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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 -
Forensic Science International. Genetics May 2022The Hardy-Weinberg law is shown to be transitive in the sense that a multi-allelic polymorphism that is in equilibrium will retain its equilibrium status if any allele...
The Hardy-Weinberg law is shown to be transitive in the sense that a multi-allelic polymorphism that is in equilibrium will retain its equilibrium status if any allele together with its corresponding genotypes is deleted from the population. Similarly, the transitivity principle also applies if alleles are joined, which leads to the summation of allele frequencies and their corresponding genotype frequencies. These basic polymorphism properties are intuitive, but they have apparently not been formalized or investigated. This article provides a straightforward proof of the transitivity principle, and its usefulness in genetic data analysis is explored, using high-quality autosomal microsatellite databases from the US National Institute of Standards and Technology. We address the reduction of multi-allelic polymorphisms to variants with fewer alleles, two in the limit. Equilibrium test results obtained with the original and reduced polymorphisms are generally observed to be coherent, in particular when results obtained with length-based and sequence-based microsatellites are compared. We exploit the transitivity principle in order to identify disequilibrium-related alleles, and show its usefulness for detecting population substructure and genotyping problems that relate to null alleles and allele imbalance.
Topics: Alleles; Gene Frequency; Genotype; Humans; Polymorphism, Genetic
PubMed: 35313226
DOI: 10.1016/j.fsigen.2022.102680 -
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 -
Planta Jun 2023The present review illustrates a comprehensive overview of the allele mining for genetic improvement in vegetable crops, and allele exploration methods and their... (Review)
Review
The present review illustrates a comprehensive overview of the allele mining for genetic improvement in vegetable crops, and allele exploration methods and their utilization in various applications related to pre-breeding of economically important traits in vegetable crops. Vegetable crops have numerous wild descendants, ancestors and terrestrial races that could be exploited to develop high-yielding and climate-resilient varieties resistant/tolerant to biotic and abiotic stresses. To further boost the genetic potential of economic traits, the available genomic tools must be targeted and re-opened for exploitation of novel alleles from genetic stocks by the discovery of beneficial alleles from wild relatives and their introgression to cultivated types. This capability would be useful for giving plant breeders direct access to critical alleles that confer higher production, improve bioactive compounds, increase water and nutrient productivity as well as biotic and abiotic stress resilience. Allele mining is a new sophisticated technique for dissecting naturally occurring allelic variants in candidate genes that influence important traits which could be used for genetic improvement of vegetable crops. Target-induced local lesions in genomes (TILLINGs) is a sensitive mutation detection avenue in functional genomics, particularly wherein genome sequence information is limited or not available. Population exposure to chemical mutagens and the absence of selectivity lead to TILLING and EcoTILLING. EcoTILLING may lead to natural induction of SNPs and InDels. It is anticipated that as TILLING is used for vegetable crops improvement in the near future, indirect benefits will become apparent. Therefore, in this review we have highlighted the up-to-date information on allele mining for genetic enhancement in vegetable crops and methods of allele exploration and their use in pre-breeding for improvement of economic traits.
Topics: Vegetables; Alleles; Plant Breeding; Crops, Agricultural; Climate
PubMed: 37311932
DOI: 10.1007/s00425-023-04176-2 -
Biochemistry. Biokhimiia Jan 2024The review discusses the mechanisms of monoallelic expression, such as genomic imprinting, in which gene transcription depends on the parental origin of the allele, and... (Review)
Review
The review discusses the mechanisms of monoallelic expression, such as genomic imprinting, in which gene transcription depends on the parental origin of the allele, and random monoallelic transcription. Data on the regulation of gene activity in the imprinted regions are summarized with a particular focus on the areas controlling imprinting and factors influencing the variability of the imprintome. The prospects of studies of the monoallelic expression are discussed.
Topics: Genomic Imprinting; DNA Methylation; Alleles
PubMed: 38467547
DOI: 10.1134/S000629792401005X -
Heredity Jan 2022The two alleles an individual carries at a locus are identical by descent (ibd) if they have descended from a single ancestral allele in a reference population, and the...
