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1.
BMC Plant Biol ; 19(1): 328, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337341

RESUMO

BACKGROUND: To efficiently protect and exploit germplasm resources for marker development and breeding purposes, we must accurately depict the features of the tea populations. This study focuses on the Camellia sinensis (C. sinensis) population and aims to (i) identify single nucleotide polymorphisms (SNPs) on the genome level, (ii) investigate the genetic diversity and population structure, and (iii) characterize the linkage disequilibrium (LD) pattern to facilitate next genome-wide association mapping and marker-assisted selection. RESULTS: We collected 415 tea accessions from the Origin Center and analyzed the genetic diversity, population structure and LD pattern using the genotyping-by-sequencing (GBS) approach. A total of 79,016 high-quality SNPs were identified; the polymorphism information content (PIC) and genetic diversity (GD) based on these SNPs showed a higher level of genetic diversity in cultivated type than in wild type. The 415 accessions were clustered into three groups by STRUCTURE software and confirmed using principal component analyses (PCA)-wild type, cultivated type, and admixed wild type. However, unweighted pair group method with arithmetic mean (UPGMA) trees indicated the accessions should be grouped into more clusters. Further analyses identified four groups, the Pure Wild Type, Admixed Wild Type, ancient landraces and modern landraces using STRUCTURE, and the results were confirmed by PCA and UPGMA tree method. A higher level of genetic diversity was detected in ancient landraces and Admixed Wild Type than that in the Pure Wild Type and modern landraces. The highest differentiation was between the Pure Wild Type and modern landraces. A relatively fast LD decay with a short range (kb) was observed, and the LD decays of four inferred populations were different. CONCLUSIONS: This study is, to our knowledge, the first population genetic analysis of tea germplasm from the Origin Center, Guizhou Plateau, using GBS. The LD pattern, population structure and genetic differentiation of the tea population revealed by our study will benefit further genetic studies, germplasm protection, and breeding.


Assuntos
Camellia sinensis/genética , China , Variação Genética/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Dinâmica Populacional
2.
Egypt J Immunol ; 26(1): 113-120, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31333001

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease associated with multiple genetics and environmental factors. The aim of the study is to determine the frequency of HLA-B*08 and HLA-B*39 and its linkage disequilibrium with common risk haplotypes DR3-DQA1*05-DQB1*02, and DR4-DQA1-03-DQB1*0302 among T1D Egyptian infants. And assess different environmental factors as early exposure to cow's milk, exclusive breast feeding, mode of delivery and low birth weight. Sixty eight diabetic infants and 120 healthy controls were studied. HLA-DQB1, and DQA1 alleles were identified using homogeneous PCR and oligonucleotide hybridization assays. HLA-B*08 and HLA-B*39 genes were identified using multiplex PCR. The results showed that early exposure to cow's milk before 6 months carry a significant risk for T1D (16% in patients versus 6.6%in control group, P value=0.03). HLA-B*08 frequency was significantly higher among T1D infants than in control group (14.5% in diabetic infants versus 5%in control group, P value=0.024). DR3-DQA1*05-DQB1*02, and DR4-DQA1-03-DQB1*0302 were significantly higher in diabetic infants than controls (P value < 0.001 and 0.004 respectively). HLA-B*08 gene was found in (15.5%) of DR3-DQA1*05-DQB1*02 positive cases while in control group it was found in (13.5%) (P value=0.8). In conclusion, HLA-B*08 gene carry a risk for T1D in Egyptian infants, while DR3-DQA1*05-DQB1*02 haplotype lacks linkage disequilibrium with HLA-B*08 among T1D infants. Further studies are needed to determine which HLA-B gene is strongly linked to DR3-DQA1*05-DQB1*02 haplotype in T1D infants other than HLA-B*08 and HLA-B*18.


Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-B/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Antígeno HLA-DR3/genética , Desequilíbrio de Ligação , Leite , Alelos , Animais , Estudos de Casos e Controles , Bovinos , Egito , Predisposição Genética para Doença , Haplótipos , Humanos , Lactente , Fatores de Risco
3.
Gene ; 712: 143954, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31288058

RESUMO

BACKGROUND: Breast cancer (BC) is the highest cause of mortality among female cancer patients. In some cases, BC is due to Poly [ADP-ribose] polymerase 1 (PARP1) gene dysregulation, which has been involved in various important cellular processes. Among Iranian women, the association between PARP1 polymorphisms and BC was never studied before so in this case-control study, the genetic association of three SNPs (rs1136410, rs907187 and rs4653734) was analyzed with susceptibility to BC. METHODS: The study subjects were 386 Iranian females divided into 186 patients and 200 healthy controls. The genotypes of PARP1 variants were detected using ARMS and a combined ARMS-RFLP PCR method. RESULTS: The results showed that Carriers of CG and GG genotypes of the variant rs4653734 were at higher risk of BC compared with wild-type carriers (CC) and this variant was statistically significant under a recessive model of inheritance. Moreover, rs907187 was related to increased BC risk in the CC and GG genotypes under dominant and recessive models of inheritance. The G allele frequency of rs4653734 and rs907187 was higher in breast cancer patients than in normal subjects. No association was detected between rs1136410 and susceptibility to BC among studied groups. Furthermore, A-G-C haplotype was linked to an increased BC risk, whereas A-C-C and A-C-G haplotypes were related to a decreased risk of BC. In Silico predictions suggested that rs907187 affects E2F and E2F-4 transcription factors binding site. CONCLUSIONS: The current study suggests that rs907187 and rs4653734 have remarkable associations with BC risk among Iranian women.


Assuntos
Neoplasias da Mama/genética , Desequilíbrio de Ligação , Poli(ADP-Ribose) Polimerase-1/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Ilhas de CpG , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Irã (Geográfico)/epidemiologia , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Fatores de Transcrição/metabolismo
4.
Gene ; 717: 143987, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362037

RESUMO

To improve the accuracy and genetic progress of blue fox breeding, the relationships between genetic polymorphisms and growth and reproductive traits of the blue fox were investigated. MC4R, MC3R, INHA and INHBA were selected as candidate genes for molecular evolution and statistical analyses. Single-factor variance analyses showed that the MC4R (g.267C > T, g.423C > T, and g.731C > A) and MC3R (g.677C > T) genotypes had significant impacts on body weight, chest circumference, abdominal perimeter and body mass index (BMI) (P < 0.05) in blue fox. The MC4R and MC3R combined genotypes had significant effects on the body weight and abdominal circumference. The different genotypes of INHA g.75G > A had significant effects on female fecundity, whereas the different genotypes of INHBA g.404G > T and g.467G > T and the INHA and INHBA combined genotypes had significant effects on male fecundity. The proteins encoded by the open reading frames (ORFs) of different polymorphic loci were predicted and analysed. The aims of this study were to identify genetic markers related to growth and reproduction in the blue fox and to provide an efficient, economical and accurate theoretical approach for auxiliary fox breeding.


Assuntos
Raposas/crescimento & desenvolvimento , Raposas/genética , Polimorfismo de Nucleotídeo Único , Reprodução/genética , Animais , Tamanho Corporal/genética , Peso Corporal/genética , China , Evolução Molecular , Feminino , Raposas/fisiologia , Marcadores Genéticos , Subunidades beta de Inibinas/química , Subunidades beta de Inibinas/genética , Inibinas/química , Inibinas/genética , Desequilíbrio de Ligação , Masculino , Mutação , Receptor Tipo 3 de Melanocortina/química , Receptor Tipo 3 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/química , Receptor Tipo 4 de Melanocortina/genética
5.
Semin Ophthalmol ; 34(5): 365-374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257963

