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1.
Nat Commun ; 12(1): 5071, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417470

RESUMO

Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Doenças Neurodegenerativas/genética , Encéfalo/metabolismo , Epigênese Genética , Feto/metabolismo , Redes Reguladoras de Genes , Loci Gênicos , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Análise da Randomização Mendeliana , Mapeamento Físico do Cromossomo , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética
2.
Methods Mol Biol ; 2351: 123-145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34382187

RESUMO

The positioning of nucleosomes regulates the accessibility of genomic DNA and can impact the activities of functional elements. Nucleosome positioning is highly consistent at each genomic location in any particular cell-type, but can vary in an orchestrated fashion between different cell-types and between genomic loci according to their activities. Here, we describe a technique-"ChIP-MNase" (chromatin immunoprecipitation linked to micrococcal nuclease mapping)-to determine nucleosome positions at chosen sets of genomic features that can be defined by their molecular composition and recovered by chromatin immunoprecipitation. ChIP-MNase enables high-resolution analysis of nucleosome positioning at genomic regions-of-interest and can allow differential analysis of alleles undergoing distinct molecular processes.


Assuntos
Alelos , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Imunoprecipitação da Cromatina/métodos , Mapeamento Cromossômico/métodos , Loci Gênicos , Nuclease do Micrococo/metabolismo , Nucleossomos/metabolismo , Sítios de Ligação , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Ligação Proteica , Controle de Qualidade
3.
Am J Hum Genet ; 108(9): 1611-1630, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34343493

RESUMO

Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 7 , Loci Gênicos , Melanócitos/metabolismo , Melanoma/genética , Receptores de Hidrocarboneto Arílico/genética , Neoplasias Cutâneas/genética , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Cromatina/química , Cromatina/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanócitos/efeitos da radiação , Melanoma/metabolismo , Melanoma/patologia , Dibenzodioxinas Policloradas/toxicidade , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Banho de Sol , Raios Ultravioleta/efeitos adversos
4.
Am J Hum Genet ; 108(9): 1590-1610, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390653

RESUMO

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Loci Gênicos , Neoplasias Renais/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos , Fatores de Transcrição/imunologia
5.
Nat Commun ; 12(1): 5078, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426578

RESUMO

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.


Assuntos
Dipeptidases/genética , Ferroptose/genética , Loci Gênicos , Predisposição Genética para Doença , Nefropatias/genética , Proteínas de Transporte Vesicular/genética , Animais , Nitrogênio da Ureia Sanguínea , Cromatina/metabolismo , Cisplatino , Metilação de DNA/genética , Dipeptidases/deficiência , Dipeptidases/metabolismo , Ácido Fólico , Edição de Genes , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haploinsuficiência/genética , Humanos , Ferro/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Camundongos , Necroptose/genética , Especificidade de Órgãos , Mapeamento Físico do Cromossomo , Piroptose/genética , Locos de Características Quantitativas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/metabolismo
6.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445247

RESUMO

The utilization of heterosis is an important way to improve wheat yield, and the production of wheat hybrid seeds mainly relies on male-sterile lines. Male sterility in line 15 Fan 03 derived from a cross of 72,180 and Xiaoyan 6 is controlled by a single recessive gene. The gene was mapped to the distal region of chromosome 4BS in a genetic interval of 1.4 cM and physical distance of 6.57 Mb between SSR markers Ms4BS42 and Ms4BS199 using an F2 population with 1205 individuals. Sterile individuals had a deletion of 4.57 Mb in the region presumed to carry the Ms1 locus. The allele for sterility was therefore named ms1s. Three CAPS markers were developed and verified from the region upstream of the deleted fragment and can be used for ms1s marker-assisted selection in wheat hybrid breeding. This work will enrich the utilization of male sterility genetic resources.


Assuntos
Mapeamento Cromossômico , Genes de Plantas , Genes Recessivos , Loci Gênicos , Infertilidade das Plantas/genética , Triticum/genética , Melhoramento Vegetal
7.
BMC Plant Biol ; 21(1): 334, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34261431

RESUMO

BACKGROUND: The skin (exocarp) of fleshy fruit is hugely diverse across species. Most fruit types have a live epidermal skin covered by a layer of cuticle made up of cutin while a few create an outermost layer of dead cells (peridermal layer). RESULTS: In this study we undertook crosses between epidermal and peridermal skinned kiwifruit, and showed that epidermal skin is a semi-dominant trait. Furthermore, backcrossing these epidermal skinned hybrids to a peridermal skinned fruit created a diverse range of phenotypes ranging from epidermal skinned fruit, through fruit with varying degrees of patches of periderm (russeting), to fruit with a complete periderm. Quantitative trait locus (QTL) analysis of this population suggested that periderm formation was associated with four loci. These QTLs were aligned either to ones associated with russet formation on chromosome 19 and 24, or cuticle integrity and coverage located on chromosomes 3, 11 and 24. CONCLUSION: From the segregation of skin type and QTL analysis, it appears that skin development in kiwifruit is controlled by two competing factors, cuticle strength and propensity to russet. A strong cuticle will inhibit russeting while a strong propensity to russet can create a continuous dead skinned periderm.


