scholarly journals Detecting Long-term Balancing Selection using Allele Frequency Correlation

2017 ◽  
Author(s):  
Katherine M. Siewert ◽  
Benjamin F. Voight
Keyword(s):  
Complex Traits ◽  
Balancing Selection ◽  
Population Data ◽  
Intermediate Frequency ◽  
Summary Statistic ◽  
Computationally Efficient ◽  
Multiple Alleles ◽  
Demographic Models ◽  
Project Data

AbstractBalancing selection occurs when multiple alleles are maintained in a population, which can result in their preservation over long evolutionary time periods. A characteristic signature of this long-term balancing selection is an excess number of intermediate frequency polymorphisms near the balanced variant. However, the expected distribution of allele frequencies at these loci has not been extensively detailed, and therefore existing summary statistic methods do not explicitly take it into account. Using simulations, we show that new mutations which arise in close proximity to a site targeted by balancing selection accumulate at frequencies nearly identical to that of the balanced allele. In order to scan the genome for balancing selection, we propose a new summary statistic, β, which detects these clusters of alleles at similar frequencies. Simulation studies show that compared to existing summary statistics, our measure has improved power to detect balancing selection, and is reasonably powered in non-equilibrium demographic models or when recombination or mutation rate varies. We compute β on 1000 Genomes Project data to identify lo ci potentially subjected to long-term balancing selection in humans. We report two balanced haplotypes - localized to the genes WFS1 and CADM2 - that are strongly linked to association signals for complex traits. Our approach is computationally efficient and applicable to species that lack appropriate outgroup sequences, allowing for well-powered analysis of selection in the wide variety of species for which population data are rapidly being generated.

scholarly journals Long-term balancing selection in LAD1 maintains a missense trans-species polymorphism in humans, chimpanzees and bonobos

2014 ◽  
Author(s):  
João C. Teixeira ◽  
Cesare de Filippo ◽  
Antje Weihmann ◽  
Juan R. Meneu ◽  
Fernando Racimo ◽  
...  
Keyword(s):  
Balancing Selection ◽  
Phenotypic Diversity ◽  
Intermediate Frequency ◽  
High Genetic Diversity ◽  
Protein Coding ◽  
Missense Change ◽  
Linear Iga Disease ◽  
Filament Protein

Balancing selection maintains advantageous genetic and phenotypic diversity in populations. When selection acts for long evolutionary periods selected polymorphisms may survive species splits and segregate in present-day populations of different species. Here, we investigate the role of long-term balancing selection in the evolution of protein-coding sequences in the Homo-Pan clade. We sequenced the exome of 20 humans, 20 chimpanzees and 20 bonobos and detected eight coding trans-species polymorphisms (trSNPs) that are shared among the three species and have segregated for approximately 14 million years of independent evolution. While the majority of these trSNPs were found in three genes of the MHC cluster, we also uncovered one coding trSNP (rs12088790) in the gene LAD1. All these trSNPs show clustering of sequences by allele rather than by species and also exhibit other signatures of long-term balancing selection, such as segregating at intermediate frequency and lying in a locus with high genetic diversity. Here we focus on the trSNP in LAD1, a gene that encodes for Ladinin-1, a collagenous anchoring filament protein of basement membrane that is responsible for maintaining cohesion at the dermal-epidermal junction; the gene is also an autoantigen responsible for linear IgA disease. This trSNP results in a missense change (Leucine257Proline) and, besides altering the protein sequence, is associated with changes in gene expression of LAD1.

scholarly journals ES-1 Clinical results of tumor treating fields in patients with glioblastoma in Japan, compared with global surveillance

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii3-ii3
Author(s):  
Yoshihiro Muragaki ◽  
Masayuki Nitta ◽  
Taiichi Saito ◽  
Shunichi Tutsuki ◽  
Atsushi Fukui ◽  
...  
Keyword(s):  
Side Effects ◽  
Insurance Coverage ◽  
Intermediate Frequency ◽  
Clinical Results ◽  
Tumor Treating Fields ◽  
Post Marketing Surveillance ◽  
Post Marketing ◽  
Us Fda ◽  
Medical University