RESUMO

Purpose: In this study, we investigated the association of two polymorphisms (rs869109213 and rs2070744) in the eNOS gene and one polymorphism BglII in the α2ß1 integrin gene (ITGA2) with the risk of diabetic retinopathy (DR) in a Tunisian population. Methods: The study investigated of 110 type 2 diabetes mellitus (T2DM) and 127 DR patients. The genotypes of the eNOS 4b/4a (rs869109213) and -786T/C (rs2070744) polymorphisms and of the BglII polymorphism of ITGA2 were studied using the PCR or PCR-RFLP method. Results: The genotype distributions of the two polymorphisms in eNOS 4b4a and eNOS (-786T/C) were significantly different between T2DM and DR patients (p < .004 and p = .033, respectively). These polymorphisms were associated with the risk of DR (OR = 2.65, 95%CI [1.45-4.84], p = .002) for the eNOS 4b4a genotype and (OR = 2.43, 95%CI [1.06 - 5.56], p = .036) for the CC genotype of the eNOS gene (-786T/C). Similarly, the genotype distribution of the BglII polymorphism was significantly different between the two groups studied (p = .037). This polymorphism was associated with an increased risk of DR (OR = 4.03, 95% CI [1.17 - 7.85], p = .022) for BglII(+/+). Conclusion: The present study suggests that the polymorphisms 4b4a and -786T/C in the eNOS gene might be associated with DR. In addition, the BglII polymorphism in the ITGA2 gene was a risk factor for DR.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética/genética , Variação Genética , Integrina alfa2beta1/genética , Óxido Nítrico Sintase Tipo III/genética , Adulto , Idoso , Análise de Variância , Feminino , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Tunísia
6.
BMC Plant Biol ; 19(1): 318, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311506

RESUMO

BACKGROUND: Single Nucleotide Polymorphism (SNP) array and re-sequencing technologies have different properties (e.g. calling rate, minor allele frequency profile) and drawbacks (e.g. ascertainment bias). This lead us to study their complementarity and the consequences of using them separately or combined in diversity analyses and Genome-Wide Association Studies (GWAS). We performed GWAS on three traits (grain yield, plant height and male flowering time) measured in 22 environments on a panel of 247 F1 hybrids obtained by crossing 247 diverse dent maize inbred lines with a same flint line. The 247 lines were genotyped using three genotyping technologies (Genotyping-By-Sequencing, Illumina Infinium 50 K and Affymetrix Axiom 600 K arrays). RESULTS: The effects of ascertainment bias of the 50 K and 600 K arrays were negligible for deciphering global genetic trends of diversity and for estimating relatedness in this panel. We developed an original approach based on linkage disequilibrium (LD) extent in order to determine whether SNPs significantly associated with a trait and that are physically linked should be considered as a single Quantitative Trait Locus (QTL) or several independent QTLs. Using this approach, we showed that the combination of the three technologies, which have different SNP distributions and densities, allowed us to detect more QTLs (gain in power) and potentially refine the localization of the causal polymorphisms (gain in resolution). CONCLUSIONS: Conceptually different technologies are complementary for detecting QTLs by tagging different haplotypes in association studies. Considering LD, marker density and the combination of different technologies (SNP-arrays and re-sequencing), the genotypic data available were most likely enough to well represent polymorphisms in the centromeric regions, whereas using more markers would be beneficial for telomeric regions.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem , Haplótipos , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Zea mays/genética , Alelos , Biodiversidade , Cromossomos de Plantas , Marcadores Genéticos , Genoma de Planta , Desequilíbrio de Ligação , Zea mays/crescimento & desenvolvimento
7.
BMC Evol Biol ; 19(1): 139, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286867

