Strong association between parasitism and phenotypic variation in a supralittoral amphipod

AbstractUnderstanding the relationship between natural selection and phenotypic variation has been a long-standing challenge in human population genetics. With the emergence of biobank-scale datasets, along with new statistical metrics to approximate strength of purifying selection at the variant level, it is now possible to correlate a proxy of individual relative fitness with a range of medical phenotypes. We calculated a per-individual deleterious load score by summing the total number of derived alleles per individual after incorporating a weight that approximates strength of purifying selection. We assessed four methods for the weight, including GERP, phyloP, CADD, and fitcons. By quantitatively tracking each of these scores with the site frequency spectrum, we identified phyloP as the most appropriate weight. The phyloP-weighted load score was then calculated across 15,129,142 variants in 335,161 individuals from the UK Biobank and tested for association on 1,380 medical phenotypes. After accounting for multiple test correction, we observed a strong association of the load score amongst coding sites only on 27 traits including body mass, adiposity and metabolic rate. We further observed that the association signals were driven by common variants (derived allele frequency > 5%) with high phyloP score (phyloP > 2). Finally, through permutation analyses, we showed that the load score amongst coding sites had an excess of nominally significant associations on many medical phenotypes. These results suggest a broad impact of deleterious load on medical phenotypes and highlight the deleterious load score as a tool to disentangle the complex relationship between natural selection and medical phenotypes.Author summaryThis study aims to augment our understanding between the complex relation between natural selection and human phenotypic variation. We developed a load score to approximate the relative fitness of an individual and correlate it with a set of medical phenotypes. Association tests between the load score amongst coding sites and 1,380 phenotypes in a sample of 335,161 individuals from the UK Biobank showed a strong association with 27 traits including body mass, adiposity and metabolic rate. Furthermore, an excess of nominal associations at suggestive levels was observed between the load score amongst coding sites and medical phenotypes than would be expected under a null model. These results suggest that the aggregate effect of deleterious mutations as measured by the load score has a broad effect on human phenotypes.

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A variably imprinted epiallele impacts seed development

10.1101/339036 ◽

2018 ◽

Cited By ~ 1

Author(s):

Daniela Pignatta ◽

Katherine Novitzky ◽

P.R. V. Satyaki ◽

Mary Gehring

Keyword(s):

Dna Methylation ◽

Transcription Factor ◽

Genetic Variation ◽

Seed Development ◽

Phenotypic Variation ◽

Strong Association ◽

Endosperm Development ◽

Flowering Plants ◽

Epigenetic Variation ◽

Epigenetic Information

AbstractThe contribution of epigenetic variation to phenotypic variation is unclear. Imprinted genes, because of their strong association with epigenetic modifications, represent an opportunity for the discovery of such phenomena. In mammals and flowering plants, a subset of genes are expressed from only one parental allele in a process called gene imprinting. Imprinting is associated with differential DNA methylation and chromatin modifications between parental alleles. In flowering plants imprinting occurs in a seed tissue – endosperm. Proper endosperm development is essential for the production of viable seeds. We previously showed that in Arabidopsis thaliana intraspecific imprinting variation is correlated with naturally occurring DNA methylation polymorphisms. Here, we investigated the mechanisms and function of allele-specific imprinting of the class IV homeodomain-Leucine zipper (HD-ZIP) transcription factor HDG3. In imprinted strains, HDG3 is expressed primarily from the methylated paternally inherited allele. We manipulated the methylation state of endogenous HDG3 in a non-imprinted strain and demonstrated that methylation of a proximal transposable element is sufficient to promote HDG3 expression and imprinting. Gain of HDG3 imprinting was associated with earlier endosperm cellularization and changes in seed weight. These results indicate that epigenetic variation alone is sufficient to explain imprinting variation and demonstrate that epialleles can underlie variation in seed development phenotypes.Author SummaryThe contribution of genetic variation to phenotypic variation is well-established. By contrast, it is unknown how frequently epigenetic variation causes differences in organismal phenotypes. Epigenetic information is closely associated with but not encoded in the DNA sequence. In practice, it is challenging to disentangle genetic variation from epigenetic variation, as what appears to be epigenetic variation might have an underlying genetic basis. DNA methylation is one form of epigenetic information. HDG3 encodes an endosperm specific transcription factor that exists in two states in A. thaliana natural populations: methylated and expressed and hypomethylated and repressed. We show that pure epigenetic variation is sufficient to explain expression variation of HDG3 – a naturally lowly expressed allele can be switched to a higher expressed state by adding DNA methylation. We also show that expression of HDG3 in strains where it is normally hypomethylated and relatively repressed causes a seed development phenotype. These data indicate that naturally circulating epialleles have consequences for seed phenotypic variation.

