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1.
Nat Commun ; 11(1): 4739, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958756

RESUMO

More people globally depend on the water buffalo than any other domesticated species, and as the most closely related domesticated species to cattle they can provide important insights into the shared evolutionary basis of domestication. Here, we sequence the genomes of 79 water buffalo across seven breeds and compare patterns of between breed selective sweeps with those seen for 294 cattle genomes representing 13 global breeds. The genomic regions under selection between cattle breeds significantly overlap regions linked to stature in human genetic studies, with a disproportionate number of these loci also shown to be under selection between water buffalo breeds. Investigation of potential functional variants in the water buffalo genome identifies a rare example of convergent domestication down to the same mutation having independently occurred and been selected for across domesticated species. Cross-species comparisons of recent selective sweeps can consequently help identify and refine important loci linked to domestication.


Assuntos
Búfalos/genética , Bovinos/genética , Domesticação , Genoma/genética , Animais , Cruzamento , Búfalos/classificação , Bovinos/classificação , Evolução Molecular , Loci Gênicos/genética , Variação Genética , Fenótipo , Filogeografia , Seleção Genética
2.
Lancet Neurol ; 19(10): 840-848, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32949544

RESUMO

BACKGROUND: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. METHODS: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. FINDINGS: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. INTERPRETATION: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. FUNDING: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.


Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/epidemiologia , Predisposição Genética para Doença/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
3.
Nat Commun ; 11(1): 4544, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917861

RESUMO

Stratification of enhancers by signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We examine a distinct method of stratification that focuses on peak breadth, termed hyperacetylated chromatin domains (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does using multiple data sets. Moreover, genetic manipulations of selected gene loci suggest that some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of histone modifications across domains and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.


Assuntos
Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Loci Gênicos/genética , Ativação Transcricional , Acetilação , Animais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Sequenciamento de Cromatina por Imunoprecipitação , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Eritroblastos , Feminino , Feto , Código das Histonas/genética , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , RNA-Seq
4.
PLoS One ; 15(8): e0236054, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750053

RESUMO

INTRODUCTION: Multi-drug resistance is a major challenge in the control of tuberculosis. Despite newer modalities for diagnosis and treatment, people are still suffering from this disease. Understanding the common gene mutations conferring rifampicin and isoniazid resistance is crucial for the implementation of effective molecular tools at local and national levels. Hence, this study aimed to evaluate the molecular detection of rifampicin and isoniazid-resistant gene mutations in M.tuberculosis isolates in Addis Ababa, Ethiopia. METHOD: Health Center-based cross-sectional study was conducted between January and September 2017 in Addis Ababa, Ethiopia. The collected sputum samples were processed for mycobacterial isolation and Region of difference 9 based polymerase chain reaction for species identification. To characterize the rifampicin and isoniazid-resistant M. tuberculosis isolates, a molecular genetic assay (GenoType MTBDRplus) was used; the assay is based on DNA-STRIP technology. RESULT: Culture positivity was confirmed in 82.6% (190/230) of smear-positive newly diagnosed pulmonary tuberculosis cases enrolled in the study. From 190 isolates 93.2% were sensitive for both rifampicin and isoniazid, and 6.8% of the isolates were resistant to at least one of the tested anti-TB drugs. Gene mutations were observed in all studied multidrug resistance-associated gene loci (rpoB, katG, and inhA). Two isolates exhibited heteroresistance, a mutated, as well as wild type sequences, were detected in the respective strains. MDR-TB case was observed in 1.1% (2/190) of the cases. All the MDR-TB cases were positive for HIV and found to have a history of prior hospital admission. CONCLUSION: In our finding a relatively high prevalence of any drug resistance was observed and the overall prevalence of multidrug-resistant tuberculosis was 1.1%.The majority of drug-resistant isolates demonstrated common mutations. Heteroresistant strains were detected, signaling the existence of an M.tuberculosis population with variable responses to anti-tuberculosis drugs or of mixed infections.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Antituberculosos/uso terapêutico , Estudos Transversais , Análise Mutacional de DNA , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Etiópia , Feminino , Genes Bacterianos/genética , Loci Gênicos/genética , Humanos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Mycobacterium tuberculosis/isolamento & purificação , Reação em Cadeia da Polimerase , Rifampina/farmacologia , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto Jovem
5.
J Toxicol Sci ; 45(8): 449-473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741897

