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G3 (Bethesda, Md.) Feb 2023This paper proposes a solution to a long-standing problem concerning the joint distribution of allelic identity by descent between two individuals at two linked loci....
This paper proposes a solution to a long-standing problem concerning the joint distribution of allelic identity by descent between two individuals at two linked loci. Such distributions have important applications across various fields of genetics, and detailed formulas for selected relationships appear scattered throughout the literature. However, these results were obtained essentially by brute force, with no efficient method available for general pedigrees. The recursive algorithm described in this paper, and its implementation in R, allow efficient calculation of two-locus identity coefficients in any pedigree. As a result, many existing procedures and techniques may, for the first time, be applied to complex and inbred relationships. Two such applications are discussed, concerning the expected likelihood ratio in forensic kinship testing, and variances in realized relatedness.
Topics: Humans; Pedigree; Algorithms; Alleles; Models, Genetic
PubMed: 36525359
DOI: 10.1093/g3journal/jkac326 -
Methods in Molecular Biology (Clifton,... 2023Targeted locus amplification (TLA) allows for the detection of all genetic variation (including structural variation) in a genomic region of interest. As TLA is based on...
Targeted locus amplification (TLA) allows for the detection of all genetic variation (including structural variation) in a genomic region of interest. As TLA is based on proximity ligation, variants can be linked to each other, thereby enabling allelic phasing and the generation of haplotypes. This allows for the study of genetic variants in an allele-specific manner. Here, we provide a step-by-step protocol for TLA sample preparation and a complete bioinformatics pipeline for the allelic phasing of TLA data. Additionally, to illustrate the protocol, we show the ability of TLA to re-sequence and haplotype the complete cystic fibrosis transmembrane (CFTR) gene (> 200 kb in size) from patient-derived intestinal organoids.
Topics: Humans; Haplotypes; Genomics; Alleles; Cystic Fibrosis
PubMed: 36335490
DOI: 10.1007/978-1-0716-2819-5_2 -
Methods in Molecular Biology (Clifton,... 2024The diagnosis of alpha-1-antitrypsin (A1AT) deficiency is established by quantitation of protein concentration in serum (immunoassay) followed by determination of...
The diagnosis of alpha-1-antitrypsin (A1AT) deficiency is established by quantitation of protein concentration in serum (immunoassay) followed by determination of specific allelic variants by phenotyping (isoelectric focusing (IEF) gel electrophoresis) and/or allele-specific genotyping. Various phenotyping and genotyping methodologies are available, and each has their own advantages and disadvantages. As an alternative, mass spectrometry is emerging as a powerful tool in the identification and quantitation of proteins and peptides. The method described here, referred to as proteotyping, is a proteomic method using trypsin digestion and tandem mass spectrometry that detects the most common deficiency alleles, S and Z, associated with A1AT deficiency.This qualitative mass spectrometry method is based on the principle that the S and Z mutations lead to amino acid changes which result in a change in the mass of the A1AT protein. When the A1AT protein is proteolytically digested, multiple peptides are generated, two of which include the sites of the S and Z mutations, respectively. Peptides generated from wild-type A1AT (M alleles) differ in sequence and mass from peptides generated from the S and Z alleles at these two specific locations. The mass difference allows for differentiation of S and Z peptides, representing the deficiency alleles, from non-S and non-Z peptides, representing the wild-type alleles (M). Interpretation of the peptide patterns in conjunction with A1AT quantitation by immunoassay allows for an accurate assessment for the presence of deficiency alleles in the majority of patients.
