scholarly journals Haldane’s Probability of Mutant Survival is Not the Probability of Allele Establishment

2019 ◽  
Author(s):  
Ivan Krukov ◽  
A.P. Jason de Koning
Keyword(s):  
Odds Ratio ◽  
Short Note ◽  
Selective Advantage ◽  
Fixation Probability ◽  
Probability Of Survival ◽  
Fisher Model ◽  
Large Populations ◽  
Establishment Probability ◽  
Probability Of Fixation ◽  
Over Time

ABSTRACTHaldane notably showed in 1927 that the probability of fixation for an advantageous allele is approximately 2s, for selective advantage s. This widely known result is variously interpreted as either the fixation probability or the establishment probability, where the latter is considered the likelihood that an allele will survive long enough to have effectively escaped loss by drift. While Haldane was concerned with escape from loss by drift in the same paper, in this short note we point out that: 1) Haldane’s ‘probability of survival’ is analogous to the probability of fixation in a Wright-Fisher model (as also shown by others); and 2) This result is unrelated to Haldane’s consideration of how common an allele must be to ‘probably spread through the species’. We speculate that Haldane’s survival probability may have become misunderstood over time due to a conflation of terminology about surviving drift and ‘ultimately surviving’ (i.e., fixing). Indeed, we find that the probability of establishment remarkably appears to have been overlooked all these years, perhaps as a consequence of this misunderstanding. Using straightforward diffusion and Markov chain methods, we show that under Haldane’s assumptions, where establishment is defined by eventual fixation being more likely that extinction, the establishment probability is actually 4s when the fixation probability is 2s. Generalizing consideration to deleterious, neutral, and adaptive alleles in finite populations, if establishment is defined by the odds ratio between eventual fixation and extinction, k, the general establishment probability is (1 + k)/k times the fixation probability. It is therefore 4s when k = 1, or 3s when k = 2 for beneficial alleles in large populations. As k is made large, establishment becomes indistinguishable from fixation, and ceases to be a useful concept. As a result, we recommend establishment be generally defined as when the odds of ultimate fixation are greater than for extinction (k = 1, following Haldane), or when fixation is twice as likely as extinction (k = 2).

scholarly journals The reduction in fixation probability caused by substitutions at linked loci

1994 ◽  
Vol 64 (3) ◽  
pp. 199-208 ◽  
Author(s):  
N. H. Barton
Keyword(s):  
Genetic Map ◽  
Recombination Rate ◽  
Finite Population ◽  
Selective Advantage ◽  
Critical Value ◽  
Small Population ◽  
Fixation Probability ◽  
Probability Of Fixation ◽  
Sudden Reduction ◽  
Single Substitution

SummaryThe probability of fixation of a mutation with selective advantage s will be reduced by substitutions at other loci. The effect of a single substitution, with selective advantage , can be approximated as a sudden reduction in the frequency of the favourable allele, by a fraction w = 1 −(s/S)r/s (where r is the recombination rate). An expression for the effect of a given sequence of such catastrophes is derived. This also applies to the ecological prxoblem of finding the probability that a small population will survive, despite occasional disasters. It is shown that if substitutions occur at a rate Δ, and are scattered randomly over a genetic map of length R, then an allele is unlikely to be fixed if its advantage is less than a critical value, Scrit = (π2/6)(2ΔS/(Rlog(S/s))). This threshold depends primarily on the variance in fitness per unit map length dueto substitutions, var(W)/R = 2ΔS/R. With no recombination, the fixation probability can be calculated for a finite population. If Δ > s, it is of the same order as for a neutral allele ( ≈ Δ/(2N(Δ−s))), whilst if , fixation probability is much higher than for a neutral allele, but much lower than in the absence of hitch-hiking . These results suggest that hitch-hiking may substantially impede the accumulation of weakly favoured adaptations.

