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Annual Review of Biomedical Data Science Jul 2021Diploidy has profound implications for population genetics and susceptibility to genetic diseases. Although two copies are present for most genes in the human genome,... (Review)
Review
Diploidy has profound implications for population genetics and susceptibility to genetic diseases. Although two copies are present for most genes in the human genome, they are not necessarily both active or active at the same level in a given individual. Genomic imprinting, resulting in exclusive or biased expression in favor of the allele of paternal or maternal origin, is now believed to affect hundreds of human genes. A far greater number of genes display unequal expression of gene copies due to -acting genetic variants that perturb gene expression. The availability of data generated by RNA sequencing applied to large numbers of individuals and tissue types has generated unprecedented opportunities to assess the contribution of genetic variation to allelic imbalance in gene expression. Here we review the insights gained through the analysis of these data about the extent of the genetic contribution to allelic expression imbalance, the tools and statistical models for gene expression imbalance, and what the results obtained reveal about the contribution of genetic variants that alter gene expression to complex human diseases and phenotypes.
Topics: Alleles; Allelic Imbalance; Gene Expression; Genomic Imprinting; Humans; Sequence Analysis, RNA
PubMed: 34465174
DOI: 10.1146/annurev-biodatasci-021621-122219 -
Scientific Reports May 2022Allele-specific expression (ASE) represents differences in the magnitude of expression between alleles of the same gene. This is not straightforward for polyploids,...
Allele-specific expression (ASE) represents differences in the magnitude of expression between alleles of the same gene. This is not straightforward for polyploids, especially autopolyploids, as knowledge about the dose of each allele is required for accurate estimation of ASE. This is the case for the genomically complex Saccharum species, characterized by high levels of ploidy and aneuploidy. We used a Beta-Binomial model to test for allelic imbalance in Saccharum, with adaptations for mixed-ploid organisms. The hierarchical Beta-Binomial model was used to test if allele expression followed the expectation based on genomic allele dosage. The highest frequencies of ASE occurred in sugarcane hybrids, suggesting a possible influence of interspecific hybridization in these genotypes. For all accessions, genes showing ASE (ASEGs) were less frequent than those with balanced allelic expression. These genes were related to a broad range of processes, mostly associated with general metabolism, organelles, responses to stress and responses to stimuli. In addition, the frequency of ASEGs in high-level functional terms was similar among the genotypes, with a few genes associated with more specific biological processes. We hypothesize that ASE in Saccharum is largely a genotype-specific phenomenon, as a large number of ASEGs were exclusive to individual accessions.
Topics: Alleles; Bias; Polymorphism, Single Nucleotide; Polyploidy; Saccharum
PubMed: 35610293
DOI: 10.1038/s41598-022-12725-0 -
Trends in Genetics : TIG Mar 2004Genetic variation in populations can result in variation in levels of gene expression but the extent to which this occurs has been unclear. In this article, recent... (Review)
Review
Genetic variation in populations can result in variation in levels of gene expression but the extent to which this occurs has been unclear. In this article, recent studies of allele-specific expression among autosomal non-imprinted genes are reviewed. These new data provide evidence that differential expression is relatively common and that allelic differences are heritable and can be highly context specific.
Topics: Alleles; Gene Expression Regulation; Genetic Variation; Genome, Human; Genomic Imprinting; Humans
PubMed: 15049300
DOI: 10.1016/j.tig.2004.01.001 -
Biometrics Jun 2022The allele-based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical...
The allele-based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical allelic test is limited in practice, because the method is sensitive to the Hardy-Weinberg equilibrium (HWE) assumption, not applicable to continuous traits, and not easy to account for covariate effect or sample correlation. To develop a generalized robust allelic test, we propose a new allele-based regression model with individual allele as the response variable. We show that the score test statistic derived from this robust and unifying regression framework contains a correction factor that explicitly adjusts for potential departure from HWE and encompasses the classical allelic test as a special case. When the trait of interest is continuous, the corresponding allelic test evaluates a weighted difference between individual-level allele frequency estimate and sample estimate where the weight is proportional to an individual's trait value, and the test remains valid under Y-dependent sampling. Finally, the proposed allele-based method can analyze multiple (continuous or binary) phenotypes simultaneously and multiallelic genetic markers, while accounting for covariate effect, sample correlation, and population heterogeneity. To support our analytical findings, we provide empirical evidence from both simulation and application studies.
