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Science (New York, N.Y.) Oct 2023Epistasis between genes is traditionally studied with mutations that eliminate protein activity, but most natural genetic variation is in cis-regulatory DNA and...
Epistasis between genes is traditionally studied with mutations that eliminate protein activity, but most natural genetic variation is in cis-regulatory DNA and influences gene expression and function quantitatively. In this study, we used natural and engineered cis-regulatory alleles in a plant stem-cell circuit to systematically evaluate epistatic relationships controlling tomato fruit size. Combining a promoter allelic series with two other loci, we collected over 30,000 phenotypic data points from 46 genotypes to quantify how allele strength transforms epistasis. We revealed a saturating dose-dependent relationship but also allele-specific idiosyncratic interactions, including between alleles driving a step change in fruit size during domestication. Our approach and findings expose an underexplored dimension of epistasis, in which cis-regulatory allelic diversity within gene regulatory networks elicits nonlinear, unpredictable interactions that shape phenotypes.
Topics: Alleles; Epistasis, Genetic; Fruit; Genetic Variation; Genotype; Phenotype; Solanum lycopersicum; Gene Expression Regulation, Plant; Promoter Regions, Genetic; Gene Dosage
PubMed: 37856609
DOI: 10.1126/science.adi5222 -
Annual Review of Phytopathology Sep 2023Tomato brown rugose fruit virus (ToBRFV) is an emerging tobamovirus. It was first reported in 2015 in Jordan in greenhouse tomatoes and now threatens tomato and pepper... (Review)
Review
Tomato brown rugose fruit virus (ToBRFV) is an emerging tobamovirus. It was first reported in 2015 in Jordan in greenhouse tomatoes and now threatens tomato and pepper crops around the world. ToBRFV is a stable and highly infectious virus that is easily transmitted by mechanical means and via seeds, which enables it to spread locally and over long distances. The ability of ToBRFV to infect tomato plants harboring the commonly deployed resistance genes, as well as pepper plants harboring the resistance alleles under certain conditions, limits the ability to prevent damage from the virus. The fruit production and quality of ToBRFV-infected tomato and pepper plants can be drastically affected, thus significantly impacting their market value. Herein, we review the current information and discuss the latest areas of research on this virus, which include its discovery and distribution, epidemiology, detection, and prevention and control measures, that could help mitigate the ToBRFV disease pandemic.
Topics: Fruit; Pandemics; Solanum lycopersicum; Alleles; Piper nigrum; Tobamovirus
PubMed: 37268006
DOI: 10.1146/annurev-phyto-021622-120703 -
Biomolecules Aug 2023The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular... (Review)
Review
The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca sensors in the endoplasmic reticulum (ER) and, upon Ca store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.
Topics: Animals; Humans; Alleles; Body Fluids; Cardiovascular Diseases; Cell Membrane; Endoplasmic Reticulum; Mammals
PubMed: 37759684
DOI: 10.3390/biom13091284 -
Nature Communications Aug 2023Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which...
Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved.
Topics: Alleles; Causality; Exome; Hope; Information Dissemination
PubMed: 37644014
DOI: 10.1038/s41467-023-40909-3 -
Nature Dec 2023In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA. This is essential for haploinsufficient genes, which require biallelic...
In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA. This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developmental disorders. Whether and how a biallelic or monoallelic state is determined in a cell-type-specific manner at individual loci remains unclear. MSL2 is known for dosage compensation of the male X chromosome in flies. Here we identify a role of MSL2 in regulating allelic expression in mammals. Allele-specific bulk and single-cell analyses in mouse neural progenitor cells revealed that, in addition to the targets showing biallelic downregulation, a class of genes transitions from biallelic to monoallelic expression after MSL2 loss. Many of these genes are haploinsufficient. In the absence of MSL2, one allele remains active, retaining active histone modifications and transcription factor binding, whereas the other allele is silenced, exhibiting loss of promoter-enhancer contacts and the acquisition of DNA methylation. Msl2-knockout mice show perinatal lethality and heterogeneous phenotypes during embryonic development, supporting a role for MSL2 in regulating gene dosage. The role of MSL2 in preserving biallelic expression of specific dosage-sensitive genes sets the stage for further investigation of other factors that are involved in allelic dosage compensation in mammalian cells, with considerable implications for human disease.
Topics: Animals; Female; Male; Mice; Alleles; DNA Methylation; Dosage Compensation, Genetic; Embryonic Development; Enhancer Elements, Genetic; Gene Expression Regulation; Haploinsufficiency; Histones; Mice, Knockout; Promoter Regions, Genetic; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 38030723
DOI: 10.1038/s41586-023-06781-3 -
Proceedings of the National Academy of... Aug 2023PARP1 (poly-ADP ribose polymerase 1) is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes...