Genetic instability of multiple buds of Pinuscoulteri regenerated from tissue culture

1982 ◽  
Vol 12 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Kamlesh R. Patel ◽  
Graeme P. Berlyn
Keyword(s):  
Nuclear Dna ◽  
Internal Standard ◽  
Progressive Increase ◽  
Culture Conditions ◽  
Dna Contents ◽  
Large Populations ◽  
Multiple Buds ◽  
Chicken Erythrocytes ◽  
Cellular Dna ◽  
Over Time

Embryo expiants ofPinuscoulteri D. Don. were cultured on agar media (modified from Campbell and Durzan 1975) only supplemented with 2.25 mg•L−1 of benzyl amino purine (BAP). Nuclear DNA contents were measured in cells of the embryo explants, callus, and buds regenerated from these explants, and sand-germinated seedlings. Measurements were made at weekly intervals during 6 weeks of culture. Absolute amounts of cellular DNA were determined with a microspectrophotometer using chicken erythrocytes as an internal standard. Initially, the nuclei had a DNA level between 2C and 4C with a mean of 3C. The sand-grown seedlings remained within this range, with an increased frequency of 4C nuclei in the 6-week seedlings. However, cells from callus and regenerated buds showed a progressive increase in DNA level over time. After 42 days in culture, the buds contained large populations of cells at the 8C level and a considerable number of cells with DNA levels above 8C. In addition, the nuclei showed a considerable increase in chromosomal aberrations including bridges, micronuclei, lagging chromosomes, and fragmentation. Nuclear volume also increased over time in the regenerated buds. It is therefore concluded that culture conditions, perhaps cytokinin content, increased the levels of nuclear DNA. These increased levels could be the result of polyploidy, polyteny, hyperaneuploidy, or a combination of these types of nuclear organization.

scholarly journals How Does Health Literacy Modify Indicators of Health Behaviour and of Health? A Longitudinal Study with Trainees in North Germany

Healthcare ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 2
Author(s):  
Peter Koch ◽  
Zita Schillmöller ◽  
Albert Nienhaus
Keyword(s):  
Health Status ◽  
Health Service ◽  
Health Behaviour ◽  
Odds Ratio ◽  
Well Being ◽  
Subjective Health ◽  
Subjective Health Status ◽  
The Mean ◽  
Over Time

Background: Health literacy (HL) is a resource that can help individuals to achieve more control over their health and over factors that influence health. In the present follow-up study, we have investigated the extent to which HL in trainees changes over time and whether or to what extent HL influences health behaviour and health. Methods: In 2017, we performed a baseline survey (T0) of trainees from six different branches, who were contacted through vocational colleges in four northern federal states in Germany. The survey was repeated at the midpoint of their training in 2019 (T1). Demographic data were surveyed, together with information on HL (HLS-EU-Q16), health behaviour and on health status (psychological well-being, subjective health status). Multivariate regression analyses were performed in SPSS 26. Results: Three hundred and ninety-one (391) data sets were evaluated, with a follow-up rate of 27%; 79% of the trainees were female. The mean age was 21.2 years. Over all subjects, the mean HL increased over time ( (SD): 11.9 (2.9) to 12.2 (2.9), p = 0.070). This increase was only statistically significant for the health service trainees ( (SD): 12.1 (2.8) to 12.5 (2.9), p = 0.019). Relative to persons with adequate HL, the odds ratio over time for impaired psychological well-being was increased by 230% in persons with inadequate HL (OR: 3.3, 95% CI: 1.70–6.32, p < 0.001). For persons with problematical HL, the corresponding increase in odds ratio was 110% (OR: 2.1, 95% CI: 1.30–3.38, p = 0.002). Relative to persons with adequate HL, trainees with inadequate HL exhibited a significant increase in odds ratio of 2.8 over time for poor or less good subjective health status (OR: 2.8, 95% CI: 1.23–6.33, p = 0.014). Conclusions: We observed a positive longitudinal association between HL and health. A significant increase in HL was observed in trainees in the health service. Thus the study shows that the concept of HL may provide a potential preventive approach for trainees.

scholarly journals Unexpected heterozygosity in an island mouflon population founded by a single pair of individuals

