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Trends in Genetics : TIG Jan 2024First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across... (Review)
Review
First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across tissues derived from different germ layers within a given individual. This property, termed systemic interindividual variation (SIV), is attributed to stochastic methylation establishment before germ layer differentiation. Evidence suggests that some putative human MEs are sensitive to environmental exposures in early development. In this review we introduce key concepts pertaining to human MEs, describe methods used to identify MEs in humans, and review their genomic features. We also highlight studies linking DNAm at putative human MEs to early environmental exposures and postnatal (including disease) phenotypes.
Topics: Humans; Animals; Mice; Epigenesis, Genetic; DNA Methylation; Phenotype; Genomics; Alleles
PubMed: 38000919
DOI: 10.1016/j.tig.2023.09.007 -
Current Opinion in Genetics &... Oct 2023Killer meiotic drive elements are selfish genetic entities that manipulate the sexual cycle to promote their own inheritance via destructive means. Two broad classes are... (Review)
Review
Killer meiotic drive elements are selfish genetic entities that manipulate the sexual cycle to promote their own inheritance via destructive means. Two broad classes are sperm killers, typical of animals and plants, and spore killers, which are present in ascomycete fungi. Killer meiotic drive systems operate via toxins that destroy or disable meiotic products bearing the alternative allele. To avoid suicidal autotargeting, cells that bear these selfish elements must either lack the toxin target, or express an antidote. Historically, these systems were presumed to require large nonrecombining haplotypes to link multiple functional interacting loci. However, recent advances on fungal spore killers reveal that numerous systems are enacted by single genes, and similar molecular genetic studies in Drosophila pinpoint individual loci that distort gamete sex. Notably, many meiotic drivers duplicate readily, forming gene families that can have complex interactions within and between species, and providing substrates for their rapid functional diversification. Here, we summarize the known families of meiotic drivers in fungi and fruit flies, and highlight shared principles about their evolution and proliferation that promote the spread of these noxious genes.
Topics: Male; Animals; Semen; Alleles; Drosophila; Germ Cells; Cell Proliferation
PubMed: 37625205
DOI: 10.1016/j.gde.2023.102100 -
International Journal of Molecular... Nov 2023Autism spectrum disorder (ASD) is a neurodevelopmental disability and recent evidence suggests that autistic adults are more likely to develop Alzheimer's disease (Alz)...
Autism spectrum disorder (ASD) is a neurodevelopmental disability and recent evidence suggests that autistic adults are more likely to develop Alzheimer's disease (Alz) and other dementias compared to neurotypical (NT) adults. The ε4-allele of the Apolipoprotein E () gene is the strongest genetic risk factor for Alz and negatively impacts cognition in middle-aged and older (MA+) adults. This study aimed to determine the impact of the ε4-allele on verbal learning and memory in MA+ autistic adults (ages 40-71 years) compared to matched NT adults. Using the Auditory Verbal Learning Test (AVLT), we found that ε4 carriers performed worse on short-term memory and verbal learning across diagnosis groups, but there was no interaction with diagnosis. In exploratory analyses within sex and diagnosis groups, only autistic men carrying ε4 showed worse verbal learning ( = 0.02), compared to autistic men who were not carriers. Finally, the ε4-allele did not significantly affect long-term memory in this sample. These findings replicate previous work indicating that the ε4-allele negatively impacts short-term memory and verbal learning in MA+ adults and presents new preliminary findings that MA+ autistic men may be vulnerable to the effects of ε4 on verbal learning. Future work with a larger sample is needed to determine if autistic women may also be vulnerable.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Alleles; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Autism Spectrum Disorder; Autistic Disorder; Genotype; Neuropsychological Tests; Verbal Learning
PubMed: 37958971
DOI: 10.3390/ijms242115988 -
Nucleic Acids Research Sep 2023In adaptive immune receptor repertoire analysis, determining the germline variable (V) allele associated with each T- and B-cell receptor sequence is a crucial step....
In adaptive immune receptor repertoire analysis, determining the germline variable (V) allele associated with each T- and B-cell receptor sequence is a crucial step. This process is highly impacted by allele annotations. Aligning sequences, assigning them to specific germline alleles, and inferring individual genotypes are challenging when the repertoire is highly mutated, or sequence reads do not cover the whole V region. Here, we propose an alternative naming scheme for the V alleles, as well as a novel method to infer individual genotypes. We demonstrate the strengths of the two by comparing their outcomes to other genotype inference methods. We validate the genotype approach with independent genomic long-read data. The naming scheme is compatible with current annotation tools and pipelines. Analysis results can be converted from the proposed naming scheme to the nomenclature determined by the International Union of Immunological Societies (IUIS). Both the naming scheme and the genotype procedure are implemented in a freely available R package (PIgLET https://bitbucket.org/yaarilab/piglet). To allow researchers to further explore the approach on real data and to adapt it for their uses, we also created an interactive website (https://yaarilab.github.io/IGHV_reference_book).
Topics: Alleles; Genomics; Genotype; Receptors, Antigen, B-Cell; Immunoglobulin Heavy Chains
PubMed: 37548401
DOI: 10.1093/nar/gkad603 -
Neurology Jul 2023Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients'...
BACKGROUND AND OBJECTIVES
Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease.