Assuntos
Actinidia/genética , Frutas/genética , Genes de Plantas , Loci Gênicos , Desenvolvimento Vegetal/genética , Actinidia/crescimento & desenvolvimento , Cruzamentos Genéticos , Frutas/crescimento & desenvolvimento , Genótipo , Fenótipo , Locos de Características Quantitativas
8.
FASEB J ; 35(8): e21768, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245617

RESUMO

Insulators are cis-regulatory elements that block enhancer activity and prevent heterochromatin spreading. The binding of CCCTC-binding factor (CTCF) protein is essential for insulators to play the roles in a chromatin context. The ß-globin locus, consisting of multiple genes and enhancers, is flanked by two insulators 3'HS1 and HS5. However, it has been reported that the absence of these insulators did not affect the ß-globin transcription. To explain the unexpected finding, we have deleted a CTCF motif at 3'HS1 or HS5 in the human ß-globin locus and analyzed chromatin interactions around the locus. It was found that a topologically associating domain (TAD) containing the ß-globin locus is maintained by neighboring CTCF sites in the CTCF motif-deleted loci. The additional deletions of neighboring CTCF motifs disrupted the ß-globin TAD, resulting in decrease of the ß-globin transcription. Chromatin interactions of the ß-globin enhancers with gene promoter were weakened in the multiple CTCF motifs-deleted loci, even though the enhancers have still active chromatin features such as histone H3K27ac and histone H3 depletion. Genome-wide analysis using public CTCF ChIA-PET and ChIP-seq data showed that chromatin domains possessing multiple CTCF binding sites tend to contain super-enhancers like the ß-globin enhancers. Taken together, our results show that multiple CTCF sites surrounding the ß-globin locus cooperate with each other to maintain a TAD. The ß-globin TAD appears to provide a compact spatial environment that enables enhancers to interact with promoter.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Loci Gênicos , Regiões Promotoras Genéticas , Globinas beta/biossíntese , Fator de Ligação a CCCTC/genética , Linhagem Celular , Cromatina/genética , Humanos , Globinas beta/genética
9.
Nat Commun ; 12(1): 4571, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315874

RESUMO

Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Proteínas de Transporte de Cátions/genética , Estudo de Associação Genômica Ampla , Manganês/sangue , Mutação/genética , Proteínas de Transporte de Cátions/metabolismo , Regulação da Expressão Gênica , Ligação Genética , Loci Gênicos , Genoma Humano , Células HeLa , Hematócrito , Heterozigoto , Homeostase , Humanos , Fígado/patologia , Manganês/metabolismo , Anotação de Sequência Molecular , Fenótipo , Reprodutibilidade dos Testes
10.
BMC Plant Biol ; 21(1): 311, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210282

RESUMO

BACKGROUND: Mineral elements are important for maintaining good human health besides heavy metals. Mining genes that control mineral elements are paramount for improving their accumulation in the wheat grain. Although previous studies have reported some loci for beneficial trace elements, they have mainly focused on Zn and Fe content. However, little information is available regarding the genetic loci differences in dissecting synchronous accumulation of multiple mineral elements in wheat grains, including beneficial and heavy elements. Therefore, a genome-wide association study (GWAS) was conducted on 205 wheat accessions with 24,355 single nucleotide polymorphisms (SNPs) to identify important loci and candidate genes for controlling Ca, Fe, Zn, Se, Cu, Mn, Cd, As, and Pb accumulation in wheat grains. RESULTS: A total of 101 marker-trait associations (MTAs) (P < 10-5) loci affecting the content of nine mineral elements was identified on chromosomes 1B, 1D, 2A, 2B, 3A, 3B, 3D, 4A, 4B, 5A, 5B, 5D, 6B, 7A, 7B, and 7D. Among these, 17 major MTAs loci for the nine mineral elements were located, and four MTAs loci (P < 10-5) were found on chromosomes 1B, 6B, 7B, and 7D. Eight multi-effect MTAs loci were detected that are responsible for the control of more than one trait, mainly distributed on chromosomes 3B, 7B, and 5A. Furthermore, sixteen candidate genes controlling Ca, Fe, Zn, Se, Cd, and Pb were predicted, whose functions were primarily related to ion binding, including metals, Fe, Ca, Cu, Mg, and Zn, ATP binding, ATPase activity, DNA binding, RNA binding, and protein kinase activity. CONCLUSIONS: Our study indicated the existence of gene interactions among mineral elements based on multi-effect MTAs loci and candidate genes. Meanwhile this study provided new insights into the genetic control of mineral element concentrations, and the important loci and genes identified may contribute to the rapid development of beneficial mineral elements and a reduced content of harmful heavy metals in wheat grain.


