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Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation's phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.
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Evolução Molecular , Proteínas de Choque Térmico HSP90 , Mutação , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Seleção Genética , Variação Genética , Humanos , Animais , Aptidão GenéticaRESUMO
A new study by Schmitt et al. revealed that somatic mutations in tropical trees are passed on to their offspring. Furthermore, the study noted that the majority of inherited mutations were present at low allelic frequencies within the tree.
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Frequência do Gene , Mutação , Árvores , Árvores/genética , Clima TropicalRESUMO
Heikkinen and colleagues recently demonstrated that genetic variation, rather than dietary changes, governs gene regulation in liver. This finding highlights the impact of noncoding variants on chromatin accessibility, histone modifications, transcription factor binding, and gene expression and has implications for future research directions in understanding the genetic basis of disease.
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Cromatina , Regulação da Expressão Gênica , Humanos , Regulação da Expressão Gênica/genética , Cromatina/genética , Código das Histonas , Obesidade/genética , Variação Genética/genéticaRESUMO
CFAP58 is a testis-enriched gene that plays an important role in the sperm flagellogenesis of humans and mice. However, the effect of CFAP58 on bull semen quality and the underlying molecular mechanisms involved in spermatogenesis remain unknown. Here, we identified two single-nucleotide polymorphisms (rs110610797, A>G and rs133760846, G>T) and one indel (g.-1811_ g.-1810 ins147bp) in the promoter of CFAP58 that were significantly associated with semen quality of bulls, including sperm deformity rate and ejaculate volume. Moreover, by generating gene knockout mice, we found for the first time that the loss of Cfap58 not only causes severe defects in the sperm tail, but also affects the manchette structure, resulting in abnormal sperm head shaping. Cfap58 deficiency causes an increase in spermatozoa apoptosis. Further experiments confirmed that CFAP58 interacts with IFT88 and CCDC42. Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway. Collectively, our findings reveal that CFAP58 is required for spermatogenesis and provide genetic markers for evaluating semen quality in cattle.
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Análise do Sêmen , Sêmen , Humanos , Bovinos , Masculino , Animais , Camundongos , Cabeça do Espermatozoide , Espermatozoides , Camundongos KnockoutRESUMO
BACKGROUND: Despite advances in understanding hypertension's genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease's genetic mechanisms. METHODS: We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing. Methylation profiling in 918 males revealed allele-specific methylation and methylation quantitative trait loci. We engineered rs1275988T/C mutant mice using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), bred them for homozygosity, and subjected them to a high-salt diet. Telemetry captured their cardiovascular metrics. Protein-DNA interactions were elucidated using DNA pull-downs, mass spectrometry, and Western blots. A wire myograph assessed vascular function, and analysis of the Kcnk3 gene methylation highlighted the mutation's role in hypertension. RESULTS: We discovered that DNA methylation-associated genetic effects, especially in non-cytosine-phosphate-guanine (non-CpG) island and noncoding distal regulatory regions, significantly contribute to hypertension predisposition. We identified distinct methylation quantitative trait locus patterns in the hypertensive population and observed that the onset of hypertension is influenced by the transmission of genetic effects through the demethylation process. By evidence-driven prioritization and in vivo experiments, we unearthed rs1275988 in a cell type-specific enhancer as a notable hypertension causal variant, intensifying hypertension through the modulation of local DNA methylation and consequential alterations in Kcnk3 gene expression and vascular remodeling. When exposed to a high-salt diet, mice with the rs1275988C/C genotype exhibited exacerbated hypertension and significant vascular remodeling, underscored by increased aortic wall thickness. The C allele of rs1275988 was associated with elevated DNA methylation levels, driving down the expression of the Kcnk3 gene by attenuating Nr2f2 (nuclear receptor subfamily 2 group F member 2) binding at the enhancer locus. CONCLUSIONS: Our research reveals new insights into the complex interplay between genetic variations and DNA methylation in hypertension. We underscore hypomethylation's potential in hypertension onset and identify rs1275988 as a causal variant in vascular remodeling. This work advances our understanding of hypertension's molecular mechanisms and encourages personalized health care strategies.
