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1.
Am J Hum Genet ; 108(10): 1813-1816, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34626580

RESUMO

The use of approved nomenclature in publications is vital to enable effective scientific communication and is particularly crucial when discussing genes of clinical relevance. Here, we discuss several examples of cases where the failure of researchers to use a HUGO Gene Nomenclature Committee (HGNC)-approved symbol in publications has led to confusion between unrelated human genes in the literature. We also inform authors of the steps they can take to ensure that they use approved nomenclature in their manuscripts and discuss how referencing HGNC IDs can remove ambiguity when referring to genes that have previously been published with confusing alias symbols.


Assuntos
Bases de Dados Genéticas/normas , Genes/genética , Genoma Humano , Pesquisadores/normas , Terminologia como Assunto , Genômica , Humanos
2.
Genet Sel Evol ; 53(1): 76, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551713

RESUMO

BACKGROUND: Backfat thickness is an important carcass composition trait for pork production and is commonly included in swine breeding programmes. In this paper, we report the results of a large genome-wide association study for backfat thickness using data from eight lines of diverse genetic backgrounds. METHODS: Data comprised 275,590 pigs from eight lines with diverse genetic backgrounds (breeds included Large White, Landrace, Pietrain, Hampshire, Duroc, and synthetic lines) genotyped and imputed for 71,324 single-nucleotide polymorphisms (SNPs). For each line, we estimated SNP associations using a univariate linear mixed model that accounted for genomic relationships. SNPs with significant associations were identified using a threshold of p < 10-6 and used to define genomic regions of interest. The proportion of genetic variance explained by a genomic region was estimated using a ridge regression model. RESULTS: We found significant associations with backfat thickness for 264 SNPs across 27 genomic regions. Six genomic regions were detected in three or more lines. The average estimate of the SNP-based heritability was 0.48, with estimates by line ranging from 0.30 to 0.58. The genomic regions jointly explained from 3.2 to 19.5% of the additive genetic variance of backfat thickness within a line. Individual genomic regions explained up to 8.0% of the additive genetic variance of backfat thickness within a line. Some of these 27 genomic regions also explained up to 1.6% of the additive genetic variance in lines for which the genomic region was not statistically significant. We identified 64 candidate genes with annotated functions that can be related to fat metabolism, including well-studied genes such as MC4R, IGF2, and LEPR, and more novel candidate genes such as DHCR7, FGF23, MEDAG, DGKI, and PTN. CONCLUSIONS: Our results confirm the polygenic architecture of backfat thickness and the role of genes involved in energy homeostasis, adipogenesis, fatty acid metabolism, and insulin signalling pathways for fat deposition in pigs. The results also suggest that several less well-understood metabolic pathways contribute to backfat development, such as those of phosphate, calcium, and vitamin D homeostasis.


Assuntos
Tecido Adiposo/anatomia & histologia , Genes , Patrimônio Genético , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Suínos/anatomia & histologia , Suínos/genética , Animais , Genoma , Genômica , Genótipo , Suínos/classificação
3.
PLoS One ; 16(8): e0248454, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34411117

RESUMO

People around the world are currently affected by Major Depressive Disorder (MDD). Despite its many aspects, symptoms, manifestations and impacts, efforts have been made to identify the root causes of the disorder. In particular, genetic studies have concentrated on identifying candidate genes for MDD and exploring associations between these genes and some specific group of individuals. The aim of this research was to find out the association between single nucleotide polymorphisms in 6 candidate genes linked to the neurobiology of major depressive disorder in the North-Western population of Pakistan. We performed a case-control analysis, with 400 MDD and 232 controls. A trained psychiatrist or clinical psychologists evaluated the patients. Six polymorphisms were genotyped and tested for allele and genotype association with MDD. There were no statistical variations between MDD patients and healthy controls for genotypic and allelic distribution of all the polymorphisms observed. Thus, our analysis does not support the major role of these polymorphisms in contributing to MDD susceptibility, although it does not preclude minor impact. The statistically significant correlation between six polymorphisms and major depressive disorder in the studied population was not observed. There are inconsistencies in investigations around the world. Future research, including GWAS and association analysis on larger scale should be addressed for further validation and replication of the present findings.