Topics: Humans; Liquid Chromatography-Mass Spectrometry; Chromatography, Liquid; Proteomics; Tandem Mass Spectrometry; Alleles
PubMed: 38108970
DOI: 10.1007/978-1-0716-3605-3_9 -
Human Genomics Feb 2022CYP2D6 is a key drug-metabolizing enzyme implicated in the biotransformation of approximately 25% of currently prescribed drugs. Interindividual and interethnic... (Review)
Review
CYP2D6 is a key drug-metabolizing enzyme implicated in the biotransformation of approximately 25% of currently prescribed drugs. Interindividual and interethnic differences in CYP2D6 enzymatic activity, and hence variability in substrate drug efficacy and safety, are attributed to a highly polymorphic corresponding gene. This study aims at reviewing the frequencies of the most clinically relevant CYP2D6 alleles in the Arabs countries. Articles published before May 2021 that reported CYP2D6 genotype and allelic frequencies in the Arab populations of the Middle East and North Africa (MENA) region were retrieved from PubMed and Google Scholar databases. This review included 15 original articles encompassing 2737 individuals from 11 countries of the 22 members of the League of Arab States. Active CYP2D6 gene duplications reached the highest frequencies of 28.3% and 10.4% in Algeria and Saudi Arabia, respectively, and lowest in Egypt (2.41%) and Palestine (4.9%). Frequencies of the loss-of-function allele CYP2D6*4 ranged from 3.5% in Saudi Arabia to 18.8% in Egypt. The disparity in frequencies of the reduced-function CYP2D6*10 allele was perceptible, with the highest frequency reported in Jordan (14.8%) and the lowest in neighboring Palestine (2%), and in Algeria (0%). The reduced-function allele CYP2D6*41 was more prevalent in the Arabian Peninsula countries; Saudi Arabia (18.4%) and the United Arab Emirates (15.2%), in comparison with the Northern Arab-Levantine Syria (9.7%) and Algeria (8.3%). Our study demonstrates heterogeneity of CYP2D6 alleles among Arab populations. The incongruities of the frequencies of alleles in neighboring countries with similar demographic composition emphasize the necessity for harmonizing criteria of genotype assignment and conducting comprehensive studies on larger MENA Arab populations to determine their CYP2D6 allelic makeup and improve therapeutic outcomes of CYP2D6- metabolized drugs.
Topics: Alleles; Arabs; Cytochrome P-450 CYP2D6; Gene Frequency; Humans; Polymorphism, Genetic
PubMed: 35123571
DOI: 10.1186/s40246-022-00378-z -
Genome Biology and Evolution Aug 2020Allele-specific expression is when one allele of a gene shows higher levels of expression compared with the other allele, in a diploid organism. Recent work has...
Allele-specific expression is when one allele of a gene shows higher levels of expression compared with the other allele, in a diploid organism. Recent work has identified allele-specific expression in a number of Hymenopteran species. However, the molecular mechanism which drives this allelic expression bias remains unknown. In mammals, DNA methylation is often associated with genes which show allele-specific expression. DNA methylation systems have been described in species of Hymenoptera, providing a candidate mechanism. Using previously generated RNA-Seq and whole-genome bisulfite sequencing from reproductive and sterile bumblebee (Bombus terrestris) workers, we have identified genome-wide allele-specific expression and allele-specific DNA methylation. The majority of genes displaying allele-specific expression are common between reproductive and sterile workers and the proportion of allele-specific expression bias generally varies between genetically distinct colonies. We have also identified genome-wide allele-specific DNA methylation patterns in both reproductive and sterile workers, with reproductive workers showing significantly more genes with allele-specific methylation. Finally, there is no significant overlap between genes showing allele-specific expression and allele-specific methylation. These results indicate that cis-acting DNA methylation does not directly drive genome-wide allele-specific expression in this species.
Topics: Alleles; Animals; Bees; DNA Methylation; Female; Gene Expression; Genome, Insect
PubMed: 32597949
DOI: 10.1093/gbe/evaa132 -
Methods in Molecular Biology (Clifton,... 2017Common terms used in statistical genetics with multiple meanings are explained and the terminology used in subsequent chapters is defined. Statistical human genetics has...
Common terms used in statistical genetics with multiple meanings are explained and the terminology used in subsequent chapters is defined. Statistical human genetics has existed as a discipline for over a century, and during that time the meanings of many of the terms used have evolved, largely driven by molecular discoveries, to the point that molecular geneticists, statistical geneticists, and statisticians often have difficulty understanding each other. It is therefore imperative, now that so much of molecular genetics is becoming an in silico and statistical science, that we have a well-defined, common terminology.
Topics: Alleles; Epistasis, Genetic; Genetic Loci; Genetic Pleiotropy; Genetics; Genotype; Humans; Linkage Disequilibrium; Mutation; Phenotype; Polymorphism, Genetic; Quantitative Trait Loci; Statistics as Topic; Terminology as Topic
PubMed: 28980238
DOI: 10.1007/978-1-4939-7274-6_1 -
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 -
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 -
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 -
HLA Jan 2023Three novel HLA-DQB1 alleles HLA-DQB1*02:186, -DQB1*06:02:49, and -DQB1*06:391 alleles detected during routine next generation sequencing.
Three novel HLA-DQB1 alleles HLA-DQB1*02:186, -DQB1*06:02:49, and -DQB1*06:391 alleles detected during routine next generation sequencing.
Topics: Humans; Alleles
PubMed: 36114775
DOI: 10.1111/tan.14820