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Cold Spring Harbor Perspectives in... Sep 2016SUMMARYEpigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve... (Review)
Review
SUMMARYEpigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve DNA methylation, histone modifiers and readers, chromatin remodelers, microRNAs, and other components of chromatin. Cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome. Epigenetic therapies, in which the goal is to reverse these changes, are now one standard of care for a preleukemic disorder and form of lymphoma. The application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route.
Topics: Animals; Chromatin; DNA Methylation; Disease Progression; Epigenesis, Genetic; Gene Silencing; Genes, Tumor Suppressor; Humans; Mutation; Neoplasms; Promoter Regions, Genetic
PubMed: 27194046
DOI: 10.1101/cshperspect.a019505 -
Biological Reviews of the Cambridge... Dec 2021Dominance is a basic property of inheritance systems describing the link between a diploid genotype at a single locus and the resulting phenotype. Models for the... (Review)
Review
Dominance is a basic property of inheritance systems describing the link between a diploid genotype at a single locus and the resulting phenotype. Models for the evolution of dominance have long been framed as an opposition between the irreconcilable views of Fisher in 1928 supporting the role of largely elusive dominance modifiers and Wright in 1929, who viewed dominance as an emerging property of the structure of enzymatic pathways. Recent theoretical and empirical advances however suggest that these opposing views can be reconciled, notably using models investigating the regulation of gene expression and developmental processes. In this more comprehensive framework, phenotypic dominance emerges from departures from linearity between any levels of integration in the genotype-to-phenotype map. Here, we review how these different models illuminate the emergence and evolution of dominance. We then detail recent empirical studies shedding new light on the diversity of molecular and physiological mechanisms underlying dominance and its evolution. By reconciling population genetics and functional biology, we hope our review will facilitate cross-talk among research fields in the integrative study of dominance evolution.
Topics: Genes, Dominant; Genetics, Population; Genotype; Models, Genetic; Phenotype
PubMed: 34382317
DOI: 10.1111/brv.12786 -
Journal of Cystic Fibrosis : Official... Mar 2020Genetics is the branch of biology concerned with study of individual genes and how they work whereas genomics is involved with the analysis of all genes and their... (Review)
Review
Genetics is the branch of biology concerned with study of individual genes and how they work whereas genomics is involved with the analysis of all genes and their interactions. Both of these approaches have been applied extensively to CF. Identification of the CFTR gene initiated the dissection of CF genetics at the molecular level. Subsequently, thousands of variants were found in the gene and the functional consequences of a subset have been studied in detail. The completion of the human genome ushered in a new phase of study where the role of genes beyond CFTR could be evaluated for their contribution to the severity of CF. This will be a brief overview of the contribution of these complementary methods to our understanding of CF pathogenesis.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genes, Modifier; Genetic Association Studies; Genetic Linkage; Genetic Techniques; Genetic Testing; Humans; Severity of Illness Index
PubMed: 31879237
DOI: 10.1016/j.jcf.2019.11.003 -
Biomolecules Jan 2021Urm1 (ubiquitin related modifier 1) is a molecular fossil in the class of ubiquitin-like proteins (UBLs). It encompasses characteristics of classical UBLs, such as... (Review)
Review
Urm1 (ubiquitin related modifier 1) is a molecular fossil in the class of ubiquitin-like proteins (UBLs). It encompasses characteristics of classical UBLs, such as ubiquitin or SUMO (small ubiquitin-related modifier), but also of bacterial sulfur-carrier proteins (SCP). Since its main function is to modify tRNA, Urm1 acts in a non-canonical manner. Uba4, the activating enzyme of Urm1, contains two domains: a classical E1-like domain (AD), which activates Urm1, and a rhodanese homology domain (RHD). This sulfurtransferase domain catalyzes the formation of a C-terminal thiocarboxylate on Urm1. Thiocarboxylated Urm1 is the sulfur donor for 5-methoxycarbonylmethyl-2-thiouridine (mcmsU), a chemical nucleotide modification at the wobble position in tRNA. This thio-modification is conserved in all domains of life and optimizes translation. The absence of Urm1 increases stress sensitivity in yeast triggered by defects in protein homeostasis, a hallmark of neurological defects in higher organisms. In contrast, elevated levels of tRNA modifying enzymes promote the appearance of certain types of cancer and the formation of metastasis. Here, we summarize recent findings on the unique features that place Urm1 at the intersection of UBL and SCP and make Urm1 an excellent model for studying the evolution of protein conjugation and sulfur-carrier systems.
Topics: Gene Expression Regulation, Fungal; Genes, Fungal; Homeostasis; Phenotype; RNA, Transfer; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Small Ubiquitin-Related Modifier Proteins; Stress, Physiological; Sulfurtransferases; Thiosulfate Sulfurtransferase; Ubiquitin; Ubiquitins
PubMed: 33499055
DOI: 10.3390/biom11020139 -
International Journal of Molecular... Sep 2022Hox genes play a crucial role in morphogenesis, especially in anterior-posterior body axis patterning. The organization of Hox clusters in vertebrates is a result of... (Review)
Review
Hox genes play a crucial role in morphogenesis, especially in anterior-posterior body axis patterning. The organization of Hox clusters in vertebrates is a result of several genome duplications: two rounds of duplication in the ancestors of all vertebrates and a third round that was specific for teleost fishes. Teleostei cluster structure has been significantly modified in the evolutionary processes by Hox gene losses and co-options, while mammals show no such tendency. In mammals, the Hox gene number in a single cluster is stable and generally large, and the numbers are similar to those in the Chondrichthyes. Hox gene alternative splicing activity slightly differs between fishes and mammals. Fishes and mammals have differences in their known alternative splicing activity for Hox gene distribution along the anterior-posterior body axis. The analyzed fish groups-the Coelacanthiformes, Chondrichthyes, and Teleostei-all have higher known alternative mRNA numbers from the anterior and posterior regions, whereas mammals have a more uniform Hox transcript distribution along this axis. In fishes, most Hox transcripts produce functioning proteins, whereas mammals have significantly more known transcripts that do not produce functioning proteins.
