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1
Yu, Haibing, Shu Wang, Wei Hu, Lin Xu, Yuanlin Ding, Danli Kong, and Haiyan Pan. "Association between Single-nucleotide Polymorphisms of RXRG and Genetic Susceptibility to Type 2 Diabetes in South China." Current Molecular Medicine 20, no. 6 (June 22, 2020): 408–14. http://dx.doi.org/10.2174/1566524020666191206163951.
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Objective: To investigate the relationship between genetic polymorphisms of RXRG rs1467664, rs3753898 and the genetic susceptibility of type 2 diabetes in the Chinese Han population from South China. Methods: In our case-control study, single-nucleotide polymorphisms (SNPs) rs1467664 and rs3753898 were genotyped by SNPscanTM kit in 1092 patients with T2D as cases and 1092 normal persons as controls. The distributions of genotype and allele frequencies in two groups were analyzed by the SPSS 20.0 software. Results: The distribution of genotypes and alleles of RXRG rs3753898 was statistically significant between the two groups, but there was no significant difference in the distribution of genotypes and alleles of the rs1467664. Before and after the adjustment of age, sex and BMI, rs3753898 in the two groups had statistical significance under the additive, dominant and recessive models (P<0.05), but no statistical differences were found under the overdominance and co-dominant genetic models (P>0.05). There was no significant difference in the genetic models of rs1467664 between the two groups (P>0.05). The haplotype, which consists of rs1467664 allele T and rs3753898 allele A was a high-risk factor for T2D, OR=1.27, 95% CI (1.09-1.47), Padj=0.002. Conclusion: Our results showed that the single nucleotide polymorphism of RXRG rs3753898 may be related to genetic susceptibility of type 2 diabetes. The haplotype consisting of the allele T of rs1467664 and the allele A of rs3753898 is a risk factor for type 2 diabetes, suggesting that the genetic variation of RXRG gene may be the genetic cause of diabetes mellitus in the Chinese Han population.
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Wenne, Roman, Małgorzata Zbawicka, Lis Bach, Petr Strelkov, Mikhail Gantsevich, Piotr Kukliński, Tomasz Kijewski, et al. "Trans-Atlantic Distribution and Introgression as Inferred from Single Nucleotide Polymorphism: Mussels Mytilus and Environmental Factors." Genes 11, no. 5 (May 10, 2020): 530. http://dx.doi.org/10.3390/genes11050530.
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Large-scale climate changes influence the geographic distribution of biodiversity. Many taxa have been reported to extend or reduce their geographic range, move poleward or displace other species. However, for closely related species that can hybridize in the natural environment, displacement is not the only effect of changes of environmental variables. Another option is subtler, hidden expansion, which can be found using genetic methods only. The marine blue mussels Mytilus are known to change their geographic distribution despite being sessile animals. In addition to natural dissemination at larval phase—enhanced by intentional or accidental introductions and rafting—they can spread through hybridization and introgression with local congeners, which can create mixed populations sustaining in environmental conditions that are marginal for pure taxa. The Mytilus species have a wide distribution in coastal regions of the Northern and Southern Hemisphere. In this study, we investigated the inter-regional genetic differentiation of the Mytilus species complex at 53 locations in the North Atlantic and adjacent Arctic waters and linked this genetic variability to key local environmental drivers. Of seventy-nine candidate single nucleotide polymorphisms (SNPs), all samples were successfully genotyped with a subset of 54 SNPs. There was a clear interregional separation of Mytilus species. However, all three Mytilus species hybridized in the contact area and created hybrid zones with mixed populations. Boosted regression trees (BRT) models showed that inter-regional variability was important in many allele models but did not prevail over variability in local environmental factors. Local environmental variables described over 40% of variability in about 30% of the allele frequencies of Mytilus spp. For the 30% of alleles, variability in their frequencies was only weakly coupled with local environmental conditions. For most studied alleles the linkages between environmental drivers and the genetic variability of Mytilus spp. were random in respect to “coding” and “non-coding” regions. An analysis of the subset of data involving functional genes only showed that two SNPs at Hsp70 and ATPase genes correlated with environmental variables. Total predictive ability of the highest performing models (r2 between 0.550 and 0.801) were for alleles that discriminated most effectively M. trossulus from M. edulis and M. galloprovincialis, whereas the best performing allele model (BM101A) did the best at discriminating M. galloprovincialis from M. edulis and M. trossulus. Among the local environmental variables, salinity, water temperature, ice cover and chlorophyll a concentration were by far the greatest predictors, but their predictive performance varied among different allele models. In most cases changes in the allele frequencies along these environmental gradients were abrupt and occurred at a very narrow range of environmental variables. In general, regions of change in allele frequencies for M. trossulus occurred at 8–11 psu, 0–10 °C, 60%–70% of ice cover and 0–2 mg m−3 of chlorophyll a, M. edulis at 8–11 and 30–35 psu, 10–14 °C and 60%–70% of ice cover and for M. galloprovincialis at 30–35 psu, 14–20 °C.
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Mani, G. S., L. M. Cook, and R. Marvdashti. "WHAT CAN BE LEARNT ABOUT SELECTION FROM GENE FREQUENCY DISTRIBUTION?" Genetics 114, no. 3 (November 1, 1986): 971–82. http://dx.doi.org/10.1093/genetics/114.3.971.
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ABSTRACT Polymorphism has been studied at the Esterase 6 locus in the Yellow Fever mosquito Aedes aegypti (L.) in laboratory stocks. At least 12 alleles are present, with up to four coexisting in a stock. The allele frequency distribution is quite sharply peaked at a mode of about 0.25. The experimental data are compared with the results of simulation based on two models, one in which the initial global distribution is taken to be the stationary distribution obtained from the neutral model assuming M = 4μ Ne = 1 and the other in which the initial global distribution is generated from the experimental populations studied. The results suggest that the patterns observed are not likely to arise through random fluctuation of frequencies in neutral alleles, but that some kind of selection maintains polymorphism, either in the wild or in the laboratory, or both.
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Gan, Han L., Adrian Röllin, and Nathan Ross. "Dirichlet approximation of equilibrium distributions in Cannings models with mutation." Advances in Applied Probability 49, no. 3 (September 2017): 927–59. http://dx.doi.org/10.1017/apr.2017.27.
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AbstractConsider a haploid population of fixed finite size with a finite number of allele types and having Cannings exchangeable genealogy with neutral mutation. The stationary distribution of the Markov chain of allele counts in each generation is an important quantity in population genetics but has no tractable description in general. We provide upper bounds on the distributional distance between the Dirichlet distribution and this finite-population stationary distribution for the Wright–Fisher genealogy with general mutation structure and the Cannings exchangeable genealogy with parent independent mutation structure. In the first case, the bound is small if the population is large and the mutations do not depend too much on parent type; 'too much' is naturally quantified by our bound. In the second case, the bound is small if the population is large and the chance of three-mergers in the Cannings genealogy is small relative to the chance of two-mergers; this is the same condition to ensure convergence of the genealogy to Kingman's coalescent. These results follow from a new development of Stein's method for the Dirichlet distribution based on Barbour's generator approach and a probabilistic description of the semigroup of the Wright–Fisher diffusion due to Griffiths and Li (1983) and Tavaré (1984).
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De Sá, Nathalia Beatriz Ramos, Karina dos S. Silva, Marcelo Ribeiro-Alves, Diogo Gama Caetano, Fernanda Heloise Côrtes, Suwellen S. D. de Azevedo, Brenda Hoagland, et al. "Killer immunoglobulin-like receptor (KIR) genes are associated with the risk of episodes of high-level and detectable viremia among HIV controllers." F1000Research 10 (July 7, 2021): 546. http://dx.doi.org/10.12688/f1000research.53683.1.
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Background: HIV controllers (HICs) constitute a heterogeneous group of HIV-1 individuals able to suppress plasma viremia to low or undetectable levels in the absence of antiretroviral therapy. Host genetic factors may be involved in the sustained control of viral replication observed. We investigated the distribution and the potential impact of human leukocyte antigens (HLA)-B and -C alleles, killer immunoglobulin-like receptor (KIR) genes, single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8 and IL-1β inflammasome genes, and CCR5Δ32 mutation on the viral control among HICs. Methods: In total, 28 HICs were categorized as persistent elite controllers (PECs, n = 7), ebbing elite controllers (EECs, n = 7), and viremic controllers (VCs, n = 14) according to the level of natural suppression of viremia. HLA alleles were assigned by sequencing-based typing, KIR alleles by polymerase chain reaction (PCR) sequence-specific amplification, SNPs by real-time PCR, and the CCR5Δ32 mutation by PCR. Results: Significant differences were observed in the pairwise comparisons of protective HLA-B alleles, KIR Bx genotype, KIR2DL3 + C1 pair, KIR2DL5, and KIR2DS5 allelic carrier frequencies among the HIC groups. Multivariate models showed that HICs without the KIR2DL3 allele or without KIR2DL3 + C1/C2 pair, with the HLA-C*08 allele or with the NLRP3 rs10754558-G SNP had a higher mean hazard of a viral load above 2,000 copies/mL, while a lower mean hazard of this event was observed for HICs with KIR2DL5, KIR2DS1, KIR2DS5, and KIR3DS1 alleles. Moreover, HICs with the KIR2DS5 allele had less risk of undergoing viral load (VL) blips within the same normalized period than those participants without this allele, while HICs without the KIR2DL3 allele had a mean higher risk of experiencing VL blips. Conclusions: These results indicate that innate immune mechanisms may play an essential role in modulating the sustained control of viral replication in HICs.
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Whittaker, John C., Roger M. Harbord, Nicola Boxall, Ian Mackay, Gary Dawson, and Richard M. Sibly. "Likelihood-Based Estimation of Microsatellite Mutation Rates." Genetics 164, no. 2 (June 1, 2003): 781–87. http://dx.doi.org/10.1093/genetics/164.2.781.
