Rate Of Increase In Frequency Research Articles

The evolution of pyrimethamine resistant dhfr in Plasmodium falciparum of south-eastern Tanzania: comparing selection under SP alone vs SP+artesunate combination

BackgroundSulphadoxine-pyrimethamine (SP) resistance is now widespread throughout east and southern Africa and artemisinin compounds in combination with synthetic drugs (ACT) are recommended as replacement treatments by the World Health Organization (WHO). As well as high cure rates, ACT has been shown to slow the development of resistance to the partner drug in areas of low to moderate transmission. This study looked for evidence of protection of the partner drug in a high transmission African context. The evaluation was part of large combination therapy pilot implementation programme in Tanzania, the Interdisciplinary Monitoring Programme for Antimalarial Combination Therapy (IMPACT-TZ)MethodsThe growth of resistant dhfr in a parasite population where SP Monotherapy was the first-line treatment was measured for four years (2002-2006), and compared with the development of resistant dhfr in a neighbouring population where SP + artesunate (SP+AS) was used as the first-line treatment during the same interval. The effect of the differing treatment regimes on the emergence of resistance was addressed in three ways. First, by looking at the rate of increase in frequency of pre-existing mutant dhfr alleles under monotherapy and combination therapy. Second, by examining whether de-novo mutant alleles emerged under either treatment. Finally, by measuring diversity at three dhfr flanking microsatellite loci upstream of the dhfr gene.ResultsThe reduction in SP selection pressure resulting from the adoption of ACT slowed the rate of increase in the frequency of the triple mutant resistant dhfr allele. Comparing between the two populations, the higher levels of genetic diversity in sequence flanking the dhfr triple mutant allele in the population where the ACT regimen had been used indicates the reduction in SP selection pressure arising from combination therapy.ConclusionThe study demonstrated that, alleles containing two mutations at the dhfr have arisen at least four times independently while those containing triple mutant dhfr arose only once, and were found carrying a single unique Asian-type flanking sequence, which apparently drives the spread of pyrimethamine resistance associated dhfr alleles in east Africa. SP+AS is not recommended for use in areas where SP cure rates are less than 80% but this study reports an observed principle of combination protection from an area where pyrimethamine resistance was already high.

Relative Fitness, Teleology, and the Adaptive Landscape

The metaphor of the adaptive landscape, introduced by Sewall Wright in 1932, has played, and continues to play, a central role in much evolutionary thought. I argue that the use of this metaphor is tied to a teleological view of the evolutionary process, in which natural selection directs evolution toward an improved future state. I argue further that the use of “relative fitnesses” standardized to an arbitrary value, which is closely connected with the metaphor of an adaptive landscape, produces a disconnect between the mean fitness of a population and any real property of that population. This allows for a vague and ill-defined improvement to occur under the influence of selection. Instead, I suggest that relative fitnesses should be standardized by the mean absolute fitness (expected population growth rate), so that they express the expected rate of increase in frequency, rather than number. Under this definition, the mean relative fitness of all populations is always 1.0, and never changes as long as the population continues to exist.

Factors that affect the frequency of thioguanine-resistant lymphocytes in mice following exposure to ethylnitrosourea.

The frequency of thioguanine(TG)-resistant lymphocytes in mice treated with ethylnitrosourea (ENU) was followed for a period of 51 wk using our clonogenic assay [Jones et al, 1985a,b]. The effects of dose (0-58 mg/kg), time since treatment (2-51 wk), dose rate (5 weekly X 11.7 mg/kg versus 1 X 58 mg/kg), and age at time of treatment (3 vs 15 mo) on the frequency of TG-resistant, concanavalin A-responsive spleen cells were evaluated. The frequencies of TG-resistant spleen cells were generally dose responsive for 51 wk after exposure to ENU. They also were dependent upon the time that had elapsed since treatment with ENU, increasing to maximal values at 10 wk as previously reported [Jones et al, 1985a], and holding essentially stable at values of approximately 20% of the maximum frequency from week 15 until at least week 40 for the 3-month-old mice. Fractionation of 58 mg ENU/kg into 5 weekly doses did not affect the frequency of ENU-induced TG-resistant cells detected in the spleen but did increase the rate of appearance in the spleen, and the efficiency of induction by the unit dose, of TG-resistant cells. The mice exposed to ENU at 15 mo of age appeared to have a 4-fold reduction in the rate of increase in frequency of ENU-induced TG-resistant spleen cells. One set of control mice was found to have a 10-fold elevated frequency of TG-resistant cells in both the spleen and thymus, indicating that mutations can occur in stem cells of untreated animals.