Topics: Animals; Evolution, Molecular; Fishes; Gene Duplication; Genes, Homeobox; Mammals; Multigene Family; Phylogeny
PubMed: 36077385
DOI: 10.3390/ijms23179990 -
Mammalian Genome : Official Journal of... Mar 2022In addition to naturally occurring sequence variation and spontaneous mutations, a wide array of technologies exist for modifying the mouse genome. Standardized... (Review)
Review
In addition to naturally occurring sequence variation and spontaneous mutations, a wide array of technologies exist for modifying the mouse genome. Standardized nomenclature, including allele, transgene, and other mutation nomenclature, as well as persistent unique identifiers (PUID) are critical for effective scientific communication, comparison of results, and integration of data into knowledgebases such as Mouse Genome Informatics (MGI), Alliance for Genome Resources, and International Mouse Strain Resource (IMSR). As well as being the authoritative source for mouse gene, allele, and strain nomenclature, MGI integrates published and unpublished genomic, phenotypic, and expression data while linking to other online resources for a complete view of the mouse as a valuable model organism. The International Committee on Standardized Genetic Nomenclature for Mice has developed allele nomenclature rules and guidelines that take into account the number of genes impacted, the method of allele generation, and the nature of the sequence alteration. To capture details that cannot be included in allele symbols, MGI has further developed allele to gene relationships using sequence ontology (SO) definitions for mutations that provide links between alleles and the genes affected. MGI is also using (HGVS) variant nomenclature for variants associated with alleles that will enhance searching for mutations and will improve cross-species comparison. With the ability to assign unique and informative symbols as well as to link alleles with more than one gene, allele and transgene nomenclature rules and guidelines provide an unambiguous way to represent alterations in the mouse genome and facilitate data integration among multiple resources such the Alliance of Genome Resources and International Mouse Strain Resource.
Topics: Alleles; Animals; Databases, Genetic; Genomics; Mice; Mutation; Transgenes
PubMed: 34389871
DOI: 10.1007/s00335-021-09902-3 -
BioEssays : News and Reviews in... Oct 2016Mutations in enhancer-associated chromatin-modifying components and genomic alterations in non-coding regions of the genome occur frequently in cancer, and other... (Review)
Review
Mutations in enhancer-associated chromatin-modifying components and genomic alterations in non-coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin-modifying factors might affect enhancer activity of disease-relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on "enhancer malfunction" in disease, I propose that multiple new enhancer-regulated and disease-relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues.
Topics: Animals; Enhancer Elements, Genetic; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Mutation; Neoplasms
PubMed: 27570183
DOI: 10.1002/bies.201600106 -
Cold Spring Harbor Perspectives in... Jun 2015Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance... (Review)
Review
Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance and expressivity of causal alleles has been modest, in part because of the methodological challenges in identifying genetic modifiers. Nonetheless, the progressive discovery of modifier alleles has improved both our interpretative ability and our analytical tools to dissect such phenomena. In this review, we analyze the genetic properties and behaviors of modifiers as derived from studies in patient populations and model organisms and we highlight conceptual and technological tools used to overcome some of the challenges inherent in modifier mapping and cloning. Finally, we discuss how the identification of these modifiers has facilitated the elucidation of biological pathways and holds the potential to improve the clinical predictive value of primary causal mutations and to develop novel drug targets.
Topics: Alleles; Animals; Cloning, Molecular; Forecasting; Genes, Modifier; Humans; Mice; Mice, Inbred Strains; Models, Genetic; Multifactorial Inheritance; Mutation; Penetrance; Phenotype; Retinal Degeneration
PubMed: 26033081
DOI: 10.1101/cshperspect.a017145 -
Brain Research Jan 2020Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these... (Review)
Review
Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these diseases, a diagnostic gap of 30-60% remains. Classic models of genetic causation may be limited to fully close this gap and, thus, we review the current state and future role of alternative, non-Mendelian forms of genetics in CMT. Promising synergies exist to further define the full genetic architecture of inherited neuropathies, including affordable whole-genome sequencing, increased data aggregation and clinical collaboration, improved bioinformatics and statistical methodology, and vastly improved computational resources. Given the recent advances in genetic therapies for rare diseases, it becomes a matter of urgency to diagnose CMT patients with great fidelity. Otherwise, they will not be able to benefit from such therapeutic options, or worse, suffer harm when pathogenicity of genetic variation is falsely evaluated. In addition, the newly identified modifier and risk genes may offer alternative targets for pharmacotherapy of inherited and, potentially, even acquired forms of neuropathies.
Topics: Animals; Charcot-Marie-Tooth Disease; Genes, Modifier; Genomics; Humans; Risk Factors
PubMed: 31525351
DOI: 10.1016/j.brainres.2019.146459 -
Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of Hypomorphic Alleles.Genes Jun 2023Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in... (Review)
Review
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including , and allowed the identification of biallelic variants. Furthermore, we review the medical literature in order to report likely hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare missense variants, especially if previously unreported, remain challenging.
Topics: Adult; Humans; Alleles; Mutation, Missense; Patient Acuity; Polycystic Kidney, Autosomal Dominant; TRPP Cation Channels
PubMed: 37372410
DOI: 10.3390/genes14061230