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Abstract Microsatellites are widely used in genetic analyses, many of which require reliable estimates of microsatellite mutation rates, yet the factors determining mutation rates are uncertain. The most straightforward and conclusive method by which to study mutation is direct observation of allele transmissions in parent-child pairs, and studies of this type suggest a positive, possibly exponential, relationship between mutation rate and allele size, together with a bias toward length increase. Except for microsatellites on the Y chromosome, however, previous analyses have not made full use of available data and may have introduced bias: mutations have been identified only where child genotypes could not be generated by transmission from parents' genotypes, so that the probability that a mutation is detected depends on the distribution of allele lengths and varies with allele length. We introduce a likelihood-based approach that has two key advantages over existing methods. First, we can make formal comparisons between competing models of microsatellite evolution; second, we obtain asymptotically unbiased and efficient parameter estimates. Application to data composed of 118,866 parent-offspring transmissions of AC microsatellites supports the hypothesis that mutation rate increases exponentially with microsatellite length, with a suggestion that contractions become more likely than expansions as length increases. This would lead to a stationary distribution for allele length maintained by mutational balance. There is no evidence that contractions and expansions differ in their step size distributions.
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Schierup, Mikkel H., Xavier Vekemans, and Freddy B. Christiansen. "Evolutionary Dynamics of Sporophytic Self-Incompatibility Alleles in Plants." Genetics 147, no. 2 (October 1, 1997): 835–46. http://dx.doi.org/10.1093/genetics/147.2.835.
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The stationary frequency distribution and allelic dynamics in finite populations are analyzed through stochastic simulations in three models of single-locus, multi-allelic sporophytic self-incompatibility. The models differ in the dominance relationships among alleles. In one model, alleles act codominantly in both pollen and style (SSIcod), in the second, alleles form a dominance hierarchy in pollen and style (SSIdom). In the third model, alleles interact codominantly in the style and form a dominance hierarchy in the pollen (SSIdomcod). The SSIcod model behaves similarly to the model of gametophytic self-incompatibility, but the selection intensity is stronger. With dominance, dominant alleles invade the population more easily than recessive alleles and have a lower frequency at equilibrium. In the SSIdom model, recessive alleles have both a higher allele frequency and higher expected life span. In the SSIdomcod model, however, loss due to drift occurs more easily for pollen-recessive than for pollen-dominant alleles, and therefore, dominant alleles have a higher expected life span than the more recessive alleles. The process of allelic turnover in the SSIdomcod and SSIdom models is closely approximated by a random walk on a dominance ladder. Implications of the results for experimental studies of sporophytic self-incompatibility in natural populations are discussed.
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Ramil, E., AJ Sánchez, P. González-Pérez, A. Rodríguez-Antigüedad, N. Gómez-Lozano, P. Ortiz, R. Arroyo, V. De las Heras, C. Vilches, and A. García-Merino. "The cannabinoid receptor 1 gene (CNR1) and multiple sclerosis: an association study in two case-control groups from Spain." Multiple Sclerosis Journal 16, no. 2 (December 9, 2009): 139–46. http://dx.doi.org/10.1177/1352458509355071.
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Different studies point to the implication of the endocannabinoid system in multiple sclerosis (MS) and animal models of MS. The purpose of this study was to evaluate a possible association of MS with polymorphic markers at the CNR1 gene, encoding the cannabinoid 1 (CB1) receptor. We have performed a genetic analysis of an AAT repeat microsatellite localized in the downstream region of the CNR1 gene, in two case—control groups of MS patients and healthy controls (HC) from Spain (Madrid and Bilbao). MS patients with primary progressive MS (PPMS) had more commonly long ((AAT) ≥13) alleles and genotypes with a significant difference for genotype 7/8 in Madrid (p = 0.043) and in the sum of both groups (p = 0.016); short alleles were less frequently found in PPMS with a significant difference for allele 5 in the analysis of both groups together (p = 0.039). In patients with relapsing MS, no consistent differences in allele and genotype distribution were found. Disease severity and progression was unrelated to AAT repeat variations. In conclusion, long (AAT) ≥13 CNR1 genotypes could behave as risk factors for PPMS.
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Donnelly, Peter, and Paul Joyce. "Consistent ordered sampling distributions: characterization and convergence." Advances in Applied Probability 23, no. 02 (June 1991): 229–58. http://dx.doi.org/10.1017/s0001867800023478.
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This paper is concerned with models for sampling from populations in which there exists a total order on the collection of types, but only the relative ordering of types which actually appear in the sample is known. The need for consistency between different sample sizes limits the possible models to what are here called ‘consistent ordered sampling distributions'. We give conditions under which weak convergence of population distributions implies convergence of sampling distributions and conversely those under which population convergence may be inferred from convergence of sampling distributions. A central result exhibits a collection of ‘ordered sampling functions', none of which is continuous, which separates measures in a certain class. More generally, we characterize all consistent ordered sampling distributions, proving an analogue of de Finetti's theorem in this context. These results are applied to an unsolved problem in genetics where it is shown that equilibrium age-ordered population allele frequencies for a wide class of exchangeable reproductive models converge weakly, as the population size becomes large, to the so-called GEM distribution. This provides an alternative characterization which is more informative and often more convenient than Kingman's (1977) characterization in terms of the Poisson–Dirichlet distribution.
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Donnelly, Peter, and Paul Joyce. "Consistent ordered sampling distributions: characterization and convergence." Advances in Applied Probability 23, no. 2 (June 1991): 229–58. http://dx.doi.org/10.2307/1427746.
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This paper is concerned with models for sampling from populations in which there exists a total order on the collection of types, but only the relative ordering of types which actually appear in the sample is known. The need for consistency between different sample sizes limits the possible models to what are here called ‘consistent ordered sampling distributions'. We give conditions under which weak convergence of population distributions implies convergence of sampling distributions and conversely those under which population convergence may be inferred from convergence of sampling distributions. A central result exhibits a collection of ‘ordered sampling functions', none of which is continuous, which separates measures in a certain class. More generally, we characterize all consistent ordered sampling distributions, proving an analogue of de Finetti's theorem in this context. These results are applied to an unsolved problem in genetics where it is shown that equilibrium age-ordered population allele frequencies for a wide class of exchangeable reproductive models converge weakly, as the population size becomes large, to the so-called GEM distribution. This provides an alternative characterization which is more informative and often more convenient than Kingman's (1977) characterization in terms of the Poisson–Dirichlet distribution.
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Innan, Hideki, Ryohei Terauchi, and Naohiko T. Miyashita. "Microsatellite Polymorphism in Natural Populations of the Wild Plant Arabidopsis thaliana." Genetics 146, no. 4 (August 1, 1997): 1441–52. http://dx.doi.org/10.1093/genetics/146.4.1441.
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Variation in repeat number at 20 microsatellite loci of Arabidopsis thaliana was studied in a worldwide sample of 42 ecotypes to investigate the pattern and level of polymorphism in repetitive sequences in natural plant populations. There is a substantial amount of variation at microsatellite loci despite the selfing nature of this plant species. The average gene diversity was 0.794 and the average number of alleles per locus was 10.6. The distribution of alleles was centered around the mean of repeat number at most loci, but could not be regarded as normal. There was a significantly positive correlation between the number of repeats and the amount of variation. For most loci, the observed number of alleles was between the expected values of the infinite allele and stepwise mutation models. The two models were rejected by the sign test. Linkage disequilibrium was detected in 12.1% of the pairwise comparisons between loci. In phylogenetic tree, there was no association between ecotype and geographic origin. This result is consistent with the recent expansion of A. thaliana throughout the world.
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BARTON, N. H. "Clines in polygenic traits." Genetical Research 74, no. 3 (December 1999): 223–36. http://dx.doi.org/10.1017/s001667239900422x.
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This article outlines theoretical models of clines in additive polygenic traits, which are maintained by stabilizing selection towards a spatially varying optimum. Clines in the trait mean can be accurately predicted, given knowledge of the genetic variance. However, predicting the variance is difficult, because it depends on genetic details. Changes in genetic variance arise from changes in allele frequency, and in linkage disequilibria. Allele frequency changes dominate when selection is weak relative to recombination, and when there are a moderate number of loci. With a continuum of alleles, gene flow inflates the genetic variance in the same way as a source of mutations of small effect. The variance can be approximated by assuming a Gaussian distribution of allelic effects; with a sufficiently steep cline, this is accurate even when mutation and selection alone are better described by the ‘House of Cards’ approximation. With just two alleles at each locus, the phenotype changes in a similar way: the mean remains close to the optimum, while the variance changes more slowly, and over a wider region. However, there may be substantial cryptic divergence at the underlying loci. With strong selection and many loci, linkage disequilibria are the main cause of changes in genetic variance. Even for strong selection, the infinitesimal model can be closely approximated by assuming a Gaussian distribution of breeding values. Linkage disequilibria can generate a substantial increase in genetic variance, which is concentrated at sharp gradients in trait means.
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Evangelista, Silvane Silva, Juliana Arid, Katia Regina Felizardo Vasconcelos, Giuseppe Valduga Cruz, André Luiz Tannus Dutra, Lea Assed Bezerra da Silva, Raquel Assed Bezerra da Silva, et al. "Association Between Genetic Polymorphisms in Metaloproteinases of the Matrix and Delayed Tooth Emergence: A Cross-sectional Study." Journal of Advanced Oral Research 10, no. 2 (September 2, 2019): 91–96. http://dx.doi.org/10.1177/2320206819855590.
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Background and Aims: Animal models have been demonstrating that MMPs have an important function in the tooth eruption process. The aim of this study was to evaluate the association between genetic polymorphisms in MMP8 and MMP13 and delayed tooth eruption of permanent teeth. Materials and Methods: This cross-sectional study selected 216 children, 9- to 12-year-old, from public schools at Manaus, Amazonas, Brazil. During oral clinical examination, each permanent tooth emerged in the oral cavity was evaluated. Children were considered with delayed tooth eruption when at least one permanent tooth was delayed and were classified in 2 groups: children “with delayed tooth emergency” and “without delayed tooth emergency.” Saliva samples were collected from DNA extraction. The genetic polymorphisms rs17099443 and rs3765620 in MMP8, and rs478927 and rs2252070 in MMP13 were genotyped. Statistical Analysis: PLINK V1.07 ( http://pngu.mgh.harvard.edu/purcell/plink/ ) and GraphPad Prism 5.0 (San Diego, CA, USA) were used. The c2 or Fisher exact test was used to calculate genotypes and alleles distributions. To compare the mean number of delayed teeth according to genotypes, the Kruskal-Wallis test with multiple comparison Dunn test was used. The established alpha for all comparisons was .05. Results: The polymorphism rs17099443 in MMP8 was associated with delayed tooth eruption in the genotype distribution ( P = .05). In the allele distribution, the C allele was underrepresented in children with delayed tooth eruption ( P = .01; OR = 0.61, 95% confidence interval, 0.41–0.9). Conclusion: The genetic polymorphism rs17099443 in MMP8 is associated with delayed tooth eruption.