METHODS
The study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A () (rs12608932), calmodulin binding transcription activator 1 () (rs2412208), solute carrier family 11 member 2 () (rs407135), and zinc finger protein 512B () (rs2275294) variants, as well as ataxin-2 () polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 () GGGGCC intronic expansions (≥30).
RESULTS
The median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only (2.51 years, IQR 1.74-3.82; = 0.016), (1.82 years, IQR 1.08-2.33; < 0.001), and (2.3 years, IQR 1.3-3.9; < 0.001) significantly reduced survival. In Cox multivariable analysis, also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with and alleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants ( < 0.001); the survival of patients with alleles and intermediate polyQ repeats was 1.75 years (0.84-2.18) ( < 0.001); the survival of patients with polyQ repeats and allele was 1.33 years (0.84-1.75) ( < 0.001); the survival of patients with and allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes.
DISCUSSION
We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.
Topics: Humans; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Alleles; Phenotype; Prognosis
PubMed: 37202167
DOI: 10.1212/WNL.0000000000207367 -
Nature Communications Aug 2023To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however,...
To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.
Topics: Humans; Male; Polymorphism, Single Nucleotide; Chromatin; Acetylation; Alleles; Nucleotides; Neoplasms
PubMed: 37612286
DOI: 10.1038/s41467-023-40616-z -
Cell Reports Aug 2023The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However,...
The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.
Topics: Humans; Alleles; Astrocytes; Cell Proliferation; Clusterin; Genetic Predisposition to Disease; Induced Pluripotent Stem Cells; Oligodendrocyte Precursor Cells; Polymorphism, Single Nucleotide
PubMed: 37494190
DOI: 10.1016/j.celrep.2023.112841 -
Cells Nov 2023Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate...
Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes ( = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in rs2230199 and rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. , validated between the iAMD vs. normal comparison, and , , , , , , and , validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes and suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.
Topics: Humans; Alleles; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration; Gene Expression; Cytoskeletal Proteins; Phosphate-Binding Proteins; Carrier Proteins; Nerve Tissue Proteins; GTP-Binding Proteins; Serine-Type D-Ala-D-Ala Carboxypeptidase
PubMed: 38067097
DOI: 10.3390/cells12232668 -
International Journal of Molecular... Aug 2023Mitogen-activated protein kinase cascades play important roles in various biological programs in plants, including immune responses, but the underlying mechanisms remain...
Mitogen-activated protein kinase cascades play important roles in various biological programs in plants, including immune responses, but the underlying mechanisms remain elusive. Here, we identified the lesion mimic mutant () and determined that the mutant harbored a loss-of-function allele for . developed reddish-brown spots on its leaves at the heading stage, as well as on husks. Compared to the wild type, the mutant exhibited enhanced resistance to the fungal pathogen () and to the bacterial pathogen pv. (). OsMKK6 interacted with OsMPK4 (MITOGEN-ACTIVATED KINASE 4) in vivo, and OsMKK6 phosphorylated OsMPK4 in vitro. The mutant is also a lesion mimic mutant, with reddish-brown spots on its leaves and husks. Pathogen-related genes were significantly upregulated in , and this mutant exhibited enhanced resistance to compared to the wild type. Our results indicate that OsMKK6 and OsMPK4 form a cascade that regulates immune responses in rice.
Topics: Oryza; Disease Resistance; Mitogens; Alleles
PubMed: 37628859
DOI: 10.3390/ijms241612678 -
Molecular Biology and Evolution Oct 2023Natural selection signatures across Japanese subpopulations are under-explored. Here we conducted genome-wide selection scans with 622,926 single nucleotide...
Natural selection signatures across Japanese subpopulations are under-explored. Here we conducted genome-wide selection scans with 622,926 single nucleotide polymorphisms for 20,366 Japanese individuals, who were recruited from the main-islands of Japanese Archipelago (Hondo) and the Ryukyu Archipelago (Ryukyu), representing two major Japanese subpopulations. The integrated haplotype score (iHS) analysis identified several signals in one or both subpopulations. We found a novel candidate locus at IKZF2, especially in Ryukyu. Significant signals were observed in the major histocompatibility complex region in both subpopulations. The lead variants differed and demonstrated substantial allele frequency differences between Hondo and Ryukyu. The lead variant in Hondo tags HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01, a haplotype specific to Japanese and Korean. While in Ryukyu, the lead variant tags DRB1*15:01-DQB1*06:02, which had been recognized as a genetic risk factor for narcolepsy. In contrast, it is reported to confer protective effects against type 1 diabetes and human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis. The FastSMC analysis identified 8 loci potentially affected by selection within the past 20-150 generations, including 2 novel candidate loci. The analysis also showed differences in selection patterns of ALDH2 between Hondo and Ryukyu, a gene recognized to be specifically targeted by selection in East Asian. In summary, our study provided insights into the selection signatures within the Japanese and nominated potential sources of selection pressure.
Topics: Humans; Aldehyde Dehydrogenase, Mitochondrial; Alleles; Asian People; East Asian People; Gene Frequency; Haplotypes; Polymorphism, Single Nucleotide; Selection, Genetic; Japan
PubMed: 37903429
DOI: 10.1093/molbev/msad231