2006 ◽  
Vol 274 (1609) ◽  
pp. 527-533 ◽  
Author(s):  
Renaud Kaeuffer ◽  
David W Coltman ◽  
Jean-Louis Chapuis ◽  
Dominique Pontier ◽  
Denis Réale
Keyword(s):  
Genetic Diversity ◽  
Wild Population ◽  
Ovis Aries ◽  
Stochastic Simulations ◽  
Single Pair ◽  
Small Populations ◽  
Short Period ◽  
Large Populations ◽  
History Of ◽  
Over Time

In population and conservation genetics, there is an overwhelming body of evidence that genetic diversity is lost over time in small populations. This idea has been supported by comparative studies showing that small populations have lower diversity than large populations. However, longitudinal studies reporting a decline in genetic diversity throughout the whole history of a given wild population are much less common. Here, we analysed changes in heterozygosity over time in an insular mouflon ( Ovis aries ) population founded by two individuals in 1957 and located on one of the most isolated locations in the world: the Kerguelen Sub-Antarctic archipelago. Heterozygosity measured using 25 microsatellite markers has actually increased over 46 years since the introduction, and exceeds the range predicted by neutral genetic models and stochastic simulations. Given the complete isolation of the population and the short period of time since the introduction, changes in genetic variation cannot be attributed to mutation or migration. Several lines of evidence suggest that the increase in heterozygosity with time may be attributable to selection. This study shows the importance of longitudinal genetic surveys for understanding the mechanisms that regulate genetic diversity in wild populations.

Poliomyelitis

2020 ◽  
pp. 151-186
Author(s):  
Michael B. A. Oldstone
Keyword(s):  
Nineteenth Century ◽  
Seventeenth Century ◽  
Paralytic Poliomyelitis ◽  
Disease Entity ◽  
Poliomyelitis Virus ◽  
Specific Disease ◽  
Large Populations ◽  
Attenuated Viruses ◽  
Over Time

This chapter addresses how polio was first discovered and then controlled, the problems with its elimination, and the argument for continued vaccination to ensure control. Polio was not defined as a specific disease entity until the late seventeenth century. Meanwhile, paralytic poliomyelitis epidemics first became known in the nineteenth century. Whether or not sporadic outbreaks of paralytic poliomyelitis occurred earlier is less certain and a matter of disagreement. The chapter then looks at the three main personalities who were fundamental in developing the vaccine for poliomyelitis: Jonas Salk, Albert Sabin, and Hilary Koprowski. Jonas Salk and his colleagues chemically inactivated the poliomyelitis virus with formaldehyde and provided a vaccine that produced immunity and dramatically lowered the incidence of poliomyelitis. However, this immunity waned over time. Additionally, administration by needle made vaccinations of large populations difficult. For these and other reasons, Koprowski, Sabin, and others independently worked on the development of a vaccine with live attenuated viruses. Without such combined efforts, the vaccine would never have materialized.

scholarly journals Thrombus Migration and Fragmentation After Intravenous Alteplase Treatment

Stroke ◽  
2021 ◽  
Vol 52 (1) ◽  
pp. 203-212
Author(s):  
Tomoyuki Ohara ◽  
Bijoy K. Menon ◽  
Fahad S. Al-Ajlan ◽  
MacKenzie Horn ◽  
Mohamed Najm ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Carotid Artery ◽  
Clinical Outcome ◽  
Odds Ratio ◽  
Adjusted Odds Ratio ◽  
Internal Carotid ◽  
Artery Occlusion ◽  
Intravenous Alteplase ◽  
Over Time