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DeMille, Mellissa M. C., Kevin Tang, Chintan M. Mehta, Christopher Geissler, Jeffrey G. Malins, Natalie R. Powers, Beatrice M. Bowen, et al. "Worldwide distribution of the DCDC2 READ1 regulatory element and its relationship with phoneme variation across languages." Proceedings of the National Academy of Sciences 115, no. 19 (April 16, 2018): 4951–56. http://dx.doi.org/10.1073/pnas.1710472115.
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DCDC2 is a gene strongly associated with components of the phonological processing system in animal models and in multiple independent studies of populations and languages. We propose that it may also influence population-level variation in language component usage. To test this hypothesis, we investigated the evolution and worldwide distribution of the READ1 regulatory element within DCDC2, and compared its distribution with variation in different language properties. The mutational history of READ1 was estimated by examining primate and archaic hominin sequences. This identified duplication and expansion events, which created a large number of polymorphic alleles based on internal repeat units (RU1 and RU2). Association of READ1 alleles was studied with respect to the numbers of consonants and vowels for languages in 43 human populations distributed across five continents. Using population-based approaches with multivariate ANCOVA and linear mixed effects analyses, we found that the RU1-1 allele group of READ1 is significantly associated with the number of consonants within languages independent of genetic relatedness, geographic proximity, and language family. We propose that allelic variation in READ1 helped create a subtle cognitive bias that was amplified by cultural transmission, and ultimately shaped consonant use by different populations over time.
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Essa, Enas S., and Hagar A. Alagizy. "Association of MNS16A VNTR and hTERT rs2736098: G>A polymorphisms with susceptibility to diffuse large B-cell lymphoma." Tumori Journal 104, no. 3 (May 8, 2018): 165–71. http://dx.doi.org/10.5301/tj.5000653.
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Purpose: Genetic studies of diffuse large B-cell lymphoma (DLBCL) may serve to clarify disease pathogenesis and mark at-risk populations. Evidence of long telomeres and high telomerase activity have been demonstrated in DLBCL. We aimed to examine human telomerase gene ( hTERT) MNS16A variable number of tandem repeats and hTERT rs2736098: G>A polymorphisms in relation to DLBCL susceptibility. Methods: In a case control study, 71 patients with DLBCL and 156 controls were genotyped for MNS16A using polymerase chain reaction and hTERT rs2736098: G>A using polymerase chain reaction restriction fragment length polymorphism. Results: In both codominant and recessive models, there was a significant difference in the distribution of MNS16A genotypes between patients with DLBCL and controls (p = 0.047 and p = 0.018, respectively). In both models, carriers of S/S genotype were at higher risk to develop DLBCL (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.19-5.29 and OR 2.19, 95% CI 1.15-4.17, respectively). In the log-additive model, each copy of S allele significantly increased DLBCL risk in an additive form (p = 0.018, OR 1.57, 95% CI 1.08-2.29). The frequency distribution of MNS16A S alleles was significantly higher in patients than controls (p = 0.012). Carriers of S alleles were at higher risk to develop DLBCL than carriers of L alleles (OR 1.67, 95% CI 1.12-2.49). hTERT rs2736098: G>A genotype distribution did not differ significantly between patients with DLBCL and controls. Conclusions: MNS16A genetic variations are associated with DLBCL susceptibility.
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Lynch, Michael. "The Consequences of Fluctuating Selection for Isozyme Polymorphisms in Daphnia." Genetics 115, no. 4 (April 1, 1987): 657–69. http://dx.doi.org/10.1093/genetics/115.4.657.
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ABSTRACT Temporal sequences of allele frequencies in natural populations of Daphnia are analyzed to obtain the mean and variance of the selection coefficient for both asexual and sexual phases. In general, the alleles at enzyme loci appear to be quasi-neutral. Although significant variation exists for the estimated selection coefficients, the means are in all cases close to zero. Estimates of the variance of selection intensity are applied to existing models to demonstrate the implications of fluctuating selection for the spatial and temporal distribution of gene frequencies in Daphnia. The empirical and analytical results are shown to provide a possible solution to some previously puzzling aspects of Daphnia population genetic surveys. Neither genetic drift nor diversifying selection are necessary conditions for the local diversification of gene frequencies.
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Maia, Aline de Holanda Nunes, and Durval Dourado Neto. "Probabilistic tools for assessment of pest resistance risk associated to insecticidal transgenic crops." Scientia Agricola 61, no. 5 (October 2004): 481–85. http://dx.doi.org/10.1590/s0103-90162004000500003.
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One of the main risks associated to transgenic crops expressing Bacillus thuringiensis (Bt) toxins is the evolution of pest resistance. The adoption of Bt crops requires environmental risk assessment that includes resistance risk estimation, useful for definition of resistance management strategies aiming to delay resistance evolution. In this context, resistance risk is defined as the probability of the Bt toxin resistance allele frequency (RFreq) exceeding a critical value (CriticalFreq). Mathematical simulation models have been used to estimate (RFreq) over pest generations. In 1998, Caprio developed a deterministic simulation model with few parameters that can be used to obtain RFreq point estimates from point information about model parameters and decision variables involved in that process. In this work, the resistance risk was estimated using Caprio´s model, by incorporating uncertainty to the resistance allele initial frequency (InitialFreq). The main objective was to evaluate the influence of different probability distribution functions on the risk estimates. The simulation results showed that the influence of InitialFreq input distributions on the risk estimates changes along pest generations. The risk estimates considering input Normal distribution for InitialFreq are similar to those ones obtained considering Triangular distribution if their variances are equal. The use of Uniform distribution instead the Normal or Triangular due to the lack of information about InitialFreq leads to an overestimation of risk estimates for the initial generations and sub estimation for the generations after the one for which the critical frequency is achieved.
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Haigh, John. "How large is the support of an ESS?" Journal of Applied Probability 26, no. 1 (March 1989): 164–70. http://dx.doi.org/10.2307/3214326.
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Suppose the payoffs (aij) in the n × n matrix A are drawn independently from some continuous probability distribution. The number of tactics used in an ESS is investigated. Asymptotic results on the size of the ESS with largest support are given, using the work of Karlin and Kingman on the size of polymorphisms in one-locus multi-allele diploid selection models.
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Haigh, John. "How large is the support of an ESS?" Journal of Applied Probability 26, no. 01 (March 1989): 164–70. http://dx.doi.org/10.1017/s0021900200041899.
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Suppose the payoffs (aij ) in the n × n matrix A are drawn independently from some continuous probability distribution. The number of tactics used in an ESS is investigated. Asymptotic results on the size of the ESS with largest support are given, using the work of Karlin and Kingman on the size of polymorphisms in one-locus multi-allele diploid selection models.
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Gondek, Lukasz P., Hemant Ishwaran, Andrew Jeffrey Dunbar, Christine L. O’Keefe, Michael A. McDevitt, Denise Batista, Mikkael A. Sekeres, Ghulam J. Mufti, and Jaroslaw Maciejewski. "Array-Based Karyotyping and Genotyping Demonstrates a Non Random Selection of Allelic Variants of Genes in Clones with 5q31 Deletion Mutants." Blood 112, no. 11 (November 16, 2008): 2057. http://dx.doi.org/10.1182/blood.v112.11.2057.2057.
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Abstract Interstitial deletion of chromosome 5 has been frequently reported in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) pointing towards the pathogenic role of this region in phenotype and clonal evolution. To investigate the frequency of 5q LOH and better delineate the commonly deleted region (CDR) we applied metaphase cytogenetics (MC) and performed array-based interphase cytogenetics on DNA using high-density 250K SNP-array (SNP-A) in malignant myeloid disorders. SNP-A analysis was performed using Affymetrix 250K SNP-array on a subset of 250 patients and 118 controls. SNP-A data were analyzed using CNAG v.3.0. Using SNP-A-based karyotyping 5q abnormalities were identified in 42/250 patients vs. 29/250 by MC (17% vs. 11%, primarily as a result of resolving uninformative MC). By SNP-A, previously cryptic lesions other than 5q deletions were identified in 71% of the patients (30/42) and included e.g., upd(1)(p35.1pter), upd(17)(p13.1pter), del(7)(q21.3q36.2). In 2 patients somatic UPD5q was found. In 6 other patients 5q micro-deletions of chromosome 5 were detected likely representing CNVs. Subsequently, we undertook an SNP-A-based definition of the CDR covering approximately 1.92MB and positioned within previously reported regions. This region spans approximately from base pair 137,528,564-139,451,907 and several candidate tumor suppressor genes including those already reported e.g., CTNNA1 and EGR1 as well as CDC25, ETF1 to name a few. As mutations in any of the genes in CDR on 5q were not found, the malignant phenotype can result either from haploinsufficiency or hemizygozity for a pathogenic allele occurring otherwise in heterozygous or major allele in homozygous constellation. Previously, underexpression of RPS14 was demonstrated to be responsible for dysplastic features in 5q- syndrome, but haploinsufficiency of this gene does not explain the clonal evolution and malignant properties of clones with del5q. Utilizing another advantage of SNP-A, the ability to assign genotypes, we also performed analysis of the allele distribution within newly defined CRD on 5q31. We genotyped 987 SNPs located in the common area of LOH (5q31) to determine whether for certain loci allelic distribution in the hemizygous deletion mutant is skewed to one or the other allele (when the original diploid constellation is heterozygous). For the purpose of this study we hypothesized that informative alleles must display a very low frequency in homozygous constellation in controls. To test if the distribution of remaining alleles (and the inherent change of genotype) in the deleted region on 5q is random or skewed towards one allelic variant we applied a multinomial test statistics. Because of the discrete nature of the problem, p-values were calculated by selecting the minimum of the left or right tail of the event spectrum. This value was computed without approximation by using the exact form of the binomial distribution. We used the smaller of the two p-values from the two binomial models as our reported p-value. SNPs present in ARHGAP26 locus appeared to be most significantly skewed (p<.004 for 3 SNP loci within gene: rs2028268, rs3776227, rs17100139). For the alleles located in this gene one would expect that 14% of patient will be hemizygous for minor and 96% for major allele respectively. However, we have observed that 57% of clones showed minor constellation. ARHGAP26 and its function as a tumor suppressor may indicate involvement in the pathology and disease progression. In sum, we demonstrated that a combined genotypic and cytogenetic analysis is possible using SNP-A to investigate areas of LOH for the presence of genotypes which may convey selection advantage.
