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1.
Nat Commun ; 12(1): 2909, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006833

RESUMO

The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.


Assuntos
Encefalopatias/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Tálamo/metabolismo , Encefalopatias/classificação , Mapeamento Encefálico/métodos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Loci Gênicos/genética , Genoma Humano/genética , Humanos , Desequilíbrio de Ligação , Imageamento por Ressonância Magnética/métodos , Transtornos Mentais/classificação , Transtornos Mentais/genética , Locos de Características Quantitativas/genética , Núcleos Talâmicos/diagnóstico por imagem , Núcleos Talâmicos/metabolismo , Tálamo/diagnóstico por imagem
2.
Nat Commun ; 12(1): 2277, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859189

RESUMO

Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells follow a more complex differentiation, where Hfn4a is associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Néfrons/crescimento & desenvolvimento , Organogênese/genética , Insuficiência Renal Crônica/genética , Animais , Comunicação Celular , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Epigenômica , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Camundongos , Néfrons/citologia , Podócitos/fisiologia , Polimorfismo de Nucleotídeo Único , RNA-Seq , Insuficiência Renal Crônica/patologia , Análise de Célula Única , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismo
3.
Mol Genet Genomics ; 296(4): 877-891, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33903955

RESUMO

In a rapidly changing climate, flowering time (FL) adaptation is important to maximize seed yield in flax (Linum usitatissimum L.). However, our understanding of the genetic mechanism underlying FL in this multipurpose crop remains limited. With the aim of dissecting the genetic architecture of FL in flax, a genome-wide association study (GWAS) was performed on 200 accessions of the flax core collection evaluated in four environments. Two single-locus and six multi-locus models were applied using 70,935 curated single nucleotide polymorphism (SNP) markers. A total of 40 quantitative trait nucleotides (QTNs) associated with 27 quantitative trait loci (QTL) were identified in at least two environments. The number of QTL with positive-effect alleles in accessions was significantly correlated with FL (r = 0.77 to 0.82), indicating principally additive gene actions. Nine QTL were significant in at least three of the four environments accounting for 3.06-14.71% of FL variation. These stable QTL spanned regions that harbored 27 Arabidopsis thaliana and Oryza sativa FL-related orthologous genes including FLOWERING LOCUS T (Lus10013532), FLOWERING LOCUS D (Lus10028817), transcriptional regulator SUPERMAN (Lus10021215), and gibberellin 2-beta-dioxygenase 2 (Lus10037816). In silico gene expression analysis of the 27 FL candidate gene orthologous suggested that they might play roles in the transition from vegetative to reproductive phase, flower development and fertilization. Our results provide new insights into the QTL architecture of flowering time in flax, identify potential candidate genes for further studies, and demonstrate the effectiveness of combining different GWAS models for the genetic dissection of complex traits.


Assuntos
Linho , Topos Floridos/crescimento & desenvolvimento , Topos Floridos/genética , Linho/genética , Linho/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação , Locos de Características Quantitativas , Sementes/genética , Análise de Sequência de DNA , Fatores de Tempo
4.
Nature ; 590(7845): 300-307, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33536621

RESUMO

Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete1-3. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits4, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.


Assuntos
Doença/genética , Epigênese Genética/genética , Epigenômica , Redes Reguladoras de Genes/genética , Loci Gênicos/genética , Cromatina/genética , Elementos Facilitadores Genéticos/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial/genética , Especificidade de Órgãos/genética , Reprodutibilidade dos Testes
5.
PLoS Genet ; 17(2): e1009319, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33600456

RESUMO

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Pigmentação da Pele/genética , Deficiência de Vitamina D/genética , Adulto , Idoso , Alelos , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , Masculino , Melaninas/metabolismo , Pessoa de Meia-Idade , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etnologia
6.
Nat Commun ; 12(1): 1258, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627673

RESUMO

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Glaucoma de Ângulo Aberto/genética , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
7.
Nat Metab ; 3(2): 228-243, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619380

RESUMO

Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.