RESUMO

BACKGROUND: Pathogens evolve in an arms race, frequently evolving virulence that defeats resistance genes in their hosts. Infection of multiple hosts may accelerate this virulence evolution. Theory predicts that host diversity affects pathogen diversity, with more diverse hosts expected to harbour more diverse pathogens that reproduce sexually. We tested this hypothesis by comparing the microsatellite (SSR) genetic diversity of the barley leaf pathogen Pyrenophora teres f. teres (Ptt) from barley (monoculture) and barley grass (outbreeding). We also aim to investigate host specificity and attempt to track virulence on two barley cultivars, Maritime and Keel. RESULTS: Genetic diversity in barley Ptt populations was higher than in populations from barley grass. Barley Ptt populations also had higher linkage disequilibrium levels, indicating less frequent sexual reproduction, consistent with the Red Queen hypothesis theory that genetically diverse hosts should select for higher levels of sexual reproduction of the pathogen. SSR analyses indicate that host-associated Ptt populations do not share genotypes and have independent evolutionary histories. Pathogenicity studies showed host specificity as host-associated Ptt isolates could not cross-infect hosts. Minimum spanning network analyses indicated two major clusters of barley Ptt. One cluster represents Maritime virulent and isolates from Western Australia (WA). Low PhiPt population differentiation between WA populations and those from Maritime and Keel, indicated a WA origin of the Maritime and Keel virulences. The main minimum spanning network cluster is represented by a panmictic population structure, represented by isolates from all over Australia. CONCLUSIONS: Although barley Ptt populations are more diverse than barley grass Ptt populations, this may be a result of the size and number of founder Ptt populations to Australia, with larger and more barley Ptt populations introduced. More frequent sexual reproduction of Ptt on barley grass support the Red Queen Hypothesis and suggest evolutionary potential of pathogens on diverse hosts are high. Extensive gene flow of Ptt between regions in Australia is suggested to maintain a panmictic population structure, with human-mediated dispersal aiding in virulence evolution of Ptt on barley.


Assuntos
Ascomicetos/genética , Ascomicetos/fisiologia , Evolução Molecular , Hordeum/microbiologia , Especificidade de Hospedeiro/genética , Doenças das Plantas/microbiologia , Genótipo , Desequilíbrio de Ligação , Repetições de Microssatélites/genética
8.
Genet Sel Evol ; 51(1): 26, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170906

RESUMO

BACKGROUND: Selective breeding is a relatively recent practice in aquaculture species compared to terrestrial livestock. Nevertheless, the genetic variability of farmed salmonid lines, which have been selected for several generations, should be assessed. Indeed, a significant decrease in genetic variability due to high selection intensity could have occurred, potentially jeopardizing the long-term genetic progress as well as the adaptive capacities of populations facing change(s) in the environment. Thus, it is important to evaluate the impact of selection practices on genetic diversity to limit future inbreeding. The current study presents an analysis of genetic diversity within and between six French rainbow trout (Oncorhynchus mykiss) experimental or commercial lines based on a medium-density single nucleotide polymorphism (SNP) chip and various molecular genetic indicators: fixation index (FST), linkage disequilibrium (LD), effective population size (Ne) and inbreeding coefficient derived from runs of homozygosity (ROH). RESULTS: Our results showed a moderate level of genetic differentiation between selected lines (FST ranging from 0.08 to 0.15). LD declined rapidly over the first 100 kb, but then remained quite high at long distances, leading to low estimates of Ne in the last generation ranging from 24 to 68 depending on the line and methodology considered. These results were consistent with inbreeding estimates that varied from 10.0% in an unselected experimental line to 19.5% in a commercial line, and which are clearly higher than corresponding estimates in ruminants or pigs. In addition, strong variations in LD and inbreeding were observed along the genome that may be due to differences in local rates of recombination or due to key genes that tended to have fixed favorable alleles for domestication or production. CONCLUSIONS: This is the first report on ROH for any aquaculture species. Inbreeding appeared to be moderate to high in the six French rainbow trout lines, due to founder effects at the start of the breeding programs, but also likely to sweepstakes reproductive success in addition to selection for the selected lines. Efficient management of inbreeding is a major goal in breeding programs to ensure that populations can adapt to future breeding objectives and SNP information can be used to manage the rate at which inbreeding builds up in the fish genome.


Assuntos
Endogamia , Polimorfismo de Nucleotídeo Único , Seleção Artificial , Truta/genética , Animais , Desequilíbrio de Ligação
9.
Nat Commun ; 10(1): 2417, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160569

RESUMO

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.


