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American Journal of Human Genetics May 2017Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as...
Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4%-23% in eQTLs, 35% in GWASs of high-density lipoprotein (HDL), and 23% in GWASs of schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R = 0.85, p = 2.2 × 10), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.
Topics: Alleles; Databases, Genetic; Gene Frequency; Genetic Association Studies; Humans; Linkage Disequilibrium; Models, Molecular; Phenotype; Quantitative Trait Loci
PubMed: 28475861
DOI: 10.1016/j.ajhg.2017.04.005 -
HLA Jul 2021The Birmingham H&I laboratory performed HLA typing on 456 potential deceased solid organ donors in the UK between 2014 and 2016. Accurate DPB1 typing is essential for...
HLA-DPB1 allele frequencies in the West Midlands region of the United Kingdom: A critical evaluation against the common, intermediate and well-documented allele catalogues CWD 2.0.0, EFI CWD and CIWD 3.0.0.
The Birmingham H&I laboratory performed HLA typing on 456 potential deceased solid organ donors in the UK between 2014 and 2016. Accurate DPB1 typing is essential for determining HLA compatibility in transplantation, thus we report HLA-DPB1 for potential deceased solid organ donors. To correctly interpret HLA typing data, laboratories must understand both international and local HLA allele frequencies. In this analysis, we determined HLA-DPB1 allele and genotype frequencies for these 456 donors. HLA-DPB1 diversity was evaluated against the common and well-documented (CWD) alleles 2.0.0 catalogue, the European Federation for Immunogenetics (EFI) CWD catalogue and the common, intermediate and well-documented (CIWD) 3.0.0 catalogue. Additionally, we determined which alleles are common in our local deceased donor population. We observed 27 HLA-DPB1 alleles with DPB1*04:01 being the most frequently observed (allele frequency = 0.4342). All alleles detected locally were present in CIWD 3.0.0, however, DPB1*124:01 and *135:01 were not present in CWD 2.0.0 and DPB1*104:01 and *135:01 were not present in EFI CWD. Twenty of 27 DPB1 alleles identified were defined as locally common and also listed as common in CIWD 3.0.0 representing 62.5% of common alleles in the subset of CIWD 3.0.0 from individuals of a European geographic, ancestral or ethnic background. The alleles HLA-DPB1*16:01 and *20:01 are locally common but not listed as common in EFI CWD and DPB1*104:01 is not listed as common in CWD 2.0.0 catalogue. Our analysis showed that the detected alleles and locally common alleles within our population were aligned with the CIWD 3.0.0 catalogue.
Topics: Alleles; Gene Frequency; Genetics, Population; HLA-DP beta-Chains; Humans; Immunogenetics; Tissue Donors; United Kingdom
PubMed: 33934529
DOI: 10.1111/tan.14291 -
Journal of Theoretical Biology May 2023Understanding the role of natural selection in driving evolutionary change requires accurate estimates of the strength of selection acting at the genetic level in the...
Understanding the role of natural selection in driving evolutionary change requires accurate estimates of the strength of selection acting at the genetic level in the wild. This is challenging to achieve but may be easier in the case of populations in migration-selection balance. When two populations are at equilibrium under migration-selection balance, there exist loci whose alleles are selected different ways in the two populations. Such loci can be identified from genome sequencing by their high values of F. This raises the question of what is the strength of selection on locally-adaptive alleles. To answer this question we analyse a 1-locus 2-allele model of a population distributed between two niches. We show by simulation of selected cases that the outputs from finite-population models are essentially the same as those from deterministic infinite-population models. We then derive theory for the infinite-population model showing the dependence of selection coefficients on equilibrium allele frequencies, migration rates, dominance and relative population sizes in the two niches. An Excel spreadsheet is provided for the calculation of selection coefficients and their approximate standard errors from observed values of population parameters. We illustrate our results with a worked example, with graphs showing the dependence of selection coefficients on equilibrium allele frequencies, and graphs showing how F depends on the selection coefficients acting on the alleles at a locus. Given the extent of recent progress in ecological genomics, we hope our methods may help those studying migration-selection balance to quantify the advantages conferred by adaptive genes.
Topics: Genetics, Population; Gene Frequency; Selection, Genetic; Chromosome Mapping; Biological Evolution; Alleles; Models, Genetic
PubMed: 36914112
DOI: 10.1016/j.jtbi.2023.111463 -
Proceedings of the National Academy of... May 2022Collateral sensitivity (CS), which arises when resistance to one antibiotic increases sensitivity toward other antibiotics, offers treatment opportunities to constrain...