Background and Purpose: There is interest in what happens over time to the thrombus after intravenous alteplase. We study the effect of alteplase on thrombus structure and its impact on clinical outcome in patients with acute stroke. Methods: Intravenous alteplase treated stroke patients with intracranial internal carotid artery or middle cerebral artery occlusion identified on baseline computed tomography angiography and with follow-up vascular imaging (computed tomography angiography or first run of angiography before endovascular therapy) were enrolled from INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography). Thrombus movement after intravenous alteplase was classified into complete recanalization, thrombus migration, thrombus fragmentation, and no change. Thrombus migration was diagnosed when occlusion site moved distally and graded according to degrees of thrombus movement (grade 0–3). Thrombus fragmentation was diagnosed when a new distal occlusion in addition to the primary occlusion was identified on follow-up imaging. The association between thrombus movement and clinical outcome was also evaluated. Results: Among 427 patients in this study, thrombus movement was seen in 54% with a median time of 123 minutes from alteplase administration to follow-up imaging, and sub-classified as marked (thrombus migration grade 2–3 + complete recanalization; 27%) and mild to moderate thrombus movement (thrombus fragmentation + thrombus migration grade 0–1; 27%). In patients with proximal M1/internal carotid artery occlusion, marked thrombus movement was associated with a higher rate of good outcome (90-day modified Rankin Scale, 0–2) compared with mild to moderate movement (52% versus 27%; adjusted odds ratio, 5.64 [95% CI, 1.72–20.10]). No difference was seen in outcomes between mild to moderate thrombus movement and no change. In M1 distal/M2 occlusion, marked thrombus movement was associated with improved 90-day good outcome compared with no change (70% versus 56%; adjusted odds ratio, 2.54 [95% CI, 1.21–5.51]). Conclusions: Early thrombus movement is common after intravenous alteplase. Marked thrombus migration leads to good clinical outcomes. Thrombus dynamics over time should be further evaluated in clinical trials of acute reperfusion therapy.

scholarly journals Early predictors of epilepsy and subsequent relapse in children with acute disseminated encephalomyelitis

2019 ◽  
Vol 26 (3) ◽  
pp. 333-342 ◽  
Author(s):  
Thomas Rossor ◽  
Christina Benetou ◽  
Sukhvir Wright ◽  
Sophie Duignan ◽  
Karine Lascelles ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Acute Disseminated Encephalomyelitis ◽  
Oligoclonal Bands ◽  
Acute Presentation ◽  
The United Kingdom ◽  
Early Predictors ◽  
Immune Mediated ◽  
Intrathecal Oligoclonal Bands ◽  
Subsequent Relapse ◽  
Over Time

Objective: To identify predictors of epilepsy and clinical relapses in children presenting with acute disseminated encephalomyelitis (ADEM). Methods: Children presenting with ADEM between 2005 and 2017 and tested clinically for MOG-Ab were identified from three tertiary paediatric neurology centres in the United Kingdom. Patients were followed up for a median of 6 years (range, 1–16 years). Results: A total of 74 children were studied (38 females; median age at first presentation: 4.5 years (range, 1.4–16 years)). MOG-Ab was positive in 50/74 (67.6%) of cases, and 27 (54%) of MOG-Ab positive children presented with a neurological relapse over time. MOG-Ab was more frequently positive in the relapsing group than in the monophasic group (27/31 vs 23/43; odds ratio 5.9 (95% CI: 1.8–19.7); p = 0.002). 16/74 (22%) children had seizures during the acute presentation with ADEM and 12/74 (16.2%) patients were diagnosed with post-ADEM epilepsy. The diagnosis of post-ADEM epilepsy was more frequently observed in children with relapsing disease than monophasic disease (10/31 vs 2/43; odds ratio 9.8 (95% confidence interval (CI): 2.0–48.7); p = 0.003), in children who had positive intrathecal oligoclonal bands than those with negative bands (4/7 vs 4/30; odds ratio 8.7 (95% CI: 1.4–54.0); p = 0.027) and in children who had positive MOG-Ab than negative MOG-Ab cases (11/12 vs 39/62; odds ratio 6.5 (95% CI:0.8–53.6); p = 0.051). Conclusion: A higher relapse rate and a greater risk of post-ADEM epilepsy in children with MOG-Ab-associated disease may indicate a chronic disease with immune-mediated seizures in these children.