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Estimating the Magnitude of the Relation Between Bullying, E-Bullying, and Suicidal Behaviors Among United States Youth, 2015

Crisis ◽

10.1027/0227-5910/a000544 ◽

2019 ◽

Vol 40 (3) ◽

pp. 157-165 ◽

Cited By ~ 3

Author(s):

Kevin S. Kuehn ◽

Annelise Wagner ◽

Jennifer Velloza

Keyword(s):

Adolescent Suicide ◽

Suicide Attempts ◽

Causal Effect ◽

Strong Association ◽

Cross Sectional ◽

Average Causal Effect ◽

Effects Of Bullying ◽

Pc Algorithm ◽

Nationally Representative ◽

Significant Covariates

Abstract. Background: Suicide is the second leading cause of death among US adolescents aged 12–19 years. Researchers would benefit from a better understanding of the direct effects of bullying and e-bullying on adolescent suicide to inform intervention work. Aims: To explore the direct and indirect effects of bullying and e-bullying on adolescent suicide attempts (SAs) and to estimate the magnitude of these effects controlling for significant covariates. Method: This study uses data from the 2015 Youth Risk Behavior Surveillance Survey (YRBS), a nationally representative sample of US high school youth. We quantified the association between bullying and the likelihood of SA, after adjusting for covariates (i.e., sexual orientation, obesity, sleep, etc.) identified with the PC algorithm. Results: Bullying and e-bullying were significantly associated with SA in logistic regression analyses. Bullying had an estimated average causal effect (ACE) of 2.46%, while e-bullying had an ACE of 4.16%. Limitations: Data are cross-sectional and temporal precedence is not known. Conclusion: These findings highlight the strong association between bullying, e-bullying, and SA.

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Factors Affecting the lnteraction of Tissue Factor/Factor Vll with Factor X in a Heterogeneous Tubular Reactor

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647472 ◽

1991 ◽

Vol 65 (02) ◽

pp. 139-143 ◽

Cited By ~ 7

Author(s):

Cynthia H Gemmell ◽

Vincet T Turitto ◽

Yale Nemerson

Keyword(s):

Steady State ◽

Tissue Factor ◽

Factor Viia ◽

Transmembrane Protein ◽

Strong Association ◽

Tubular Reactor ◽

Factor Xa ◽

Phospholipid Bilayer ◽

Factor Vii ◽

Factor X

SummaryA novel reactor recently described for studying phospholipiddependent blood coagulation reactions under flow conditions similar to those occurring in the vasculature has been further charactenzed. The reactor is a capitlary whose inner wall is coated with a stable phospholipid bilayer (or two bilayers) containing tissue factor, a transmembrane protein that is required for the enzymatic activation of factor X by factor VIIa. Perfusion of the capillary at wall shear rates ranging from 25 s−1 to 1,200 s−1 with purified bovine factors X and VIIa led to steady state factor Xa levels at the outlet. Assay were performed using a chromogenic substrate, SpectrozymeTMFXa, or by using a radiometric technique. In the absence of Ca2+ or factor VIIa there was no product formation. No difference was noted in the levels of factor Xa achieved when non-activated factor VII was perfused. Once steady state was achieved further factor Xa production continued in the absence of factor VIIa implying a very strong association of factor VIIa with the tissue factor in the phospholipid membrane. In agreement with static vesicle-type studies the reactor was sensitive to wall tissue factor concentration, temperature and the presence of phosphatidylserine in the bilayer.

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Factor V Leiden Is Associated with Repeated and Recurrent Unexplained Fetal Losses

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656060 ◽

1997 ◽

Vol 77 (05) ◽

pp. 0822-0824 ◽

Cited By ~ 145

Author(s):

Elvira Grandone ◽

Maurizio Margaglione ◽

Donatella Colaizzo ◽

Marina d'Addedda ◽

Giuseppe Cappucci ◽

...

Keyword(s):

Protein C ◽

Strong Association ◽

Activated Protein C ◽

Fetal Loss ◽

Factor V Leiden ◽

Factor V ◽

Significant Difference ◽

History Of ◽

Fv Leiden ◽

Caucasian Women

SummaryActivated protein C resistance (APCR) is responsible for most cases of familial thrombosis. The factor V missense mutation Arg506>Gln (FV Leiden) has been recognized as the commonest cause of this condition. Recently, it has been suggested that APCR is associated with second trimester fetal loss. We investigated the distribution of FV Leiden in a sample (n = 43) of Caucasian women with a history of two or more unexplained fetal losses. A group (n = 118) of parous women with uneventful pregnancies from the same ethnical background served as control. We found the mutation in 7 cases (16.28%) and 5 controls (4.24%; p = 0.011). A statistically significant difference between women with only early fetal loss vs those with late events (p = 0.04) was observed. Our data demonstrate a strong association between FV Leiden and fetal loss. Furthermore, they indicate that late events are more common in these patients.

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HLA Genotype of Patients with Severe Haemophilia A due to Intron 22 Inversion with and without Inhibitors of Factor VIII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655945 ◽

1997 ◽

Vol 77 (02) ◽

pp. 238-242 ◽

Cited By ~ 129

Author(s):

J Oldenburg ◽

J K Picard ◽

R Schwaab ◽

H H Brackmann ◽

E G D Tuddenham ◽

...