PARP1 (poly-ADP ribose polymerase 1) is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin and recruits other DNA repair factors, including XRCC1 and DNA Ligase 3, to maintain genomic stability. Here we show that, in contrast to the normal development of Parp1-null mice, heterozygous expression of catalytically inactive Parp1 (E988A, ) acts in a dominant-negative manner to disrupt murine embryogenesis. As such, all the surviving F1 mice are chimeras with mixed (neoR retention) cells that act similarly to . Pure F2 embryos were found at Mendelian ratios at the E3.5 blastocyst stage but died before E9.5. Compared to cells, genotype and expression-validated pure cells retain significant ADP-ribosylation and PARylation activities but accumulate markedly higher levels of sister chromatid exchange and mitotic bridges. Despite proficiency for homologous recombination and nonhomologous end-joining measured by reporter assays and supported by normal lymphocyte and germ cell development, cells are hypersensitive to base damages, radiation, and Topoisomerase I and II inhibition. The sensitivity of cells to base damages and Topo inhibitors exceed controls. The findings show that the enzymatically inactive PARP1 dominant negatively blocks DNA repair in selective pathways beyond wild-type PARP1 and establishes a crucial physiological difference between PARP1 inactivation vs. deletion. As a result, the expression of enzymatically inactive PARP1 from one allele is sufficient to abrogate murine embryonic development, providing a mechanism for the on-target side effect of PARP inhibitors used for cancer therapy.
Topics: Female; Pregnancy; Animals; Mice; Causality; Alleles; Genotype; Genomic Instability; ADP-Ribosylation
PubMed: 37487079
DOI: 10.1073/pnas.2301972120 -
American Journal of Respiratory and... Jul 2023
Topics: Humans; Child; Cystic Fibrosis; Alleles; Iodine
PubMed: 37167625
DOI: 10.1164/rccm.202305-0785ED -
Plant Communications Mar 2024
Topics: Gene Editing; 3' Untranslated Regions; Alleles; Plants; CRISPR-Cas Systems
PubMed: 37946411
DOI: 10.1016/j.xplc.2023.100745 -
International Journal of Molecular... Sep 2023Imprinted genes play diverse roles in mammalian development, homeostasis, and disease. Most imprinted chromosomal domains express one or more long non-coding RNAs... (Review)
Review
Imprinted genes play diverse roles in mammalian development, homeostasis, and disease. Most imprinted chromosomal domains express one or more long non-coding RNAs (lncRNAs). Several of these lncRNAs are strictly nuclear and their mono-allelic expression controls in the expression of protein-coding genes, often developmentally regulated. Some imprinted lncRNAs act in as well, controlling target gene expression elsewhere in the genome. The regulation of imprinted gene expression-including that of imprinted lncRNAs-is susceptible to stochastic and environmentally triggered epigenetic changes in the early embryo. These aberrant changes persist during subsequent development and have long-term phenotypic consequences. This review focuses on the expression and the - and -regulatory roles of imprinted lncRNAs and describes human disease syndromes associated with their perturbed expression.
Topics: Humans; Animals; RNA, Long Noncoding; Alleles; Embryo, Mammalian; Epigenesis, Genetic; Homeostasis; Mammals
PubMed: 37686455
DOI: 10.3390/ijms241713647 -
Iranian Biomedical Journal Jan 2024Celiac disease (CD) is a complex disorder influenced by genetic and environmental factors. When people with a genetic predisposition to CD consume gluten, an... (Review)
Review
Celiac disease (CD) is a complex disorder influenced by genetic and environmental factors. When people with a genetic predisposition to CD consume gluten, an inflammatory response is triggered in the small intestine, and this reaction can be alleviated by the elimination of gluten from the diet. The clinical manifestations of CD vary greatly from person to person and begin at a young age or in adulthood. Influence of genetic factors on CD development is evident in carriers of the DQ2 and/or DQ8 allele. HLA genotypes are associated with gut colonization by bacteria, particularly in individuals suffering from CD. In addition, beneficial gut microbes are crucial for the production of DPP-4, which plays a key role in immune function, as well as metabolic and intestinal health. Therefore, probiotics have been recommended as a complementary food supplement in CD.
Topics: Humans; Celiac Disease; Glutens; Alleles; Genetic Predisposition to Disease; Genotype
PubMed: 38444380
DOI: 10.61186/ibj.4028