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Bereketoğlu, Ceyhun, Mülkiye Kasap, and Ayfer Pazarbaşı. "Studies on Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Genotype Distributions in Turkish Preeclampsia Patients." Journal of Pregnancy 2012 (2012): 1–4. http://dx.doi.org/10.1155/2012/108206.
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Placental, immune and genetic factors are thought to play an important role in preeclampia (PE)’s pathophysiology. Angiotensin-Converting Enzyme (ACE) plays a vital role in the renin-angiotensin-system (RAS) which regulates blood pressure by converting angiotensin I into a powerfull vasoconstrictor angiotensin II. A deletion polymorphism (D allele) has been reported to be associated with elevated ACE activity. The aim of the this study was to investigate whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and PE. In this study, 120 preeclamptic and 116 normotensive Turkish pregnant women were genotyped for ACE I/D polymorphism and the distribution of genotype and allele frequencies of this polymorphism in preeclampsia and controls were evaluated. Codominant, dominant and recessive models were appplied in ACE gene I/D polymorphism. In the codominant model, DD genotype was found significantly more frequent in preeclampsia than controls (P=0.016). Moreover, in dominant model (DD frequency versus DI+II frequency) there was a significant relation between DD genotype and preeclampsia (P=0.006). D allele frequency was 64.6% in preeclampsia while it was 56.1% in controls (P=0.062). In conclusion, there was significant difference in genotype distribution between preeclampsia and controls.
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Manomohan, Vandana, Saravanan Ramasamy, Rudolf Pichler, Murali Nagarajan, Sivakumar Karuppusamy, Sudhakar Krovvidi, Raja K. Nachiappan, Sunday O. Peters, and Kathiravan Periasamy. "Assessment of Mutation Drift Equilibrium and the Occurrence of a Recent Genetic Bottleneck in South Indian Zebu Cattle." Animals 12, no. 14 (July 19, 2022): 1838. http://dx.doi.org/10.3390/ani12141838.
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During the last few decades, the effective population size of indigenous zebu cattle breeds has declined drastically, resulting in the classification of some of them into the vulnerable, endangered, or critically endangered category. Drastic reductions in the effective size of a population may result in genetic bottlenecks and can affect within-breed genetic variability and its viability. The present study was undertaken with the objective of evaluating South Indian zebu cattle populations for mutation drift equilibrium and to detect the occurrence of recent genetic bottleneck events. A total of 293 cattle from eight indigenous breeds were genotyped at 27 FAO/ISAG-recommended microsatellite marker loci. Three different statistical tests, viz., the sign test, standardized differences test, and Wilcoxon sign rank test were performed using allele frequency data to detect loci with heterozygosity excess under the infinite alleles, stepwise, and two-phase mutation models. Under the infinite alleles model, the observed number of loci with heterozygosity excess (He > Heq) ranged between 10 and 19 among the investigated cattle breeds. However, the observed heterozygosity excess was not statistically significant (p > 0.05) in any of the studied breeds. Similarly, the standardized differences test and Wilcoxon sign rank test revealed no concrete evidence for the occurrence of a recent genetic bottleneck in South Indian zebu cattle breeds. The qualitative test for mode-shift distortion revealed a normal L-shaped distribution of allele frequencies, suggesting a lack of evidence for the loss of low-frequency alleles in all the investigated South Indian zebu cattle breeds.
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Saul, A. "Computer model of the maintenance and selection of genetic heterogeneity in polygamous helminths." Parasitology 111, no. 4 (November 1995): 531–36. http://dx.doi.org/10.1017/s003118200006604x.
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SUMMARYA stochastic simulation model of the transmission and maintenance of genetic heterogeneity in the absence and presence of external selection pressures is presented for polygamous intestinal helminths such as Ascaris. The model assumes that the density distribution of the adult parasites is highly aggregated and that density-dependent effects on fecundity are important. The model gives rise to stable infection rates in the host. Where the parasite population contains genetic heterogeneity, with the exception of stochastic fluctuations which models genetic drift, the ratio of the different alleles remained constant over extended periods of time. This result contrasts with that of an earlier analytical model (Anderson, R. M., May, M. R. & Gutpa S. (1989) Parasitology 99, S59–S79), in which uneven mating probabilities for the different combinations of worm possible in a host was postulated to inevitably lead to fixation of the most abundant allele. New results suggest that in spite of the restricted choice of mating available to a worm in the confines of a host, selection pressure always leads to enrichment of the parasites carrying resistant alleles.
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Choi, Jaeyoun, Myungwoo Nam, Stanislav Fridland, Jinyoung Hwang, Chan Mi Jung, Christmann Low, and Young Kwang Chae. "18 New method of assessing tumor heterogeneity utilizing both circulating tumor DNA and tissue DNA to predict the response to immunotherapy." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A18. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0018.
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BackgroundTumor heterogeneity assessment may help predict response to immunotherapy. In melanoma mouse models, tumor heterogeneity impaired immune response.1 In addition, among lung cancer patients receiving immunotherapy, the high clonal neoantigen group had favorable survival and outcomes.2 Ideal methods of quantifying tumor heterogeneity are multiple biopsies or autopsy. However, these are not feasible in routine clinical practice. Circulating tumor DNA (ctDNA) is emerging as an alternative. Here, we reviewed the current state of tumor heterogeneity quantification from ctDNA. Furthermore, we propose a new tumor heterogeneity index(THI) based on our own scoring system, utilizing both ctDNA and tissue DNA.MethodsSystematic literature search on Pubmed was conducted up to August 18, 2020. A scoring system and THI were theoretically derived.ResultsTwo studies suggested their own methods of assessing tumor heterogeneity. One suggested clustering mutations with Pyclone,3 and the other suggested using the ratio of allele frequency (AF) to the maximum somatic allele frequency (MSAF).4 According to the former, the mutations in the highest cellular prevalence cluster can be defined as clonal mutations. According to the latter, the mutations with AF/MSAF<10% can be defined as subclonal mutations. To date, there have been no studies on utilizing both ctDNA and tissue DNA simultaneously to quantify tumor heterogeneity. We hypothesize that a mutation found in only one of either ctDNA or tissue DNA has a higher chance of being subclonal.We suggest a scoring system based on the previously mentioned methods to estimate the probability for a mutant allele to be subclonal. Adding up the points that correspond to the conditions results in a subclonality score (table 1). In a given ctDNA, the number of alleles with a subclonality score greater than or equal to 2 divided by the total number of alleles is defined as blood THI (bTHI) (figure 1). We can repeat the same calculation in a given tissue DNA for tissue THI (tTHI) (figure 2). Finally, we define composite THI (cTHI) as the mean of bTHI and tTHI.Abstract 18 Table 1Subclonality scoreAbstract 18 Figure 1Hypothetical distribution of all alleles found in ctDNA bTHI = the number of alleles with a subclonality score greater than or equal to 2/the total number of alleles found in ctDNA = 10/20 =50%Abstract 18 Figure 2Hypothetical distribution of all alleles found in tissue DNA tTHI= the number of alleles with a subclonality score greater than or equal to 2/the total number of alleles found in tissue DNA = 16/40 = 40% cTHI= (bTHI + tTHI)/2 = 45%ConclusionsTumor heterogeneity is becoming an important biomarker for predicting response to immunotherapy. Because autopsy and multiple biopsies are not feasible, utilizing both ctDNA and tissue DNA is the most comprehensive and practical approach. Therefore, we propose cTHI, for the first time, as a quantification measure of tumor heterogeneity.ReferencesWolf Y, Bartok O. UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Cell 2019;179:219–235.McGranahan N, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Ma F, Guan Y. Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer. Int J Cancer 2020;146:1359–1368.Liu Z, Xie Z. Presence of allele frequency heterogeneity defined by ctDNA profiling predicts unfavorable overall survival of NSCLC. Transl Lung Cancer Res 2019;8:1045–1050.
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Bay, Rachael A., Ryan J. Harrigan, Vinh Le Underwood, H. Lisle Gibbs, Thomas B. Smith, and Kristen Ruegg. "Genomic signals of selection predict climate-driven population declines in a migratory bird." Science 359, no. 6371 (January 4, 2018): 83–86. http://dx.doi.org/10.1126/science.aan4380.
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The ongoing loss of biodiversity caused by rapid climatic shifts requires accurate models for predicting species’ responses. Despite evidence that evolutionary adaptation could mitigate climate change impacts, evolution is rarely integrated into predictive models. Integrating population genomics and environmental data, we identified genomic variation associated with climate across the breeding range of the migratory songbird, yellow warbler (Setophaga petechia). Populations requiring the greatest shifts in allele frequencies to keep pace with future climate change have experienced the largest population declines, suggesting that failure to adapt may have already negatively affected populations. Broadly, our study suggests that the integration of genomic adaptation can increase the accuracy of future species distribution models and ultimately guide more effective mitigation efforts.
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Liu, Xuerong, Xiaogang Bai, Jing Zhao, Chaoqun Gao, Peng Du, Jin-an Zhang, and Sheli Li. "Associations between NLRC4 Gene Polymorphisms and Autoimmune Thyroid Disease." BioMed Research International 2020 (August 4, 2020): 1–9. http://dx.doi.org/10.1155/2020/1378427.