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Metilação de DNA , Hipertensão , Locos de Características Quantitativas , Animais , Humanos , Masculino , Camundongos , Pressão Sanguínea/genética , Epigênese Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Camundongos Endogâmicos C57BL , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans is not fully defined, we used an unbiased computational approach to assess the clinical significance of rare G-protein-coupled receptor 37-like 1 (GPR37L1) genetic variants found among 51,289 whole-exome sequences from the DiscovEHR cohort. Rare GPR37L1 coding variants were binned according to predicted pathogenicity and analyzed by sequence kernel association testing to reveal significant associations with disease diagnostic codes for epilepsy and migraine, among others. Since associations do not prove causality, rare GPR37L1 variants were functionally analyzed in SK-N-MC cells to evaluate potential signaling differences and pathogenicity. Notably, receptor variants exhibited varying abilities to reduce cAMP levels, activate mitogen-activated protein kinase (MAPK) signaling, and/or upregulate receptor expression in response to the agonist prosaptide (TX14(A)), as compared with the wild-type receptor. In addition to signaling changes, knock-out (KO) of GPR37L1 or expression of certain rare variants altered cellular cholesterol levels, which were also acutely regulated by administration of the agonist TX14(A) via activation of the MAPK pathway. Finally, to simulate the impact of rare nonsense variants found in the large patient cohort, a KO mouse line lacking Gpr37l1 was generated. Although KO animals did not recapitulate an acute migraine phenotype, the loss of this receptor produced sex-specific changes in anxiety-related disorders often seen in chronic migraineurs. Collectively, these observations define the existence of rare GPR37L1 variants associated with neuropsychiatric conditions in the human population and identify the signaling changes contributing to pathological processes.
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Transtornos de Enxaqueca , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Animais , Humanos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Camundongos , Masculino , Feminino , Camundongos Knockout , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Camundongos Endogâmicos C57BL , Variação Genética/genéticaRESUMO
Previously, expression of the Arabidopsis thaliana GLABRA3 (GL3) induced trichome formation in Brassica napus. GL3 orthologues were examined from glabrous (B. oleracea), semi-glabrous (B. napus), moderately hirsute (B. rapa), and very hirsute (B. villosa) Brassica species. Ectopic expression of BnGL3, BrGL3 alleles, or BvGL3 induced trichome formation in glabrous B. napus with the effect on trichome number commensurate with density in the original accessions. Chimeric GL3 proteins in which the B. napus amino terminal region, which interacts with MYB proteins, or the middle region, which interacts with the WD40 protein TTG1, was exchanged with corresponding regions from A. thaliana were as stimulatory to trichome production as AtGL3. Exchange of the carboxy-terminal region containing a bHLH domain and an ACT domain did not alter the trichome stimulatory activity, although modeling of the ACT domain identified differences that could affect GL3 dimerization. B. napus A- and C-genomes orthologues differed in their abilities to form homo- and heterodimers. Modeling of the amino-terminal region revealed a conserved domain that may represent the MYB factor binding pocket. This region interacted with the MYB factors GL1, CPC, and TRY, as well as with JAZ8, which is involved in jasmonic acid-mediated regulation of MYC-like transcription factors. Protein interaction studies indicated that GL1 interaction with GL3 from B. napus and A. thaliana may underlie the difference in their respective abilities to induce trichome formation.
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Proteínas de Arabidopsis , Brassica napus , Proteínas de Plantas , Tricomas , Brassica napus/genética , Brassica napus/metabolismo , Tricomas/metabolismo , Tricomas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Arabidopsis/genética , Arabidopsis/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Plantas Geneticamente Modificadas , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome.
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BACKGROUND: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS, KRAS, and less frequently, NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders. METHODS: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF. RESULTS: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica. CONCLUSION: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up.
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Nevo , Dermatopatias , Neoplasias Cutâneas , Humanos , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas p21(ras)/genética , Nevo/genética , Nevo/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.
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Transtorno do Espectro Autista , Autoantígenos , Epigênese Genética , Proteínas Nucleares , Feminino , Humanos , Masculino , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/imunologia , Transtorno Autístico/genética , Transtorno Autístico/patologia , Sequenciamento do Exoma , Predisposição Genética para Doença , Mutação , Linhagem , Transdução de Sinais/genética , Autoantígenos/genética , Proteínas Nucleares/genéticaRESUMO
BACKGROUND: The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant. METHODS: We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT. RESULTS: Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant. CONCLUSIONS: The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.