RESUMO

Although peroxisome proliferator-activated receptor α (PPARα) agonists are obviously hepatocarcinogenic in rodents, they have been widely used for dyslipidemia and proven to be safe for clinical use without respect to the species difference. It is established that PPARα acts as a part of the transcription factor complex, but its precise mechanism is still unknown. Using the data of Toxicogenomics Database, reliable genes responsive to PPARα agonists, clofibrate, fenofibrate and WY-14,643, in rat liver, were extracted from both in vivo and in vitro data, and sorted by their fold increase. It was found that there were many genes responding to fibrates exclusively in vivo. Most of the in vivo specific genes appear to be unrelated to lipid metabolism and are not upregulated in the kidney. Fifty-seven genes directly related to cell proliferation were extracted from in vivo data, but they were not induced in vitro at all. Analysis of PPAR-responsive elements could not explain the observed difference in induction. To evaluate possible interaction between neighboring genes in gene expression, the correlation of the fold changes of neighboring genes for 22 drugs with various PPARα agonistic potencies were calculated for the genes showing more than 2.5 fold induction by 3 fibrates in vivo, and their genomic location was compared with that of the human orthologue. In the present study, many candidates of genes other than lipid metabolism were selected, and these could be good starting points to elucidate the mechanism of PPARα agonist-induced rodent-specific toxicity.


Assuntos
Bases de Dados Genéticas , Fenofibrato/toxicidade , Loci Gênicos/genética , Armazenamento e Recuperação da Informação/métodos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , PPAR alfa/agonistas , Pirimidinas/toxicidade , Animais , Epistasia Genética , Expressão Gênica , Estudos de Associação Genética , Masculino , Ratos Sprague-Dawley , Especificidade da Espécie
6.
Nature ; 584(7822): 589-594, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32814899

RESUMO

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , Fractais , Predisposição Genética para Doença , Coração/anatomia & histologia , Coração/fisiologia , Miocárdio/metabolismo , Adulto , Idoso , Animais , Doenças Cardiovasculares/fisiopatologia , Citoesqueleto/genética , Citoesqueleto/fisiologia , Técnicas de Inativação de Genes , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Coração/embriologia , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Miocárdio/citologia , Oryzias/embriologia , Oryzias/genética , Fenótipo
7.
Nature ; 584(7819): 130-135, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581364

RESUMO

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1-10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.


Assuntos
Envelhecimento/genética , Aberrações Cromossômicas , Cromossomos Humanos/genética , Células Clonais/metabolismo , Genoma Humano/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Idoso de 80 Anos ou mais , Alelos , Linhagem da Célula , Células Clonais/citologia , Células Clonais/patologia , Estudos de Coortes , Feminino , Loci Gênicos/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Japão , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia de Células T/genética , Leucemia de Células T/patologia , Masculino , Mosaicismo , Reino Unido
8.
Leg Med (Tokyo) ; 46: 101719, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32512465

RESUMO

In order to create an autosomal STR loci population database for Himachal Pradesh, 259 blood samples were taken from people residing in various regions of the state and AmpFlSTR® Identifiler® Plus PCR amplification kit was used for evaluation of 15 autosomal STR markers. A total of 149 alleles were investigated in this study with a mean allele number of 9.933 per locus. The locus D2S1338 was most informative in our data, as it had the highest discrimination power (PD-0.967) and the highest polymorphic information content (PIC-0.86). The matching probability and typical paternity index for all the studied loci were observed as 2.9x10-18 and 4.7x105, respectively. Discrimination power (CPD) and exclusion power (CPE) for all the studied loci were observed as 1 and 0.999998.


Assuntos
Impressões Digitais de DNA , Bases de Dados Genéticas , Genética Forense/métodos , Loci Gênicos/genética , Repetições de Microssatélites/genética , Alelos , Genômica , Humanos , Índia , Reação em Cadeia da Polimerase
9.
Leg Med (Tokyo) ; 46: 101726, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32526672