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Background. Many studies have shown that NLRC4 inflammasome polymorphisms are associated with a variety of autoimmune diseases, but the associations between NLRC4 polymorphisms and autoimmune thyroid diseases (AITDs) are unclear. Our research was aimed at identifying the correlations between NLRC4 polymorphisms and AITDs. Methods. Hi-SNP high-throughput genotyping technology was used for detecting four single-nucleotide polymorphisms (SNPs) of NLRC4 in 1005 AITDs patients (including 629 Graves’ disease and 376 Hashimoto’s thyroiditis) and 781 healthy controls. Results. Compared with healthy controls, the allele frequencies and genotype distribution of rs385076 were statistically related to AITDs (P=0.016 and P=0.048, respectively) and Hashimoto’s thyroiditis (P=0.022 and P=0.046, respectively). Before adjusting for age and gender, rs385076 and AITDs had a significant association in three models of allele model, dominant model, and homozygous model. After adjusting for age and gender, in the above three models, there is still a clear relationship between them. Before adjusting for age and gender, there were prominent discrepancy between rs385076 and Hashimoto’s thyroiditis in the allele model (OR=0.81, 95% CI 0.67-0.97; P=0.021) and the dominant model (OR=0.73, 95% CI 0.57-0.94; P=0.014), after adjusting for age and gender, rs385076 and Hashimoto’s thyroiditis were significantly related to allele model, dominant model, and homozygous model. However, rs455060, rs212704, and rs675712 were not related to AITDs in our study. Conclusion. NLRC4 rs385076 was found to have a significant association with Hashimoto’s thyroiditis for the first time. It laid a foundation for the disclosure of the pathogenesis of AITDs, and provided a possible treatment prospect for HT.
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Motro, Uzi, and Glenys Thomson. "THE AFFECTED SIB METHOD. I. STATISTICAL FEATURES OF THE AFFECTED SIB-PAIR METHOD." Genetics 110, no. 3 (July 1, 1985): 525–38. http://dx.doi.org/10.1093/genetics/110.3.525.
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ABSTRACT The distribution of the number of HLA haplotypes shared by sibs affected with the same HLA-linked disease can be used to obtain information on the genetics of the disease. Since the inception of the use of sib-pair methods for the analysis of the HLA-associated diseases, the question has been raised of how to include families with more than two affected sibs in the sib-pair analysis. This paper presents appropriate weighting schemes. A procedure for estimating the frequency of the disease allele in the general population, under the assumptions of single-allele recessive, additive, dominant and intermediate models, with negligible recombination (θ = 0) between the disease-predisposing gene and the HLA region, and no selective disadvantage of the trait, is also given. Cluster-sampling techniques are used in the analysis.
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Weinstein, Lee S., Jie Liu, Akio Sakamoto, Tao Xie, and Min Chen. "Minireview: GNAS: Normal and Abnormal Functions." Endocrinology 145, no. 12 (December 1, 2004): 5459–64. http://dx.doi.org/10.1210/en.2004-0865.
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Abstract GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein α-subunit (Gsα) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating Gsα mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating Gsα mutations lead to Albright hereditary osteodystrophy. Gsα is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific Gsα imprinting. Mouse knockout models show that Gsα and the alternative Gsα isoform XLαs that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.
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REEVE, JEFF P. "Predicting long-term response to selection." Genetical Research 75, no. 1 (February 2000): 83–94. http://dx.doi.org/10.1017/s0016672399004140.
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Lande's equation for predicting the response of trait means to a shift in optimal trait values is tested using a stochastic simulation model. The simulated population is finite, and each individual has a finite number of loci. Therefore, selection may cause allele frequencies and distributions to change over time. Since the equation assumes constant genetic parameters, the degree to which such allelic changes affect predictions can be examined. Predictions are based only on information available at generation zero of directional selection. The quality of the predictions depends on the nature of allelic distributions in the original population. If allelic effects are approximately normally distributed, as assumed in Lande's Gaussian approximation to the continuum-of-alleles model, the predictions are very accurate, despite small changes in the G matrix. If allelic effects have a leptokurtic distribution, as is likely in Turelli's ‘house-of-cards’ approximation, the equation underestimates the rate of response and correlated response, and overestimates the time required for the trait means to reach their equilibrium values. Models with biallelic loci have limits as to the amount of trait divergence possible, since only two allelic values are available at each of a finite set of loci. If the new optimal trait values lie within these limits, predictions are good. if not, singularity in the G matrix results in suboptimal equilibria, despite the presence of genetic variance for each individual trait.
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Rousset, François. "Equilibrium Values of Measures of Population Subdivision for Stepwise Mutation Processes." Genetics 142, no. 4 (April 1, 1996): 1357–62. http://dx.doi.org/10.1093/genetics/142.4.1357.
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Abstract Expected values of Wright'sF-statistics are functions of probabilities of identity in state. These values may be quite different under an infinite allele model and under stepwise mutation processes such as those occurring at microsatellite loci. However, a relationship between the probability of identity in state in stepwise mutation models and the distribution of coalescence times can be deduced from the relationship between probabilities of identity by descent and the distribution of coalescence times. The values of FIS and FST can be computed using this property. Examination of the conditional probability of identity in state given some coalescence time and of the distribution of coalescence times are also useful for explaining the properties of FIS and FST at high mutation rate loci, as shown here in an island model of population structure.
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Jones, Adam G., Gunilla Rosenqvist, Anders Berglund, and John C. Avise. "Clustered Microsatellite Mutations in the Pipefish Syngnathus typhle." Genetics 152, no. 3 (July 1, 1999): 1057–63. http://dx.doi.org/10.1093/genetics/152.3.1057.
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Abstract Clustered mutations are copies of a mutant allele that enter a population's gene pool together due to replication from a premeiotic germline mutation and distribution to multiple successful gametes of an individual. Although the phenomenon has been studied in Drosophila and noted in a few other species, the topic has received scant attention despite claims of being of major importance to population genetics theory. Here we capitalize upon the reproductive biology of male-pregnant pipefishes to document the occurrence of clustered microsatellite mutations and to estimate their rates and patterns from family data. Among a total of 3195 embryos genetically screened from 110 families, 40% of the 35 detected de novo mutant alleles resided in documented mutational clusters. Most of the microsatellite mutations appeared to involve small-integer changes in repeat copy number, and they arose in approximately equal frequency in paternal and maternal germlines. These findings extend observations on clustered mutations to another organismal group and motivate a broader critique of the mutation cluster phenomenon. They also carry implications for the evolution of microsatellites with respect to mutational models and homoplasy among alleles.
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Nguyen, Thi Trung Thu, and Quang Binh Tran. "DISTRIBUTION OF KCNJ11 E23K POLYMORPHISM IN VIETNAMESE POPULATION AND ITS ASSOCIATION WITH HYPERGLYCEMIA." Tạp chí Dinh dưỡng và Thực phẩm 18, no. 2E (June 15, 2022): 1–8. http://dx.doi.org/10.56283/1859-0381/104.
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Background: KCNJ11 gene, encoding ATP-sensitive channel subunits, involves in insulin secretion. The study aimed at investigating the distribution of the KCNJ11 E23K (rs5219) polymorphism and its association with prediabetes and type 2 diabetes (T2D) in Vietnamese population.
Methods: A cross-sectional study randomly recruited 2.676 participants aged 40-64 years from a general population in Ha Nam province, Vietnam. Glycemic status of the subjects was classified based on fasting plasma glucose and oral glucose tolerance test. PCR-restriction fragment length polymorphism method was applied to detect the KCNJ11-rs5219 polymorphism. Genotype frequencies were compared to find the distribution difference among normoglycemic, prediabetes, and T2D groups. Generalized linear models and multinomial logistic regression analysis were used to determine the associations of the KCNJ11-rs5219 polymorphism with prediabetes and T2D.
Results: The frequencies of minor K allele in normoglycemic, prediabetes and T2D groups were 33.2, 32.6 and 35.4%, respectively. Genotypic distribution of the E23K polymorphism was in Hardy-Weinberg equilibrium and not significantly different among the three glucose groups (p > 0.05). Fasting plasma glucose and 2-h glucose levels were not significantly different among three genotypes EE, EK, and KK (p > 0.05). After adjusted for age, sex, anthropometric and environmental factors, no significant association was found between the KCNJ11-rs5219 polymorphism and prediabetes or T2D with ORs from 0.80 to 1.29.
Conclusion: The minor K allele was predominant and genotype frequency in the population was remained constant among generations. The study suggests no significant association beween the KCNJ11-rs5219 polymorphism and hyperglycemia in the Vietnamese population.
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Ferguson, Jake M., and Erkan Ozge Buzbas. "Inference from the stationary distribution of allele frequencies in a family of Wright–Fisher models with two levels of genetic variability." Theoretical Population Biology 122 (July 2018): 78–87. http://dx.doi.org/10.1016/j.tpb.2018.03.004.
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Tourjee, Kenneth R., James Harding, and Thomas G. Byrne. "COMPLEX SEGREGATION ANALYSIS (CSA) OF GERBERA FLOWER COLOR." HortScience 29, no. 12 (December 1994): 1409b—1409. http://dx.doi.org/10.21273/hortsci.29.12.1409b.
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The frequency distribution of gerbera flower hue in the Davis population of gerbera appears continuous and bimodal. This suggests that a gene of large effect may be segregating in a background of polygenic variation. CSA is a statistical technique developed in genetic epidemiology for investigating such complex traits without the need of inbred lines. The REGC program of SAGE (Elston, LSU Medical Center, New Orleans) uses the regressive models of G. Bonney (1984) through pedigree analysis to provide estimates of major gene parameters and residual correlations among relatives. Pedigrees obtained from generations 14, 15, and 16 indicate that a major dominant gene for hue is segregating and accounting for -0.66 of the total variation. The genotypic means are 32 degrees and 71 degrees for the aa and bb genotypes, respectively. The a allele is dominant to the b allele and has a frequency of 0.55. The residual parent-offspring correlation estimate is 0.2 and measures the genetic contribution to the remainder of the variance.
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Tourjee, Kenneth R., James Harding, and Thomas G. Byrne. "050 Complex Segregation Analysis (CSA) of Gerbera Flower Color." HortScience 29, no. 5 (May 1994): 435b—435. http://dx.doi.org/10.21273/hortsci.29.5.435b.
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The frequency distribution of gerbera flower hue in the Davis Population of Gerbera appears continuous and bimodal. This suggests that a gene of large effect may be segregating in a background of polygenic variation. CSA is a statistical technique developed in genetic epidemiology for investigating such complex traits, without the need of inbred lines. The REGC program of SAGE (Elston, LSU Med. Center, New Orleans) utilizes the regressive models of G. Bonney (1984) through pedigree analysis to provide estimates of major gene parameters and residual correlations among relatives. Pedigrees obtained from generations 14, 15, and 16 indicate that a major dominant gene for hue is segregating and accounting for ∼ 0.66 of the total variation. The genotypic means are 32 degrees and 71 degrees for the aa and bb genotypes, respectively. The `a' allele is dominant to the `b' allele and has a frequency of 0.55. The residual parent-offspring correlation estimate is 0.2, and measures the genetic contribution to the remainder of the variance.
