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Nature Aug 2021The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile... (Review)
Review
The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as 'junk DNA' and 'molecular parasites'. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.
Topics: Aging; Animals; DNA Damage; Disease; Gene Silencing; Genome, Human; Genomics; Humans; Immunity, Innate; Retroelements
PubMed: 34349292
DOI: 10.1038/s41586-021-03542-y -
Biomolecules May 2021Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine [...].
Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine [...].
Topics: Animals; Biochemistry; Disease; Homocysteine; Humans; Molecular Biology
PubMed: 34063494
DOI: 10.3390/biom11050737 -
Science (New York, N.Y.) Oct 2022Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic... (Review)
Review
Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic cellular barcodes, paired with single-cell readouts of cell state, have markedly increased our knowledge of clonal dynamics and genealogies of the cells that compose a variety of tissues and organs. These advances hold promise to redefine our view of human disease. Here, we provide an overview of cellular barcoding approaches, discuss applications to gain new insights into disease mechanisms, and provide an outlook on future applications. We discuss unanticipated insights gained through barcoding in studies of cancer and blood cell production and describe how barcoding can be applied to a growing array of medical fields, particularly with the increasing recognition of clonal contributions in human diseases.
Topics: Humans; DNA Barcoding, Taxonomic; Clonal Evolution; Disease; Single-Cell Analysis
PubMed: 36227997
DOI: 10.1126/science.abm5874 -
Science (New York, N.Y.) May 2023Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown...
Most variants associated with complex traits and diseases identified by genome-wide association studies (GWAS) map to noncoding regions of the genome with unknown effects. Using ancestrally diverse, biobank-scale GWAS data, massively parallel CRISPR screens, and single-cell transcriptomic and proteomic sequencing, we discovered 124 -target genes of 91 noncoding blood trait GWAS loci. Using precise variant insertion through base editing, we connected specific variants with gene expression changes. We also identified -effect networks of noncoding loci when target genes encoded transcription factors or microRNAs. Networks were themselves enriched for GWAS variants and demonstrated polygenic contributions to complex traits. This platform enables massively parallel characterization of the target genes and mechanisms of human noncoding variants in both and .
Topics: Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Genetic Predisposition to Disease; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Proteomics; Quantitative Trait Loci; Single-Cell Analysis; Multifactorial Inheritance; Blood Cells; RNA-Seq; Disease
PubMed: 37141313
DOI: 10.1126/science.adh7699 -
Annual Review of Pathology Jan 2020The human eosinophil has long been thought to favorably influence innate mucosal immunity but at times has also been incriminated in disease pathophysiology. Research... (Review)
Review
The human eosinophil has long been thought to favorably influence innate mucosal immunity but at times has also been incriminated in disease pathophysiology. Research into eosinophil biology has uncovered a number of interesting contributions by eosinophils to health and disease. However, it appears that not all eosinophils from all species are created equal. It remains unclear, for example, exactly how having eosinophils benefits the human host when helminth infections in the developed world have become scarce. This review focuses on our current state of knowledge as it relates to human eosinophils. When information is lacking, we discuss lessons learned from mouse studies that may or may not directly apply to human biology and disease. It is an exciting time to be an "eosinophilosopher" because the use of biologic agents that selectively target eosinophils provides an unprecedented opportunity to define the contribution of this cell to eosinophil-associated human diseases.
Topics: Animals; Disease; Eosinophils; Helminthiasis; Humans; Immunity, Innate; Leukocyte Count; Mice
PubMed: 31977298
DOI: 10.1146/annurev-pathmechdis-012419-032756 -
Science (New York, N.Y.) May 2022Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we...
Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.
Topics: Biomarkers; Cell Nucleus; Disease; Genome-Wide Association Study; Humans; Organ Specificity; Phenotype; RNA-Seq
PubMed: 35549429
DOI: 10.1126/science.abl4290 -
Nature Reviews. Molecular Cell Biology Dec 2020Non-homologous DNA end joining (NHEJ) is the predominant repair mechanism of any type of DNA double-strand break (DSB) during most of the cell cycle and is essential for... (Review)
Review
Non-homologous DNA end joining (NHEJ) is the predominant repair mechanism of any type of DNA double-strand break (DSB) during most of the cell cycle and is essential for the development of antigen receptors. Defects in NHEJ result in sensitivity to ionizing radiation and loss of lymphocytes. The most critical step of NHEJ is synapsis, or the juxtaposition of the two DNA ends of a DSB, because all subsequent steps rely on it. Recent findings show that, like the end processing step, synapsis can be achieved through several mechanisms. In this Review, we first discuss repair pathway choice between NHEJ and other DSB repair pathways. We then integrate recent insights into the mechanisms of NHEJ synapsis with updates on other steps of NHEJ, such as DNA end processing and ligation. Finally, we discuss NHEJ-related human diseases, including inherited disorders and neoplasia, which arise from rare failures at different NHEJ steps.
Topics: Animals; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Disease; Genetic Diseases, Inborn; Humans; Neoplasms; Signal Transduction
PubMed: 33077885
DOI: 10.1038/s41580-020-00297-8 -
Molecules (Basel, Switzerland) Aug 2021Black garlic (BG) is a form of aged garlic obtained from raw garlic () via Millard reaction under high temperature (60-90 °C) and humidity (70-90%) for a period of... (Review)
Review
Black garlic (BG) is a form of aged garlic obtained from raw garlic () via Millard reaction under high temperature (60-90 °C) and humidity (70-90%) for a period of time. Several studies reported higher contents of water-soluble antioxidants compounds (S-allyl cysteine, S-allyl-mercapto cysteine), 5-hydroxymethylfurfural, organosulfur compounds, polyphenol, volatile compounds, and products of other Millard reactions compared to fresh garlic after the thermal processing. Recent studies have demonstrated that BG and its bioactive compounds possess a wide range of biological activities and pharmacological properties that preserve and show better efficacy in preventing different types of diseases. Most of these benefits can be attributed to its anti-oxidation, anti-inflammation, anti-obesity, hepatoprotection, hypolipidemia, anti-cancer, anti-allergy, immunomodulation, nephroprotection, cardiovascular protection, and neuroprotection. Substantial studies have been conducted on BG and its components against different common human diseases in the last few decades. Still, a lot of research is ongoing to find out the therapeutic effects of BG. Thus, in this review, we summarized the pre-clinical and clinical studies of BG and its bioactive compounds on human health along with diverse bioactivity, a related mode of action, and also future challenges.
Topics: Disease; Food Handling; Garlic; Health; Humans
PubMed: 34443625
DOI: 10.3390/molecules26165028 -
Nucleic Acids Research Jan 2021The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze...
The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.
Topics: Animals; Biological Ontologies; Computational Biology; Databases, Factual; Disease; Disease Models, Animal; Genome; Genotype; Humans; Infant, Newborn; International Cooperation; Internet; Neonatal Screening; Pharmacogenetics; Phenotype; Software; Terminology as Topic
PubMed: 33264411
DOI: 10.1093/nar/gkaa1043 -
Nature Reviews. Genetics Oct 2020In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field... (Review)
Review
In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.
Topics: Disease; Genetics; Genome, Human; Genome-Wide Association Study; Genomics; Humans
PubMed: 32839576
DOI: 10.1038/s41576-020-0272-6