Assuntos
Transtorno Bipolar/genética , Modelos Genéticos , Modelos Estatísticos , Herança Multifatorial , Esquizofrenia/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
10.
Medicine (Baltimore) ; 98(23): e15921, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169709

RESUMO

The study was performed to investigate the genetic associations of IGF-1 polymorphisms rs35767, rs5742714, and rs972936 with susceptibility to osteonecrosis of the femoral head (ONFH) among Chinese Han population.Totally, 101 ONFH patients and 128 healthy controls were enrolled. Hardy-Weinberg equilibrium (HWE) was detected with chi-square test in control group. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the relationship between IGF-1 polymorphisms and ONFH risk. Besides, hyplotype analysis was performed to examine linkage disequilibrium between the studied polymorphisms.Genotype AA and allele A of polymorphism rs35767 were more frequent in control group, and offered protection for ONFH onset (AA: OR = 0.382, 95% CI = 0.158-0.923; A: OR = 0.650, 95% CI = 0.442-0.956). Furthermore, the negative relationship was also observed between ONFH risk and polymorphism rs5742714 under the comparisons CG vs CC, and G vs C (OR = 0.395, 95%CI = 0.199-0.787; OR = 0.346, 95%CI = 0.191-0.627). While the polymorphism rs972936 significantly enhanced the disease risk (CT vs CC: OR = 2.434, 95% CI = 1.184-5.003; TT vs CC: OR = 2.497, 95% CI = 1.040-5.990). Furthermore, haplotype analysis demonstrated that C-T (rs5742714-rs972936) could increase ONFH risk (OR = 2.177, 95% CI = 1.444-3.283), while G-T might be a protective factor for ONFH (OR = 0.472, 95% CI = 0.254-0.878).IGF-1 polymorphisms rs35767, rs5742714, and rs972936 show significant association with ONFH risk.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Necrose da Cabeça do Fêmur/genética , Predisposição Genética para Doença/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Grupos Étnicos/genética , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances
11.
Anim Genet ; 50(4): 381-385, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179563

RESUMO

Polledness has been shown to have autosomal Mendelian inheritance, with the polled locus being dominant to the horned locus. This trait was mapped to the BTA1 centromeric end in several breeds. One of the distinctive attributes of Creole cattle, such as the Argentinean Creole, is the presence of long, lyre-shaped horns. However, polled native animals were reported before the introduction of modern selected European breeds. Here, we studied the origin of the polled mutation, either independent or introgressed, in a Creole line from the Creole cattle founder group at the IIACS-INTA Leales Experimental Station (northwest Argentina). The study sample (65 animals: 26 horned and 39 polled) was genotyped using high-density SNP microarrays and three previously reported genetic markers (P202 ID , P80kb ID and PG ). A genome-wide association study, selection signatures, linkage disequilibrium analysis and copy number variations were used to detect the responsible region and the segregating haplotypes/alleles. The interval mapped in the Leales herd (1.23-2.13 Mb) overlapped with the region previously reported in several European cattle breeds, suggesting that the same locus could be segregating in this population. The previously reported variants PF and PG were not detected, thus dismissing the Holstein-Friesian and Nellore origins of the polled phenotype in this native breed. Conversely, the presence of the Celtic variant PC suggests an almost complete co-segregation. The cluster analysis rejected the hypothesis of recent introgression, which is compatible with the historical record of polled Creole cattle in northwest Argentina.


Assuntos
Bovinos/genética , Cornos/fisiologia , Animais , Argentina , Bovinos/classificação , Cromossomos de Mamíferos , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Mutação , Fenótipo
12.
BMC Plant Biol ; 19(1): 259, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208337

RESUMO

BACKGROUND: Cultivated rice (Oryza sativa L.) is one of the staple food for over half of the world's population. Thus, improvement of cultivated rice is important for the development of the world. It has been shown that abundant elite genes exist in rice landraces in previous studies. RESULTS: A genome-wide association study (GWAS) performed with EMMAX for 12 agronomic traits measured in both Guangzhou and Hangzhou was carried out using 150 accessions of Ting's core collection selected based on 48 phenotypic traits from 2262 accessions of Ting's collection, the GWAS included more than 3.8 million SNPs. Within Ting's core collection, which has a simple population structure, low relatedness, and rapid linkage disequilibrium (LD) decay, we found 32 peaks located closely to previously cloned genes such as Hd1, SD1, Ghd7, GW8, and GL7 or mapped QTL, and these loci might be natural variations in the cloned genes or QTL which influence potentially agronomic traits. Furthermore, we also detected 32 regions where new genes might be located, and some peaks of these new candidate genes such as the signal on chromosome 11 for heading days were even higher than that of Hd1. Detailed annotation of these significant loci were shown in this study. Moreover, according to the estimated LD decay distance of 100 to 350 kb on the 12 chromosomes in this study, we found 13 identical significant regions in the two locations. CONCLUSIONS: This research provided important information for further mining these elite genes within Ting's core collection and using them for rice breeding.


