agonism can interfere with the antihypertensive efficacy of beta 1-selective adrenoceptor blockers, two separate studies were carried out to evaluate the effects on blood pressure and heart rate of three beta 1-selective blockers with or without varying degree of beta 1-selective agonism. In hypertensive patients at rest, the greatest blood pressure reduction and bradycardia were found with atenolol, a beta 1-selective blocker without any agonistic activity; a consistently smaller effect on blood pressure and heart rate was observed with Visacor (ICI 141 292), a beta 1-selective blocker with moderate beta 1-selective agonism, whereas no clinically relevant decrease in blood pressure occurred with Corwin (ICI 118 587), the beta 1-selective blocker with high beta 1-selective agonism. In contrast, during exercise-induced sympathetic activation, all three compounds reduced systolic blood pressure and heart rate to a similar degree.

Adrenergic beta-Agonists↗
PubMed1991

Effects of artificial stabilizing selection on Drosophila populations subjected to directional selection for another trait.

Stabilizing selection for a set of morphometric wing traits was combined with directional selection for the increased expression of radius incompletus (ri) mutation of Drosophila melanogaster. Three experimental regimes were used: directional and stabilizing selection (stabilized lines); directional selection (unstabilized lines); no selection (controls). Response to selection for ri expression was similar in all selected lines but variation of this character was higher in the unstabilized lines compared to the stabilized ones. The competitive indices measured after termination of selection did not significantly differ under different treatments while fluctuating asymmetry was significantly lower in stabilized than in unstabilized lines. The possible causes of these differences are discussed.

Animals↗
PubMed1976

Selection for geotaxis in Drosophila melanogaster: heritability, degree of dominance, and correlated responses to selection.

Selection for geotaxis was carried out with flies from a natural population of Drosophila melanogaster; geotactic behavior was measured by means of a Hirsch classification maze. The population was initally almost neutral to gravity, and it responded to both positive (downward) and negative (upward) selection with a realized heritability of about 0.13. Stabilizing selection toward neutral gravity was carried out simultaneously. At generations 6, 9, and 10, all possibly hybrid crosses between pairs of the selected populations were generated and tested. The geotactic scores of hybrids in generations 6 and 9 were not significantly different from the midparent values, while the scores of hybrids in generation 10 deviated significantly from the midparent values in the direction of positive geotaxis. The frequencies of polymorphic inversions declined in every population during selection, but the population under neutral selection seemed to maintain a higher chromosomal polymorphism than those under positive or negative selection. There was no significant depression of productivity, measured as number of progeny, in any population during nine generations of selection.

Animals↗
PubMed1997

Positive Darwinian selection on two homologous fertilization proteins: what is the selective pressure driving their divergence?

Most examples of positive selection inferred from nucleotide sequence data involve hostpathogen interactions. However, positive selection also promotes the divergence of proteins mediating sperm-egg recognition in marine invertebrates. The abalone spermatozoon has a large acrosomal vesicle containing two proteins of 16 kDa and 18 kDa. Lysin, the 16-kDa protein, exhibits species-specificity in dissolving a hole in the egg vitelline envelope through which the sperm swims to reach the egg plasma membrane. The 18-kDa protein coats the sperm acrosomal process and probably mediates fusion of the two gametes. In this review, we compare sequences of both proteins from five species of California abalones. Both proteins show extensive divergence which has been promoted by positive Darwinian selection. The ratios of nonsynonymous to synonymous nucleotide substitutions may be the highest yet discovered for full-length sequences. Although extensive divergence has occurred, there is conservation of the shape and polarity of residues in both proteins. The two acrosomal proteins arose by a gene duplication followed by their extensive divergence. Five hypotheses are presented which attempt to explain the nature of the unknown selective force responsible for the robust positive selection. The positive selection may, in some unknown way, be related to the establishment of prezygotic barriers to reproduction. Because positive selection promotes the divergence of unrelated, species-specific gamete recognition proteins in both abalones and sea urchins, we predict that positive selection may be a general phenomenon in the evolution of gamete recognition systems in marine invertebrates.

Amino Acid Sequence↗
PubMed2004

Marker-evaluated selection in rice: shifts in allele frequency among bulks selected in contrasting agricultural environments identify genomic regions of importance to rice adaptation and breeding.

Conventional methods for quantitative trait locus (QTL) mapping require the selection of particular traits to be measured based on assumptions as to their importance. We have tested an alternative approach for the location of QTLs-marker-evaluated selection-that makes no prior assumptions as to which traits are important. The results of phenotype selection were evaluated in the products of modified bulk-population breeding that was replicated across a range of rice ecosystems. Selection was carried out in close collaboration with farmers in bulk populations that were all derived from a cross between an Indian upland variety (Kalinga III) and a high-yielding semi-dwarf variety (IR64).Twenty-seven diverse bulks were produced that were screened with molecular markers in order to determine whether shifts could be detected in marker allele frequency as a result of selection and if such changes varied by genomic region across ecosystems. Marker loci linked to important traits for adaptation to specific environments were identified without making any prior assumptions about which traits might be important. Genomic regions from Kalinga III were strongly selected in the upland environments and regions from IR64 in the lowland ones.However, exceptions occurred where the upland parent contributed positively to lowland adaptation and vice versa. The results can be used as a basis for the development of second-cycle varieties, using marker-assisted selection to produce genotypic ideotypes for specific target environments. The very strong selection for genomic regions from the adapted parents of the wide(upland x lowland) cross indicates that, in non-marker-assisted breeding, where genetically distant parents have been used, modified backcross breeding should be efficient. A single backcross to the adapted parent for aspecific ecosystem will result in a higher frequency of segregants with the desired high genetic contribution from the adapted parent.

Acclimatization↗
PubMed2004

Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage.