The two alleles an individual carries at a locus are identical by descent (ibd) if they have descended from a single ancestral allele in a reference population, and the probability of such identity is the inbreeding coefficient of the individual. Inbreeding coefficients can be predicted from pedigrees with founders constituting the reference population, but estimation from genetic data is not possible without data from the reference population. Most inbreeding estimators that make explicit use of sample allele frequencies as estimates of allele probabilities in the reference population are confounded by average kinships with other individuals. This means that the ranking of those estimates depends on the scope of the study sample and we show the variation in rankings for common estimators applied to different subdivisions of 1000 Genomes data. Allele-sharing estimators of within-population inbreeding relative to average kinship in a study sample, however, do have invariant rankings across all studies including those individuals. They are unbiased with a large number of SNPs. We discuss how allele sharing estimates are the relevant quantities for a range of empirical applications.
Topics: Alleles; Gene Frequency; Humans; Inbreeding; Models, Genetic; Pedigree; Polymorphism, Single Nucleotide
PubMed: 34824382
DOI: 10.1038/s41437-021-00471-4 -
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 -
HLA Jul 2023Genetic variation in the MICA and MICB genes located within the major histocompatibility complex region has been reported to be associated with transplantation outcome...
Genetic variation in the MICA and MICB genes located within the major histocompatibility complex region has been reported to be associated with transplantation outcome and susceptibility to autoimmune diseases and infections. Only limited data of polymorphism in these genes in different populations are available. We here report allelic variation at 2-field resolution and the haplotypes of the MICA and MICB genes in Finland (n = 1032 individuals), a north European population with historical bottleneck and founder effects. Altogether 24 MICA and 18 MICB alleles were found, forming 70 estimated MICA-MICB haplotypes. As compared to other populations frequency differences were found, for example, MICA*010:01 was found to be at an allele frequency of 0.133 in Finland which is higher than in other European populations (0.021-0.077), but close to Asian populations (0.151-0.220). Three novel alleles with amino acid change are described. The results demonstrate a relatively high level of polymorphism and population differences in MICA and MICB allele distribution.
Topics: Humans; Alleles; Histocompatibility Antigens Class I; Finland; Polymorphism, Genetic; Gene Frequency; Haplotypes
PubMed: 36919857
DOI: 10.1111/tan.15023 -
Methods in Molecular Biology (Clifton,... 2019Allele-specific expression is traditionally studied by bulk RNA sequencing, which measures average gene expression across cells. Single-cell RNA sequencing (scRNA-seq)...
Allele-specific expression is traditionally studied by bulk RNA sequencing, which measures average gene expression across cells. Single-cell RNA sequencing (scRNA-seq) allows the comparison of expression distribution between the two alleles of a diploid organism, and characterization of allele-specific bursting. Here we describe SCALE, a bioinformatic and statistical framework for allele-specific gene expression analysis by scRNA-seq. SCALE estimates genome-wide bursting kinetics at the allelic level while accounting for technical bias and other complicating factors such as cell size. SCALE detects genes with significantly different bursting kinetics between the two alleles, as well as genes where the two alleles exhibit non-independent bursting processes. Here, we illustrate SCALE on a mouse blastocyst single-cell dataset with step-by-step demonstration from the upstream bioinformatic processing to the downstream biological interpretation of SCALE's output.
Topics: Algorithms; Alleles; Animals; Blastocyst; Computational Biology; Diploidy; Gene Expression; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Mice; RNA; Sequence Analysis, RNA; Single-Cell Analysis; Software
PubMed: 30758826
DOI: 10.1007/978-1-4939-9057-3_11 -
Trends in Ecology & Evolution Mar 2020The particular combinations of alleles that define haplotypes along individual chromosomes can be determined with increasing ease and accuracy by using current... (Review)
Review
The particular combinations of alleles that define haplotypes along individual chromosomes can be determined with increasing ease and accuracy by using current sequencing technologies. Beyond allele frequencies, haplotype data collected in population samples contain information about the history of allelic associations in gene genealogies, and this is of tremendous potential for conservation genomics. We provide an overview of how haplotype information can be used to assess historical demography, gene flow, selection, and the evolutionary outcomes of hybridization across different timescales relevant to conservation issues. We address technical aspects of applying such approaches to nonmodel species. We conclude that there is much to be gained by integrating haplotype-based analyses in future conservation genomics studies.
Topics: Alleles; Gene Flow; Gene Frequency; Genomics; Haplotypes
PubMed: 31810774
DOI: 10.1016/j.tree.2019.10.012