1,543 research outputs found
Non-equilibrium theory of the allele frequency spectrum
A forward diffusion equation describing the evolution of the allele frequency
spectrum is presented. The influx of mutations is accounted for by imposing a
suitable boundary condition. For a Wright-Fisher diffusion with or without
selection and varying population size, the boundary condition is , where is the frequency
spectrum of derived alleles at independent loci at time and is
the relative population size at time . When population size and selection
intensity are independent of time, the forward equation is equivalent to the
backwards diffusion usually used to derive the frequency spectrum, but the
forward equation allows computation of the time dependence of the spectrum both
before an equilibrium is attained and when population size and selection
intensity vary with time. From the diffusion equation, we derive a set of
ordinary differential equations for the moments of and express the
expected spectrum of a finite sample in terms of those moments. We illustrate
the use of the forward equation by considering neutral and selected alleles in
a highly simplified model of human history. For example, we show that
approximately 30% of the expected heterozygosity of neutral loci is
attributable to mutations that arose since the onset of population growth in
roughly the last years.Comment: 24 pages, 7 figures, updated to accomodate referees' suggestions, to
appear in Theoretical Population Biolog
Bayesian inference of natural selection from allele frequency time series
The advent of accessible ancient DNA technology now allows the direct
ascertainment of allele frequencies in ancestral populations, thereby enabling
the use of allele frequency time series to detect and estimate natural
selection. Such direct observations of allele frequency dynamics are expected
to be more powerful than inferences made using patterns of linked neutral
variation obtained from modern individuals. We develop a Bayesian method to
make use of allele frequency time series data and infer the parameters of
general diploid selection, along with allele age, in non-equilibrium
populations. We introduce a novel path augmentation approach, in which we use
Markov chain Monte Carlo to integrate over the space of allele frequency
trajectories consistent with the observed data. Using simulations, we show that
this approach has good power to estimate selection coefficients and allele age.
Moreover, when applying our approach to data on horse coat color, we find that
ignoring a relevant demographic history can significantly bias the results of
inference. Our approach is made available in a C++ software package.Comment: 27 page
Opioid-Induced Constipation in Advanced Illness: Safety and Efficacy of Methylnaltrexone Bromide
Constipation, one of the major side effects of opiates used in palliative care, can impair patients’ quality of life to a point where it prevents sufficient pain control. Methylnaltrexone is a novel μ-receptor antagonist, which does not pass the blood brain barrier. It is licensed to treat opiate induced constipation for patients with advanced diseases. This review article presents an overview of pharmacology and safety of its application, evidence of its efficacy and economic aspects of its use in clinical practice. Available data are limited but strongly suggest that methylnaltrexone causes laxation in less than 24 hours for at least half of those patients over the first two weeks of usage without impairing pain control or causing serious adverse effects. To avoid danger of gastrointestinal perforation it is contraindicated for patients at risk for that complication. More research is needed to evaluate its long-term efficacy and economic impact
Peripherally acting mu-opioid antagonist for the treatment of opioid-induced constipation: Systematic review and meta-analysis
Background and Aim Opioid-induced constipation (OIC) is a frequent adverse event (AE) that impairs patients' quality of life (QOL). Peripherally acting mu-opioid receptor antagonists (PAMORAs) have been recognized as a treatment option for OIC, but the effect consistent across the studies has not been evaluated. Methods We conducted a quantitative meta-analysis to explore the efficacy of PAMORA for OIC (registered with PROSPERO: CRD42018085298). We systematically searched randomized controlled trials (RCTs) in Medline, Embase, and Central databases. Change from baseline in spontaneous bowel movements, pooled proportion of responders, QOL, and AEs were calculated and compared with results in placebo cases. Results We included 31 RCTs with 7849 patients. A meta-analysis revealed that patients under PAMORA therapy had considerably improved spontaneous bowel movement from baseline compared with those given placebo (20 RCTs; mean difference, 1.43; 95% confidence interval [CI], 1.18-1.68; n = 5622) and more responded (21 RCTs; risk ratio [RR], 1.81; 95% CI, 1.55-2.12; n = 4821). Moreover, QOL of patients receiving PAMORA was significantly better (8 RCTs; mean difference, -0.22; 95% CI, -0.28 to -0.17; n = 2884). AEs were increased significantly in the PAMORA group (26 RCTs; RR, 1.10; 95% CI, 1.06-1.15; n = 7715), especially in gastrointestinal disorders, whereas serious AEs were not significant (17 RCTs; RR, 1.04; 95% CI, 0.85-1.28; n = 5890). Conclusion Peripherally acting mu-opioid receptor antagonist has been shown to be effective and durable for patients with OIC and is the only drug with confirmed evidence in meta-analysis. The possibility of publication bias was the limitation of this study.ArticleJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY.34(5):818-829(2019)journal articl