Keyword(s):

Factor Viii ◽

Major Gene ◽

Statistical Significance ◽

Strong Association ◽

Molecular Genetic ◽

Single Mutation ◽

Severe Haemophilia ◽

Extended Haplotype ◽

Intron 22 Inversion ◽

Hla Genotype

SummaryMolecular genetic studies have shown that development of antibodies to factor VIII (inhibitors) occurs most frequently in patients with severe haemophilia due to major gene lesions including inversions, stop codons and large deletions. Previous studies of HLA type were performed on inhibitor and non-inhibitor patients with diverse uncharacterised mutations which may have confounded detection of significant associations. We therefore selected a group of patients with a single mutation type, the prevalent intron 22 inversion, with or without inhibitors, to determine HLA genotype. Seventy-one such patients, 42 without and 29 with inhibitors (13 high, 9 low and 7 transient responders) were genotyped for MHC Class I HLA-A, -B, -C and Class II HLA-DQA, -DQB and -DRB loci. No strong correlation of any HLA-allele to inhibitor or non-inhibitor status was found. However, alleles of the haplotype HLA-A3, HLA-B7, HLA-C7, HLA-DQA0102, HLA-DQB0602, HLA-DR15 occurred more often in inhibitor patients. Since the alleles of this extended haplotype are common in the North European population only a very strong association would achieve statistical significance. Further studies of groups of patients similar to those studied here will be needed to confirm or exclude this association.

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Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

Melatonin Research ◽

10.32794/nr11250011 ◽

2019 ◽

Vol 2 (1) ◽

pp. 44-66 ◽

Cited By ~ 3

Author(s):

Dun-Xian Tan ◽

Russel. J. Reiter

Keyword(s):

Ischemia Reperfusion ◽

Surface Membrane ◽

Strong Association ◽

Membrane Receptors ◽

Melatonin Receptors ◽

Metabolic Enzyme ◽

Intermembrane Space ◽

Antitumor Effects ◽

The Matrix ◽

Surprising Discovery

It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated.

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Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

Melatonin Research ◽

10.32794/mr11250011 ◽

2019 ◽

Vol 2 (1) ◽

pp. 44-66 ◽

Cited By ~ 57

Author(s):

Dun-Xian Tan ◽

Russel. J. Reiter

Keyword(s):

Ischemia Reperfusion ◽

Surface Membrane ◽

Strong Association ◽

Membrane Receptors ◽

Melatonin Receptors ◽

Metabolic Enzyme ◽

Intermembrane Space ◽

Antitumor Effects ◽

The Matrix ◽

Surprising Discovery

It was a surprising discovery when mitochondria, as the power houses of cells, were also found to synthesize the potent mitochondrial targeted antioxidant, melatonin. The melatonin synthetic enzyme serotonin N-acetyltransferase (SNAT) was found in matrix and also in the intermembrane space of mitochondria. We hypothesize that the melatonin synthesis occurs in the matrix due to substrate (N-acetyl co-enzyme A) availability while the intermembrane space may serve as the recycling pool of SNAT to regulate the melatonin circadian rhythm. Another surprise was that the melatonin membrane receptors, including MT1 and MT2, were also present in mitochondria. The protective effects of melatonin against neuronal injury induced by brain ischemia/reperfusion were proven to be mainly mediated by mitochondrial melatonin receptors rather than the cell surface membrane receptors which is contrary to the classical principle. In addition, melatonin metabolic enzyme has also been identified in the mitochondria. This enzyme can convert melatonin to N-acetylserotonin to strengthen the antitumor effects of melatonin. Thus, mitochondria are the generator, battle ground and metabolic sites of melatonin. The biological significance of the strong association between mitochondria and melatonin should be intensively investigated.

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Competitive and Complementary Relations in International Travel: The Case of British Travel to Cyprus

Journal of Business and Economics ◽

10.15341/jbe(2155-7950)/05.10.2019/004 ◽

2019 ◽

Vol 10 (5) ◽

pp. 395-420

Author(s):

Petros Anastasopoulos ◽

Keyword(s):

Strong Association ◽

International Travel ◽

Relative Price ◽

Annual Data ◽

Export Demand ◽

Relative Prices ◽

Vector Error Correction ◽

Vector Error ◽

The Mediterranean ◽

Demand Equations

This is an econometric analysis of demand for travel to Cyprus by Britons. We examined the competitive and complementary relations between travel to Cyprus and other well-established travel destinations in the Mediterranean basin. Because many package tours include several countries in their destinations within a given journey, and because individual travelers find it more advantageous to visit more than one country in a single trip, it may be meaningful to examine international travel within the contest of groups of countries rather than a single country competing for international travelers. Specifically, we provide an analysis of the competitive and complementary relations existing between the tourism sectors of Cyprus and that of Greece, Spain and Portugal for British travelers. We provide estimates of income and relative price elasticities based of export demand equations upon annual data from 1980-2016. We tested for the stationarity of the variables and derived estimates of the Vector Error Correction Model (VECM). These tests confirm a strong association between the incomes of Britons and their decision to travel to Cyprus. Furthermore, we show the relative prices between Cyprus and other competing destinations in the Mediterranean to play an important role in determining British travel to Cyprus.

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