Collateral sensitivity (CS), which arises when resistance to one antibiotic increases sensitivity toward other antibiotics, offers treatment opportunities to constrain or reverse the evolution of antibiotic resistance. The applicability of CS-informed treatments remains uncertain, in part because we lack an understanding of the generality of CS effects for different resistance mutations, singly or in combination. Here, we address this issue in the gram-positive pathogen Streptococcus pneumoniae by measuring collateral and fitness effects of clinically relevant gyrA and parC alleles and their combinations that confer resistance to fluoroquinolones. We integrated these results in a mathematical model that allowed us to evaluate how different in silico combination treatments impact the dynamics of resistance evolution. We identified common and conserved CS effects of different gyrA and parC alleles; however, the spectrum of collateral effects was unique for each allele or allelic pair. This indicated that allelic identity can impact the evolutionary dynamics of resistance evolution during monotreatment and combination treatment. Our model simulations, which included the experimentally derived antibiotic susceptibilities and fitness effects, and antibiotic-specific pharmacodynamics revealed that both collateral and fitness effects impact the population dynamics of resistance evolution. Overall, we provide evidence that allelic identity and interactions can have a pronounced impact on collateral effects to different antibiotics and suggest that these need to be considered in models examining CS-based therapies.
Topics: Alleles; Anti-Bacterial Agents; Drug Resistance, Bacterial; Fluoroquinolones; Microbial Sensitivity Tests
PubMed: 35476512
DOI: 10.1073/pnas.2121768119 -
Animal Genetics Dec 2020Transmission ratio distortion (TRD) is defined as the observed deviation from the expected Mendelian inheritance of alleles from heterozygous parents. This phenomenon is...
Transmission ratio distortion (TRD) is defined as the observed deviation from the expected Mendelian inheritance of alleles from heterozygous parents. This phenomenon is attributed to various biological mechanisms acting on germ cells, embryos or fetuses, or even in early postnatal life. Current statistical approaches typically use two independent parametrizations assuming that TRD relies on allele- or genotype-related mechanisms, although they have never been tested and compared. This study compared allele- and genotype-related TRD models on simulated datasets with 1000 genotyped offspring and real data from 168 sire-dam-offspring beef cattle trios. The analysis of simulated datasets favored the true model of analysis in most cases (>93%), and a low percentage of missidentification occurred under (almost) null dominance (genotype-related model) or similar and moderate-to-low sire- and dam-specific TRD parameters (allele-related model). Moreover, the correlation between simulated and predicted distortion parameters was high (>0.97) under the true model. The comparison of allele- and genotype-related TRD models is an appealing tool to infer the biological source of TRD (i.e. haploid vs. diploid cells) when screening the whole genome. The analysis of beef cattle data corroborated a TRD region previously reported in chromosome 4, although discarding allele-related mechanisms and favoring the genotype-related model as the more reliable one. The results of this study highlight the relevance of implementing and comparing different parametrizations to capture all kinds of TRD, and to compare them using appropriate statistical methods.
Topics: Alleles; Animals; Cattle; Female; Genotype; Heterozygote; Inheritance Patterns; Male; Models, Genetic
PubMed: 32996622
DOI: 10.1111/age.13007 -
Plant Communications Jul 2021Hybrids are always a focus of botanical research and have a high practical value in agricultural production. To better understand allele regulation and differences in...
Hybrids are always a focus of botanical research and have a high practical value in agricultural production. To better understand allele regulation and differences in DNA methylation in hybrids, we developed a phasing pipeline for hybrid rice based on two parental genomes (PP2PG), which is applicable for Iso-Seq, RNA-Seq, and Bisulfite sequencing (BS-Seq). Using PP2PG, we analyzed differences in gene transcription, alternative splicing, and DNA methylation in an allele-specific manner between parents and progeny or different progeny alleles. The phasing of Iso-Seq data provided a great advantage in separating the whole gene structure and producing a significantly higher separation ratio than RNA-Seq. The interaction of hybrid alleles was studied by constructing an allele co-expression network that revealed the dominant allele effect in the network. The expression variation between parents and the parental alleles in progeny showed tissue- or environment-specific patterns, which implied a preference for -acting regulation under different conditions. In addition, by comparing allele-specific DNA methylation, we found that CG methylation was more likely to be inherited than CHG and CHH methylation, and its enrichment in genic regions was connected to gene structure. In addition to an effective phasing pipeline, we also identified differentiation in gene structure that may have led to the expansion of allele functions in hybrids. In summary, we developed a phasing pipeline and provided valuable insights into alternative splicing, interaction networks, acting regulation, and the inheritance of DNA methylation in hybrid rice.
Topics: Alleles; DNA Methylation; Epigenome; Gene Expression Regulation, Plant; Genome, Plant; Inheritance Patterns; Oryza; Transcriptome
PubMed: 34327321
DOI: 10.1016/j.xplc.2021.100185 -
Western Journal of Nursing Research Apr 2017Twenty-three percent to 50% of heart failure (HF) patients have memory loss. Objectives were to (a) characterize major allelic frequency of 2 variants in apolipoprotein...