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BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
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Epilepsias Parciais , Proteínas de Homeodomínio , Espasmos Infantis , Animais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Epilepsias Parciais/genética , Epilepsias Parciais/tratamento farmacológico , Sequenciamento do Exoma , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Mutação , Espasmos Infantis/genética , DrosophilaRESUMO
BACKGROUND: Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR). METHODS: A retrospective chart review of patients with epilepsy seen at Columbia University Irving Medical Center (CUIMC). One hundred seventy-eight cases met the following criteria: (1) visited any provider within the Pediatric Neurology Clinic at CUIMC, (2) had an ICD code indicating a diagnosis of epilepsy, (3) underwent NGS testing after March 2015 and (4) had self-reported ancestry that fit into a single dichotomous category of either historically represented or under-represented in biomedical research. RESULTS: UBR cases had significantly higher rates of uncertain results when compared with RBR cases (79.2% UBR, 20.8% RBR; p value=0.002). This finding remained true after controlling for potential confounding factors, including sex, intellectual disability or developmental delay, epilepsy type, age of onset, number of genes tested and year of testing. CONCLUSION: Our results add to the literature that individuals who are of ancestries historically under-represented in genetics research are more likely to receive uncertain genetic results than those of represented majority ancestral groups and establishes this finding in an epilepsy cohort.
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Epilepsia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Epilepsia/genética , Masculino , Feminino , Criança , Adolescente , Pré-Escolar , Variação Genética/genética , Estudos Retrospectivos , Estudos de Coortes , Predisposição Genética para Doença , LactenteRESUMO
Genomic technologies have transformed clinical genetic testing, underlining the importance of accurate molecular genetic diagnoses. Variant classification, ranging from benign to pathogenic, is fundamental to these tests. However, variant reclassification, the process of reassigning the pathogenicity of variants over time, poses challenges to diagnostic legitimacy. This review explores the medical and scientific literature available on variant reclassification, focusing on its clinical implications.Variant reclassification is driven by accruing evidence from diverse sources, leading to variant reclassification frequency ranging from 3.6% to 58.8%. Recent studies have shown that significant changes can occur when reviewing variant classifications within 1 year after initial classification, illustrating the importance of early, accurate variant assignation for clinical care.Variants of uncertain significance (VUS) are particularly problematic. They lack clear categorisation but have influenced patient treatment despite recommendations against it. Addressing VUS reclassification is essential to enhance the credibility of genetic testing and the clinical impact. Factors affecting reclassification include standardised guidelines, clinical phenotype-genotype correlations through deep phenotyping and ancestry studies, large-scale databases and bioinformatics tools. As genomic databases grow and knowledge advances, reclassification rates are expected to change, reducing discordance in future classifications.Variant reclassification affects patient diagnosis, precision therapy and family screening. The exact patient impact is yet unknown. Understanding influencing factors and adopting standardised guidelines are vital for precise molecular genetic diagnoses, ensuring optimal patient care and minimising clinical risk.
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Predisposição Genética para Doença , Variação Genética , Humanos , Testes Genéticos , Estudos de Associação Genética , GenômicaRESUMO
BACKGROUND: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario. METHODS: DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category). RESULTS: Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%). CONCLUSIONS: The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.
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Testes Genéticos , Variação Genética , Humanos , Testes Genéticos/métodos , Ontário/epidemiologia , Mutação em Linhagem Germinativa/genética , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/classificação , Feminino , Laboratórios Clínicos , Técnicas de Diagnóstico Molecular/métodosRESUMO
PURPOSE: To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context. METHODS: We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit and sheep), mapped coordinates to the human reference genome and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400 000 individuals with suspected rare disorders. RESULTS: Of 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% CI 4.1 to 12.0, p<0.0001), compared with all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity. CONCLUSION: Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.
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Genômica , Mutação de Sentido Incorreto , Mutação de Sentido Incorreto/genética , Animais , Humanos , Genômica/métodos , Bovinos , Cães , Frequência do Gene , Cavalos , Coelhos , Bases de Dados Genéticas , Ovinos , Suínos , Gatos , Genoma Humano/genética , Cabras/genética , Galinhas/genética , Doenças Raras/genéticaRESUMO
BACKGROUND: We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. RESULTS: Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030). CONCLUSIONS: The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.