Assuntos
Transtorno Depressivo Maior/genética , Genes/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
4.
Nutrients ; 13(8)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34444981

RESUMO

AIMS: This systematic review examines the association between maternal lifestyle, diet and physical activity, and epigenetic changes in the offspring. METHODS: A literature search was conducted using multiple science databases: PubMed, Embase and Cochrane Library, on 10 March 2021. RCT and Cohort studies in English or Scandinavian languages were included. Exposure variables included diet, lifestyle, meal patterns or physical activity. Studies using dietary supplements as exposure variables were excluded. Outcome variables included were DNA methylation, microRNA or histone changes in placenta, cord blood or offspring. Two independent authors screened, read and extracted data from the included papers. The Cochrane risk-of-bias tool for randomized trials (RoB2) and The Critical Appraisal Skills Program (CASP) Cohort Study Checklist were used to assess risk of bias in the included studies. A qualitative approach was employed due to heterogeneity of exposures and results of the studies. RESULTS: 16 studies and 3617 participants were included in the final analysis. The exposure variables included physical activity, carbohydrate, low glycemic index diet, added sugar, fat, Mediterranean diet and pro-inflammatory diet. The outcome variables identified were differences in DNA methylation and microRNA. Most studies described epigenetic changes in either placenta or cord blood. Genes reported to be methylated were GR, HSD2, IGF-2, PLAG1, MEG-3, H19 and RXRA. However, not all studies found epigenetic changes strong enough to pass multiple testing, and the study quality varied. CONCLUSION: Despite the variable quality of the included studies, the results in this review suggest that there may be an association between the mother's lifestyle, diet and level of physical activity during pregnancy and epigenetic changes in the offspring.


Assuntos
Dieta , Epigênese Genética , Exercício Físico , Comportamento Alimentar , Desenvolvimento Fetal , Estilo de Vida , Gestantes , Metilação de DNA , Epigenômica , Feminino , Genes , Histonas , Humanos , MicroRNAs , Mães , Gravidez
5.
Res. soc. adm. pharm ; 17(7): 1347-1355, July. 2021. graf.
Artigo em Inglês | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1283429

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide. OBJECTIVES: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH). METHODS: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients. SUMMARY: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.


Assuntos
Farmacogenética , Doença da Artéria Coronariana , Epigenômica , Genes , Hipercolesterolemia
6.
PLoS Comput Biol ; 17(7): e1008984, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34329294

RESUMO

Erroneous conversion of gene names into other dates and other data types has been a frustration for computational biologists for years. We hypothesized that such errors in supplementary files might diminish after a report in 2016 highlighting the extent of the problem. To assess this, we performed a scan of supplementary files published in PubMed Central from 2014 to 2020. Overall, gene name errors continued to accumulate unabated in the period after 2016. An improved scanning software we developed identified gene name errors in 30.9% (3,436/11,117) of articles with supplementary Excel gene lists; a figure significantly higher than previously estimated. This is due to gene names being converted not just to dates and floating-point numbers, but also to internal date format (five-digit numbers). These findings further reinforce that spreadsheets are ill-suited to use with large genomic data.


Assuntos
Biologia Computacional/normas , Genes/genética , Anotação de Sequência Molecular/normas , Humanos , PubMed , Software , Terminologia como Assunto
7.
Philos Trans R Soc Lond B Biol Sci ; 376(1833): 20200104, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34304589