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Weidong, J., H. Xuezhu, G. Tianyou, Y. Chuang, L. Qianqian, X. Yong, and G. Lanting. "Nicotinic Acetylcholine Receptor α4 Subunit Gene Variation Associated with Chinese Han Patients with Attention Deficit Hyperactivity Disorder." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70635-2.
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Previous pharmacological, human genetical, and animal models have implicated the nicotinic acetylcholine receptor α4 subunit (CHRNA4) gene in the pathogenesis of ADHD. The objective of this study is to examine genetic association between single nucleotide polymorphisms (SNPs) in the CHRNA4 gene (rs2273502, rs1044396, rs1044397 and rs3827020 loci) and ADHD. Both case-control and family-based design were used in this study. Children aged 6 to 16 years were interviewed and assessed with the CBCL and CPRS-R to identify probands. No significant differences in frequency distribution of genotypes or alleles between the case and control groups were found. However, further haplotype analyses showed CCGG haplotype on risk for ADHD in 164 case-control sample and TDT analysis suggested that the allele C of rs2273502 over-transferred in 98 ADHD parent-offspring trios. Our findings suggest that CHRNA4 gene may play a role in the pathogenesis of ADHD, and further work is necessary to replicate and confirm what role the CHRNA4 gene may play in the etiology and pathogenesis of ADHD in large independent samples.
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Zintzaras, Elias, Paraskevi Rodopoulou, and George N. Koukoulis. "BsmI, TaqI, ApaI and FokI Polymorphisms in the Vitamin D Receptor (VDR) Gene and the Risk of Osteoporosis: A Meta-Analysis." Disease Markers 22, no. 5-6 (2006): 317–26. http://dx.doi.org/10.1155/2006/921694.
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A meta-analysis regarding BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and their associations with osteoporosis in females is reported. The meta-analysis involved 14, seven, seven and three studies for BsmI, TaqI, ApaI and FokI polymorphisms, respectively. The studies were association studies with osteoporotic cases and controls free of osteoporosis that provided the genotype distribution of individual cases and controls. For the BsmI polymorphism, the allele contrast b vs. B showed heterogeneity among studies (p< 0.01, I2> 50%) and the random effects (RE) pooled odds ratio (OR) was non-significant: 0.94 [95% confidence interval (CI) 0.63–1.38]. Caucasians, postmenopausal cases and studies with WHO diagnostic criteria showed no association under any genetic contrast. However, in East Asians, the OR for the dominant model [fixed effects OR = 0.14 (95% CI 0.04–0.50) and RE OR = 0.16 (95% CI 0.03–0.84)] was significant, indicating prevention. Overall, for the TaqI, ApaI and FokI polymorphisms, the allele contrast showed heterogeneity and the pooled RE ORs were non-significant [OR = 1.06 (95% CI 0.71–1.60), OR = 0.99 (95% CI 0.72–1.37) and OR = 1.17 (95% CI 0.76–1.80), respectively]. The allele contrast for Caucasians, East Asians, postmenopausal cases and studies with WHO diagnostic criteria showed no association for TaqI, ApaI, and FokI. The allele contrast of homozygotes, and the recessive and dominant models the results followed the same pattern as the allele contrast. Therefore, the relationship between the VDR polymorphisms and osteoporosis remains an unresolved issue and other probable genetic-environmental risk factors interacting with the above polymorphisms should be investigated.
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Li, Ya-Ting, Ming-Kun Xie, and Jin Wu. "Association between Ocular Axial Length-Related Genes and High Myopia in a Han Chinese Population." Ophthalmologica 235, no. 1 (October 21, 2015): 57–60. http://dx.doi.org/10.1159/000439446.
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Aims: A previous genome-wide association study of high myopia identified five genome-wide loci for ocular axial length (C3orf26, ZC3H11B, RSPO1, GJD2, and ZNRF3). The aim of our study was to investigate the association between high myopia and genetic variants in the five loci in Han Chinese subjects. Methods: Five single nucleotide polymorphisms were genotyped in 296 unrelated high-myopia subjects and 300 matched emmetropic controls by the SNaPshot method. The distribution of genotypes in the cases and controls was compared in codominant, dominant, and recessive genetic models by using SNPStats online software. Results: Significant associations between rs994767 near ZC3H11B (p = 0.001), rs4074961 in RSPO1 (p < 0.001), and rs11073058 in GJD2 (p = 0.029) and high myopia were observed. Odds ratios (95% confidence intervals) were 1.532 (1.200-1.955), 1.603 (1.267-2.029), and 1.290 (1.027-1.621) for the rs994767 T allele, rs4074961 T allele, and rs11073058 T allele, respectively. But rs9811920 in C3orf26 and rs12321 in ZNRF3 were not associated with high myopia. Conclusion: Our findings suggested that genetic variants in ZC3H11B, RSPO1, and GJD2 are associated with susceptibility to the development of high myopia in a Han Chinese population. Functional roles of ZC3H11B, RSPO1, and GJD2 in the pathology of high myopia need to be further investigated.
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Olsen, Kelly Shea, Hancong Tang, Junke Wang, Sarah Entwistle, Dante S. Bortone, Steven Vensko, Loreall Pooler, et al. "Population Distribution of GvL and GvH Minor Histocompatibility Antigens." Blood 136, Supplement 1 (November 5, 2020): 23–25. http://dx.doi.org/10.1182/blood-2020-141120.
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Background: Donor-derived T cells that target minor histocompatibility antigens (mHAs) in allogeneic hematopoietic cell transplant (HCT) mediate graft versus leukemia (GvL) and graft versus host (GvH) effects. Prediction of mHAs that drive GvL has garnered interest for targeted immunotherapy, but there have been few large-scale studies of population prevalence of predicted mHAs. Prioritization of mHAs that are shared among patients would allow for treatment of more individuals with mHA-targeting therapies. We report here population metrics of predicted mHAs in a dataset of over 3000 patients treated with HCT and reported to CIBMTR from 2000-2011. Our goal is to identify the most common mHAs within leukemia and Myelodysplastic Syndrome (MDS) patient populations to target with T cell immunotherapies or graft engineering techniques. Methods: Data is derived from two cohorts of donor recipient HCT pairs (DRPs) treated for Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), and MDS from the CIBMTR and previously analyzed in DISCOVeRY-BMT. Cohort 1 included 2609 10/10 HLA-matched DRPs treated from 2000-2008, and Cohort 2 included 572 10/10 HLA-matched DRPs treated from 2009-2011 plus 351 8/8 HLA-matched DRPs treated from 2000-2011 (Hahn et al. 2015, Biol Blood Marrow Transplant). Cohorts were combined for analyses. Approximately 20,000 missense SNPs were extracted from Illumina HumanOmni Express genotyping data. Computational mHA prediction was performed according to prior work from our lab (Lansford et al. 2018, Blood Adv.). Minor mismatches were predicted based on coding SNPs present in the recipient but not donor. mHAs were defined as mismatches that would lead to variant peptides predicted to bind at least 1 recipient HLA molecule and be expressed in leukemia cells (GvL mHA) and/or acute GvHD target organs (GvH mHA). GvL mHAs were categorized as "GvL,No_GvH" or "GvL" based on transcripts per million (TPM) corresponding to GvH organs, with "GvL" indicating between 5-50 TPM and "GvL,No_GvH" indicating <5 TPM. GvH mHAs were categorized similarly with respect to expression in leukemia cells. "GvL,GvH" indicated mHAs expressed highly in both leukemia and in GvHD target organs. Results: Patient demographics and number of total predicted mHAs from each ethnic group are shown in Table 1. Number of predicted mHAs per patient varied widely both within and between HLA types (Figure 1). Despite underrepresentation of some ethnic groups in our dataset, we identified thousands of potential mHAs in each group (Figure 2A). GvL mHA and GvH mHA proportions were similar across recipient ethnicities (Figure 2A-B). GvL mHA made up approximately half of predicted mHAs for each ethnic group (Figure 2B). Total numbers of mHAs per HCT recipient were significantly different between recipient ethnic groups within each cohort (Figure 2C). Although proportions of GvL vs GvH mHAs were stable across HLA alleles, there were substantial differences in number of predicted mHA by allele (Figure 3). Despite limited representation of some HLA types in our dataset, we were able to identify GvL mHAs for potential therapeutic targeting corresponding to 56 HLA alleles. We generated ranked lists of the most common shared mHA for each HLA allele, using an implementation of the standard greedy algorithm solution to the maximum set coverage problem. With this method, we identified the fewest number of mHA peptides needed to cover desired percentages of the recipient population with at least one mHA. For example, for HLA A*02:01, HLA*B07:02, and HLA*C07:01, engineering T cells to target the top nine to twelve peptides would allow for treatment of 80% of the patient population in our cohorts (Figure 4). These represent common HLA alleles in Caucasian, African American, Hispanic, and Asian populations, indicating that this technique can identify targets that could be therapeutically beneficial for a greater diversity of patients than standard treatments. mHA pools can also be filtered on peptide expression or HLA binding to ensure that the targeted peptides are highly expressed and presented. Conclusions: Despite differences in predicted number of mHA by ethnicity and HLA alleles, shared GvL mHA exist across common HLA. To the extent that these are targetable by adoptive cellular therapy, we can expand equal access to mHA targeted immunotherapies, improving upon traditional models where only the most prevalent HLA types are covered. Disclosures Armistead: Cell Microsystems: Patents & Royalties: Patent application U.S. 16/347,104 "Automated collection of a specified number of cells"; GeneCentric: Consultancy. Vincent:GeneCentric Therapeutics: Consultancy.
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Dostanko, N., E. Siniauskaya, V. Yagur, R. Goncharova, and H. Yatskiu. "AB0010 ASSOCIATION OF SOME NON-HLA GENE POLYMORPHISMS WITH SUSCEPTIBILITY TO SYSTEMIC LUPUS ERYTHEMATOSUS IN WOMEN IN BELARUSIAN POPULATION." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1140.2–1141. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3090.