Assuntos
Oryza/genética , Característica Quantitativa Herdável , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Genes de Plantas/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação/genética , Locos de Características Quantitativas/genética
13.
Nat Commun ; 10(1): 2434, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164647

RESUMO

To date, genome-wide association studies have implicated at least 35 loci in osteoarthritis but, due to linkage disequilibrium, the specific variants underlying these associations and the mechanisms by which they contribute to disease risk have yet to be pinpointed. Here, we functionally test 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identify six single nucleotide polymorphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that the most significant SNP, rs4730222, exhibits differential nuclear protein binding in electrophoretic mobility shift assays and drives increased expression of an alternative isoform of HBP1 in a heterozygote chondrosarcoma cell line, in a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients. This study provides a framework for prioritization of GWAS variants and highlights a role of HBP1 and Wnt signaling in osteoarthritis pathogenesis.


Assuntos
Condrócitos/metabolismo , Redes Reguladoras de Genes , Proteínas de Grupo de Alta Mobilidade/genética , Osteoartrite/genética , Proteínas Repressoras/genética , Alelos , Cartilagem Articular/citologia , Linhagem Celular Tumoral , Ensaio de Desvio de Mobilidade Eletroforética , Técnicas de Introdução de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Desequilíbrio de Ligação , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Isoformas de Proteínas , Proteínas Repressoras/metabolismo , Via de Sinalização Wnt
14.
Nat Immunol ; 20(7): 824-834, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209403

RESUMO

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.


Assuntos
Regulação da Expressão Gênica , Variação Genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1 , RNA Antissenso/genética , RNA Longo não Codificante/genética , Receptores CCR5/genética , Regiões 3' não Traduzidas , Alelos , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Membrana Celular/metabolismo , Genes Reporter , Genótipo , Infecções por HIV/metabolismo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética , Prognóstico , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR5/metabolismo , Carga Viral
15.
BMC Plant Biol ; 19(1): 187, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064322

RESUMO

BACKGROUND: It is important to explore renewable alternatives (e.g. biofuels) that can produce energy sources to help reduce reliance on fossil oils, and reduce greenhouse gases and waste solids resulted from fossil oils consumption. Camelina sativa is an oilseed crop which has received increasing attention due to its short life cycle, broader adaptation regions, high oil content, high level of omega-3 unsaturated fatty acids, and low-input requirements in agriculture practices. To expand its Camelina production areas into arid regions, there is a need to breed for new drought-tolerant cultivars. Leaf cuticular wax is known to facilitate plant development and growth under water-limited conditions. Dissecting the genetic loci underlying leaf cuticular waxes is important to breed for cultivars with improved drought tolerance. RESULTS: Here we combined phenotypic data and single nucleotide polymorphism (SNP) data from a spring C. sativa diversity panel using genotyping-by-sequencing (GBS) technology, to perform a large-scale genome-wide association study (GWAS) on leaf wax compositions. A total of 42 SNP markers were significantly associated with 15 leaf wax traits including major wax components such as total primary alcohols, total alkanes, and total wax esters as well as their constituents. The vast majority of significant SNPs were associated with long-chain carbon monomers (carbon chain length longer than C28), indicating the important effects of long-chain carbon monomers on leaf total wax biosynthesis. These SNP markers are located on genes directly or indirectly related to wax biosynthesis such as maintaining endoplasmic reticulum (ER) morphology and enabling normal wax secretion from ER to plasma membrane or Golgi network-mediated transport. CONCLUSIONS: These loci could potentially serve as candidates for the genetic control involved in intracellular wax transport that might directly or indirectly facilitate leaf wax accumulation in C. sativa and can be used in future marker-assisted selection (MAS) to breed for the cultivars with high wax content to improve drought tolerance.