RESUMO

Hybrids provide an interesting model to study the evolution of sex-determining genes and sex chromosome systems as they offer the opportunity to see how independently evolving sex-determining pathways interact in vivo. In this context, the genus Xenopus represents a stimulating model, since species with non-homologous sex chromosomes and different sex-determining genes have been identified. In addition, the possibility of interspecies breeding is favoured in this group, which arose by alloploidization events, with species ploidy ranging from 2n = 2x = 20 in X. tropicalis (the only diploid representative of the genus) to 2n = 12x = 108 in X. ruwenzoriensis. To study how two sex-determining genes interact in vivo, X. laevis × X. tropicalis hybrids were produced. Gonadal differentiation in these hybrids revealed that the dm-w gene is dominant over X. tropicalis male-determining sex chromosomes (Y or Z), even though the Y chromosome is dominant in X. tropicalis (Y > W>Z). In the absence of the dm-w gene (the Z chromosome from X. laevis is present), the W chromosome from X. tropicalis is able to trigger ovarian development. Testicular differentiation will take place in the absence of W chromosomes from any of the parental species. The dominance/recessivity relationships between these sex-determining loci in the context of either parental genome remains unknown. This article is part of the theme issue 'Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part II)'.


Assuntos
Hibridização Genética , Ovário/crescimento & desenvolvimento , Cromossomos Sexuais , Processos de Determinação Sexual , Testículo/crescimento & desenvolvimento , Xenopus/genética , Animais , Feminino , Genes , Masculino , Ovário/anatomia & histologia , Testículo/anatomia & histologia
8.
Nucleic Acids Res ; 49(15): 8471-8487, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34313777

RESUMO

There is a pressing need today to mechanistically interpret sets of genomic variants associated with diseases. Here we present a tool called 'VarSAn' that uses a network analysis algorithm to identify pathways relevant to a given set of variants. VarSAn analyzes a configurable network whose nodes represent variants, genes and pathways, using a Random Walk with Restarts algorithm to rank pathways for relevance to the given variants, and reports P-values for pathway relevance. It treats non-coding and coding variants differently, properly accounts for the number of pathways impacted by each variant and identifies relevant pathways even if many variants do not directly impact genes of the pathway. We use VarSAn to identify pathways relevant to variants related to cancer and several other diseases, as well as drug response variation. We find VarSAn's pathway ranking to be complementary to the standard approach of enrichment tests on genes related to the query set. We adopt a novel benchmarking strategy to quantify its advantage over this baseline approach. Finally, we use VarSAn to discover key pathways, including the VEGFA-VEGFR2 pathway, related to de novo variants in patients of Hypoplastic Left Heart Syndrome, a rare and severe congenital heart defect.


Assuntos
Genômica/métodos , Polimorfismo de Nucleotídeo Único , Software , Algoritmos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Interpretação Estatística de Dados , Feminino , Genes , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/metabolismo , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transdução de Sinais/genética
9.
Cells ; 10(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208388

RESUMO

Pulmonary arterial hypertension is a debilitating chronic disorder marked by the progressive obliteration of the pre-capillary arterioles. This imposes a pressure overload on the right ventricle (RV) pushing the latter to undergo structural and mechanical adaptations that inexorably culminate in RV failure and death. Thanks to the advances in molecular biology, it has been proposed that some aspects of the RV and pulmonary vascular remodeling processes are orchestrated by a subversion of developmental regulatory mechanisms with an upregulation of a suite of genes responsible for the embryo's early growth and normally repressed in adults. In this review, we present relevant background regarding the close relationship between overactivation of fetal genes and cardiopulmonary remodeling, exploring whether the reawakening of developmental factors plays a causative role or constitutes a protective mechanism in the setting of PAH.


Assuntos
Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes , Hipertensão Arterial Pulmonar/prevenção & controle , Animais , Humanos , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia
10.
Commun Biol ; 4(1): 706, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108613

RESUMO

Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10-22 and OR = 4.2 for heterozygotes, P = 5.7 × 10-27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.


Assuntos
Perda Auditiva/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Feminino , Genes/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Genes (Basel) ; 12(5)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069634

RESUMO

Variability is the source on which selective pressure acts, allowing genome evolution and adaptation [...].


Assuntos
Genes/genética , Genoma Humano/genética , Adaptação Fisiológica/genética , Animais , Evolução Molecular , Humanos , Fenótipo , Plantas/genética
12.
Commun Biol ; 4(1): 736, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127790

RESUMO

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time. Primary screens performed in SH-SY5Y cells, identified positive and negative regulators of tau protein levels. Hit validation of the top 43 candidate genes was performed using Ngn2-induced human cortical excitatory neurons. Using this approach, genes and pathways involved in modulation of endogenous tau levels were identified, including chromatin modifying enzymes, neddylation and ubiquitin pathway members, and components of the mTOR pathway. TSC1, a critical component of the mTOR pathway, was further validated in vivo, demonstrating the relevance of this screening strategy. These findings may have implications for treating neurodegenerative diseases in the future.