Abstract INTRODUCTION: The tumor treatment field induces apoptosis of tumor cells by providing a low intensity, intermediate frequency, alternating current electric field via a transducer array. TTFields is based on Phase 3 EF-11 and EF-14 trials for glioblastoma in the US FDA and Japan PMDA. Therefore, I will report the statistics of TTFields use in Japan along with recent papers. METHODS: 410 patients were treated with TTFields in Japan (December 2017-), of which 17 were at Tokyo Women’s Medical University. We also referred to papers about global post-marketing surveillance and recent studies. RESULTS: Of the 410 patients, 409 (99.8%) were diagnosed with ndGBM(male: female, 66.8%: 33.2%). As of June 2020, 222 patients (54.1%) were on treatment and 188 (45.9%) were discontinued. In 17 cases at TWMU, the average age was 46.3 years. The average treatment period was 218 days, with 6 patients (35%) continuing treatment, 6 patients (35%) discontinuing due to patient wishes, and 5 patients (30%) discontinuing treatment due to recurrence. Side effects were contact dermatitis under the array in 9 patients (57%) and mild malaise in 7 patients (43%). We experienced long-term progression-free cases with TTF use of 25 months (survival 30 months after surgery) with a glioma partially resected and 21 months (survival 27 months after surgery) with a biopsied glioma. In the biopsy case, bevacizumab was used in combination during the treatment. Conclusion: In global surveillance, use for rGBM accounts for 39%, but Japan is limited to use for ndGBM due to insurance coverage. In terms of side effects, it showed a good safety profile comparable to previous trials. Long-term progression-free cases have been observed, and it is necessary to examine the characteristics of patients who respond to treatment and the effect of concomitant use with bevacizumab by prospective studies

scholarly journals Successful Implementation of Newborn Screening for Hemoglobin Disorders in the Philippines

2021 ◽  
Vol 7 (2) ◽  
pp. 30
Author(s):  
Carmencita D. Padilla ◽  
Bradford L. Therrell ◽  
Maria Melanie Liberty B. Alcausin ◽  
Reynaldo C. de Castro ◽  
Maria Beatriz P. Gepte ◽  
...  
Keyword(s):  
Newborn Screening ◽  
High Performance ◽  
Population Data ◽  
The Philippines ◽  
Successful Implementation ◽  
Clinical Experiences ◽  
Term Care ◽  
Confirmatory Testing ◽  
Newborn Bloodspot Screening

The Philippine newborn bloodspot screening (NBS) program began in 1996 with 24 hospitals and was formalized by legislation in 2004. The NBS panel was recently expanded to include a number of additional hereditary congenital conditions. Expertise and experiences from other NBS programs already screening for hemoglobinopathies were essential to its successful integration into the ongoing dried bloodspot NBS program in the Philippines. Building on clinical experiences and population data from Filipinos born in California, USA, hemoglobinopathies (including thalassemias) were selected for inclusion in the expanded screening panel. Hemoglobinopathy NBS, using high performance liquid chromatography, was implemented in a stepwise manner into the seven regional NBS screening laboratories. A central university laboratory provides confirmatory testing using both capillary electrophoresis and molecular methodologies. NBS results indicating carriers are followed up with educational fact sheets, while results of presumptive disease are referred for confirmatory testing and follow-up with a hematologist. Long-term care is provided through newborn screening continuity clinics across the country. Hemoglobinopathy NBS is now included in the national insurance package and screening uptake continues to increase nationally, exceeding 90% of all newborns in 7400+ hospitals and birthing centers nationwide prior to the COVID-19 pandemic.

scholarly journals Long-term effects of fine particulate matter exposure on the progression of arterial stiffness

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Dianqin Sun ◽  
Yue Liu ◽  
Jie Zhang ◽  
Jia Liu ◽  
Zhiyuan Wu ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Health Management ◽  
Ankle Brachial Index ◽  
Population Data ◽  
Average Concentration ◽  
Air Pollutant ◽  
Stiffness Index ◽  
Long Term Effects ◽  
Annual Average

Abstract Background Prior studies have investigated the association of PM2.5 exposure with arterial stiffness measured by ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV), of which conclusions are inconsistent. Moreover, limited evidence is available on the contributory role of PM2.5 exposure on the arterial stiffness index. Methods We used the population data from the Beijing Health Management Cohort and conducted a longitudinal analysis. The annual average concentration of PM2.5 for 35 air pollutant monitoring sites in Beijing from 2014 to 2018 was used to estimate individual exposure by different interpolation methods. Multivariate logistic regression and linear regression were conducted to assess the association of annual average PM2.5 concentration with the incidence of higher baPWV, the progression of ABI, and baPWV, respectively. Results The association between PM2.5 exposure and incidence of higher baPWV was not significant (OR = 1.11, 95% CI: 0.82–1.50, P = 0.497). There was − 0.16% (95% CI: − 0.43-0.11%) decrease in ABI annually and 1.04% (95% CI: 0.72–1.37%) increase in baPWV annually with each increment of 10 μg/m3 average PM2.5 concentration. Conclusions Long-term exposure to PM2.5 was associated with the progression of arterial stiffness in Beijing. This study suggests that improvement of air quality may help to prevent arterial stiffness.