RESUMO

China harbors 56 ethnic groups and Han is the largest population. It is informative and useful to explore the available population genetic characteristics of Chinese Han population from Fujian Province, Southeast China. In our study, we explored the genetic characteristics of 20 autosomal Short tandem repeat (STR) loci in 1555 unrelated Chinese Han individuals from Zhangzhou City, Southeastern China using the SureID® 21G Human STR Identification Kit. Moreover, phylogenetic analysis was performed between the Zhangzhou Han population and other relevant populations based on the shared autosomal STR genotyping. The neighbor-joining tree and multidimensional scaling analysis were analyzed based on the Nei's standard genetic distance. We found 262 alleles among 1555 unrelated individuals and the corresponding allele frequencies ranged from 0.5521 to 0.0003. The combined power of discrimination and exclusion of the 20 autosomal STR loci were 0.99999999999999999999999943 and 0.999999996166537, respectively. Population comparison revealed that the Zhangzhou Han population were lining up together with the southern Han populations in China while showed significant differences from other China populations. Our results found that the 20 autosomal STR loci in Zhangzhou Han population are meaningful for forensic medicine and human genetic. The genetics characteristic of Zhangzhou Han population is similar with the southern Han population in China.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Medicina Legal , Loci Gênicos/genética , Genética Populacional/métodos , Repetições de Microssatélites/genética , China , Humanos , Polimorfismo Genético
10.
Am J Hum Genet ; 106(6): 764-778, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32386560

RESUMO

Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individuals, followed by replication in independent samples (∼42,000 for resting Tpe and ∼22,000 for Tpe response to exercise and recovery), all from UK Biobank. Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise, respectively, were formally replicated. In a full dataset GWAS, 13 further loci for resting Tpe, 1 for Tpe response to exercise and 1 for Tpe response to exercise were genome-wide significant (p ≤ 5 × 10-8). Sex-specific analyses indicated seven additional loci. In total, we identify 32 loci for resting Tpe, 3 for Tpe response to exercise and 3 for Tpe response to recovery modulating ventricular repolarization, as well as cardiac conduction and contraction. Our findings shed light on the genetic basis of resting Tpe and Tpe response to exercise and recovery, unveiling plausible candidate genes and biological mechanisms underlying ventricular excitability.


Assuntos
Eletrocardiografia , Exercício Físico/fisiologia , Estudo de Associação Genômica Ampla , Função Ventricular/genética , Adulto , Idoso , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Descanso/fisiologia , Caracteres Sexuais , Reino Unido , Função Ventricular/fisiologia
11.
DNA Cell Biol ; 39(6): 1012-1022, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32352843

RESUMO

Kisspeptin has been identified as a key regulatory protein in the release of gonadotropin-releasing hormone (GnRH), which subsequently increases gonadotropin secretion during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. The effects of variants in the KISS1, KISS1R, and GNRHR genes and their possible association with assisted reproduction outcomes remain to be elucidated. In this study, we used next-generation sequencing to investigate the associations of the genetic diversity at the candidate loci for KISS1, KISS1R, and GNRHR with the hormonal profiles and reproductive outcomes in 86 women who underwent in vitro fertilization treatments. Variants in the KISS1 and KISS1R genes were associated with luteinizing hormone (rs35431622:T>C), anti-Mullerian hormone (rs71745629delT), follicle-stimulating hormone (rs73507529:C>A), and estradiol (rs73507527:G>A, rs350130:A>G, and rs73507529:C>A) levels, as well as with reproductive outcomes such as the number of oocytes retrieved (s35431622:T>C), metaphasis II oocytes (rs35431622:T>C), and embryos (rs1132506:G>C). Additionally, variants in the GNRHR UTR3' (rs1038426:C>A, rs12508464:A>C, rs13150734:C>A, rs17635850:A>G, rs35683646:G>A, rs35610027:C>G, rs35845954:T>C, rs17635749:C>T, and rs7666201:C>T) were associated with low prolactin levels. A conjoint analysis of clinical, hormonal, and genetic variables using a generalized linear model identified two variants of the KISS1 gene (rs71745629delT and rs1132506:G>C) that were significantly associated with hormonal variations and reproductive outcomes. The findings suggest that variants in KISS1, KISS1R, and GNRHR genes can modulate hormone levels and reproductive outcomes.


Assuntos
Variação Genética , Hormônio Liberador de Gonadotropina/metabolismo , Kisspeptinas/genética , Receptores de Kisspeptina-1/genética , Receptores LHRH/genética , Reprodução/genética , Adulto , Feminino , Loci Gênicos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Infertilidade/genética
12.
DNA Cell Biol ; 39(6): 949-957, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32397755

RESUMO

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. This study proposed to screen candidate PACG-associated variants in Chinese Han people. Whole exome sequencing was applied to five confirmed PACG patients and two primary angle closure suspect individuals within a PACG-enriched Chinese Han family. A series of bioinformatics analyses were implemented to obtain high-risk single nucleotide variant (SNV) loci for PACG, which were subsequently used for linkage analysis for identifying linkage genome regions. In addition, MassARRAY SNV genotyping was applied to high-risk PACG loci as well as those within linkage regions in another independent cohort including 251 PACG and 251 normal samples to further screen high-confidence SNVs. A total of 27 loci in 19 genes remained after linkage analysis. The 19 genes were significantly enriched in biological processes tightly related to PACG, including retinol metabolism and salmonella infection. Two nonsynonymous SNV loci, rs897804 in exon15 of HOOK2 and rs3745193 in exon7 of GTPBP3, were recognized with higher variant frequency in PACG samples than that in control samples after association analysis of MassARRAY SNV genotyping data. This study sheds new light on the understanding of PACG incidence among Chinese Han people.