Assuntos
Adiposidade/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Obesidade/genética , Adipócitos/metabolismo , Adipócitos Marrons/fisiologia , Adipócitos Brancos/fisiologia , Tecido Adiposo/metabolismo , Alelos , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Família Multigênica/genética , Obesidade/complicações , Medição de Risco , Transdução de Sinais/fisiologia
8.
BMC Bioinformatics ; 22(1): 12, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407074

RESUMO

BACKGROUND: Multi-locus genotype data are widely used in population genetics and disease studies. In evaluating the utility of multi-locus data, the independence of markers is commonly considered in many genomic assessments. Generally, pairwise non-random associations are tested by linkage disequilibrium; however, the dependence of one panel might be triplet, quartet, or other. Therefore, a compatible and user-friendly software is necessary for testing and assessing the global linkage disequilibrium among mixed genetic data. RESULTS: This study describes a software package for testing the mutual independence of mixed genetic datasets. Mutual independence is defined as no non-random associations among all subsets of the tested panel. The new R package "mixIndependR" calculates basic genetic parameters like allele frequency, genotype frequency, heterozygosity, Hardy-Weinberg equilibrium, and linkage disequilibrium (LD) by mutual independence from population data, regardless of the type of markers, such as simple nucleotide polymorphisms, short tandem repeats, insertions and deletions, and any other genetic markers. A novel method of assessing the dependence of mixed genetic panels is developed in this study and functionally analyzed in the software package. By comparing the observed distribution of two common summary statistics (the number of heterozygous loci [K] and the number of share alleles [X]) with their expected distributions under the assumption of mutual independence, the overall independence is tested. CONCLUSION: The package "mixIndependR" is compatible to all categories of genetic markers and detects the overall non-random associations. Compared to pairwise disequilibrium, the approach described herein tends to have higher power, especially when number of markers is large. With this package, more multi-functional or stronger genetic panels can be developed, like mixed panels with different kinds of markers. In population genetics, the package "mixIndependR" makes it possible to discover more about admixture of populations, natural selection, genetic drift, and population demographics, as a more powerful method of detecting LD. Moreover, this new approach can optimize variants selection in disease studies and contribute to panel combination for treatments in multimorbidity. Application of this approach in real data is expected in the future, and this might bring a leap in the field of genetic technology. AVAILABILITY: The R package mixIndependR, is available on the Comprehensive R Archive Network (CRAN) at: https://cran.r-project.org/web/packages/mixIndependR/index.html .


Assuntos
Loci Gênicos/genética , Genômica/métodos , Software , Bases de Dados Genéticas , Genótipo , Desequilíbrio de Ligação/genética
9.
Lancet Child Adolesc Health ; 5(3): 201-209, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33453761

RESUMO

BACKGROUND: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. METHODS: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. FINDINGS: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10-8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10-11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10-8). All associated variants in the chromosome 6 locus were replicated (p<8 × 10-3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. INTERPRETATION: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. FUNDING: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Enurese Noturna/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Criança , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 6/genética , Desamino Arginina Vasopressina/uso terapêutico , Feminino , Variação Genética/genética , Humanos , Masculino , Enurese Noturna/tratamento farmacológico , Fenótipo
10.
Sci Rep ; 11(1): 48, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420178

RESUMO

Childhood obesity is a global public health problem. Understanding the molecular mechanisms that underlie early origins of childhood obesity can facilitate interventions. Consistent phenotypic and genetic correlations have been found between childhood obesity traits and birth weight (a proxy for in-utero growth), suggesting shared genetic influences (pleiotropy). We aimed to (1) investigate whether there is significant shared genetic influence between birth weight and childhood obesity traits, and (2) to identify genetic loci with shared effects. Using a statistical approach that integrates summary statistics and functional annotations for paired traits, we found strong evidence of pleiotropy (P < 3.53 × 10-127) and enrichment of functional annotations (P < 1.62 × 10-39) between birth weight and childhood body mass index (BMI)/obesity. The pleiotropic loci were enriched for regulatory features in skeletal muscle, adipose and brain tissues and in cell lines derived from blood lymphocytes. At 5% false discovery rate, 6 loci were associated with birth weight and childhood BMI and 13 loci were associated with birth weight and childhood obesity. Out of these 19 loci, one locus (EBF1) was novel to childhood obesity and one locus (LMBR1L) was novel to both birth weight and childhood BMI/obesity. These findings give evidence of substantial shared genetic effects in the regulation of both fetal growth and childhood obesity.