Future Costs of Long-term Care in Japan and Sweden

2017 ◽  
Vol 48 (1) ◽  
pp. 128-147 ◽  
Author(s):  
Mårten Lagergren ◽  
Noriko Kurube ◽  
Yasuhiko Saito
Keyword(s):  
Long Term Care ◽  
Population Change ◽  
Population Aging ◽  
Population Data ◽  
Epidemiological Data ◽  
The Other ◽  
Age Group ◽  
Term Care ◽  
And Gender

Population aging is expected to increase long-term care (LTC) costs in both Japan and Sweden. This study projected LTC costs for 2010 through 2040 for different assumptions of population change, LTC need by age group and gender, and LTC provided per level of need and cost in Japan and Sweden. Population data were taken from the official national forecasts. Needs projections were based on epidemiological data from the Nihon University Japanese Longitudinal Study of Aging and the Swedish Survey of Living Conditions. Data on LTC provision by need and cost were taken from nine Japanese municipalities collected by assessments in the LTC insurance system and from surveys in eight Swedish municipalities. Total initial costs were calibrated to official national figures. Two projections based on two different scenarios were made for each country from 2010 to 2040. The first scenario assumed a constant level of need for LTC by age group and gender, and the other assumed a continuation of the present LTC need trends until 2025. For Japan, this resulted in a projected cost increase of 93% for the one and 80% for the other; for Sweden it was 52% and 24%, respectively. The results reflected differences in population aging and health development.

scholarly journals Recent Selection Changes in Human Genes under Long-Term Balancing Selection

2016 ◽  
Vol 33 (6) ◽  
pp. 1435-1447 ◽  
Author(s):  
Cesare de Filippo ◽  
Felix M. Key ◽  
Silvia Ghirotto ◽  
Andrea Benazzo ◽  
Juan R. Meneu ◽  
...  
Keyword(s):  
Balancing Selection ◽  
Human Genes ◽  
Recent Selection

Supergene degeneration opposes polymorphism: The curious case of balanced lethals

2021 ◽  
Author(s):  
Emma Berdan ◽  
Alexandre Blanckaert ◽  
Roger K Butlin ◽  
Thomas Flatt ◽  
Tanja Slotte ◽  
...  
Keyword(s):  
Equilibrium State ◽  
Balancing Selection ◽  
Mutation Accumulation ◽  
Small Population ◽  
Quasi Equilibrium ◽  
Deleterious Mutations ◽  
Critical Factors ◽  
Critical Aspect ◽  
Allopatric Divergence

Supergenes offer some of the most spectacular examples of long-term balancing selection in nature but their origin and maintenance remain a mystery. A critical aspect of supergenes is reduced recombination between arrangements. Reduced recombination protects adaptive multi-trait phenotypes, but can also lead to degeneration through mutation accumulation. Mutation accumulation can stabilize the system through the emergence of associative overdominance (AOD), destabilize the system, or lead to new evolutionary outcomes. One such outcome is the formation of balanced lethal systems, a maladaptive system where both supergene arrangements have accumulated deleterious mutations to the extent that both homozygotes are inviable, leaving only heterozygotes to reproduce. Here, we perform a simulation study to understand the conditions under which these different outcomes occur, assuming a scenario of introgression after allopatric divergence. We found that AOD aids the invasion of a new supergene arrangement and the establishment of a polymorphism. However, this polymorphism is easily destabilized by further mutation accumulation. While degradation may strengthen AOD, thereby stabilizing the supergene polymorphism, it is often asymmetric, which is the key disrupter of the quasi-equilibrium state of the polymorphism. Furthermore, mechanisms that accelerate degeneration also tend to amplify asymmetric mutation accumulation between the supergene arrangements and vice versa. As the evolution of a balanced lethal system requires symmetric degradation of both arrangements, this leaves highly restricted conditions under which such a system could evolve. We show that small population size and low dominance coefficients are critical factors, as these reduce the efficacy of selection. The dichotomy between the persistence of a polymorphism and degradation of supergene arrangements likely underlies the rarity of balanced lethal systems in nature.

VERITAS OBSERVATIONS OF RELATIVISTIC OUTFLOWS IN LOW- AND INTERMEDIATE-FREQUENCY-PEAKED BL LAC OBJECTS

2014 ◽  
Vol 28 ◽  
pp. 1460178
Author(s):  
◽  
HEIKE PROKOPH
Keyword(s):  
Gamma Ray ◽  
Intermediate Frequency ◽  
Bl Lac Objects ◽  
Bl Lacertae ◽  
Bl Lac ◽  
Bl Lacs ◽  
Gamma Ray Telescopes ◽  
Very High

The majority of blazars detected at very high energies (VHE; E > 100 GeV) are high-frequency-peaked BL Lac objects (HBLs). Low- and intermediate-frequency-peaked BL Lacs (LBLs/IBLs with synchrotron-peak frequencies in the infrared and optical regime) are generally more powerful, more luminous, and have a richer jet environment than HBLs. However, only a handful of these IBL and LBLs have been detected by ground-based gamma-ray telescopes, typically during high-flux states. The VERITAS array has been monitoring five known VHE LBLs/IBLs since 2009: 3C 66A, W Comae, PKS 1424+240, S5 0716+714 and BL Lacertae, with typical exposures of 5-10 hours per year. The results of these long-term observations are presented, including a bright, subhour-scale VHE flare of BL Lacertae in June 2011, the first low-state detections of 3C 66A and W Comae, and the detection and characterization of the IBL B2 1215+30.

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