Assuntos
Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/genética , Glaucoma de Ângulo Fechado/genética , Proteínas Associadas aos Microtúbulos/genética , Polimorfismo de Nucleotídeo Único , Feminino , Loci Gênicos/genética , Humanos , Masculino , Linhagem , Sequenciamento Completo do Exoma
13.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
14.
Gene ; 753: 144804, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32445920

RESUMO

We have investigated 765 unrelated individuals from Azerbaijan using AmpFlSTR® Identifiler® Plus PCR Amplification Kit. For each STR locus basic population-genetic and forensic parameters were determined. The calculated P-values (PHWE) for the accuracy of the Hardy-Weinberg equilibrium (HWE) tests, showed that this parameter had a statistically significant value (PHWE = 0.0000) only for the THO1, D18S51 and FGA loci. The values of parameters for the set of 15 STR loci such as CPE, CPD, CTPI and the PP showed that the given set of loci can be confidently used to solve identification problems for the studied population. Multiple population differentiation tests performed between Azerbaijan and other 17 world populations revealed that between Azerbaijan and Iraqi, Iranian, Turkish populations there were no significant differences on all STR loci. Additionally, comparisons of Fischer genetic distance indices (FST) P-values did not reveal any statistically significant difference between Azerbaijan and Iranian populations at P < 0.05. However, with South African black population differences at all STR loci were detected. Both tests did not reveal a locus by which our population would differ from all the other compared populations. PCA and PCoA analyzes showed that the Azerbaijani population was grouped with different populations in different quarters, showing a negative and zero correlation, respectively. Regarding the location of the Azerbaijan population, there are some differences between NJ and UPGMA phylogenetic trees. For example, in the NJ tree, Azerbaijan population was grouped with Iranian, but in the UPGMA tree, it was grouped with the Turkish population. Based on Nei's genetic distance between populations the second tree has a more realistic outcome.


Assuntos
Variação Genética/genética , Genética Populacional/métodos , Repetições de Microssatélites/genética , Adulto , Alelos , Azerbaijão/etnologia , Feminino , Fibrinogênio/genética , Frequência do Gene/genética , Loci Gênicos/genética , Humanos , Irã (Geográfico) , Masculino , Proteínas Nucleares/genética , Filogenia , Reação em Cadeia da Polimerase , Turquia
15.
Nat Genet ; 52(5): 494-504, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341527

RESUMO

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.


Assuntos
Predisposição Genética para Doença/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Fenótipo , Pigmentação/genética , Polimorfismo de Nucleotídeo Único/genética
16.
PLoS One ; 15(3): e0223939, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196497

RESUMO

Whilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.


Assuntos
Artrite Reumatoide/genética , Loci Gênicos/genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , RNA-Seq , Transcriptoma
17.
Gene ; 743: 144600, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32217139

RESUMO

Exploring molecular markers related to economic traits of livestock is of great significance to breeding. Long-chain fatty acid COA synthetase (ACSL) plays a crucial role in lipid synthesis and metabolism, which may affect animal growth. This study was to investigate the polymorphism of ACSL gene and its association with the growth trait of the donkey. Three insertions and two deletions were detected on the introns of ACSL3 gene in 450 Dezhou donkeys using polyacrylamide gel electrophoresis. After that, linkage disequilibrium analysis found that there was a strong linkage among ACSL3 gene loci in Dezhou donkey. Association analysis of growth traits showed that ACSL3-1, ACSL3-2, ACSL3-3, and ACSL3-4 loci were significantly associated with body weight and other growth traits (P < 0.05). Furthermore, five high frequency haplotypes were identified in Dezhou donkey, and haplotype combination analysis showed that among the first three high-frequency combinations, the low-frequency Hap3Hap3 (II-DD-II-DD-DD) homozygous haplotype combination was lower than the other two groups (Hap1Hap1, Hap5Hap5) in the chest width and chest depth (P < 0.05) of the female. Conclusively, the results of this study indicated that the polymorphisms in ACSL3 gene can be used as molecular markers to participate in donkey breeding.