Gene-history correlation and population structure
Correlation of gene histories in the human genome determines the patterns of
genetic variation (haplotype structure) and is crucial to understanding genetic
factors in common diseases. We derive closed analytical expressions for the
correlation of gene histories in established demographic models for genetic
evolution and show how to extend the analysis to more realistic (but more
complicated) models of demographic structure. We identify two contributions to
the correlation of gene histories in divergent populations: linkage
disequilibrium, and differences in the demographic history of individuals in
the sample. These two factors contribute to correlations at different length
scales: the former at small, and the latter at large scales. We show that
recent mixing events in divergent populations limit the range of correlations
and compare our findings to empirical results on the correlation of gene
histories in the human genome.Comment: Revised and extended version: 26 pages, 5 figures, 1 tabl
Recommended from our members
Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations
In this report we discuss some issues considered in selecting initial protocols for boron neutron capture therapy (BNCT) of human glioblastoma multiforme. First the tolerance of normal tissues, especially the brain, to the radiation field. Radiation doses limits were based on results with human and animal exposures. Estimates of tumor control doses were based on the results of single-fraction photon therapy and single fraction BNCT both in humans and experimental animals. Of the two boron compounds (BSH and BPA), BPA was chosen since a FDA-sanctioned protocol for distribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH
The geography of recent genetic ancestry across Europe
The recent genealogical history of human populations is a complex mosaic
formed by individual migration, large-scale population movements, and other
demographic events. Population genomics datasets can provide a window into this
recent history, as rare traces of recent shared genetic ancestry are detectable
due to long segments of shared genomic material. We make use of genomic data
for 2,257 Europeans (the POPRES dataset) to conduct one of the first surveys of
recent genealogical ancestry over the past three thousand years at a
continental scale. We detected 1.9 million shared genomic segments, and used
the lengths of these to infer the distribution of shared ancestors across time
and geography. We find that a pair of modern Europeans living in neighboring
populations share around 10-50 genetic common ancestors from the last 1500
years, and upwards of 500 genetic ancestors from the previous 1000 years. These
numbers drop off exponentially with geographic distance, but since genetic
ancestry is rare, individuals from opposite ends of Europe are still expected
to share millions of common genealogical ancestors over the last 1000 years.
There is substantial regional variation in the number of shared genetic
ancestors: especially high numbers of common ancestors between many eastern
populations likely date to the Slavic and/or Hunnic expansions, while much
lower levels of common ancestry in the Italian and Iberian peninsulas may
indicate weaker demographic effects of Germanic expansions into these areas
and/or more stably structured populations. Recent shared ancestry in modern
Europeans is ubiquitous, and clearly shows the impact of both small-scale
migration and large historical events. Population genomic datasets have
considerable power to uncover recent demographic history, and will allow a much
fuller picture of the close genealogical kinship of individuals across the
world.Comment: Full size figures available from
http://www.eve.ucdavis.edu/~plralph/research.html; or html version at
http://ralphlab.usc.edu/ibd/ibd-paper/ibd-writeup.xhtm
Genome sequencing reveals fine scale diversification and reticulation history during speciation in Sus
Background Elucidating the process of speciation requires an in-depth understanding of the evolutionary history of the species in question. Studies that rely upon a limited number of genetic loci do not always reveal actual evolutionary history, and often confuse inferences related to phylogeny and speciation. Whole-genome data, however, can overcome this issue by providing a nearly unbiased window into the patterns and processes of speciation. In order to reveal the complexity of the speciation process, we sequenced and analyzed the genomes of 10 wild pigs, representing morphologically or geographically well-defined species and subspecies of the genus Sus from insular and mainland Southeast Asia, and one African common warthog. Results Our data highlight the importance of past cyclical climatic fluctuations in facilitating the dispersal and isolation of populations, thus leading to the diversification of suids in one of the most species-rich regions of the world. Moreover, admixture analyses revealed extensive, intra- and inter-specific gene-flow that explains previous conflicting results obtained from a limited number of loci. We show that these multiple episodes of gene-flow resulted from both natural and human-mediated dispersal. Conclusions Our results demonstrate the importance of past climatic fluctuations and human mediated translocations in driving and complicating the process of speciation in island Southeast Asia. This case study demonstrates that genomics is a powerful tool to decipher the evolutionary history of a genus, and reveals the complexity of the process of speciation
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