Assuntos
Redes e Vias Metabólicas/genética , Neurônios/metabolismo , Proteínas tau/metabolismo , Animais , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Edição de Genes , Genes/genética , Genes/fisiologia , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Neuroblastoma/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
13.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072943

RESUMO

Coronary artery disease remains one of the primary healthcare problems due to the high cost of treatment, increased number of patients, poor clinical outcomes, and lack of effective therapy. Though pharmacological and surgical treatments positively affect symptoms and arrest the disease progression, they generally exhibit a limited effect on the disease outcome. The development of alternative therapeutic approaches towards ischemic disease treatment, especially of decompensated forms, is therefore relevant. Therapeutic angiogenesis, stimulated by various cytokines, chemokines, and growth factors, provides the possibility of restoring functional blood flow in ischemic tissues, thereby ensuring the regeneration of the damaged area. In the current study, based on the clinically approved plasmid vector pVax1, multigenic constructs were developed encoding vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF2), and the DsRed fluorescent protein, integrated via picornaviruses' furin-2A peptide sequences. In vitro experiments demonstrated that genetically modified cells with engineered plasmid constructs expressed the target proteins. Overexpression of VEGF and FGF2 resulted in increased levels of the recombinant proteins. Concomitantly, these did not lead to a significant shift in the general secretory profile of modified HEK293T cells. Simultaneously, the secretome of genetically modified cells showed significant stimulating effects on the formation of capillary-like structures by HUVEC (endothelial cells) in vitro. Our results revealed that when the multicistronic multigene vectors encoding 2A peptide sequences are created, transient transgene co-expression is ensured. The results obtained indicated the mutual synergistic effects of the growth factors VEGF and FGF2 on the proliferation of endothelial cells in vitro. Thus, recombinant multicistronic multigenic constructs might serve as a promising approach for establishing safe and effective systems to treat ischemic diseases.


Assuntos
Doença da Artéria Coronariana/genética , Fator 2 de Crescimento de Fibroblastos/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Indutores da Angiogênese/farmacologia , Proliferação de Células/genética , Doença da Artéria Coronariana/terapia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Furina/genética , Regulação da Expressão Gênica/genética , Genes/genética , Vetores Genéticos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Patológica/terapia , Neovascularização Fisiológica/genética , Peptídeos/genética , Peptídeos/farmacologia , Plasmídeos/genética , Plasmídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
14.
Nucleic Acids Res ; 49(W1): W153-W161, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34125897

RESUMO

As a result of the advent of high-throughput technologies, there has been rapid progress in our understanding of the genetics underlying biological processes. However, despite such advances, the genetic landscape of human diseases has only marginally been disclosed. Exploiting the present availability of large amounts of biological and phenotypic data, we can use our current understanding of disease genetics to train machine learning models to predict novel genetic factors associated with the disease. To this end, we developed DGLinker, a webserver for the prediction of novel candidate genes for human diseases given a set of known disease genes. DGLinker has a user-friendly interface that allows non-expert users to exploit biomedical information from a wide range of biological and phenotypic databases, and/or to upload their own data, to generate a knowledge-graph and use machine learning to predict new disease-associated genes. The webserver includes tools to explore and interpret the results and generates publication-ready figures. DGLinker is available at https://dglinker.rosalind.kcl.ac.uk. The webserver is free and open to all users without the need for registration.