Assuntos
Peso Corporal/genética , Coenzima A Ligases/genética , Equidae/genética , Haplótipos , Animais , Cruzamento , Equidae/crescimento & desenvolvimento , Feminino , Loci Gênicos/genética , Íntrons/genética , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
18.
Nat Commun ; 11(1): 1237, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144282

RESUMO

Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.


Assuntos
Doenças Autoimunes/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Linhagem Celular Tumoral , Predisposição Genética para Doença , Variação Genética/imunologia , Haplótipos/genética , Haplótipos/imunologia , Humanos , Desequilíbrio de Ligação , Herança Multifatorial/imunologia , Estudo de Prova de Conceito
19.
PLoS One ; 15(3): e0229782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126126

RESUMO

African Oryza glaberrima and Oryza sativa landraces are considered valuable resources for breeding traits due to their adaptation to local environmental and soil conditions. They often possess superior resistance to endemic pests and tolerance to drought and nutrient deficiencies when compared to the "imported" high production Asian rice varieties. In contrast, "domestication traits" such as seed shattering, lodging, and seed yield are not well established in these African landraces. Therefore, the use of these African varieties for high production agriculture is limited by unpredictable yield and grain quality. We are addressing this shortcoming by developing protocols for genetically transforming African landraces to allow the use of CRISPR-Cas mediated breeding approaches. Here we use as proof of concept the cultivated African landrace Kabre to target selected known "domestication loci" and improve the agronomic potential of Kabre rice. Stable genetic transformation with CRISPR-Cas9-based vectors generated single and simultaneous multiple gene knockouts. Plants with reduced stature to diminish lodging were generated by disrupting the HTD1 gene. Furthermore, three loci shown to control seed size and/or yield (GS3, GW2 and GN1A) were targeted using a multiplex CRISPR-Cas9 construct. This resulted in mutants with significantly improved seed yield. Our study provides an example of how new breeding technologies can accelerate the development of highly productive African landrace rice varieties, an important advancement considering that Africa is a hotspot for worldwide population growth and therefore prone to food shortage.


Assuntos
Domesticação , Grão Comestível/genética , Edição de Genes/métodos , Oryza/genética , Melhoramento Vegetal/métodos , Aclimatação/genética , África , Sistemas CRISPR-Cas/genética , DNA de Plantas/genética , Técnicas de Inativação de Genes/métodos , Genes de Plantas/genética , Loci Gênicos/genética , Plantas Geneticamente Modificadas/genética , Estudo de Prova de Conceito , Fatores de Tempo
20.
PLoS One ; 15(3): e0229245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130259

RESUMO

Aquaporins (AQPs) are membrane channels that provide for transport of water and other small molecules across the lipid bilayer of cells. Their function is essential for physiologic processes such as cell volume regulation, chondrocyte hypertrophy during appendicular skeletal growth, water reabsorption in the kidney tubules, and water excretion by the salivary glands. The ten AQP isoforms show tissue specificity and are involved in different pathologies and inflammatory diseases. This study addresses the hypothesis that arthritis, periodontitis, and temporomandibular joint disorders (TMDs) can be influenced by variation in the AQP genes at 12q13.12 locus. Salivary samples of 688 individuals were obtained from the Dental Registry and DNA Repository project at the University of Pittsburgh. Ten polymorphisms in four AQP genes (AQP1, 2, 5, and 6) were genotyped and correlated to disease status as reported by patients. Associations were found between the single nucleotide polymorphism (SNP) rs467323 in AQP2 and TMD in both genotypic (p = 0.03) and recessive (p = 0.02) models, and between rs1996315 in AQP6 and periodontitis (p = 0.05). Combined analysis of TMD and periodontitis showed an association with rs3741559 in AQP2 (p = 0.02). When conducting haplotype analysis of rs467323 and rs10875989 in AQP2, the haplotype CT showed an association with the TMD phenotype (p = 0.007). Our results suggest that the aquaporin locus at 12q13.12 may contribute to the pathogenesis of inflammatory conditions such as periodontitis and TMD. Thus, oral and skeletal health are correlated and potential susceptibility screening strategies may be developed.


Assuntos
Aquaporinas/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Periodontite/complicações , Transtornos da Articulação Temporomandibular/complicações , Transtornos da Articulação Temporomandibular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
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