Assuntos
Genoma de Planta , Minerais/metabolismo , Estações do Ano , Sementes/genética , Triticum/genética , Alelos , Mapeamento Cromossômico , Loci Gênicos , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Fenótipo
11.
Transl Psychiatry ; 11(1): 407, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301917

RESUMO

Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208-795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20-22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.


Assuntos
Transtorno Bipolar , Doenças Cardiovasculares , Transtorno Bipolar/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
12.
Commun Biol ; 4(1): 864, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294844

RESUMO

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Transtornos de Enxaqueca/genética , Adulto , Afro-Americanos/genética , Idoso , Americanos Asiáticos/genética , Mapeamento Cromossômico , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etnologia , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
13.
Transl Psychiatry ; 11(1): 368, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34226488

RESUMO

Neuroticism is associated with poor health, cardiovascular disease (CVD) risk factors and coronary artery disease (CAD). The conditional/conjunctional false discovery rate method (cond/conjFDR) was applied to genome wide association study (GWAS) summary statistics on neuroticism (n = 432,109), CAD (n = 184,305) and 12 CVD risk factors (n = 188,577-339,224) to investigate genetic overlap between neuroticism and CAD and CVD risk factors. CondFDR analyses identified 729 genomic loci associated with neuroticism after conditioning on CAD and CVD risk factors. The conjFDR analyses revealed 345 loci jointly associated with neuroticism and CAD (n = 30), body mass index (BMI) (n = 96) or another CVD risk factor (n = 1-60). Several loci were jointly associated with neuroticism and multiple CVD risk factors. Seventeen of the shared loci with CAD and 61 of the shared loci with BMI are novel for neuroticism. 21 of 30 (70%) neuroticism risk alleles were associated with higher CAD risk. Functional analyses of the genes mapped to the shared loci implicated cell division, nuclear receptor, elastic fiber formation as well as starch and sucrose metabolism pathways. Our results indicate polygenic overlap between neuroticism and CAD and CVD risk factors, suggesting that genetic factors may partly cause the comorbidity. This gives new insight into the shared molecular genetic basis of these conditions.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Doenças Cardiovasculares/genética , Doença da Artéria Coronariana/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Neuroticismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199768

RESUMO

Single mutations can confer resistance to antibiotics. Identifying such mutations can help to develop and improve drugs. Here, we systematically screen for candidate quinolone resistance-conferring mutations. We sequenced highly diverse wastewater E. coli and performed a genome-wide association study (GWAS) to determine associations between over 200,000 mutations and quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including 1 located at the active site of the biofilm dispersal gene bdcA and 6 silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrase (gyrA) and topoisomerase IV (parC). In summary, we demonstrate that GWAS effectively and comprehensively identifies resistance mutations without a priori knowledge of targets and mode of action. The results suggest that mutations in the bdcA and valS genes, which are involved in biofilm dispersal and translation, may lead to novel resistance mechanisms.


Assuntos
Farmacorresistência Bacteriana/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Mutação/genética , Quinolonas/farmacologia , Valina-tRNA Ligase/genética , Águas Residuárias/microbiologia , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Loci Gênicos , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação/genética , Modelos Moleculares , Fenótipo , Filogenia
15.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203440

RESUMO

Admixed populations arise when two or more ancestral populations interbreed. As a result of this admixture, the genome of admixed populations is defined by tracts of variable size inherited from these parental groups and has particular genetic features that provide valuable information about their demographic history. Diverse methods can be used to derive the ancestry apportionment of admixed individuals, and such inferences can be leveraged for the discovery of genetic loci associated with diseases and traits, therefore having important biomedical implications. In this review article, we summarize the most common methods of global and local genetic ancestry estimation and discuss the use of admixture mapping studies in human diseases.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Pesquisa Biomédica , Loci Gênicos/genética , Genótipo , Humanos
16.
Hum Genet ; 140(9): 1353-1365, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34268601