Assuntos
Brassicaceae/genética , Folhas de Planta/química , Polimorfismo de Nucleotídeo Único , Ceras/química , Ceras/metabolismo , Álcoois/metabolismo , Aldeídos/metabolismo , Algoritmos , Alcanos/metabolismo , Transporte Biológico/genética , Genética Populacional , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Fenótipo , Folhas de Planta/genética
16.
Medicine (Baltimore) ; 98(19): e15583, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083239

RESUMO

The study was designed to reveal the relationship of toll-like receptor 4 (TLR4, rs1927914 and rs1927907) polymorphisms with risk of age-related macular degeneration (AMD), as well as the adjustment of this association by some environmental and lifestyle factors in Chinese Han population.TLR4 polymorphisms were genotyped by polymerase chain reaction-restricted fragment length polymorphisms and direct sequencing method in 138 AMD patients and 146 healthy controls. Genotype distribution in the control group was checked with Hardy-Weinberg equilibrium. Association of TLR4 polymorphisms and AMD risk was evaluated by χ test and adjusted by age and sex, smoking and drinking. Odds ratio (OR) with 95% confidence interval (95% CI) was used to represent the association strength. Logistic regressive analysis was used to calculate the adjusted OR values.CC genotype of rs1927914 had significantly lower frequency in AMD patients (P = .010), indicated a negative association with AMD risk (crude: OR = 0.358, 95% CI = 0.162-0.791; adjusted: OR = 0.355, 95% CI = 0.160-0.789). C allele of rs1927914 might decrease the susceptibility of AMD (crude: OR = 0.698, 95% CI = 0.497-0.982; adjusted: OR = 0.698, 95% CI = 0.495-0.984). No significant association has been discovered between TLR4 rs1927907 polymorphism and AMD susceptibility. Strong linkage disequilibrium existed between rs1927914 and rs1927907 polymorphisms. C-C haplotype was negatively associated with AMD risk (OR = 0.242, 95% CI = 0.121-0.485; OR = 0.242, 95% CI = 0.120-0.488).CC genotype and C allele of rs1927914 were significantly associated with the decreased AMD susceptibility.


Assuntos
Predisposição Genética para Doença , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Receptor 4 Toll-Like/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Degeneração Macular/epidemiologia , Masculino , Polimorfismo de Fragmento de Restrição
17.
Chem Biol Interact ; 307: 154-157, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071335

RESUMO

Butyrylcholinesterase (BChE) is a serine hydrolase widely distributed throughout the body. It provides protection against administrated or inhaled poisons by hydrolyzing or sequestering the toxic compounds. The most frequent genetic variant of BCHE gene - K variant (p.A539T) is located in the C-terminal tetramerization domain, outside of the catalytic center. Many studies tried to reveal the nature of the lower activity of BChE K-variant but results and conclusions were often contradictory. The aim of this study is to estimate K allele frequency and its coexisting alterations in BCHE gene in a population of 162 individuals, as well as, assess influence on the enzyme activity in serum. We present three haplotypes of BChE-K variant, two of them coexist in strong linkage disequilibrium with alterations in 5'UTR (rs1126680), intron 2 (rs55781031) or in exon 2 (rs1799807). We demonstrate a negative role of these alterations on enzyme activity. By oneself BCHE-K (with no other alterations in BCHE gene) haplotype exhibits wild type enzyme activity. Based on our previous and presented results we conclude that SNPs localized outside the coding sequence, in 5'UTR or/and in intron 2 of BCHE gene, but not solely in K-variant alteration (p.A539T) itself, are responsible for reduced enzyme activity.