The Wright–Fisher model with varying selection

1986 ◽  
Vol 23 (02) ◽  
pp. 504-508
Author(s):  
N. C. Weber
Keyword(s):  
Population Growth ◽  
Population Size ◽  
Sufficient Conditions ◽  
Selective Advantage ◽  
Fisher Model ◽  
Ultimate Homozygosity ◽  
Varying Population

The Wright–Fisher model with varying population size is examined in the case where the selective advantage varies from generation to generation. Models are considered where the selective advantage is not always in favour of a particular genotype. Sufficient conditions in terms of the selection coefficients and the population growth are given to ensure ultimate homozygosity.

Twenty years of chemotherapy for colorectal cancer (CRC): Progress made, insights gleaned.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 596-596
Author(s):  
Irfan Jawed ◽  
Julia Wilkerson ◽  
Austin G. Duffy ◽  
Antonio Tito Fojo
Keyword(s):  
Supportive Care ◽  
Odds Ratio ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Negative Effects ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Large Phase ◽  
And Control ◽  
Over Time

596 Background: The past 20 years have seen progress in CRC therapy with more effective agents and better medical, surgical and supportive care. Methods: We conducted a systematic review of 101 phase III and large phase II trials in CRC to quantify benefit over time with first-line and subsequent therapies. Outcomes examined in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), overall survival (OS) and post-treatment survival (PTS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly the OS of CA improved 0.58 mos/yr likely reflecting use of experimental therapies in CA in subsequent studies and improvement in CRC care over time as suggested by: (1) modest improvements of PFS: 0.33 [EA] and 0.26 [CA] mos/yr; (2) PTS gains of 0.48 [EA] and 0.29 [CA] mos/yr, accounting for majority of OS gains; and (3) lack of OS improvement in 14 second/subsequent line trials. Using logistic regression to examine all drugs as class predictors of increasing OS, oxaliplatin [OX], bevacizumab [BEV], and irinotecan [IRI] were significant in the EA, but only OX and BEV were significant in the CA. Capecitabine [CAP] and cetuximab/panitumumab [CET/PAN] were not significant in EA or CA, with CAP odds ratio towards null and CET/PAN odds ratio away from null. The lack of IRI effect in CA concurs with observation that only IRI regimens had worse OS in CA compared with EA. The CET/PAN results likely reflect lack of efficacy/harm in patients with WT KRAS tumors. As expected PFS and PTS correlate highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD emerged as an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of CRC patients has improved gradually over past two decades, with gains from chemotherapy but also other factors, such as lead-time bias, more loco-regional approaches and improved supportive care. IRI performed better in EA than in CA. CET/PAN had negative effects in the entire population. In CRC, ORR correlates highly with OS, while SD portends a poor outcome.

scholarly journals On the evolution of recombination and meiosis

1999 ◽  
Vol 73 (2) ◽  
pp. 119-131 ◽  
Author(s):  
DAMIAN D. G. GESSLER ◽  
SHIZHONG XU
Keyword(s):  
Dominant Gene ◽  
Optimal Level ◽  
Present Evidence ◽  
Mendelian Genetics ◽  
Large Populations ◽  
Unicellular Organisms ◽  
Mean Fitness ◽  
Probability Of Fixation ◽  
Allele Model

Theories on the evolution of recombination in regard to its ability to increase mean fitness require a consistent source of negative linkage disequilibrium among loci affecting fitness to show an advantage to recombination. Here we present evidence that, at least theoretically, genetic variation for recombination can spread in very large populations under a strictly multiplicative-fitness, deleterious-allele model. The model uses only Mendelian genetics in a multi-locus context to show that a dominant gene for recombination can spread when rare and resist invasion when common. In non-equilibrium populations driven by Muller's ratchet, the gene increases its probability of fixation by increasing the probability of being associated with the best individuals. This occurs at an optimal level of recombination. Its action results in both an immediate and a long-term advantage to recombination amongst the proto-meiotic organisms modelled. The genetic mechanism lends itself naturally to a model for the evolution of meiosis, where modern-day gametes are seen as derivative of ancient unicellular organisms.

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