On fitness and adaptedness and their role in evolutionary explanation.

This paper deals with the structure of evolutionary explanations that are based on natural selection. Scientific explanations have two components: the explanandum, or phenomenon to be explained, and the explanans, or that which does the explaining.' In evolutionary explanations derived from natural selection, the explanandum is the presence of some trait in a certain frequency or its rate of increase in frequency over time; in other words, the explanandum is usually fitness in the operational sense of Fisher. The explanans of natural selection explanations invariably make reference to design characteristics of the trait, or its adaptedness. Indeed, many evolutionary explanations, such as those that are commonplace in evolutionary ecology, make reference only to adaptedness. In this essay I discuss situations in which fitness and adaptedness are only indirectly related and are sometimes totally decoupled, in the sense that factors other than adaptedness dominate in the determination of fitness. I argue that one of the main processes contributing to this masking of adaptedness is sexual reproduction. Thus a portion of my argument is concerned with the evolution of sexual reproduction. In my discussion of fitness and adaptedness I distinguish between the intrinsic or genetic aspects of a fitness component and its extrinsic or environmental aspects, and argue that the concept of adaptedeness should apply only to the former. I use the term "fitness" to mean "per capita rate of increase," a usage that was originally Fisher's.2 Thus the fitness of any type -

Response characteristics of cutaneous warm receptors in the monkey.

1. The receptive fields of 48 specific cold units, located in the hairy and glaborous skin of fore- and hindlimbs of rhesus monkeys, were mapped and scale drawings made. Forty-five percent had single spotlike receptive fields of 1-2 mm diameter or were up to 2 mm wide and 3-5 mm long, and formed straight, crescent, or right-angle shapes. The remaining 55% had two to five discrete spots or small areas innervated by a single fiber. Area or number of receptive fields per unit did not vary significantly along the limb axis. 2. Of the 48 specific cold units, 15 were held sufficiently long to record their dynamic responses to intensity-rate series of temperature changes from several adapting temperatures (ATs) between 20 and 45 degrees C. Six cold units showed a paradoxical increase in the steady-state response at the 45 degrees C compared to that at the 40 degrees C AT. Of the 15 cold units, 7 discharged in bursts at the 35 degrees C or lower ATs. The proportion of short intervals (intraburst intervals) increased as the adapting temperature decreased. 3. Both the latency and the temperature change at the onset of the dynamic response to cooling remained relatively constant for ATs up to and including 35 degrees C. The response latencies were approximately 200-400 ms, while the temperature changes at response onset were -0.02 to -0.06 degrees C. Both increased sharply at the 40 degrees C and still more at the 45 degrees C ATs. 4. The rate of increase in the frequency of the dynamic response to cooling by the fast rate increased to maximum at the 30 degrees C AT and then decreased at the higher ATs. For the slow rate the highest rate of increase in frequency occurred at the 20 degrees C AT. The fast rate of cooling always induced a faster rate of increase in frequency than slow rate of cooling. 5. Four indices of response magnitude were used in the analysis of the dynamic responses. These were peak frequency, cumulative impulses in the first 4 s following stimulus onset, average frequency during stimulations plus 3 s, and the total impulses during stimulation. The first three indices gave similar representations of the dynamic responses to the rate and intensity of cooling and the effect of the AT. The slow rate of cooling invariably yielded a smaller index of response magnitude than the fast rate. The difference became more pronounced as the intensity of cooling increased. The stimulus intensity-response magnitude functions were nonlinear. This nonlinearity was more pronounced at the low than at the high ATs. As the AT was increased, the response indices approached linearity at the 35 and 40 degrees C ATs. The greatest sensitivity of cold units to cooling was from the 35 degrees C AT. The fourth index, total impulses during stimulation minus steady state, gave a different picture. This index of response magnitude was linearly related to stimulus intensity for both rates of cooling from all adapting temperatures except for the slow rate of cooling from the 45 degrees C AT...