Monoamine oxidase A (MAOA) is the X-linked gene responsible for deamination and subsequent degradation of several neurotransmitters and other amines. Among other activities, the gene has been shown to play a role in locomotion, circadian rhythm, and pain sensitivity and to have a critical influence on behavior and cognition. Previous studies have reported a non-neutral evolution of the gene attributable to positive selection in the human lineage. To determine whether this selection was human-exclusive or shared with other species, we performed a population genetic analysis of the pattern of nucleotide variation in non-human species, including bonobo, chimpanzee, gorilla, and orangutan. Footprints of positive selection were absent in all analyzed species, suggesting that positive selection has been recent and unique to humans. To determine which human-unique genetic changes could have been responsible for this differential evolution, the coding region of the gene was compared between human, chimpanzee, and gorilla. Only one human exclusive non-conservative change is present in the gene: Glu151Lys. This human substitution affects protein dimerization according to a three-dimensional structural model that predicts a non-negligible functional shift. This is the only candidate position at present to have been selected to fixation in humans during an episode of positive selection. Divergence analysis among species has shown that, even under positive selection in the human lineage, the MAOA gene did not experience accelerated evolution in any of the analyzed lineages, and that tools such as K(a)/ K(s) would not have detected the selective history of the gene.

Amino Acid Sequence↗
PubMed2004

Genotype-assisted optimum contribution selection to maximize selection response over a specified time period.

Genotype-assisted selection (GAS), i.e. selection for an identified quantitative trait locus (QTL) and polygenic background genes, has been shown to increase short-term genetic gain but may reduce long-term genetic gains. In order to avoid this reduction of long-term gain, multi-generation optimization of truncation selection schemes is needed. This paper presents a multi-generation optimization of optimum contribution (OC) selection with selection on an identified QTL. This genotype-assisted optimum contribution (GAOC) selection method assumes that the optimum selection differential at the QTL is constant over the time horizon, and achieves this by controlling the increase of the frequency of the positive QTL allele. Implementation was straightforward by an additional linear restriction in the OC algorithm. GAOC achieved 35.2%, 2.3% and 1.1%, respectively, more cumulative genetic gain than OC selection (ignoring the QTL) using time horizons of 5, 10 and 15 generations. When one-generation optimization of GAS was used instead of multi-generation optimization, these figures were 2.8%, 3.1% and 3.2%, respectively. Simulated annealing was used to optimize the increases of the frequency of the positive QTL allele in order to test the optimality of GAOC. This latter resulted in genetic gains that were always within 0.4% of those of GAOC. In practice, short-term genetic gains are also important, which makes one-generation optimization of genetic gain closer to optimal.

Data Interpretation, Statistical↗
PubMed1973

Effects of population size and selection intensity of short-term response to selection for postweaning gain in mice.

The effects of population size and selection intensity on the mean response was examined after 14 generations of within full-sib family selection for postweaning gain in mice. Population sizes of 1, 2, 4, 8 and 16 pair matings were each evaluated at selection intensities of 100% (control), 50% and 25% in a replicated experiment. Selection response per generation increased as selection intensity increased. Selection response and realized heritability tended to increase with increasing population size. Replicate variability in realized heritability was large at population sizes of 1, 2 and 4 pairs. Genetic drift was implicated as the primary factor causing the reduced response and lowered repeatability at the smaller population sizes. Lines with intended effective population sizes of 62 yielded larger selection responses per unit selection differential than lines with effective population sizes of 30 or less.

Analysis of Variance↗
PubMed1974

Effects of population size and selection intensity on responses to disruptive selection in Drosophila melangaster.

Disruptive selection for sternopleural bristle number with opportunity for random mating was done in the four treatment combinations of two population sizes (40 pairs and 8 pairs of selected parents) and two selection intensities (1 in 40 and 1 in 2). In each generation, matings among selected parents were observed in a mating chamber, and progeny collected separately from each female parent. In the high number, high selection intensity treatment, divergence between the high and low parts ceased about generation 11. The isolation index increased rapidly to generation 3, but then fluctuated to termination of the population at generation 17. The overall isolation index was significant, indicating a real tendency to assortative mating. The failure of the isolation index to increase after generation 3 was attributed to lower average mating fitness of high males (due to inbreeding) and reduced receptivity of low females (due to a homozygous lethal gene with a large effect on sternopleural bristle number in heterozygotes). In the two low number treatments, isolation indices fluctuated from generation to generation with no obvious trends, and none of the overall isolation indices were significantly different from zero. The high number, low selection intensity treatment showed very little divergence, and one of the replicates showed, in contrast with expectation and the high number, high selection intensity treatment, a significant tendency to disassortative mating. Intense disruptive selection may lead to assortative mating.

Animals↗
PubMed1980

Genetic variance and correlation after selection for two traits by index, independent culling levels and extreme selection.

Three two-trait selection methods were analyzed for their effects on genetic variance and correlation by multivariate methods, two-locus methods and computer simulation. The two-trait selection methods studied were independent culling levels (ICL), index (IND) and extreme (EXT) selection. The effects of the selection methods on genetic variance and correlation were partitioned into permanent effects due to changes in gene frequencies and temporary effects due to nonrandom association of alleles at different loci. Multivariate methods were used to predict temporary effects from a single generation of selection by each method and from several generations of index selection. Two-locus theory was used to determine the stability and rank of temporary effects on genetic correlation for all three methods. Predictions were compared to computer simulation results. When selection increased the means of both traits, EXT had the lowest (closest to -1.0) genetic correlation and highest variances, while ICL tended to have the highest (closest to 1.0) genetic correlation. When selection increased the mean of one trait and decreased th mean of the other, EXT had the highest genetic variances and correlation, while ICL had the lowest genetic variance and correlation.

Alleles↗