Twenty-three percent to 50% of heart failure (HF) patients have memory loss. Objectives were to (a) characterize major allelic frequency of 2 variants in apolipoprotein ( APOE) gene in HF patients, (b) evaluate differences in memory and serum brain-derived neurotrophic factor (BDNF) levels based on APOE ε4 allele(s), and (c) estimate effect sizes (ESs) and confidence intervals (CIs). In this pilot, 29 HF patients were enrolled and 26 completed. Recall and delayed recall memory were measured at baseline and 12 weeks. Serum was collected at baseline and 8 weeks. Seven (24.1%) patients had APOE ε4 allele. No significant differences were found in recall and delayed recall memory or serum BDNF levels based on APOE ε4 allele. ESs were small to medium; CIs indicated ES precision was small. Future studies are needed to fully understand how genotypic and neuropsychological phenotypic variables influence response to computerized cognitive training.
Topics: Alleles; Apolipoprotein E4; Brain-Derived Neurotrophic Factor; Cognition; Female; Genotype; Heart Failure; Humans; Male; Memory; Mental Recall; Middle Aged; Neuropsychological Tests
PubMed: 27733670
DOI: 10.1177/0193945916670145 -
Fa Yi Xue Za Zhi Jun 2023Tri-allelic pattern in autosomal STR is a common abnormal typing phenomenon in forensic DNA analysis, which brings difficulties and uncertainties to the evaluation of... (Review)
Review
Tri-allelic pattern in autosomal STR is a common abnormal typing phenomenon in forensic DNA analysis, which brings difficulties and uncertainties to the evaluation of the evidence weight in actual cases. This paper reviews the types, formation mechanism, occurrence frequency, genetic pattern and quantitative evaluation of evidence of the tri-allelic pattern in autosomal STR in forensic DNA analysis. This paper mainly explains the formation mechanism and genetic patterns based on different types of tri-allelic pattern. This paper also discusses the determination of tri-allelic pattern and the quantitative method of evidence evaluation in paternity testing and individual identification. This paper aims to provide references for scientific and standardized analysis of this abnormal typing phenomenon in forensic DNA analysis.
Topics: Alleles; DNA; Forensic Medicine; Gene Frequency; Microsatellite Repeats; Humans
PubMed: 37517011
DOI: 10.12116/j.issn.1004-5619.2023.530210 -
Biomedica : Revista Del Instituto... Mar 2016The genetic variability present in the APOE gene polymorphism is considered an important factor associated with predisposition to diseases affecting lipid metabolism, as...
INTRODUCTION
The genetic variability present in the APOE gene polymorphism is considered an important factor associated with predisposition to diseases affecting lipid metabolism, as well as heart diseases and Alzheimer's disease, among others. Understanding it as a risk factor in different populations and ethnic groups is a useful tool.
OBJECTIVE
To analyze the APOE gene polymorphism and determine allelic and genotypic frequencies of a representative sample of population from Barranquilla, Colombia.
MATERIALS AND METHODS
We performed a descriptive and comparative study. The sample size was 227 unrelated individuals from Barranquilla, Colombia.
RESULTS
The most frequent allele was the ε3, with 85%, followed by the ε4 allele (13%) and ε2 (1.8%). The genotypes found were: ε3/ε3: 71.8%, ε3/ε4: 24.2%, ε2/ε3: 2.2%, ε2/ε4: 1.3% and ε4/ε4: 0.4%. The ε2/ε2 genotype was not found in this study. The sample exhibited the Hardy-Weinberg equilibrium.
CONCLUSION
The frequency of the ε3 allele and the ε3/ε3 genotype was similar to that reported in the literature in countries like Brazil, Mexico, Colombia, and in some Colombian Amerindian ethnic groups. The ε2/ε2 genotype was absent. This result is consistent with those found in other population groups worldwide. The frequency of the ε4 allele and the genotypes associated in this population could be related to the presence of diseases such as hypercholesterolemia, myocardial infarction and Alzheimer.
Topics: Adolescent; Adult; Alleles; Apolipoproteins E; Colombia; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Young Adult
PubMed: 27622438
DOI: 10.7705/biomedica.v36i1.2612 -
Forensic Science International. Genetics Nov 2022The maximum allele count (MAC) across loci and the total allele count (TAC) are often used to gauge the number of contributors to a DNA mixture. Computational strategies...
The maximum allele count (MAC) across loci and the total allele count (TAC) are often used to gauge the number of contributors to a DNA mixture. Computational strategies that predict the total number of alleles in a mixture arising from a certain number of contributors of a given population have been developed. Previous work considered the restricted case where all of the contributors to a mixture are unrelated. We relax this assumption and allow mixture contributors to be related according to a pedigree. We introduce an efficient computational strategy. This strategy based on first determining a probability distribution on the number of independent alleles per locus, and then conditioning on this distribution to compute a distribution of the number of distinct alleles per locus. The distribution of the number of independent alleles per locus is obtained by leveraging the Identical by Descent (IBD) pattern distribution which can be computed from the pedigree. We explain how allelic dropout and a subpopulation correction can be accounted for in the calculations.
Topics: Humans; Alleles; DNA Fingerprinting; DNA; Probability
PubMed: 35961259
DOI: 10.1016/j.fsigen.2022.102748