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BackgroundDespite the recent progress in our understanding of the genetic predisposition to systemic lupus erythematosus (SLE) its clinical and functional significance is not fully clarified yet and needs to be implemented in personalized care [1].ObjectivesTo estimate the association between some single nucleotide polymorphisms (SNPs) of 9 non-HLA genes-candidates as STAT4 rs7574865, PTPN2 rs2542151, PTPN22 rs2476601, AGER rs1035798, TRAF1/C5 rs3761847, SLC7A11 rs13128867, RUNX1 rs9979383, IL6 rs1800795, IL6R rs2228145, IL6R rs4845618 and susceptibility to SLE in Belarusian women for the following predictive model development.MethodsWe examined 316 women: among them 59 SLE patients (mean age 39.84, CI95% 36.62-43.06) classified according to the 1997 American College of Rheumatology (ACR) revised classification criteria and 257 age-matched healthy controls (blood donors, mean age 38.12, 95% confidence interval (CI95%) 36.77-39.46). Deoxyribonucleic acid was extracted from peripheral blood samples by phenol-chloroform method. Genotyping was performed by real-time PCR with fluorescent probes. Descriptive analysis, test for Hardy–Weinberg equilibrium, multiple inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive) for single SNPs, Akaike information criteria (AIC) and Bayesian information criteria (BIC) were analyzed using SNPStats web tool [2]. Pearson χ 2 (χ 2), two-way Fisher exact test (F, p 2-t), odds ratio (OR), likelihood ratio of positive (LR +) and negative (LR –) tests with corresponding CI95% were also calculated.ResultsExact test for all genotype frequencies distribution of all studied SNPs didn’t reveal significant differences with Hardy-Weinberg equilibrium in all controls and SLE groups. We noted significant increase of minor ТТ genotype frequency of STAT4 rs7574865 in SLE vs healthy women with recessive inheritance model as the best-fitting one according to its less AIC and BIC values (OR=3.78 (CI95% 1.35-10.62); p=0.016; LR + =3.45 (CI95% 1.37-8.60); LR – =0.91 (CI95% 0.84-0.98)). We revealed protection of minor A allele of AGER rs1035798 carriership with log-additive model of inheritance as the best-fitting one according to AIC and BIC values against SLE development in women (OR=0.52 (CI95% 0.33-0.83); p=0.004; LR + =0.70 (CI95% 0.50-0.93); LR – =1.47 (CI95% 1.10-1.86)). We also noted significant increase of minor allele G frequency of TRAF1/C5 rs3761847 in SLE vs healthy women with dominant inheritance model (OR=3.61 (CI95% 1.05-12.38); p=0.019; LR + =1.30 (CI95% 1.03-1.43); LR – =0.36 (CI95% 0.12-0.92)) and increase of AA genotype frequency in healthy women (p 2-t =0.041). We revealed that minor allele G of PTPN2 rs2542151 is more frequent in SLE women vs healthy controls and has overdominant model of inheritance (OR=1.98 (CI95% 1.09-3.59); p=0.026; LR + =1.57 (CI95% 1.07-2.20); LR – =0.79 (CI95% 0.62-0.97)).There were no significant differences in genotypes and alleles distribution for PTPN22 rs2476601, RUNX1 rs9979383, SLC7A11 rs13128867 and IL6 rs1800795 in studied population and we noted only non-significant tendency in minor SNP genotypes distribution of IL6R rs4845618 and IL6R rs2228145 between healthy controls and women with SLE.ConclusionOur data suggest the susceptibility to SLE in women with ТТ genotype of STAT4 rs7574865 polymorphism and allele G carriers of both TRAF1/C5 rs3761847 and PTPN2 rs2542151 as well as protective role of AGER rs1035798 A allele carriership againt SLE development in women of Belarusian population.References[1]Ghodke-Puranik Y, Niewold TB. Immunogenetics of systemic lupus erythematosus: A comprehensive review. J Autoimmun. 2015;64:125-36.[2]Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006;22(15):1928–29.AcknowledgementsThis research was supported by The Research Technical Program “DNA Identification” (2017–2021), project number: 6.4Disclosure of InterestsNone declared
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Calvano Küchler, E., J. Arid, M. Palinkas, M. Ayumi Omori, RM de Lara, LM Napolitano Gonçalves, SC Hallak Regalo, C. Paes Torres Mantovani, A. Rezende Vieira, and K. Diaz-Serrano. "Genetic Polymorphisms in ACTN3 Contribute to the Etiology of Bruxism in Children." Journal of Clinical Pediatric Dentistry 44, no. 3 (January 1, 2020): 180–84. http://dx.doi.org/10.17796/1053-4625-44.3.8.
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Objective: Bruxism is a condition defined as a masticatory muscle activity with an unexplored genetic background. The aim of this study was to evaluate the association between genetic polymorphisms in ACTN3 and bruxism. Study design: A total of 151 biological-unrelated children, aged 7–12 years were included in a case control ratio of 1:1.5. The data collection was performed during interview and clinical examination. Saliva samples were collected from all children and 3 genetic polymorphisms in the ACTN3 (rs678397, rs1671064 and rs1815739) were selected for genotyping using real time PCR. Pearson chisquare calculation was used to assess Hardy-Weinberg equilibrium and to evaluate the association between genotypes and alleles frequencies for each genetic polymorphism in the co-dominant and recessive models. An alpha of 5% was used. Results: The genetic polymorphisms rs678397, rs1671064 and rs1815739 were associated with bruxism in the co-dominate model and in the recessive model (p<0.05). Allele distribution was also associated with bruxism for the polymorphisms rs678397 and rs1671064 (p<0.05). Conclusion: The genetic polymorphisms rs678397, rs1671064 and rs1815739 in ACTN3 are associated with bruxism and can contribute to the etiology of this condition in children.
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Yang, Aotian, David Miller, and Qing Pan. "Constrained maximum entropy models to select genotype interactions associated with censored failure times." Journal of Bioinformatics and Computational Biology 16, no. 06 (December 2018): 1840024. http://dx.doi.org/10.1142/s0219720018400243.
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We propose a novel screening method targeting genotype interactions associated with disease risks. The proposed method extends the maximum entropy conditional probability model to address disease occurrences over time. Continuous occurrence times are grouped into intervals. The model estimates the conditional distribution over the disease occurrence intervals given individual genotypes by maximizing the corresponding entropy subject to constraints linking genotype interactions to time intervals. The EM algorithm is employed to handle observations with uncertainty, for which the disease occurrence is censored. Stepwise greedy search is proposed to screen a large number of candidate constraints. The minimum description length is employed to select the optimal set of constraints. Extensive simulations show that five or so quantile-dependent intervals are sufficient to categorize disease outcomes into different risk groups. Performance depends on sample size, number of genotypes, and minor allele frequencies. The proposed method outperforms the likelihood ratio test, Lasso, and a previous maximum entropy method with only binary (disease occurrence, non-occurrence) outcomes. Finally, a GWAS study for type 1 diabetes patients is used to illustrate our method. Novel one-genotype and two-genotype interactions associated with neuropathy are identified.
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Chen, Yan-li, Li-Qiang Zheng, Tie-Jun Li, Zhao-Qing Sun, Ying Hao, Bao-Gang Wu, and Ying-Xian Sun. "Association between rs20456 and rs6930913 of Kinesin-Like Family 6 and Hypertension in a Chinese Cohort." International Journal of Hypertension 2021 (December 18, 2021): 1–7. http://dx.doi.org/10.1155/2021/1061800.
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This study aimed to investigate the relationship between kinesin-like family 6 (KIF6) polymorphisms and hypertension in a northeast Chinese cohort. In this study, two single nucleotide polymorphisms of KIF6 (rs20456 and rs6930913) and their haplotype were analyzed in 382 hypertension patients and 378 controls with SHEsis analysis platform, and the gene-environmental interactions were evaluated with logistic regression analysis. After adjusting for confounding factors, significantly lower risk of hypertension was observed in participants with genotype TC (0.416 (CI 0.299–0.578), p < 0.001 ) and CC (0.577 (0.389–0.857), p = 0.007 ) of rs20456 compared with TT. For rs6930913, allele T (0.522 (0.386–0.704), p < 0.001 ), genotype TT (0.325 (0.205–0.515), p < 0.001 ), and genotype CT (0.513 (0.379–0.693), p < 0.001 ) were significantly associated with lower risk of hypertension than allele C and CC genotype, respectively. Gene-environment analyses confirmed the significant influence on hypertension by the interactions between genotypes distribution in rs20456 (CT: p = 0.036 , TT: p = 0.022 ) and smoking status. No interactions were found between smoking and rs6930913, except those with dominant or recessive genetic models (both P s = 0.006 ). There were no interactions between KIF6 and overweight (all P s > 0.05 ). Haplotype analyses showed that CC ( p = 0.005 ) and TC ( p = 0.001 ) of rs20456 and rs6930913 were significantly associated with a statistically increased risk of hypertension. The false-positive report probability (FPRP) analysis was used to verify significant findings. In conclusions, KIF6 might affect the susceptibility of hypertension. The allele C (rs20456) and allele T (rs690913) were inclined to protect individuals from hypertension both in genotype and haplotype analyses.
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Kniazkova, Polina V., and Viktoriia Yu Harbuzova Viktoriia Yu. Harbuzova. "ANALYSIS OF THE ASSOCIATION OF RS4977574-POLYMORPHIC VARIANTS OF THE ANRIL GENE WITH THE DEVELOPMENT OF ACUTE CORONARY SYNDROME IN INDIVIDUALS WITH DIFFERENT BODY MASS INDEX IN THE UKRAINIAN POPULATION." Eastern Ukrainian Medical Journal 10, no. 2 (2022): 147–54. http://dx.doi.org/10.21272/eumj.2022;10(2):147-154.