Assuntos
Butirilcolinesterase/metabolismo , Regiões 5' não Traduzidas , Adulto , Butirilcolinesterase/química , Butirilcolinesterase/genética , Éxons , Feminino , Haplótipos , Humanos , Íntrons , Cinética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
Gene ; 707: 1-8, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31054364

RESUMO

BACKGROUND: Genome-wide association studies have captured a large proportion of genetic variation related to type 1 diabetes mellitus (T1D). However, most of these studies are performed in populations of European ancestry and therefore the disease risk estimations can be inaccurate when extrapolated to other world populations. METHODS: We conducted a case-control study in 1866 individuals from the three major populations of the Republic of Bashkortostan (Russians, Tatars, and Bashkirs) in Russian Federation, using single-locus and multilocus approach to identify genetic predictors of T1D. RESULTS: We found that LTA rs909253 and TNF rs1800629 polymorphisms were associated with T1D in the group of Tatars. Meta-analysis of the association study results in the three ethnic groups has confirmed the association between the T1D risk and LTA rs909253 genetic variant. LTA rs909253 and TNF rs1800629 loci were also featured in combinations most significantly associated with T1D. CONCLUSION: Our findings suggest that LTA rs909253 and TNF rs1800629 polymorphisms are associated with the risk of T1D both independently and in combination with polymorphic markers in other inflammatory genes, and the analysis of multi-allelic combinations provides valuable insight in the study of polygenic traits.


Assuntos
Diabetes Mellitus Tipo 1/genética , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Bashkiria/etnologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Nat Genet ; 51(5): 857-864, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31036963

RESUMO

We report a map of 4.97 million single-nucleotide polymorphisms of the chickpea from whole-genome resequencing of 429 lines sampled from 45 countries. We identified 122 candidate regions with 204 genes under selection during chickpea breeding. Our data suggest the Eastern Mediterranean as the primary center of origin and migration route of chickpea from the Mediterranean/Fertile Crescent to Central Asia, and probably in parallel from Central Asia to East Africa (Ethiopia) and South Asia (India). Genome-wide association studies identified 262 markers and several candidate genes for 13 traits. Our study establishes a foundation for large-scale characterization of germplasm and population genomics, and a resource for trait dissection, accelerating genetic gains in future chickpea breeding.


Assuntos
Cicer/genética , Cicer/classificação , DNA de Plantas/genética , Domesticação , Marcadores Genéticos , Variação Genética , Genoma de Planta , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Desequilíbrio de Ligação , Filogenia , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Análise de Sequência de DNA
20.
Genome Biol ; 20(1): 103, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126313

RESUMO

BACKGROUND: Inherited factors contribute to lung cancer risk, but the mechanism is not well understood. Defining the biological consequence of GWAS hits in cancers is a promising strategy to elucidate the inherited mechanisms of cancers. The tag-SNP rs753955 (A>G) in 13q12.12 is highly associated with lung cancer risk in the Chinese population. Here, we systematically investigate the biological significance and the underlying mechanism behind 13q12.12 risk locus in vitro and in vivo. RESULTS: We characterize a novel p53-responsive enhancer with lung tissue cell specificity in a 49-kb high linkage disequilibrium block of rs753955. This enhancer harbors 3 highly linked common inherited variations (rs17336602, rs4770489, and rs34354770) and six p53 binding sequences either close to or located between the variations. The enhancer effectively protects normal lung cell lines against pulmonary carcinogen NNK-induced DNA damages and malignant transformation by upregulating TNFRSF19 through chromatin looping. These variations significantly weaken the enhancer activity by affecting its p53 response, especially when cells are exposed to NNK. The effect of the mutant enhancer alleles on TNFRSF19 target gene in vivo is supported by expression quantitative trait loci analysis of 117 Chinese NSCLC samples and GTEx data. Differentiated expression of TNFRSF19 and its statistical significant correlation with tumor TNM staging and patient survival indicate a suppressor role of TNFRSF19 in lung cancer. CONCLUSION: This study provides evidence of how the inherited variations in 13q12.12 contribute to lung cancer risk, highlighting the protective roles of the p53-responsive enhancer-mediated TNFRSF19 activation in lung cells under carcinogen stress.


Assuntos
Cromossomos Humanos Par 13 , Elementos Facilitadores Genéticos , Neoplasias Pulmonares/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Linhagem Celular Tumoral , Reparo do DNA , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células HEK293 , Humanos , Desequilíbrio de Ligação , Neoplasias Pulmonares/metabolismo , Polimorfismo de Nucleotídeo Único
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