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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 -
Proceedings of the National Academy of... Sep 2010We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number...
We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of "ASCAT profiles" (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in near-triploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development.
Topics: Alleles; Breast Neoplasms; Carcinoma; Female; Gene Dosage; Genes, Neoplasm; Genome, Human; Humans; Ploidies
PubMed: 20837533
DOI: 10.1073/pnas.1009843107 -
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 -
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 -
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 -
Scientific Reports May 2022The emergence of genome-wide association studies (GWAS) has led to the creation of large repositories of human genetic variation, creating enormous opportunities for... (Meta-Analysis)
Meta-Analysis
The emergence of genome-wide association studies (GWAS) has led to the creation of large repositories of human genetic variation, creating enormous opportunities for genetic research and worldwide collaboration. Methods that are based on GWAS summary statistics seek to leverage such records, overcoming barriers that often exist in individual-level data access while also offering significant computational savings. Such summary-statistics-based applications include GWAS meta-analysis, with and without sample overlap, and case-case GWAS. We compare performance of leading methods for summary-statistics-based genomic analysis and also introduce a novel framework that can unify usual summary-statistics-based implementations via the reconstruction of allelic and genotypic frequencies and counts (ReACt). First, we evaluate ASSET, METAL, and ReACt using both synthetic and real data for GWAS meta-analysis (with and without sample overlap) and find that, while all three methods are comparable in terms of power and error control, ReACt and METAL are faster than ASSET by a factor of at least hundred. We then proceed to evaluate performance of ReACt vs an existing method for case-case GWAS and show comparable performance, with ReACt requiring minimal underlying assumptions and being more user-friendly. Finally, ReACt allows us to evaluate, for the first time, an implementation for calculating polygenic risk score (PRS) for groups of cases and controls based on summary statistics. Our work demonstrates the power of GWAS summary-statistics-based methodologies and the proposed novel method provides a unifying framework and allows further extension of possibilities for researchers seeking to understand the genetics of complex disease.
Topics: Alleles; Genome-Wide Association Study; Genotype; Humans; Phenotype; Polymorphism, Single Nucleotide
PubMed: 35581276
DOI: 10.1038/s41598-022-12185-6 -
Human Molecular Genetics Oct 2010Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these... (Review)
Review
Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these types of allelic asymmetries, along with allele-specific transcription factor binding (ASTF), have turned out to be far more pervasive-affecting many non-imprinted autosomal genes in normal human tissues. ASM, ASE and ASTF have now been mapped genome-wide by microarray-based methods and NextGen sequencing. Multiple studies agree that all three types of allelic asymmetries, as well as the related phenomena of expression and methylation quantitative trait loci, are mostly accounted for by cis-acting regulatory polymorphisms. The precise mechanisms by which this occurs are not yet understood, but there are some testable hypotheses and already a few direct clues. Future challenges include achieving higher resolution maps to locate the epicenters of cis-regulated ASM, using this information to test mechanistic models, and applying genome-wide maps of ASE/ASM/ASTF to pinpoint functional regulatory polymorphisms influencing disease susceptibility.
Topics: Alleles; Binding Sites; DNA Methylation; Genomic Imprinting; Humans; Transcription Factors
PubMed: 20855472
DOI: 10.1093/hmg/ddq376 -
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 -
Epigenetics Mar 2020We previously identified sequence-dependent allele-specific methylation (sd-ASM) in adult human peripheral blood leukocytes, in which ASM occurs in cis depending on...
We previously identified sequence-dependent allele-specific methylation (sd-ASM) in adult human peripheral blood leukocytes, in which ASM occurs in cis depending on adjacent polymorphic sequences. A number of groups have identified sd-ASM sites in the human and mouse genomes, illustrating the prevalence of sd-ASM in mammalian genomes. In addition, sd-ASM can lead to sequence-dependent allele-specific expression of neighbouring genes. Imprinted genes also often exhibit parent-of-origin-dependent allele-specific methylation (pd-ASM), which causes parent-of-origin-dependent allele-specific expression. However, whether most of the already known sd-ASM and pd-ASM sites are methylated or hydroxymethylated remains unclear due to technical restrictions. Accordingly, a novel method that enables examination of allelic methylation and hydroxymethylation status and also overcomes the drawbacks of conventional methods is needed. Such a method could also be used to elucidate the mechanisms underlying polymorphism-associated inter-individual differences in disease susceptibility and the mechanism of genomic imprinting. Here, we developed a simple method to determine allelic hydroxymethylation status and identified novel sequence- and parent-of-origin-dependent allele-specific hydroxymethylation sites. Correlation analyses of TF binding sequences and methylation or hydroxymethylation between three mouse strains revealed the involvement of in strain-specific methylation and hydroxymethylation in exon 7 of .
Topics: Alleles; Animals; DNA Methylation; Epigenomics; Mice; Mice, Inbred C57BL; Protein Binding; Sequence Analysis, DNA; Transcription Factors
PubMed: 31533538
DOI: 10.1080/15592294.2019.1664228 -
Bioscience, Biotechnology, and... Nov 2007In many organisms, allelic diversity generates phenotypic variations and contributes to many events, such as development, adaptation to changing environment, and genome... (Review)
Review
In many organisms, allelic diversity generates phenotypic variations and contributes to many events, such as development, adaptation to changing environment, and genome evolution. Allelic diversity is generally defined by the difference in nucleotide sequences that code for a gene. However, a heritable epigenetic modification, in which the modification is attributable to the degree of methylation of a gene and not to the change in its sequence, sometimes occurs and can affect the level of gene expression by reducing its transcriptional level. Some examples of epigenetic phenomena mediated by allele-specific DNA methylation in plants found to date include genomic imprinting, nucleolar dominance, and paramutation. Unlike the case in mammals, epigenetic modifications of plant genes are thought to be mitotically and meiotically stable, but recent studies of allele-specific demethylation at the FWA and MEDEA loci and recessive allele-specific methylation of Brassica self-incompatibility alleles indicate that DNA methylation patterns in plants can vary temporally and spatially in each generation. In this review, we describe various epigenetic phenomena regulated by allele-specific DNA methylation and their possible underlying mechanisms.
Topics: Alleles; DNA Methylation; DNA, Plant; Gene Expression Regulation, Plant; Gene Silencing; Genomic Imprinting; Heterochromatin; Plants; RNA; RNA Interference
PubMed: 17986765
DOI: 10.1271/bbb.70339