Assuntos
Peso ao Nascer/genética , Pleiotropia Genética , Obesidade Pediátrica/genética , Índice de Massa Corporal , Criança , Pré-Escolar , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável
11.
Diabetes Res Clin Pract ; 173: 108582, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33307130

RESUMO

AIMS: To determine if HLA-DP loci independently contribute to classic type 1 diabetes (T1D) of all ages, childhood-onset T1D and latent autoimmune diabetes in adults (LADA) among Chinese Han population. METHODS: A total of 518 patients with classic T1D (Among them 180 participants manifested T1D between 1 and 14 years), 519 patients with LADA and 527 normal controls were genotyped for both HLA-DPA1 and -DPB1 loci. The frequencies of DP alleles and haplotypes in patients were directly compared to those in controls, followed by adjustment for linkage disequilibrium (LD) with DR-DQ haplotypes. RESULTS: In the direct comparison, DPA1*01:03, DPB1*04:01 and DPA1*01:03-DPB1*04:01 showed disease-predisposing effects in both the overall T1D group and the childhood-onset T1D group mainly due to their conjunction with the known susceptible DR3 haplotype. Conditioning on DR-DQ haplotypes, only DPA1*02:02-DPB1*02:02 significantly increased T1D risk among those diagnosed during childhood (OR = 2.02, 95% CI = 1.35-3.01). Whether or not adjusted for LD, no statistically significant HLA-DP association could be observed for LADA. CONCLUSION: HLA-DP is implicated in the pathogenesis of childhood-onset T1D in Chinese, independent of the predominant DR-DQ loci and might serve as additional markers in genetic models for the recognition of those genetically at-risk individuals.


Assuntos
Diabetes Mellitus Tipo 1/genética , Frequência do Gene/genética , Loci Gênicos/genética , Cadeias beta de HLA-DP/genética , Diabetes Autoimune Latente em Adultos/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Nat Hum Behav ; 5(1): 59-70, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32989287

RESUMO

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.


Assuntos
Lateralidade Funcional/genética , Variação Genética/genética , Adulto , Idoso , Feminino , Frequência do Gene/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Fatores Sexuais
13.
Nat Hum Behav ; 5(1): 49-58, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32895543

RESUMO

It has been known since 1904 that, in humans, diverse cognitive traits are positively intercorrelated. This forms the basis for the general factor of intelligence (g). Here, we directly test whether there is a partial genetic basis for individual differences in g using data from seven different cognitive tests (n = 11,263-331,679) and genome-wide autosomal single-nucleotide polymorphisms. A genetic g factor accounts for an average of 58.4% (s.e. = 4.8%) of the genetic variance in the cognitive traits considered, with the proportion varying widely across traits (range, 9-95%). We distil genetic loci that are broadly relevant for many cognitive traits (g) from loci associated specifically with individual cognitive traits. These results contribute to elucidating the aetiology of a long-known yet poorly understood phenomenon, revealing a fundamental dimension of genetic sharing across diverse cognitive traits.


Assuntos
Cognição , Característica Quantitativa Herdável , Adulto , Idoso , Feminino , Estudos de Associação Genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Individualidade , Inteligência/genética , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único/genética
14.
Int J Infect Dis ; 103: 220-225, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33307222

RESUMO

OBJECTIVES: To explore the evolutionary history of Mycobacterium tuberculosis Latin American and Mediterranean (L4.3/LAM) sublineage in Tunisia, where it predominates. METHODS: High-resolution genotyping of 252 L4.3/LAM clinical strains was undertaken, and whole-genome sequencing was performed on 31 representative isolates. RESULTS: Genotyping data coupled with Bayesian analyses split the Tunisian L4.3/LAM strain collection into two divergent entities (65.07% vs 34.92%): a major subpopulation, dominated by a single clonal complex (CC), TUN4.3_CC1 (94.51%); and a minor subpopulation, dominated by TUN4.3_CC2 (42.04%). TUN4.3_CC1 is clearly thriving in Tunisia, accounting for 61.5% of the L4.3/LAM sublineage. TUN4.3_CC1 displayed higher mean allelic richness compared with TUN4.3_CC2 and predominated throughout the entire region, indicating a long-established history. The very low proportion of drug resistance among TUN4.3_CC1 isolates is indicative of their intrinsic ability to spread successfully in the host population. Genomic analyses further confirmed the clear genetic separation between the two main CCs (pairwise fixation index 0.56), and suggested the relatively ancient origin of TUN4.3_CC1. Consistent with its successful expansion, TUN4.3_CC1 showed reduced mean pairwise genetic distance between genomes. CONCLUSIONS: These findings link the successful expansion of L4.3/LAM in Tunisia to a single long-established clone.