Assuntos
Doença/genética , Software , Esclerose Amiotrófica Lateral/genética , Gráficos por Computador , Genes , Humanos , Aprendizado de Máquina
15.
Nucleic Acids Res ; 49(W1): W317-W325, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34086934

RESUMO

Gene set enrichment (GSE) analysis plays an essential role in extracting biological insight from genome-scale experiments. ORA (overrepresentation analysis), FCS (functional class scoring), and PT (pathway topology) approaches are three generations of GSE methods along the timeline of development. Previous versions of KOBAS provided services based on just the ORA method. Here we presented version 3.0 of KOBAS, which is named KOBAS-i (short for KOBAS intelligent version). It introduced a novel machine learning-based method we published earlier, CGPS, which incorporates seven FCS tools and two PT tools into a single ensemble score and intelligently prioritizes the relevant biological pathways. In addition, KOBAS has expanded the downstream exploratory visualization for selecting and understanding the enriched results. The tool constructs a novel view of cirFunMap, which presents different enriched terms and their correlations in a landscape. Finally, based on the previous version's framework, KOBAS increased the number of supported species from 1327 to 5944. For an easier local run, it also provides a prebuilt Docker image that requires no installation, as a supplementary to the source code version. KOBAS can be freely accessed at http://kobas.cbi.pku.edu.cn, and a mirror site is available at http://bioinfo.org/kobas.


Assuntos
Genes , Software , Expressão Gênica , Ontologia Genética , Aprendizado de Máquina , Proteínas/genética
16.
Nature ; 594(7861): 77-81, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33953399

RESUMO

The divergence of chimpanzee and bonobo provides one of the few examples of recent hominid speciation1,2. Here we describe a fully annotated, high-quality bonobo genome assembly, which was constructed without guidance from reference genomes by applying a multiplatform genomics approach. We generate a bonobo genome assembly in which more than 98% of genes are completely annotated and 99% of the gaps are closed, including the resolution of about half of the segmental duplications and almost all of the full-length mobile elements. We compare the bonobo genome to those of other great apes1,3-5 and identify more than 5,569 fixed structural variants that specifically distinguish the bonobo and chimpanzee lineages. We focus on genes that have been lost, changed in structure or expanded in the last few million years of bonobo evolution. We produce a high-resolution map of incomplete lineage sorting and estimate that around 5.1% of the human genome is genetically closer to chimpanzee or bonobo and that more than 36.5% of the genome shows incomplete lineage sorting if we consider a deeper phylogeny including gorilla and orangutan. We also show that 26% of the segments of incomplete lineage sorting between human and chimpanzee or human and bonobo are non-randomly distributed and that genes within these clustered segments show significant excess of amino acid replacement compared to the rest of the genome.


Assuntos
Evolução Molecular , Genoma/genética , Genômica , Pan paniscus/genética , Filogenia , Animais , Fator de Iniciação 4A em Eucariotos/genética , Feminino , Genes , Gorilla gorilla/genética , Anotação de Sequência Molecular/normas , Pan troglodytes/genética , Pongo/genética , Duplicações Segmentares Genômicas , Análise de Sequência de DNA
17.
Nature ; 594(7862): 283-288, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33981036

RESUMO

Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle1-3. Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci4-10, but how transcription promotes HR is poorly understood. Here we develop an assay to assess the effect of local transcription on HR. Using this assay, we find that transcription stimulates HR to a substantial extent. Tethering RNA transcripts to the vicinity of DSBs recapitulates the effects of local transcription, which suggests that transcription enhances HR through RNA transcripts. Tethered RNA transcripts stimulate HR in a sequence- and orientation-dependent manner, indicating that they function by forming DNA-RNA hybrids. In contrast to most HR proteins, RAD51-associated protein 1 (RAD51AP1) only promotes HR when local transcription is active. RAD51AP1 drives the formation of R-loops in vitro and is required for tethered RNAs to stimulate HR in cells. Notably, RAD51AP1 is necessary for the DSB-induced formation of DNA-RNA hybrids in donor DNA, linking R-loops to D-loops. In vitro, RAD51AP1-generated R-loops enhance the RAD51-mediated formation of D-loops locally and give rise to intermediates that we term 'DR-loops', which contain both DNA-DNA and DNA-RNA hybrids and favour RAD51 function. Thus, at DSBs in transcribed regions, RAD51AP1 promotes the invasion of RNA transcripts into donor DNA, and stimulates HR through the formation of DR-loops.