Response characteristics of cutaneous cold receptors in the monkey

1. The receptive fields of 48 specific cold units, located in the hairy and glaborous skin of fore- and hindlimbs of rhesus monkeys, were mapped and scale drawings made. Forty-five percent had single spotlike receptive fields of 1-2 mm diameter or were up to 2 mm wide and 3-5 mm long, and formed straight, crescent, or right-angle shapes. The remaining 55% had two to five discrete spots or small areas innervated by a single fiber. Area or number of receptive fields per unit did not vary significantly along the limb axis. 2. Of the 48 specific cold units, 15 were held sufficiently long to record their dynamic responses to intensity-rate series of temperature changes from several adapting temperatures (ATs) between 20 and 45 degrees C. Six cold units showed a paradoxical increase in the steady-state response at the 45 degrees C compared to that at the 40 degrees C AT. Of the 15 cold units, 7 discharged in bursts at the 35 degrees C or lower ATs. The proportion of short intervals (intraburst intervals) increased as the adapting temperature decreased. 3. Both the latency and the temperature change at the onset of the dynamic response to cooling remained relatively constant for ATs up to and including 35 degrees C. The response latencies were approximately 200-400 ms, while the temperature changes at response onset were -0.02 to -0.06 degrees C. Both increased sharply at the 40 degrees C and still more at the 45 degrees C ATs. 4. The rate of increase in the frequency of the dynamic response to cooling by the fast rate increased to maximum at the 30 degrees C AT and then decreased at the higher ATs. For the slow rate the highest rate of increase in frequency occurred at the 20 degrees C AT. The fast rate of cooling always induced a faster rate of increase in frequency than slow rate of cooling. 5. Four indices of response magnitude were used in the analysis of the dynamic responses. These were peak frequency, cumulative impulses in the first 4 s following stimulus onset, average frequency during stimulations plus 3 s, and the total impulses during stimulation. The first three indices gave similar representations of the dynamic responses to the rate and intensity of cooling and the effect of the AT. The slow rate of cooling invariably yielded a smaller index of response magnitude than the fast rate. The difference became more pronounced as the intensity of cooling increased. The stimulus intensity-response magnitude functions were nonlinear. This nonlinearity was more pronounced at the low than at the high ATs. As the AT was increased, the response indices approached linearity at the 35 and 40 degrees C ATs. The greatest sensitivity of cold units to cooling was from the 35 degrees C AT. The fourth index, total impulses during stimulation minus steady state, gave a different picture. This index of response magnitude was linearly related to stimulus intensity for both rates of cooling from all adapting temperatures except for the slow rate of cooling from the 45 degrees C AT...

Evolution of over-dominance during the initial spread of new alleles.

Bodmer and Parsons1–3 have discussed a model for the initial increase in the frequency of newly arising, favourable mutations in a large undivided population and under different mating systems. They argued that over-dominance (higher fitness of heterozygotes over the homozygotes) has evolved in out breeding species during this process as follows: (1) a new allele, say A1, at locus A1–A2 occurs principally in the heterozygotes when it is initially at a low frequency in the population; (2) selection favouring heterozygotes allows a rapid rate of increase in frequency of A1; (3) hence, the modifiers that primarily enhance the fitness of A1A2 particularly when linked, would themselves increase rapidly in frequency and accumulate to form the linked gene complexes; (4) such gene combinations would exhibit so-called segmental (or associative4) over-dominance maintaining a balanced polymorphism.