Assuntos
Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único/genética , Tuberculose/microbiologia , Teorema de Bayes , Loci Gênicos/genética , Genética Populacional , Genômica , Genótipo , Humanos , América Latina , Região do Mediterrâneo , Filogenia , Tuberculose/epidemiologia , Tunísia/epidemiologia , Sequenciamento Completo do Genoma
15.
Plant Cell Rep ; 40(2): 351-359, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33247387

RESUMO

KEY MESSAGE: Identification of an EST-SSR molecular marker associated with Blister blight, a common fungal disease of tea, facilitating marker-assisted selection, marking a milestone in tea molecular breeding. lister blight (BB) leaf disease of tea, caused by the fungus Exobasidium vexans, results in 25-30% crop loss annually. BB is presently controlled by Cu based fungicides, but genetic resistance is the most viable option in disease management. Tea is a naturally out-crossing, woody perennial necessitating a long time for completion of a breeding programme. Marker-assisted selection (MAS) is vital to expedite breeding programmes and also for better accuracy in gene identification. The aim of the current research was to derive marker-trait associations using an F1 population segregating for BB. The population was genotyped at 11 expressed sequence tag simple sequence repeat loci followed by detecting the alleles by fragment analysis. The genotypic and phenotypic data were subjected to single-marker analysis resulting in the identification of EST-SSR073 as a diagnostic marker amplifying three alleles of the sizes, 168, 170 and 190 bp in F1. Of them, alleles 190 and 168 bp were confirmed to concur BB resistance and susceptibility, respectively. The alleles were validated in a panel of 64 tea cultivars, resulting in the amplification of 12 alleles at EST-SSR073. The EST-SSR073 allele sequences matched with Camellia sinensis photosystem-I reaction center subunit-II. The marker EST-SSR073 can be effectively used in breeding tea against BB, recording a milestone in MAS in tea.


Assuntos
Basidiomycota/fisiologia , Camellia sinensis/genética , Resistência à Doença/genética , Marcadores Genéticos/genética , Repetições de Microssatélites/genética , Doenças das Plantas/imunologia , Alelos , Camellia sinensis/imunologia , Camellia sinensis/microbiologia , Embaralhamento de DNA , Etiquetas de Sequências Expressas , Loci Gênicos/genética , Genótipo , Fenótipo , Melhoramento Vegetal , Doenças das Plantas/microbiologia , Folhas de Planta/genética , Folhas de Planta/imunologia , Folhas de Planta/microbiologia , Chá
16.
Gene ; 764: 145099, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32861879

RESUMO

Down syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. >480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors' age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Síndrome de Down/genética , Epigênese Genética , Miocárdio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Epigenômica , Feminino , Loci Gênicos/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Adulto Jovem
17.
Leg Med (Tokyo) ; 48: 101825, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33338949

RESUMO

This study investigated 22 autosomal short tandem repeat (STR) loci in 156 unrelated individuals from the Mong ethnic minority in Ha Giang Province, Vietnam. Allele frequencies and forensic parameters were calculated, showing the combined Powers of Discrimination reaching 1.000000000000000000000000000000 and the combined Power of Exclusion greater than 0.999999986623. Phylogenetic analysis indicated that the Vietnamese Mong population has close genetic relationships with other Hmong-Mien populations.