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The objective was to analyze the association of rs4977574-polymorphic variants of the ANRIL gene with the development of acute coronary syndrome in individuals with different body mass index. Materials and methods. The venous blood of 429 people (234 patients with acute coronary syndrome and 195 people in the control group) was used for the study. Genotyping of patients by rs4977574-polymorphic variants of the ANRIL gene was performed by real-time polymerase chain reaction (Real-time PCR) in the presence of TaqMan assay C_31720978_30. Statistical analysis of the results of the study was performed using SPSS software (version 17.0). Results. The distribution of genotypes according to SNP rs4977574 of the ANRIL gene in the group of patients with ACS and the control group among individuals with BMI < 25 kg/m2 does not differ. Among patients with BMI 25 kg/m2 the genotype distribution of the rs4977574-polymorphic variant of the ANRIL gene was statistically significant (р = 0.035). In the group of patients with BMI > 25 kg/m2 according to recessive (Pobserv = 0.014; ORobserv = 1.876, 95 % СІ = 1.137–3.095) and additive (Рobserv = 0.014; ORobserv = 2.118, 95% СІ = 1.166–3.849) models of inheritance before making adjustment, people with G/G genotype had a double risk of acquiring ACS than carriers of the dominant allele. After the adjustment, corresponding models of inheritance had the same risk rate – for recessive model (Рadjust = 0.013; ORadjust = 1.951, 95% СІ = 1.149–3.313) and additive model (Рadjust = 0.026; ORadjust = 2.039, 95 % СІ = 1.087–3.826). Conclusions. Individuals with BMI > 25 kg/m2, which were carriers of G/G genotype had a 2 times higher risk to acquire ACS than the individuals with the dominant allele. Prospects for further research. Further research will be aimed at studying the impact of ANRIL polymorphism upon the risk of ACS development depending on other risk factors.
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Kuramoto, Takashi, Satoshi Nakanishi, and Tadao Serikawa. "Functional polymorphisms in inbred rat strains and their allele frequencies in commercially available outbred stocks." Physiological Genomics 33, no. 2 (April 2008): 205–11. http://dx.doi.org/10.1152/physiolgenomics.00222.2007.
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Polymorphisms that have been proven to influence gene functions are called functional polymorphisms. It is significant to know the distribution of functional polymorphisms in the rat, widely used in animal models for human diseases. In this study, we assessed 16 functional polymorphisms consisting of 3 coat color and 13 disease-associated genes in 136 rat strains, as a part of the genetic profiling program of the National Bio Resource Project for the Rat (NBRP-Rat). Polymorphisms of Cdkn1a, Fcgr3, Grp10, Lss, and Fdft1, which were proven to function in prostate tumorigenesis, glomerulonephritis, hyperphagia, and cholesterol biosynthesis, were shared among various inbred strains. These findings indicated that most rat strains harbored the disease-associated alleles and suggested that many unidentified functional polymorphisms might exist in inbred rat strains. The functional polymorphisms shared in inbred strains were also observed within outbred stocks available commercially. Therefore, this implies that experimental plans based on either rat inbred strains or outbred stocks need to be carefully designed with a full understanding of the genetic characteristics of the animals. To select the most suitable strains for experiments, the NBRP-Rat will periodically improve and update the genetic profiles of rat strains.
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Gao, Song, Edward C. Bell, Yun Zhang, and Dong Liang. "Racial Disparity in Drug Disposition in the Digestive Tract." International Journal of Molecular Sciences 22, no. 3 (January 21, 2021): 1038. http://dx.doi.org/10.3390/ijms22031038.
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The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.
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Zachaki, Sophia, Chryssa Stavropoulou, Aggeliki Daraki, Marina Kalomoiraki, Panagoula Kollia, Vassiliki Aleporou, Gabriel Pantelias, Emmanuel Kanavakis, and Constantina Sambani. "Association of A313g Glutathione S-Transferase P1 (GSTP1) Inborn Polymorphism with Susceptibility to De Novo MDS." Blood 120, no. 21 (November 16, 2012): 1445. http://dx.doi.org/10.1182/blood.v120.21.1445.1445.
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Abstract Abstract 1445 Models for the pathogenesis of myelodysplastic syndromes (MDS) imply the role of individual genetic variations in genes involved in detoxification mechanisms. GSTP1 enzyme plays a key role in detoxification of a variety of electrophilic compounds, such as benzo [a]-pyrene and other polycyclic aromatic hydrocarbons (PAHs), chemotherapy drugs and products of oxidative stress. GSTP1 acts through a common mechanism of conjugating reactive oxygen species (ROS) with glutathione, enabling their detoxification and elimination and thus defending tissues against DNA damage. The corresponding gene is subject to a single-nucleotide polymorphism (A313G) leading to abolished enzyme activity. Thus, individuals homozygous for the variant G allele (G/G) have a lower conjugating activity than individuals homozygous for the wild type A allele (A/A), while heterozygotes (A/G) display intermediate activity. The aim of the present study was to evaluate whether the GSTP1 polymorphism influences susceptibility to MDS and/or promote specific chromosomal aberrations. We conducted a case-control study in 310 de novo MDS patients and 370 unrelated healthy controls using both a conventional PCR-RFLP assay and a novel Real-Time PCR genotyping method using hybridization probe technology. The GSTP1 gene status was also evaluated in relation to patients' characteristics and chromosomal abnormalities. Comparison of the genotype distribution between controls and MDS cases revealed a significantly higher frequency of the variant genotypes (heterozygotes A/A and homozygotes G/G) among MDS patients, as compared to controls (p<0.0001, χ2=31.167, df=2). The most marked statistical difference between MDS patients and controls was observed between the wild-type (A/A) and the homozygous variant genotype (G/G), since subjects carrying the G/G variant genotype showed a 4.1-fold increased risk of MDS prevalence than subjects carrying the wild-type A/A genotype (p=0.000, χ2=30.5, d.f.=1, OR=4.098, 95%CI=[2.433–6.897]). Allele frequencies distribution analysis between patients and controls, showed that MDS patients exhibited a 1.9-fold increased risk of carrying at least one variant G allele, as compared to the controls (p<0.0001, d.f.=1, OR =1.9, 95%CI=[1.48–2.34]). There was no association between the GSTP1 polymorphism and gender or any specific cytogenetic subgroup, while stratification of patients according to age showed a differential GSTP1 genotype distribution (p=0.007). Our results, derived from the larger series of primary MDS cases tested for the GSTP1 genetic background, reveal an increased incidence of the GSTP1 variant genotypes among MDS patients, providing evidence for a potential pathogenetic role of the GSTP1 polymorphism on de novo MDS risk. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Jingwei, Lin Jiao, Jiajia Song, Tao Wu, Hao Bai, Tangyuheng Liu, Zhenzhen Zhao, Xuejiao Hu, and Binwu Ying. "Genetic and Functional Evaluation of the Role of FOXO1 in Antituberculosis Drug-Induced Hepatotoxicity." Evidence-Based Complementary and Alternative Medicine 2021 (June 19, 2021): 1–13. http://dx.doi.org/10.1155/2021/3185874.
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Background. The accumulation of the hepatotoxic substance protoporphyrin IX (PPIX) induced by aminolevulinate synthase 1 (ALAS1) activation is one of the important mechanisms of antituberculosis drug-induced hepatotoxicity (ATDH). Forkhead box protein O1 (FOXO1) may activate ALAS1 transcription. However, little is known about their roles in ATDH; we performed a study to determine the association between polymorphisms in the two genes and ATDH susceptibility. Then, we verified this possible association by cellular functional experiments. Materials and Methods. Tag single-nucleotide polymorphisms (TagSNPs) in the two genes were genotyped in 746 tuberculosis patients. The frequencies of the alleles, genotypes, genetic models, and haplotype distribution of the variants were compared between the case and control groups. L-02 cells and HepG2 cells were incubated with the indicated concentration of isoniazid (INH) and rifampicin (RIF) for the desired times, and then the expression levels of ALAS1 and FOXO1 mRNAs and proteins were detected. HepG2 cells were transiently transfected with FOXO1 siRNA to observe the effect of changes in the FOXO1 expression on the cell survival rate and ALAS1 expression. Results. The C allele at rs2755237 and the T allele at rs4435111 in the FOXO1 gene were associated with a decreased risk of ATDH. The expression of ALAS1 in both L-02 cells and HepG2 cells was increased by the coadministration of INH/RIF (600/200 μM) for 24 h. Although FOXO1 expression was reduced slightly by the same treatment, its content in the nucleus was significantly increased. However, the cell survival rate and ALAS1 expression level were not significantly altered by the downregulation of FOXO1 in HepG2 cells. Conclusions. Variants of the rs4435111 and rs2755237 loci in the FOXO1 gene were associated with susceptibility to ATDH. Coadministration of INH/RIF promoted the transfer of FOXO1 from the cytoplasm to the nucleus, but the functional significance of its nuclear translocation requires further verification.
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Harrap, Stephen B., Nilesh J. Samani, David Lodwick, J. Michael Connor, Robert Fraser, David L. Davies, Anthony F. Lever, Chris J. W. Foy, and Graham C. M. Watt. "The SA Gene: Predisposition to Hypertension and Renal Function in Man." Clinical Science 88, no. 6 (June 1, 1995): 665–70. http://dx.doi.org/10.1042/cs0880665.
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1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin—angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin—angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.
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Kniazkova, P. V., and V. Yu Harbuzova. "Analysis of the redistribution of rs4977574-polymorphic variants of the ANRIL gen in patients with acute coronary syndrome of different sex." Reports of Vinnytsia National Medical University 26, no. 1 (March 28, 2022): 108–12. http://dx.doi.org/10.31393/reports-vnmedical-2022-26(1)-20.
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Annotation. The aim of the study was to analyze the distribution of rs4977574-polymorphic variants of the ANRIL gene in patients with acute coronary syndrome of different sex. The venous blood of 234 patients with acute coronary syndrome (ACS) and 195 people without cardiac pathology was used for the study. DNA was isolated from whole venous blood using the GeneJET Whole Blood Genomic DNA Purification Mini Kit (ThermoFisher Scientific, USA). rs4977574 ANRIL gene polymorphism was studied by real-time PCR reaction in the presence of TaqMan assay C_31720978_30. Statistical analysis of the study was performed using the SPSS program (version 17.0). A difference was found when comparing the frequencies of genotypes at the polymorphic site rs4977574 of the ANRIL gene in their distribution (p=0,035). According to the results of logistic regression, it was detected that in the recessive (p=0,015) and additive (p=0,012) inheritance models, carriers of the G/G genotype are approximately 2 times more likely to develop ACS than carriers of the A-allele. The reliability of the results was maintained after adjustments for gender, age, B<I, smoking habits, diabetes and stress (p=0,049 for the recessive model; p=0,037 for the additive model). Thus, individuals with the rs4977574 G/G genotype polymorphism of the ANRIL long non-coding RNA gene have a 2 times higher risk of developing ACS than dominant allele carriers. Further research will focus on the association of ANRIL polymorphism with the risk of ACS depending on other risk factors.