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COVID-19 , Síndrome da Liberação de Citocina , Haplótipos , Proteína Antagonista do Receptor de Interleucina 1 , Polimorfismo de Nucleotídeo Único , SARS-CoV-2 , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/sangue , COVID-19/mortalidade , COVID-19/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , SARS-CoV-2/genética , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/mortalidade , Adulto , Genótipo , Biomarcadores/sangueRESUMO
Changes in the structure of RNA and protein, have an important impact on biological functions and are even important determinants of disease pathogenesis and treatment. Some genetic variations, including copy number variation, single nucleotide variation, and so on, can lead to changes in biological function and increased susceptibility to certain diseases by changing the structure of RNA or protein. With the development of structural biology and sequencing technology, a large amount of RNA and protein structure data and genetic variation data resources has emerged to be used to explain biological processes. Here, we reviewed the effects of genetic variation on the structure of RNAs and proteins, and investigated their impact on several diseases. An online resource (http://www.onethird-lab.com/gems/) to support convenient retrieval of common tools is also built. Finally, the challenges and future development of the effects of genetic variation on RNA and protein were discussed.
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Variações do Número de Cópias de DNA , RNA , RNA/genética , Proteínas/químicaRESUMO
BACKGROUND: Genetic ancestry, inferred from genomic data, is a quantifiable biological parameter. While much of the human genome is identical across populations, it is estimated that as much as 0.4% of the genome can differ due to ancestry. This variation is primarily characterized by single nucleotide variants (SNVs), which are often unique to specific genetic populations. Knowledge of a patient's genetic ancestry can inform clinical decisions, from genetic testing and health screenings to medication dosages, based on ancestral disease predispositions. Nevertheless, the current reliance on self-reported ancestry can introduce subjectivity and exacerbate health disparities. While genomic sequencing data enables objective determination of a patient's genetic ancestry, existing approaches are limited to ancestry inference at the continental level. RESULTS: To address this challenge, and create an objective, measurable metric of genetic ancestry we present SNVstory, a method built upon three independent machine learning models for accurately inferring the sub-continental ancestry of individuals. We also introduce a novel method for simulating individual samples from aggregate allele frequencies from known populations. SNVstory includes a feature-importance scheme, unique among open-source ancestral tools, which allows the user to track the ancestral signal broadcast by a given gene or locus. We successfully evaluated SNVstory using a clinical exome sequencing dataset, comparing self-reported ethnicity and race to our inferred genetic ancestry, and demonstrate the capability of the algorithm to estimate ancestry from 36 different populations with high accuracy. CONCLUSIONS: SNVstory represents a significant advance in methods to assign genetic ancestry, opening the door to ancestry-informed care. SNVstory, an open-source model, is packaged as a Docker container for enhanced reliability and interoperability. It can be accessed from https://github.com/nch-igm/snvstory .
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Etnicidade , Genética Populacional , Humanos , Reprodutibilidade dos Testes , Frequência do Gene , Etnicidade/genética , Testes Genéticos , Genoma Humano , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Because the universe of possible DNA sequences is inconceivably vast, organisms have evolved mechanisms for exploring DNA sequence space while substantially reducing the hazard that would otherwise accrue to any process of random, accidental mutation. One such mechanism is meiotic recombination. Although sexual reproduction imposes a seemingly paradoxical 50% cost to fitness, sex evidently prevails because this cost is outweighed by the advantage of equipping offspring with genetic variation to accommodate environmental vicissitudes. The potential adaptive utility of additional mechanisms for producing genetic variation has long been obscured by a presumption that the vast majority of mutations are deleterious. Perhaps surprisingly, the probability for adaptive variation can be increased by several mechanisms that generate mutations abundantly. Such mechanisms, here called 'mutation protocols', implement implicit 'constraints that deconstrain'. Like meiotic recombination, they produce genetic variation in forms that minimize potential for harm while providing a reasonably high probability for benefit. One example is replication slippage of simple sequence repeats (SSRs); this process yields abundant, reversible mutations, typically with small quantitative effect on phenotype. This enables SSRs to function as adjustable 'tuning knobs'. There exists a clear pathway for SSRs to be shaped through indirect selection favouring their implicit tuning-knob protocol. Several other molecular mechanisms comprise probable components of additional mutation protocols. Biologists might plausibly regard such mechanisms of mutation not primarily as sources of deleterious genetic mistakes but also as potentially adaptive processes for 'exploring' DNA sequence space.