Assuntos
DNA/genética , DNA/metabolismo , Recombinação Homóloga/genética , Estruturas R-Loop/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , DNA/química , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Genes/genética , Genes Reporter/genética , Proteínas de Fluorescência Verde/genética , Humanos , Técnicas In Vitro , RNA Mensageiro/química , Proteínas de Ligação a RNA/metabolismo , Rad51 Recombinase/metabolismo
18.
PLoS Genet ; 17(5): e1009548, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34014919

RESUMO

Fisher's partitioning of genotypic values and genetic variance is highly relevant in the current era of genome-wide association studies (GWASs). However, despite being more than a century old, a number of persistent misconceptions related to nonadditive genetic effects remain. We developed a user-friendly web tool, the Falconer ShinyApp, to show how the combination of gene action and allele frequencies at causal loci translate to genetic variance and genetic variance components for a complex trait. The app can be used to demonstrate the relationship between a SNP effect size estimated from GWAS and the variation the SNP generates in the population, i.e., how locus-specific effects lead to individual differences in traits. In addition, it can also be used to demonstrate how within and between locus interactions (dominance and epistasis, respectively) usually do not lead to a large amount of nonadditive variance relative to additive variance, and therefore, that these interactions usually do not explain individual differences in a population.


Assuntos
Genes/genética , Variação Genética , Estudo de Associação Genômica Ampla , Internet , Software , Epistasia Genética , Frequência do Gene , Genes Dominantes , Loci Gênicos/genética , Genótipo , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
19.
Sci Rep ; 11(1): 9457, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947934

RESUMO

The application of polygenic scores has transformed our ability to investigate whether and how genetic and environmental factors jointly contribute to the variation of complex traits. Modelling the complex interplay between genes and environment, however, raises serious methodological challenges. Here we illustrate the largely unrecognised impact of gene-environment dependencies on the identification of the effects of genes and their variation across environments. We show that controlling for heritable covariates in regression models that include polygenic scores as independent variables introduces endogenous selection bias when one or more of these covariates depends on unmeasured factors that also affect the outcome. This results in the problem of conditioning on a collider, which in turn leads to spurious associations and effect sizes. Using graphical and simulation methods we demonstrate that the degree of bias depends on the strength of the gene-covariate correlation and of hidden heterogeneity linking covariates with outcomes, regardless of whether the main analytic focus is mediation, confounding, or gene × covariate (commonly gene × environment) interactions. We offer potential solutions, highlighting the importance of causal inference. We also urge further caution when fitting and interpreting models with polygenic scores and non-exogenous environments or phenotypes and demonstrate how spurious associations are likely to arise, advancing our understanding of such results.


Assuntos
Genes/genética , Herança Multifatorial/genética , Causalidade , Meio Ambiente , Interação Gene-Ambiente , Genética , Humanos , Fenótipo , Viés de Seleção
20.
Nat Genet ; 53(5): 638-649, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33859415

RESUMO

A central question in the post-genomic era is how genes interact to form biological pathways. Measurements of gene dependency across hundreds of cell lines have been used to cluster genes into 'co-essential' pathways, but this approach has been limited by ubiquitous false positives. In the present study, we develop a statistical method that enables robust identification of gene co-essentiality and yields a genome-wide set of functional modules. This atlas recapitulates diverse pathways and protein complexes, and predicts the functions of 108 uncharacterized genes. Validating top predictions, we show that TMEM189 encodes plasmanylethanolamine desaturase, a key enzyme for plasmalogen synthesis. We also show that C15orf57 encodes a protein that binds the AP2 complex, localizes to clathrin-coated pits and enables efficient transferrin uptake. Finally, we provide an interactive webtool for the community to explore our results, which establish co-essentiality profiling as a powerful resource for biological pathway identification and discovery of new gene functions.


Assuntos
Redes Reguladoras de Genes , Genes , Genoma , Clatrina/metabolismo , Endocitose , Epigênese Genética , Regulação da Expressão Gênica , Células HeLa , Humanos , Anotação de Sequência Molecular , Neoplasias/genética , Plasmalogênios/biossíntese , Transdução de Sinais/genética
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