Assuntos
Cromossomos Humanos/genética , Loci Gênicos/genética , Genética Populacional , Repetições de Microssatélites/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Humanos , Masculino , Filogenia , Vietnã
18.
PLoS One ; 15(12): e0243085, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33259564

RESUMO

The soybean is agro-economically the most important among all cultivated legume crops, and its seed color is considered one of the most attractive factors in the selection-by-breeders. Thus, genome-wide identification of genes and loci associated with seed colors is critical for the precision breeding of crop soybeans. To dissect seed pigmentation-associated genomic loci and genes, we employed dual approaches by combining reference-based genome-wide association study (rbGWAS) and k-mer-based reference-free GWAS (rfGWAS) with 438 Glycine accessions. The dual analytical strategy allowed us to identify four major genomic loci (designated as SP1-SP4 in this study) associated with the seed colors of soybeans. The k-mer analysis enabled us to find an important recombination event that occurred between subtilisin and I-cluster B in the soybean genome, which could describe a special structural feature of ii allele within the I locus (SP3). Importantly, mapping analyses of both mRNAs and small RNAs allowed us to reveal that the subtilisin-CHS1/CHS3 chimeric transcripts generate and act as an initiator towards 'mirtron (i.e., intron-harboring miRNA precursor)'-triggered silencing of chalcone synthase (CHS) genes. Consequently, the results led us to propose a working model of 'mirtron-triggered gene silencing (MTGS)' to elucidate a long-standing puzzle in the genome-wide CHS gene silencing mechanism. In summary, our study reports four major genomic loci, lists of key genes and genome-wide variations that are associated with seed pigmentation in soybeans. In addition, we propose that the MTGS mechanism plays a crucial role in the genome-wide silencing of CHS genes, thereby suggesting a clue to currently predominant soybean cultivars with the yellow seed coat. Finally, this study will provide a broad insight into the interactions and correlations among seed color-associated genes and loci within the context of anthocyanin biosynthetic pathways.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Genômica , Pigmentação/genética , Sementes/metabolismo , Soja/genética , Soja/metabolismo , Genes de Plantas/genética , Glicina , MicroRNAs/genética
19.
PLoS One ; 15(12): e0243781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362267

RESUMO

The programmable sequence specificity of CRISPR has found uses in gene editing and diagnostics. This manuscript describes an additional application of CRISPR through a family of novel DNA enrichment technologies. CAMP (CRISPR Associated Multiplexed PCR) and cCAMP (chimeric CRISPR Associated Multiplexed PCR) utilize the sequence specificity of the Cas9/sgRNA complex to target loci for the ligation of a universal adapter that is used for subsequent amplification. cTRACE (chimeric Targeting Rare Alleles with CRISPR-based Enrichment) also applies this method to use Cas9/sgRNA to target loci for the addition of universal adapters, however it has an additional selection for specific mutations through the use of an allele-specific primer. These three methods can produce multiplex PCR that significantly reduces the optimization required for every target. The methods are also not specific to any downstream analytical platform. We additionally will present a mutation specific enrichment technology that is non-amplification based and leaves the DNA in its native state: TRACE (Targeting Rare Alleles with CRISPR-based Enrichment). TRACE utilizes the Cas9/sgRNA complex to sterically protect the ends of targeted sequences from exonuclease activity which digests both the normal variant as well as any off-target sequences.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Edição de Genes/métodos , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único/genética , Sequência de Bases , Genoma Humano/genética , Humanos
20.
Genes (Basel) ; 11(12)2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317201

RESUMO

Immune-mediated diseases (IMDs) are complex pathologies that are strongly influenced by environmental and genetic factors. Associations between genetic loci and susceptibility to these diseases have been widely studied, and hundreds of risk variants have emerged during the last two decades, with researchers observing a shared genetic pattern among them. Nevertheless, the pathological mechanism behind these associations remains a challenge that has just started to be understood thanks to functional genomic approaches. Transcriptomics, regulatory elements, chromatin interactome, as well as the experimental characterization of genomic findings, constitute key elements in the emerging understandings of how genetics affects the etiopathogenesis of IMDs. In this review, we will focus on the latest advances in the field of functional genomics, centering our attention on systemic rheumatic IMDs.


Assuntos
Genômica/métodos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/fisiopatologia , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Sequências Reguladoras de Ácido Nucleico/genética , Transcriptoma/genética
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