RESUMO

Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Loci Gênicos , Leiomioma/genética , Proteínas de Neoplasias/genética , Proteína Wnt4/genética , Endometriose/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Síndrome do Ovário Policístico/genética
17.
Nat Commun ; 12(1): 4250, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253730

RESUMO

Variable number tandem repeats (VNTRs) are composed of consecutive repetitive DNA with hypervariable repeat count and composition. They include protein coding sequences and associations with clinical disorders. It has been difficult to incorporate VNTR analysis in disease studies that use short-read sequencing because the traditional approach of mapping to the human reference is less effective for repetitive and divergent sequences. In this work, we solve VNTR mapping for short reads with a repeat-pangenome graph (RPGG), a data structure that encodes both the population diversity and repeat structure of VNTR loci from multiple haplotype-resolved assemblies. We develop software to build a RPGG, and use the RPGG to estimate VNTR composition with short reads. We use this to discover VNTRs with length stratified by continental population, and expression quantitative trait loci, indicating that RPGG analysis of VNTRs will be critical for future studies of diversity and disease.


Assuntos
Variação Genética , Genética Populacional , Genoma Humano , Repetições Minissatélites/genética , Mapeamento Cromossômico , Regulação da Expressão Gênica , Loci Gênicos , Humanos , Motivos de Nucleotídeos/genética , Locos de Características Quantitativas/genética
18.
Nat Commun ; 12(1): 3809, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155212

RESUMO

Bacterial microcompartments (BMCs) are organelles that segregate segments of metabolic pathways which are incompatible with surrounding metabolism. BMCs consist of a selectively permeable shell, composed of three types of structurally conserved proteins, together with sequestered enzymes that vary among functionally distinct BMCs. Genes encoding shell proteins are typically clustered with those for the encapsulated enzymes. Here, we report that the number of identifiable BMC loci has increased twenty-fold since the last comprehensive census of 2014, and the number of distinct BMC types has doubled. The new BMC types expand the range of compartmentalized catalysis and suggest that there is more BMC biochemistry yet to be discovered. Our comprehensive catalog of BMCs provides a framework for their identification, correlation with bacterial niche adaptation, experimental characterization, and development of BMC-based nanoarchitectures for biomedical and bioengineering applications.


Assuntos
Bactérias/genética , Organelas/genética , Bactérias/classificação , Bactérias/citologia , Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Compartimento Celular , Transferência Genética Horizontal , Loci Gênicos , Variação Genética , Organelas/classificação , Organelas/metabolismo , Filogenia
19.
Nat Commun ; 12(1): 3595, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127677

RESUMO

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.


Assuntos
Catarata/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Envelhecimento , Animais , Caspase 7/genética , Estudos de Coortes , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Cristalino , Modelos Logísticos , Camundongos , Camundongos Knockout , Epidemiologia Molecular , Ribonucleoproteínas/genética , Fatores Sexuais
20.
Nat Commun ; 12(1): 3426, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103516

RESUMO

Adaptive plasticity in stress responses is a key element of plant survival strategies. For instance, moderate heat stress (HS) primes a plant to acquire thermotolerance, which allows subsequent survival of more severe HS conditions. Acquired thermotolerance is actively maintained over several days (HS memory) and involves the sustained induction of memory-related genes. Here we show that FORGETTER3/ HEAT SHOCK TRANSCRIPTION FACTOR A3 (FGT3/HSFA3) is specifically required for physiological HS memory and maintaining high memory-gene expression during the days following a HS exposure. HSFA3 mediates HS memory by direct transcriptional activation of memory-related genes after return to normal growth temperatures. HSFA3 binds HSFA2, and in vivo both proteins form heteromeric complexes with additional HSFs. Our results indicate that only complexes containing both HSFA2 and HSFA3 efficiently promote transcriptional memory by positively influencing histone H3 lysine 4 (H3K4) hyper-methylation. In summary, our work defines the major HSF complex controlling transcriptional memory and elucidates the in vivo dynamics of HSF complexes during somatic stress memory.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/fisiologia , Regulação da Expressão Gênica de Plantas , Fatores de Transcrição de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Complexos Multiproteicos/metabolismo , Transcrição Genética , Proteínas de Arabidopsis/genética , Epistasia Genética , Genes de Plantas , Loci Gênicos , Fatores de Transcrição de Choque Térmico/genética , Histonas/metabolismo , Cinética , Lisina/metabolismo , Metilação , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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