Topics: Alleles; Computer Simulation; Gene Frequency; Genotype; Models, Genetic; Phenotype
PubMed: 33729547
DOI: 10.1111/biom.13456 -
Current Opinion in Neurobiology Dec 2019Typically, it is assumed that the maternal and paternal alleles for most genes are equally expressed. Known exceptions include canonical imprinted genes, random... (Review)
Review
Typically, it is assumed that the maternal and paternal alleles for most genes are equally expressed. Known exceptions include canonical imprinted genes, random X-chromosome inactivation, olfactory receptors and clustered protocadherins. Here, we highlight recent studies showing that allele-specific expression is frequent in the genome and involves subtypes of epigenetic allelic effects that differ in terms of heritability, clonality and stability over time. Different forms of epigenetic allele regulation could have different roles in brain development, function, and disease. An emerging area involves understanding allelic effects in a cell-type and developmental stage-specific manner and determining how these effects influence the impact of genetic variants and mutations on the brain. A deeper understanding of epigenetics at the allele and cellular level in the brain could help clarify the mechanisms underlying phenotypic variance.
Topics: Alleles; Brain; Epigenesis, Genetic; Genomic Imprinting; X Chromosome Inactivation
PubMed: 31153086
DOI: 10.1016/j.conb.2019.04.012 -
Nature Reviews. Genetics Jul 2023Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in... (Review)
Review
Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state - representing dominant inheritance - but others only with the biallelic presence of pathogenic variants - representing recessive inheritance - is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.
Topics: Genetics, Medical; Genotype; Phenotype; Mutation; Alleles
PubMed: 36806206
DOI: 10.1038/s41576-023-00574-0 -
Current Issues in Molecular Biology Apr 2003Single nucleotide polymorphism (SNP) detection technologies are used to scan for new polymorphisms and to determine the allele(s) of a known polymorphism in target... (Review)
Review
Single nucleotide polymorphism (SNP) detection technologies are used to scan for new polymorphisms and to determine the allele(s) of a known polymorphism in target sequences. SNP detection technologies have evolved from labor intensive, time consuming, and expensive processes to some of the most highly automated, efficient, and relatively inexpensive methods. Driven by the Human Genome Project, these technologies are now maturing and robust strategies are found in both SNP discovery and genotyping areas. The nearly completed human genome sequence provides the reference against which all other sequencing data can be compared. Global SNP discovery is therefore only limited by the amount of funding available for the activity. Local, target, SNP discovery relies mostly on direct DNA sequencing or on denaturing high performance liquid chromatography (dHPLC). The number of SNP genotyping methods has exploded in recent years and many robust methods are currently available. The demand for SNP genotyping is great, however, and no one method is able to meet the needs of all studies using SNPs. Despite the considerable gains over the last decade, new approaches must be developed to lower the cost and increase the speed of SNP detection.
Topics: Alleles; Automation; Chromatography, High Pressure Liquid; Genetic Techniques; Genome, Human; Genotype; Humans; Polymorphism, Single Nucleotide; Time Factors
PubMed: 12793528
DOI: No ID Found -
Current Protocols in Human Genetics Jan 2008The 5'-nuclease allelic discrimination assay, or TaqMan assay, is a PCR-based assay for genotyping single nucleotide polymorphisms (SNPs). The region flanking the SNP is...
The 5'-nuclease allelic discrimination assay, or TaqMan assay, is a PCR-based assay for genotyping single nucleotide polymorphisms (SNPs). The region flanking the SNP is amplified in the presence of two allele-specific fluorescent probes. The probes do not fluoresce in solution because of a quencher at the 3' end. The presence of two probes allows the detection of both alleles in a single tube. Moreover, because probes are included in the PCR, genotypes are determined without any post-PCR processing, a feature that is unavailable with most other genotyping methods. This unit describes probe and primer design and PCR conditions.
Topics: Alleles; DNA Primers; Genotype; Oligonucleotide Probes; Polymerase Chain Reaction; Polymorphism, Single Nucleotide
PubMed: 18428424
DOI: 10.1002/0471142905.hg0210s56 -
Turkiye Parazitolojii Dergisi Nov 2022The study aims to determine the presence of L1014F, L1014S, L1014C alleles, which are responsible for knockdown resistance and G119S alleles, which are responsible for...
OBJECTIVE
The study aims to determine the presence of L1014F, L1014S, L1014C alleles, which are responsible for knockdown resistance and G119S alleles, which are responsible for acetylcholinesterase insensitivity in , the secondary vector of malaria in Turkey.
METHODS
In this study, 60 adult females were collected from Aydın, Denizli, and Muğla provinces. Then, allele-specific primers for L1014F, L1014S, and L1014C alleles, and the G119S allele were designed. The presence of these alleles was screened in three populations by allele-specific polymerase chain reaction.
RESULTS
Although L1014S allele frequency was too low in Aydın, Muğla, and Denizli populations, neither L1014F and L1014C nor G119S mutations were found in any population.
CONCLUSION
In this study, L1014S mutation was detected for the first time in the Aegean populations.
Topics: Female; Animals; Alleles; Acetylcholinesterase; Anopheles; Mosquito Vectors; Polymerase Chain Reaction; Mutation
PubMed: 36444406
DOI: 10.4274/tpd.galenos.2022.20592 -
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